Diabetes Ebook:Clinical dilemmas in diabetes

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Clinical Dilemmas in Diabetes provides evidence-based clinical guidance on the most common and problematic areas of concern encountered in diagnosing, treating and managing patients with diabetes. Each chapter is highly topical and has been selected due to current interest, specific recent developments, and areas of controversy. This valuable guide provides assistance in managing the life-long treatment of diabetes and the complications that often develop in patients. Clinical Dilemmas in Diabetes guides the medical team in their decision-making, particularly when there are conflicts in the treatment for the disease and the complications. Part of the Clinical Dilemmas series, the well-focused chapter structure allows for quick retrieval of information, and each opens with a “Learning Points” box to aid easy assimilation of the main issues. With a leading team of contributors and editors, Professor Robert A. Rizza is the immediate Past-President of the American Diabetes Association. This book is perfect for use on the wards and clinics as well as for self-study by diabetologists, diabetes specialist nurses, endocrinologists, GPs and cardiologists.


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Clinical Dilemmas in Diabetes

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Clinical Dilemmas in Diabetes

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Clinical Dilemmas in Diabetes Want To Diabetes Free Life Click Here E D I T E D B Y Adrian Vella MD Associate Professor of Medicine Department of Endocrinology Mayo Clinic Rochester MN USA Robert A. Rizza MD Professor of Medicine Department of Endocrinology Mayo Clinic Rochester MN USA

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A John Wiley Sons Ltd. Publication

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This edition first published 2011 C 2011 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific T echnical and Medical business to form Wiley-Blackwell. Registered office: John Wiley Sons Ltd The Atrium Southern Gate Chichester West Sussex PO19 8SQ UK Editorial offices: 9600 Garsington Road Oxford OX4 2DQ UK The Atrium Southern Gate Chichester West Sussex PO19 8SQ UK 111 River Street Hoboken NJ 07030-5774 USA For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the UK Copyright Designs and Patents Act 1988 without the prior permission of the publisher. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required the services of a competent professional should be sought. The contents of this work are intended to further general scientific research understanding and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method diagnosis or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research equipment modifications changes in governmental regulations and the constant flow of information relating to the use of medicines equipment and devices the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine equipment or device for among other things any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Clinical dilemmas in diabetes / Edited by Adrian Vella MD Associate Professor of Medicine Department of Endocrinology Mayo Clinic Rochester MN USA Robert A. Rizza MD Professor of Medicine Department of Endocrinology Mayo Clinic Rochester MN USA. p. cm. Includes bibliographical references and index. ISBN 978-1-4051-6928-8 pbk. : alk. paper 1. Diabetes. 2. Evidence-based medicine. I. Vella Adrian editor. II. Rizza Robert A. editor. DNLM: 1. Diabetes Mellitus–therapy. 2. Diabetes Mellitus–diagnosis. 3. Evidence-Based Medicine–methods. WK 810 RC660.C4635 2011 616.4 62–dc22 A catalogue record for this book is available from the British Library. 2010052327 This book is published in the following electronic formats: ePDF 9781444340266 Wiley Online Library 9781444340280 ePub 9781444340273 Set in 8.75 /12pt Minion by Aptara R Inc. New Delhi India 1 2011

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Contents To Cure Diabetes Naturally Click Here Contributors vii Preface ix Part I Prediabetes and the Diagnosis of Diabetes 1 Is prediabetes a risk factor or is it a disease 3 Kalpana Muthusamy and Adrian Vella 2 Early diagnosis of type 1 diabetes: Useful or a phyrrhic victory 11 Chiara Guglielmi and Paolo Pozzilli 3 How should secondary causes of diabetes be excluded 22 Aonghus O ’Loughlin and Sean F. Dinneen 4 Screening patients with prediabetes and diabetes for cardiovascular disease 34 Deepika S. Reddy and Vivian Fonseca Part II Initial Evaluation and Management of Diabetes 5 What is the role of self-monitoring in diabetes Is there a role for postprandial glucose monitoring How does continuous glucose monitoring integrate into clinical practice 43 Rami Almokayyad and Robert Cuddihy 6 The optimal diet for diabetes is 56 Maria L. Collazo-Clavell 7 How to determine when to pursue lifestyle change alone versus pharmacotherapy at diagnosis 64 Galina Smushkin and F. John Service 8 Insulin sensitizers versus secretagogues as first-line therapy for diabetes: Rationale for clinical choice 71 Robert J. Richards L. Yvonne Melendez-Ramirez and William T. Cefalu 9 Are insulin sensitizers useful additions to insulin therapy 79 John W. Richard III and Philip Raskin 10 Is there a role for incretin-based therapy in combination with insulin 91 Matheni Sathananthan and Adrian Vella 11 HbA1c: Is it the most important therapeutic target in outpatient management of diabetes 96 Steven A. Smith Part III Management of Associated Risk Factors and Disease 12 Primary therapy for obesity as the treatment of type 2 diabetes 107 Manpreet S. Mundi and Michael D. Jensen 13 Are statins the optimal therapy for cardiovascular risk in patients with diabetes Are triglycerides an important independent risk factor for diabetes 116 Michael O ’Reilly and Timothy O ’Brien 14 The role of bariatric surgery in obese patients with diabetes: Primary or rescue therapy 127 Praveena Gandikota and Blandine Laferr` ere 15 Hyperglycemia should be avoided in critical illness and the postoperative period 134 Kalpana Muthusamy and John M. Miles 16 Is there an optimal revascularization strategy in diabetic patients with ischemic heart disease 145 Stephen H. McKellar Morgan L. Brown and Robert L. Frye Index 153

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Contributors To Stop Diabetes In Few Days Click Here Rami Almokayyad MD Endocrine Fellow Division of Endocrinology Department of Medicine University of Minnesota Medical School University of Minnesota Minneapolis MN USA Sean F . Dinneen MD FRCPI Senior Lecturer in Medicine Department of Medicine Clinical Science Institute NUI Galway Galway Ireland Blandine Laferre ` re MD Assistant Professor of Medicine Division of Endocrinology Diabetes and Nutrition Obesity Research Center Department of Medicine St Luke’s Roosevelt Hospital Center Columbia University College of Physicians Vivian Fonseca MD and Surgeons Morgan L. Brown MD PhD Professor of Medicine and Pharmacology New Y ork NY USA Resident Tullis Tulane Alumni Chair in Diabetes University of Alberta Chief Section of Endocrinology Stephen H. McKellar MD MSc Edmonton AB Canada Tulane University Health Sciences Center Resident New Orleans LA USA Division of Cardiovascular Surgery William T. Cefalu MD Mayo Clinic Douglas L. Manship Sr. Professor of Robert L. Frye MD Rochester MN USA Diabetes Professor of Medicine Chief Joint Program on Diabetes Division of Cardiovascular Diseases L. Yvonne Melendez- Endocrinology and Metabolism Mayo Clinic Ramirez MD Pennington Biomedical Research Center Rochester MN USA Assistant Professor of Medicine LSUHSC School of Medicine Joint Program on Diabetes Endocrinology New Orleans LA and Baton Rouge LA USA Praveena Gandikota MD Endocrine Fellow Endocrine Diabetes and Nutrition Division and Metabolism Pennington Biomedical Research Center LSUHSC School of Medicine Maria L. Collazo-Clavell MD Department of Medicine New Orleans LA Baton Rouge LA USA Associate Professor of Medicine Division of Endocrinology Diabetes Metabolism Nutrition Mayo Clinic Rochester MN USA Robert M. Cuddihy MD Medical Director International Diabetes Center World Health Organization Collaborating Center for Diabetes Education Translation and Computer T echnology Minneapolis MN USA St Luke’s Roosevelt Hospital New Y ork NY USA Chiara Guglielmi MD PhD PostDoc Fellow Department of Endocrinology Diabetes University Campus Bio-Medico Rome Italy Michael D. Jensen MD T omas J. Watson Jr. Professor in Honor of Dr. Robert L. Frye Mayo Foundation Rochester MN USA John M. Miles MD Professor of Medicine Endocrine Research Unit Mayo Clinic Rochester MN USA Manpreet S. Mundi MD Senior Associate Consultant Division of Endocrinology Mayo Clinic Rochester MN USA Kalpana Muthusamy MD Clinical Fellow Division of Endocrinology Mayo Clinic Rochester MN USA

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viii Contributors Timothy O’Brien MD PhD Professor of Medicine Consultant Endocrinologist/Director of REMEDI Department of Medicine and Endocrinology/Diabetes Mellitus University College Hospital/National University of Ireland Galway Galway Ireland Paolo Pozzilli MD Professor of Endocrinology Head of Department of Endocrinology Diabetes University Campus Bio-Medico Rome Italy Professor of Diabetes Research Barts the London School of Medicine Dentistry London UK Robert J. Richards MD Associate Professor of Medicine Joint Program on Diabetes Endocrinology and Metabolism Pennington Biomedical Research Center LSUHSC School of Medicine New Orleans LA and Baton Rouge LA USA Matheni Sathananthan MD Aonghus O’Loughlin MB Endocrinology Fellow MRCPI Philip Raskin MD Division of Endocrinology Diabetes Specialist Registrar in Professor of Medicine Nutrition and Metabolism Endocrinology/Diabetes Mellitus Clifton and Betsy Robinson Chair in Mayo Clinic Department of Medicine and Biomedical Research Rochester MN USA Endocrinology/Diabetes Mellitus University of Texas Southwestern Medical University College Hospital/National Center at Dallas F . John Service MD PhD University of Ireland Galway Ireland Dallas TX USA Professor of Medicine Mayo Clinic College of Medicine Deepika S. Reddy MD Rochester MN USA Michael O’Reilly MB BCh BAO Assistant Professor MRCPI Department of Endocrinology Steven A. Smith MD Specialist Registrar in Scott White Clinic Associate Professor of Medicine Endocrinology/Diabetes Mellitus T emple TX USA Medical Director Mayo Patient Education Department of Medicine and Consultant in Endocrinology Diabetes Endocrinology/Diabetes Mellitus John W. Richard III MD Nutrition and Metabolism University College Hospital/National Endocrinology Fellow Health Care Policy Research University of Ireland Division of Endocrinology Diabetes Mayo Clinic Galway Ireland Nutrition and Metabolism Rochester MN USA University of Texas Southwestern Medical Center at Dallas Dallas TX USA Galina Smushkin MD Fellow Mayo Clinic Division of Endocrinology Rochester MN USA

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Preface To Get Best Natural Diabetes Treatment Click Here Clinical Dilemmas in Diabetes is a book that arose out of several different motivations. The primary motivator may have been a desire to shed some light onto how to translate results of clinical trials to individual patient care. Indeed the passage of time continues to demonstrate that “common sense” is still unfortunately an uncommon commodity but one which is necessary for the optimal management of Diabetes. Another potential motivator is the realization that blind adherence to algorithm-based approaches to clinical care is a poor substitute for informed decision making in the clinic. With this in mind we chose several subjects of relevance to diabetes that deserve discussion and debate. We hope this will be the first iteration of a book that will develop and grow over time – assimilating new chapters and topics for debate – in much the same way that diabetes care continues to develop. Adrian V ella Robert A. Rizza February 2011

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PART I Prediabetes and the Diagnosis of Diabetes To Get Rid Of Diabetes Permanently Click Here

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1 Is prediabetes a risk factor or is it a disease 2 To Kill Diabetes Forever Click Here 3 Kalpana Muthusamy 1 and Adrian Vella 2 1 Clinical Fellow Division of Endocrinology Mayo Clinic Rochester MN USA 2 Associate Professor of Medicine Department of Endocrinology Mayo Clinic Rochester MN USA L E A R N I N G P OIN T S The diagnostic criteria for prediabetes and diabetes are based on the relationship of hyperglycemia with microvascular disease. Defects in insulin secretion and action occur in people with impaired fasting glucose and impaired glucose tolerance. An oral glucose tolerance test may help to better characterize patients at higher risk of progression to type 2 diabetes. Intervention may delay the progression to diabetes. Prediabetes as previously defined by the American Diabetes Association ADA includes subjects with fasting plasma glucose FPG 100 mg/dl and 126 mg/dl and/or 2-hour plasma glucose following a 75-g oral glucose load 140 mg/dl and 200 mg/dl. The rate of progression to dia- betes without any intervention is about 28.9 over a 3-year period as seen in the placebo arm of the Diabetes Preven- tion Program 1. A 9-year longitudinal study from Olmsted County Minnesota reported a similar rate of diabetes pro- gression of 34 2. The prevalence rate of prediabetes in the American adult population as reported by CDC from 2003 to 2006 was 25.9 3. This represents 57 million American adults a significant number of whom are pre- disposed to developing diabetes if adequate intervention is not undertaken. Therefore understanding the definition of prediabetes its implications pathogenesis and appropriate management becomes critical to any clinician. Prediabetes includes two categories impaired fasting glucose IFG and impaired glucose tolerance IGT. Exam- ining the evolution of these criteria will help us understand not only the basis of the current definitions but also provide us guidance for the necessary evaluation and management. Prediabetes diabetes micro- and macrovascular disease Impaired glucose tolerance IGT is defined by a plasma glucose 2 hours after a 75-g oral glucose load 140 mg/dl and 200 mg/dl while impaired fasting glucose IFG is defined by a fasting plasma glucose 100 mg/dl and 126 mg/dl. IGT is a terminology that has been long known and has been a part of the ADA classification since 1979 4. IFG as a separate entity was established in an ADA report published in 1997 5 and was later adopted by an expert WHO panel in 1999 6. These categories were intended to be seen as risk factors for future diabetes and cardiovascular disease rather than distinct clinical groups. The definition for IGT has undergone little change since its inception. IFG was initially defined as fasting plasma glucose 110 mg/dl and 126 mg/dl. This classification was rather arbitrary and reflected the then available evidence suggesting an insulin secretory defect and an increased risk of cardiovascular disease. Brunzell et al. performed intravenous glucose tolerance tests in 66 subjects with a wide range of fasting glycemia 7. Acute insulin response and glucose disappearance rate were markedly lower in subjects with fasting plasma glucose above 115 mg/dl in comparison to those with a fasting glu- cose below 115mg/dl. The main limitation of this data was Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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4 Prediabetes and the diagnosis of diabetes the relatively small number of patients in the fasting plasma glucose group 115–149 mg/dl n 3. The Paris Prospective Study noted an increasing risk of diabetes with incremental fasting plasma glucose despite normal glucose tolerance 2-hour-value after a 75-g oral glucose tolerance test 140 mg/dl. The relative risk of developing subsequent diabetes in the IGT and IFG fasting plasma glucose 109 mg/dl groups was 9.6 and 5.6 respectively 8. The impact of hyperglycemia on cardiovascular mortality was also exam- ined in this study with the age-adjusted relative risk for coronary heart disease death noted to be 1.32 1.04–1.67 in subjects in the fasting plasma glucose category of 104–124 mg/dl in comparison to the group 104 mg/dl 9. A similar increase in risk was observed with increased post-challenge glucose in the Whitehall study that followed 18403 male civil servants for a total of 7.5 years 10. The microvascular effects of prediabetes were investi- gated in a few studies with mostly uniform results. Subjects with a capillary blood glucose between 120 and 200 mg/dl following a 50-g oral glucose load did not have any dis- cernible difference from controls in the prevalence of retinal abnormalities over a 10-year follow-up period 11. Klein et al. evaluated the effect of impaired glucose tolerance with plasma glucose between 140 and 200 mg/dl after a stan- dard 75-g oral glucose load 12. Age-adjusted frequency of visual impairment as measured by visual acuity of ≤ 20/40 was higher in the IGT group when compared to men with diabetes and normoglycemic women. However the rates of retinopathy were uniformly low across all groups with no significant intergroup differences. In another report from two different groups of patients including Pima Indians and male civil servants development of retinopathy was mostly confined to subjects with 2-hour plasma glucose exceeding 200 mg/dl without any marked change in the intermediate groups 13. Following these earlier studies one of the important debates that ensued was the comparability between IGT and IFG with regard to outcomes. Data from a longitudinal study of Pima Indians showed greater prevalence of IGT over IFG among nondiabetic subjects 14. However the 5-year cumulative incidence of diabetes was much higher for IFG at 31 in comparison to 19.9 for subjects with IGT. The combination of these two risk factors was better than either alone with an incidence of 41.2. A receiver operating characteristic ROC curve analysis showed that by defining IFG using a fasting glucose ≥ 102 mg/dl the prevalence in the two groups was mirrored. This might not have necessarily led to identifying the same set of sub- jects as these two cohorts might have included subjects who were mutually exclusive. However the sensitivity and specificity of diabetes prediction was equaled in the IFG and IGT groups when using a definition of IFG 103 mg/dl as opposed to 110 mg/dl. In a Mauritian 15 cohort of 3229 nondiabetic subjects 148 had IFG alone in comparison to 489 with isolated impaired post-challenge glucose. A com- bination of IFG and IGT was present in 118 subjects. The sensitivity specificity and positive predictive value for pre- diction of progression to diabetes were 50 84 and 24 respectively for IGT. Although IFG was less sensitive it had a better specificity and positive predictive value at 26 94 and 29 respectively. These data would suggest that IFG defines a smaller yet a more extreme category of glycemia that progresses to diabetes more predictably. However from a population perspective IFG identifies a lesser percentage of people progressing to diabetes making it difficult to suc- cessfully implement diabetes prevention measures based on fasting plasma glucose alone. In this study the optimal def- inition of IFG that gave the best combination of sensitivity and specificity for diabetes prediction was a fasting glucose 99 mg/dl 16. These data formed the basis for the revised IFG criteria of plasma glucose 100 mg/dl and less than 125 mg/dl in a follow-up report in 2003 17. It is important to remember that in clinical practice the risk of progression to diabetes follows a gradient across a seamless continuum of glucose levels 16. While scrutiniz- ing the evidence to decide the optimal definitions of IGT and IFG and their individual value it is critical to under- stand if IGT and IFG act as risk factors for micro- and macrovascular disease independently of diabetes. It is generally accepted that microvascular disease such as retinopathy neuropathy and nephropathy is a function of the degree and duration of hyperglycemia. Contrary to the earlier studies that did not reveal an increased frequency of retinopathy among people with prediabetes some recent studies demonstrated an elevated risk of microvascular dis- ease even in subjects with hyperglycemia less than the dia- betic range. A subset of the Diabetes Prevention Program cohort was investigated with fundus photographs at a mean 5.6 years of follow-up 18. Changes of diabetic retinopathy were reported in 7.9 of the impaired glucose group and in 12.6 of the group that developed diabetes on follow- up. Although the subjects who developed retinal changes were not significantly different from those without these changes in the impaired glucose group they tend to have a higher baseline prevalence of hypertension lower HDL higher triglycerides and a history of gestational diabetes.

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Is prediabetes a risk factor or is it a disease 5 The rates of retinopathy and nephropathy were higher in individuals with impaired fasting glucose in comparison to those with impaired glucose tolerance on 10 years of follow-up of a group of Pima Indians also supporting the previous evidence that IFG might denote a metabolically advanced state 19. As opposed to these results the inci- dence of diabetic retinopathy was reported to be very low at 28–31/10000 person-years of follow-up in a large Japanese cohort of atomic bomb survivors with impaired glycemia 20. A steep rise in the incidence and prevalence of fun- dus changes were noted only when the fasting plasma glu- cose was 125 mg/dl and the 2–hour post-challenge glu- cose 198 mg/dl. A similar threshold for retinopathy also evolved in the AusDiab study 21. A clear threshold effect was not evident for microalbuminuria and the relation to rise in glucose was more gradual. Subjects with neuropathy were more likely to have retinopathy and microalbuminuria in the AusDiab cohort with impaired glucose metabolism 22. Collectively although there is evidence for increased prevalence and incidence of microvascular changes before the onset of diabetes these changes predominantly occur with higher levels of glycemia. In summary the recently proposed definitions of predi- abetes are dependent on their ability to identify individuals with a high risk of progression to diabetes. Defining IFG using a fasting glucose 100mg/dl increased the prevalence of prediabetes from 19.3 to 36.3 on evaluation of the NHANES III data 23. Whether this definition portends true benefit or places a higher societal burden for preventive measures has been questioned 24. We also have to factor in the behavioral impact of this labeling on individuals 25. Strong antagonistic opinions to the new cutoff cite the lack of net proven benefit based on a detailed decision analysis 26. Most recently in 2010 the title “Prediabetes” was renamed as “Categories of increased risk for diabetes” to reflect the risk of progression to diabetes rather than the subsequent micro- and macrovascular outcomes. An equiv- alent intermediate category for A1C was also identified with values between 5.7 and 6.4 indicating a height- ened risk for diabetes development 27–29. Prediabetes and atherosclerosis: Why do they associate and how to best predict the risk A progressive increase in cardiovascular risk has been shown with rising blood sugars across a spectrum ranging from normal to significant hyperglycemia. The DECODE study group showed a J-shaped relationship between all-cause mortality and plasma glucose whether fasting or post- challenge 30. A plausible and intuitive explanation for the increased cardiovascular risk is the clustering of other well- known traditional risk factors in patients who develop pre- diabetes 31. The San Antonio Heart Study followed 614 nondiabetic Mexican American individuals and demon- strated that subjects who developed diabetes had a more atherogenic profile at baseline including higher triglyc- erides LDL and total cholesterol BMI blood pressure insulin and lower HDL than the group that did not develop diabetes 32. The clustering of risk variables explained all the observed metabolic features rather than a single under- lying etiology 33. Low cardiorespiratory fitness had a sig- nificant impact on all-cause mortality in women with IFG in the 16-year follow-up in the Aerobic Center Longitudinal Study ACLS 34. Studies that examined the ability of IGT and IFG to pre- dict cardiovascular risk and mortality suggest that IGT is a better predictor of all-cause mortality 35 36 and car- diovascular disease 37–39. In contrast data from Nor- wegians followed over 22 years showed that fasting plasma glucose was an important predictor of cardiovascular death 40. Adding to these already varied results a Chinese study showed equivalent performance of IGT and IFG in predict- ing cardiovascular disease risk 41. The Atherosclerosis Risk in Communities Study ARIC also showed that both IGT and IFG were associated with an increased prevalence of cardiovascular risk factors with none being worse than the other 42. It is also important to remember the impor- tant role of other cardiovascular risk factors in the devel- opment of atherogenesis. In agreement the Framingham Offspring and San Antonio Heart Studies have shown that the knowledge we gain from post-challenge hyperglycemia might add little to what we might already know from tra- ditional cardiovascular risk factors 43 44. Is there a role for OGTT in clinical practice This has been a topic of considerable debate which was fueled by the 1997 ADA recommendation to favor the use of fasting plasma glucose over OGTT. The huge influx of data that followed in favor and disfavor of this recommen- dation has helped shape the definition of prediabetes as reviewed earlier. Prevalent use of OGTT has been limited by its inconvenience cost and poor reproducibility. Marked

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6 Prediabetes and the diagnosis of diabetes intra- and interindividual variation in postload glucose has been demonstrated in multiple studies 45–48. McDonald et al. showed that the standard deviation for fasting glucose was about 5 mg/dl whereas it was substantially higher for 1- and 2-hour postload glucose where the deviation around the mean was 20–30 mg/dl 46. This degree of fluctuation leads to misclassification with nearly 39 of people diag- nosed with IGT found to be normal on a repeat OGTT within 2–6 weeks 49. Given that individuals spend at least 6–9 hours on a given day in the postprandial state knowledge gained from a standardized glucose load cannot be ignored 50. As discussed earlier IGT is a better predictor of diabetes and macrovascular risk than fasting glucose. Although in prac- tice clinicians almost never use the OGTT except in special situations such as pregnancy it continues to remain a valu- able epidemiological tool. What is the underlying pathogenesis and natural history of IGT and IFG Hyperglycemia develops when in response to impaired insulin sensitivity the secretion of insulin declines. As we would expect the spectrum of disorders with disturbed glu- cose metabolism en route from normoglycemia to devel- opment of diabetes would encompass defects of insulin action and β-cell secretion. Butler et al. using pancreatic tissue obtained from autopsy showed that β-cell volume is decreased by 40 in IFG compared to normoglycemic individuals 51. It has also been shown that the usual 0.7 per year rate of β-cell deterioration is doubled in IGT with accelerated progression to diabetes 52. There have been attempts to dissect IGT and IFG to denote specific defects in glucose homeostasis but these have yielded contrasting results. Most studies reported increased insulin resistance in IGT 53–55 and decreased β-cell function in IFG 53 54 56 as the predominant metabolic derangements using data from insulin clamps and glucose tolerance tests. In contrast the Botnia study concluded that IFG is more char- acterized by insulin resistance and IGT by impaired insulin secretion with decreased I/G ratio Insulin/glucose ratio 57. The amplitude of insulin secretion and its response to oscillations in glucose were blunted in IGT 58. Bock et al. reported both defective insulin secretion and action with meal ingestion in IGT whereas in individuals with isolated IFG the postprandial glucose metabolism was completely normal but they had an inappropriately elevated fasting endogenous glucose production 59. Understandably a combination of IGT and IFG presents a morphologically advanced group with more severe metabolic impairments than isolated presentation of either 56. In the progression from normoglycemia it is not imper- ative that both IGT and IFG develop before transition to diabetes as we have learnt from the Baltimore Longitudinal Study of Aging 60. During a 10-year follow-up only 37 with IFG went on to develop IGT and only 15 with IGT developed IFG. The progression from baseline IGT/IFG to diabetes happened at an accelerated rate of 39.3. This has also been confirmed in a cohort of Pima Indians where one-fourth of the subjects with IGT developed diabetes in 5 years and two-thirds in 10 years 61. The best predictors of this progression were age male gender BMI and central obesity 60 61. The progression from normoglycemia to diabetes is more slow and gradual with a 10-year cumula- tive incidence of 7.01 by 2-hour glucose and 1.48 by fasting glucose. Management of prediabetes Relatively few studies have addressed the role of interven- tion in people with prediabetes. In the Diabetes Prevention Program DPP 1 lifestyle intervention in affected indi- viduals decreased the incidence of diabetes by 58 and by 31 when treated with metformin in comparison to the control group. The average weight loss achieved was 0.1 2.1 and 5.6 kg in the placebo metformin and lifestyle groups respectively. Similar studies have been replicated in different populations with the Finnish Diabetes Preven- tion Study demonstrating a comparable weight loss of 4.2 kg with lifestyle modification and a 58 reduction in dia- betes incidence over 3.2 years 62. In the Indian Diabetes Prevention Programme and the Da Qing IGT and Diabetes Study in accordance with the impression that the South Asians represent a metabolically disadvantaged group for a given weight the BMI of the subjects with prediabetes was lower in comparison to Caucasians 25–26 kg/m 2 63 64. They experienced a more rapid rate of progression to diabetes of 55 and 67 in their control groups respec- tively over 3–6 years. Despite minimal or no weight loss with lifestyle intervention they still had a 28 and a 46 reduction in diabetes progression. Apart from metformin the pharmacologic agents that have been utilized in this setting include troglitazone in sev- eral studies and acarbose in STOP-NIDDM. Troglitazone

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Is prediabetes a risk factor or is it a disease 7 during its short span of use in DPP before the drug dis- continuation in 1998 due to concerns of liver toxicity low- ered the diabetes incidence rate more significantly in com- parison to the other groups 65. Two short-term studies concluded that the ability of this drug to prevent progres- sive secretory dysfunction and improve insulin action con- tributed to its effect on slowing diabetes progression 66 67. The increased glycemic durability of rosiglitazone in the ADOPT trial and the decreased incidence of diabetes in the rosiglitazone subgroup in the DREAM trial suggests that this is a class effect for the thiazolidinediones 68 69. On the other hand there are potential risks associated with thiazolidinedione use that must be considered—including an increased risk of hospitalization for heart failure edema and fracture. Acarbose although successful in decreasing the inci- dence of diabetes in the STOP-NIDDM study had a 31 discontinuation rate due to gastrointestinal side effects 70. Blockade of the renin angiotensin system did not offer any significant advantage as noted in the DREAM trial but a modest 3.7 absolute risk reduction in the incidence of diabetes by valsartan was reported in the recently published NAVIGATOR trial 71. The nateglinide arm in the NAVI- GATOR trial did not show any benefit despite the associa- tion of postprandial hyperglycemia with diabetes and car- diovascular risk 72. Collectively despite variable glycemic effects none of the therapeutic agents have been shown to have micro- or macrovascular benefit in the prediabetes population. One of the commonly cited criticisms of DPP is the repli- cability of the aggressive lifestyle intervention in their pro- tocol in common practice. The support and the education offered to the subjects were individualized and included a total of 22 visits in the first year. This is in sharp con- trast to current practice even in the diabetic population. Despite these challenges we should note that the moderate weight loss achieved in these trials had significant beneficial effects on blood pressure and cholesterol 1 73. Risk factor reduction in this population is highly desirable given the high incidence of cardiovascular disease and mortality with diabetes development. Lifestyle modification also resulted in an overall change to healthier habits in this cohort with reduction in smoking. The 10-year follow-up of the DPP cohort confirms that the glycemic benefits of lifestyle inter- vention are long lasting 74. One of the key points to be addressed is if successful intervention at this stage apart from lowering glycemia would also lower the risk of future macrovascular disease. The emergent macrovascular and mortality benefits noted from early glycemic intervention in the 10-year follow-up of the UKPDS cohort in compar- ison to the ADVANCE and ACCORD trials that included subjects with advanced diabetes mandate further investi- gation in the prediabetic population. The beneficial effect in the UKPDS cohort was most pronounced in the met- formin arm. The strongest intervention trial in individuals with prediabetes DPP has established the superior efficacy of lifestyle intervention over metformin in the short term. This further strengthens our argument to favor behavior and lifestyle modification over early initiation of drugs. The cost–benefit analysis of this approach in people with pre- diabetes is sparse 75. Further research into the long-term cost-effectiveness of early lifestyle intervention is needed. In conclusion prediabetes identifies a group of individ- uals at high risk of progression to diabetes and who have increased cardiovascular mortality compared to the nor- moglycemic population. Clustering of other cardiovascu- lar risk factors might explain the increased macrovascular events in this group. Early lifestyle intervention is needed to decrease the risk of progression to diabetes and potentially offer protection against accelerated atherogenesis. Reference 1. Knowler WC Barrett-Connor E Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 3466:393–403 2002. 2. Dinneen SF Maldonado D IIIrd Leibson CL et al. Effects of changing diagnostic criteria on the risk of developing diabetes. Diabetes Care. 219:1408–1413 1998. 3. National Diabetes Fact Sheet 2007 cited 2010 Febru- ary 17th Available from: http://www.searchfordiabetes.org/ public/documents/CDCFact2008.pdf 4. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intoler- ance. Diabetes. 2812:1039–1057 1979. 5. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 207: 1183–1197 1997. 6. Alberti KG Zimmet PZ. Definition diagnosis and classi- fication of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 157:539–553 1998. 7. Brunzell JD Robertson RP Lerner RL et al. Relationships between fasting plasma glucose levels and insulin secretion

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8 Prediabetes and the diagnosis of diabetes during intravenous glucose tolerance tests. J Clin Endocrinol Metab. 422:222–229 1976. 8. Charles MA Fontbonne A Thibult N Warnet JM Rosselin GE Eschwege E. Risk factors for NIDDM in white pop- ulation. Paris prospective study. Diabetes. 407:796–799 1991. 9. Charles MA Balkau B Vauzelle-Kervroedan F Thibult N Eschwege E. Revision of diagnostic criteria for diabetes. Lancet. 3489042:1657–1658 1996. 10. Fuller JH Shipley MJ Rose G Jarrett RJ Keen H. Coronary- heart-disease risk and impaired glucose tolerance. The Whitehall study. Lancet. 18183:1373–1376 1980. 11. McCartney P Keen H Jarrett RJ. The Bedford Survey: obser- vations on retina and lens of subjects with impaired glucose tolerance and in controls with normal glucose tolerance. Diabete Metab. 94:303–305 1983. 12. Klein R Barrett-Connor EL Blunt BA Wingard DL. Visual impairment and retinopathy in people with normal glucose tolerance impaired glucose tolerance and newly diagnosed NIDDM. Diabetes Care. 1410:914–918 1991. 13. Jarrett RJ Keen H. Hyperglycaemia and diabetes mellitus. Lancet. 27993:1009–1012 1976. 14. Gabir MM Hanson RL Dabelea D et al. The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. Diabetes Care. 238:1108–1112 2000. 15. Shaw JE Zimmet PZ de Courten M et al. Impaired fasting glucose or impaired glucose tolerance. What best predicts future diabetes in Mauritius Diabetes Care. 223:399–402 1999. 16. Shaw JE Zimmet PZ Hodge AM et al. Impaired fasting glucose: how low should it go Diabetes Care. 231:34–39 2000. 17. Genuth S Alberti KG Bennett P et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2611: 3160–3167 2003. 18. Diabetes Prevention Program Research Group. The preva- lence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 242:137–144 2007. 19. Gabir MM Hanson RL Dabelea D et al. Plasma glucose and prediction of microvascular disease and mortality: evalua- tion of 1997 American Diabetes Association and 1999 World Health Organization criteria for diagnosis of diabetes. Dia- betes Care. 238:1113–1118 2000. 20. Ito C Maeda R Ishida S Harada H Inoue N Sasaki H. Importance of OGTT for diagnosing diabetes mellitus based on prevalence and incidence of retinopathy. Diabetes Res Clin Pract. 492–3:181–186 2000. 21. Tapp RJ Zimmet PZ Harper CA et al. Diagnostic thresholds for diabetes: the association of retinopathy and albumin- uria with glycaemia. Diabetes Res Clin Pract. 733:315–321 2006. 22. Barr EL Wong TY Tapp RJ et al. Is peripheral neuropathy associated with retinopathy and albuminuria in individuals with impaired glucose metabolism The 1999–2000 Aus- Diab. Diabetes Care. 295:1114–1116 2006. 23. Benjamin SM Cadwell BL Geiss LS Engelgau MM Vinicor F. A change in definition results in an increased number of adults with prediabetes in the United States. Arch Intern Med. 16421:2386 2004. 24. Davidson MB Landsman PB Alexander CM. Lowering the criterion for impaired fasting glucose will not provide clinical benefit. Diabetes Care. 2612:3329–3330 2003. 25. Lara C Ponce de Leon S Foncerrada H Vega M. Diabetes or impaired glucose tolerance: does the label matter Diabetes Care. 3012:3029-3030 2007. 26. Schriger DL Lorber B. Lowering the cut point for impaired fasting glucose: where is the evidence Where is the logic Diabetes Care. 272:592–601 2004. 27. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 33Suppl 1:S62–S69. 28. Edelman D Olsen MK Dudley TK Harris AC Oddone EZ. Utility of hemoglobin A1c in predicting diabetes risk. J Gen Intern Med. 1912:1175–1180 2004. 29. Pradhan AD Rifai N Buring JE Ridker PM. Hemoglobin A1c predicts diabetes but not cardiovascular disease in non- diabetic women. Am J Med. 1208:720–727 2007. 30. The DECODE Study Group and on behalf of the European Diabetes Epidemiology Group. Is the current definition for diabetes relevant to mortality risk from all causes and car- diovascular and noncardiovascular diseases Diabetes Care. 263:688–696 2003. 31. Douaihy K. Prediabetes atherosclerosis: what’s the con- nection Nurse Pract. 306:24–35 quiz 6–7 2005. 32. Haffner SM Stern MP Hazuda HP Mitchell BD Patter- son JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes JAMA. 26321: 2893–2898 1990. 33. Meigs JB D’Agostino RB Sr. Wilson PW Cupples LA Nathan DM Singer DE. Risk variable clustering in the insulin resistance syndrome. The Framingham Offspring Study. Diabetes. 4610:1594–1600 1997. 34. Lyerly GW Sui X Lavie CJ Church TS Hand GA Blair SN. The association between cardiorespiratory fitness and risk of all-cause mortality among women with impaired fasting glucose or undiagnosed diabetes mellitus. Mayo Clin Proc. 849:780–786 2009. 35. Sorkin JD Muller DC Fleg JL Andres R. The relation of fasting and 2-h postchallenge plasma glucose concentrations to mortality: data from the Baltimore Longitudinal Study of

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Is prediabetes a risk factor or is it a disease 9 Aging with a critical review of the literature. Diabetes Care. 2811:2626–2632 2005. 36. Shaw JE Hodge AM de Courten M Chitson P Zimmet PZ. Isolated post-challenge hyperglycaemia confirmed as a risk factor for mortality. Diabetologia. 429:1050–1054 1999. 37. The DECODE Study Group and on behalf of the Euro- pean Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 1613:397–405 2001. 38. T ominaga M Eguchi H Manaka H Igarashi K Kato T Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 226:920–924 1999. 39. Smith NL Barzilay JI Shaffer D et al. Fasting and 2-hour postchallenge serum glucose measures and risk of inci- dent cardiovascular events in the elderly: the Cardiovascular Health Study. Arch Intern Med. 1622:209–216 2002. 40. Bjornholt JV Erikssen G Aaser E et al. Fasting blood glu- cose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care. 221:45–49 1999. 41. Chien KL Hsu HC Su TC Chen MF Lee YT Hu FB. Fasting and postchallenge hyperglycemia and risk of cardiovascular disease in Chinese: the Chin-Shan Community Cardiovas- cular Cohort study. Am Heart J. 1565:996–1002 2008. 42. Pankow JS Kwan DK Duncan BB et al. Cardiometabolic risk in impaired fasting glucose and impaired glucose toler- ance: the Atherosclerosis Risk in Communities Study. Dia- betes Care. 302:325–331 2007. 43. Meigs JB Nathan DM D’Agostino RB Sr. Wilson PW. Fasting and postchallenge glycemia and cardiovascular dis- ease risk: the Framingham Offspring Study. Diabetes Care. 2510:1845–1850 2002. 44. Stern MP Fatehi P Williams K Haffner SM. Predicting future cardiovascular disease: do we need the oral glucose tolerance test Diabetes Care. 2510:1851–1856 2002. 45. Feskens EJ Bowles CH Kromhout D. Intra- and interindi- vidual variability of glucose tolerance in an elderly popula- tion. J Clin Epidemiol. 449:947–953 1991. 46. McDonald GW Fisher GF Burnham C. Reproducibility of the Oral Glucose Tolerance Test. Diabetes. 14:473–480 1965. 47. Riccardi G Vaccaro O Rivellese A Pignalosa S Tutino L Mancini M. Reproducibility of the new diagnostic crite- ria for impaired glucose tolerance. Am J Epidemiol. 1213: 422–429 1985. 48. Eschwege E Charles MA Simon D Thibult N Balkau B. Reproducibility of the diagnosis of diabetes over a 30- month follow-up: the Paris Prospective Study. Diabetes Care. 2411:1941–1944 2001. 49. Mooy JM Grootenhuis PA de Vries H et al. Intra-individual variation of glucose specific insulin and proinsulin concen- trations measured by two oral glucose tolerance tests in a general Caucasian population: the Hoorn Study. Diabetolo- gia. 393:298–305 1996. 50. Tuomilehto J. Point: a glucose tolerance test is important for clinical practice. Diabetes Care. 2510:1880–1882 2002. 51. Butler AE Janson J Bonner-Weir S Ritzel R Rizza RA Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 521:102–110 2003. 52. Szoke E Shrayyef MZ Messing S et al. Effect of aging on glu- cose homeostasis: accelerated deterioration of beta-cell func- tion in individuals with impaired glucose tolerance. Diabetes Care. 313:539–543 2008. 53. Wasada T Kuroki H Katsumori K Arii H Sato A Aoki K. Who are more insulin resistant people with IFG or people with IGT Diabetologia. 474:758–759 2004. 54. Davies MJ Raymond NT Day JL Hales CN Burden AC. Impaired glucose tolerance and fasting hyperglycaemia have different characteristics. Diabet Med. 176:433–440 2000. 55. van Haeften TW Pimenta W Mitrakou A et al. Relative conributions of beta-cell function and tissue insulin sensi- tivity to fasting and postglucose-load glycemia. Metab: Clin Exp. 4910:1318–1325 2000. 56. Weyer C Bogardus C Pratley RE. Metabolic characteristics of individuals with impaired fasting glucose and/or impaired glucose tolerance. Diabetes. 4811:2197–2203 1999. 57. Tripathy D Carlsson M Almgren P et al. Insulin secre- tion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study. Diabetes. 496:975–980 2000. 58. Polonsky KS. Evolution of beta-cell dysfunction in impaired glucose tolerance and diabetes. Exp Clin Endocrinol Diabetes. 107Suppl 4:S124–S127 1999. 59. Bock G Dalla Man C Campioni M et al. Pathogenesis of prediabetes: mechanisms of fasting and postprandial hyper- glycemia in people with impaired fasting glucose and/or impaired glucose tolerance. Diabetes. 5512:3536–3549 2006. 60. Meigs JB Muller DC Nathan DM Blake DR Andres R. The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging. Diabetes. 526:1475–1484 2003. 61. Saad MF Knowler WC Pettitt DJ Nelson RG Mott DM Bennett PH. The natural history of impaired glucose toler- ance in the Pima Indians. N Engl J Med. 31923:1500-1506 1988. 62. Tuomilehto J Lindstrom J Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among

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10 Prediabetes and the diagnosis of diabetes subjects with impaired glucose tolerance. N Engl J Med. 34418: 1343–1350 2001. 63. Ramachandran A Snehalatha C Mary S Mukesh B Bhaskar AD Vijay V . The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance IDPP-1. Diabetologia. 492:289–297 2006. 64. Pan XR Li GW Hu YH et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose toler- ance. The Da Qing IGT and Diabetes Study. Diabetes Care. 204:537–544 1997. 65. Knowler WC Hamman RF Edelstein SL et al. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes. 544:1150–1156 2005. 66. Buchanan TA Xiang AH Peters RK et al. Preservation of pancreatic beta-cell function and prevention of type 2 dia- betes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 519:2796–2803 2002. 67. Nolan JJ Ludvik B Beerdsen P Joyce M Olefsky J. Improve- ment in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 33118: 1188–1193 1994. 68. Kahn SE Haffner SM Heise MA et al. Glycemic durability of rosiglitazone metformin or glyburide monotherapy. N Engl J Med. 35523:2427–2443 2006. 69. Bosch J Yusuf S Gerstein HC et al. Effect of ramipril on the incidence of diabetes. N Engl J Med. 35515:1551–1562 2006. 70. Chiasson JL Josse RG Gomis R Hanefeld M Karasik A Laakso M. Acarbose for prevention of type 2 diabetes melli- tus: the STOP-NIDDM randomised trial. Lancet. 3599323: 2072–2077 2002. 71. The NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 362:1477–1490 2010. 72. The NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes and cardiovascular events. New Engl J Med. 362: 1463–1476 2010. 73. Eriksson KF Lindgarde F. Prevention of type 2 non-insulin- dependent diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia. 3412: 891–898 1991. 74. Knowler WC Fowler SE Hamman RF et al. 10-year follow- up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 3749702: 1677–1686 2009. 75. Ramachandran A Snehalatha C Y amuna A Mary S Ping Z. Cost-effectiveness of the interventions in the primary pre- vention of diabetes among Asian Indians: within-trial results of the Indian Diabetes Prevention Programme IDPP. Dia- betes Care. 3010:2548–2552 2007.

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2 Early diagnosis of type 1 diabetes: Useful or a phyrrhic victory Click Here For Best Diabetes Treatment Chiara Guglielmi 1 and Paolo Pozzilli 2 1 PostDoc Fellow Department of Endocrinology Diabetes University Campus Bio-Medico Rome Italy 2 Professor of Endocrinology Head of Department of Endocrinology Diabetes University Campus Bio-Medico Rome Italy Professor of Diabetes Research Barts the London School of Medicine Dentistry London UK L E A R N I N G P OIN T S Type 1 diabetes T1D is one of the most widespread chronic diseases in the world affecting children adolescents and young adults. Early diagnosis of T1D is crucial because it is a condition leading to early complications. Genetic immunological and environmental factors are involved in the pathogenesis of T1D. The importance of understanding the natural history of immune-mediated prediabetes lies in the development of prevention strategies. Many clinical trials are attempting to modify the course of disease progress at many points along the presumed pathogenic pathway. Introduction Type 1 diabetes T1D is one of the most widespread chronic diseases of childhood affecting children adolescents and young adults. In 1985 30 million people worldwide were reported with diabetes all types included in 1995 135 million in 2001 approximately 177 million and it is pre- dicted that some 285 million people worldwide will live with diabetes in 2010 1. As the prevalence of diabetes continues to grow world- wide disease-related morbidity and mortality are emerg- ing as major health care problems. Epidemiologic evidence suggests the relationship between diabetes and complica- tions begins early in the progression from normal glucose tolerance to impaired fasting glucose IFG and impaired glucose tolerance IGT to diabetes than previously thought. These observations indicate that early identifi- cation and management of individuals with diabetes and prediabetes have the potential to reduce both the incidence of diabetes and its related complications. The global incidence of T1D in children and adoles- cents is rising with an estimated overall annual increase of approximately 3. The increase in incidence of T1D has been shown in countries having both high and low preva- lence figures with an indication of a steeper increase in some of the low-prevalence countries. Several European studies have suggested that in relative terms the increase is more pronounced in young children. Although T1D usually accounts for only a minority of the total burden of diabetes in a population it is the predominant form of the disease in younger age groups in most developed countries. T1D accounts for about 10 of all cases of diabetes occurs most commonly in people of European descent and affects 2 million people in Europe and North America. The lowest incidence has been found in Asia and Oceania the highest in Europe. T1D results from the autoimmune destruction of insulin-producing beta cells in the pancreas. Genetic metabolic and environmental factors act together to precipitate the onset of the disease. The excess mortality associated with complications of T1D and the increasing incidence of childhood T1D emphasize the importance of therapeutic strategies to prevent this chronic metabolic disorder. Increasingly efforts need to be directed toward early diagnosis of T1D because it is a condition leading to early complications and the potential availability of disease-modifying interventions underscore the need for early diagnosis. Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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β-cell mass 12 Pre-diabetes and the diagnosis of diabetes Pathogenesis of T1D: an update in view of defining preventive tools There are three main categories of factors involved in the pathogenesis of T1D. These are genetic immunological and environmental factors Figure 2.1. Like other organ-specific autoimmune diseases T1D has human leukocyte antigen HLA associations. The HLA complex on chromosome 6 comprises the first gene shown to be associated with the disease which is considered to con- tribute about half of the familial basis of T1D. Two combina- tions of HLA haplotypes are of particular importance. They are DR4-DQ8 and DR3-DQ2 which are present in 90 of children with T1D 2. A third haplotype DR15-DQ6 is found in less than 1 of children with T1D compared with more than 20 of the general population and is considered to be protective. The genotype combining the two suscep- tibility haplotypes DR4-DQ8/DR3-DQ2 contributes the greatest risk of disease and is most common in children in whom the disease develops very early in life. First-degree relatives of these children are themselves at greater risk of T1D than are the relatives of children in whom the disease develops later. Candidate gene studies also identified the insulin gene on chromosome 11 as the second most important genetic susceptibility factor contributing 10 of the genetic sus- ceptibility to T1D 3. An allele of the gene acting as a negative regulator of T-cell activation cytotoxic T lympho- cyte antigen 4 CTLA-4 found on chromosome 2q33 is considered to be another susceptibility gene for T1D and has been associated with increased levels of soluble CTLA-4 and the frequency of regulatory T cells 4. A variant of PTPN22 the gene encoding lymphoid phosphatase LYP also a suppressor of T-cell activation has been deemed as another susceptibility gene 5. The observation that these four most important susceptibility genes for T1D can all be represented on a single diagram of antigen presentation to T cells emphasizes the potential importance of current therapeutic strategies targeting this interaction. Genetic studies have highlighted the importance of large well-characterized populations in the identification of sus- ceptibility genes for T1D. Recruitment of increasingly large populations of patients with T1D and their families is required to provide statistically powerful cohorts in which to identify other disease-associated genes. Some genes have a relatively minor individual impact on susceptibility to dis- ease but identify important pathways in the pathogenesis of T1D which could be targets for drug development. The presence of autoantibodies to beta cells is the hall- mark of T1D. Abnormal activation of the T-cell-mediated immune system in susceptible individuals leads to an inflammatory response within the islets as well as to a humoral response with production of antibodies to beta- cell antigens. Islet cell antibodies ICA were the first described followed by more specific autoantibodies to insulin IAA glutamic acid decarboxylase GAD and the protein tyrosine phosphatase IA-2 all of which can be easily detected by sensitive radioimmunoassay to identify subjects at risk of developing T1D 6. These autoantibod- ies are common in both childhood and adult onset T1D with many subjects being positive for multiple autoanti- bodies. The type of immune response is age-dependent but seroconversion to multiple autoantibody positivity usually Immune dysregulation Environmental triggers and regulators IAA Modern model Interactions between genes imparting GADA ICA512A ICA Loss of first phase insulin response IVGTT Variable insulitis susceptibility and resistance β-cell sensitivity to injury Glucose intolerance Absence of C-peptide Prediabetes Time Overt diabetes FIG 2.1 Pathogenesis and natural history of type 1 diabetes. Atkinson MA Eisenbarth GS. Lancet 2001.

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Early diagnosis of type 1 diabetes: Useful or a phyrrhic victory 13 occurs in close temporal relationship and is associated with higher genetic risk. The presence of one or more types of antibody can pre- cede the clinical onset of T1D by years or even decades. These autoantibodies are usually persistent although a small group of individuals may revert back to being seroneg- ative without progressing to clinical diabetes. The presence and persistence of positivity to multiple antibodies increases the likelihood of progression to clinical disease. Continuing destruction of beta cells leads to a progressive reduction of insulin-secretory reserve and loss of first-phase insulin secretion in response to an intravenous glucose tol- erance test followed by clinical diabetes when insulin secre- tion falls below a critical amount and finally to a state of absolute insulin deficiency. What are the environmental factors As regards the role of environmental factors it should be underlined that the increase in incidence of T1D is too rapid to be caused by alterations in the genetic background and is likely to be the result of environmental changes. Certain viral infections may play a role in the pathogen- esis of human T1D. Congenital rubella is the classical exam- ple of virus-induced diabetes in human beings but effective immunization programs have eliminated congenital rubella in most Western countries. Currently the main candidates for a viral trigger of human diabetes are members of the group of Enterovirus 7. They are small nonenveloped RNA viruses which belong to the Picornavirus family. They consist of more than 60 different serotypes with the Polioviruses being their best-known representatives. Enterovirus infections are frequent among children and adolescents causing aseptic meningitis myocarditis rash hand-food-and-mouth disease paralysis respiratory infec- tions and severe systemic infections in newborn infants. Most infections however are subclinical or manifest with mild respiratory symptoms. The primary replication of the virus occurs in the lymphoid tissues of the pharynx and small intestine and during the following viremic phase the virus can spread to various organs including the beta cells. Theoretically Enterovirus could cause beta-cell dam- age by two main mechanisms. Enterovirus may infect beta cells and destroy them directly or they may induce an autoimmune response against beta cells. Direct virus- induced damage has been supported by studies showing that Enteroviruses are present in beta cells in patients who have died from severe systemic Enterovirus infection and that the islet cells of these patients are damaged. Enterovirus can also infect and damage beta cells in vitro and induce the expression of interferon-alpha and HLA-class I molecules in beta cells thus mimicking the situation observed in the pancreas of patients affected by T1D. The first reports con- necting Enterovirus infections to T1D were published more than 30 years ago showing that the seasonal variation in the onset of T1D follows that of Enterovirus infections. At the same time antibodies against Coxsackievirus B serotypes were found to be more frequent in patients with newly diag- nosed T1D than in control subjects 8. Enteroviruses have also been isolated from patients with newly diagnosed T1D. In one case report Coxsackievirus B4 was isolated from the pancreas of a child who had died from diabetic ketoacidosis and this virus caused diabetes when transferred to a suscep- tible mouse strain. The beta cells of diabetic patients also express interferon-alpha a cytokine that is induced during viral infections suggesting the presence of some virus in the beta cells. Prospective studies are particularly valuable in the evaluation of viral triggers because they cover all stages of the beta-cell damaging process. Enteroviruses are not the only viruses that have been connected to the pathogenesis of T1D. Mumps measles cytomegalovirus and retroviruses also have been found to be associated with T1D but the evidence is less convincing than that for Enterovirus. The role of cow’s milk There is evidence that cow’s milk proteins can act as triggers for the autoimmune process of beta-cell destruction based on studies indicating bottle feeding as a triggering factor for an autoimmune response to beta cells. There are several arguments for the milk hypothesis in T1D including the following reviewed in ref. 9: Epidemiological studies show increased risk for T1D if the breastfeeding period is short and cow’s milk is intro- duced before 3–4 months of age. Skim milk powder can be “diabetogenic” in diabetes- prone BB rats. Patients with T1D have increased levels of antibodies against cow’s milk constituents. Milk albumin and beta casein have some structural simi- larity to the islet autoantigen ICA69 and GLUT2 respec- tively. A number of hypotheses have been postulated to explain the pathogenic role of cow’s milk. One of the most

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14 Pre-diabetes and the diagnosis of diabetes convincing ones is that immature gut mucosa allows the passage of high molecular weight potentially antigenic pro- teins which share some molecular mimicry with pancreatic beta cells. Among diabetogenic proteins in cow’s milk beta casein beta lactoglobulin and albumin have been impli- cated as sources of potential antigens. Casein represents the major protein in cow’s milk. Human and bovine beta casein are approximately 70 homologous and 30 identical. There are several reasons why it is thought that beta casein is a good candidate to explain the observed association between cow’s milk con- sumption and T1D: a it has several structural differences from the homologous human protein b casein is probably the milk fraction promoting diabetes in the NOD mouse since a protein-free diet prevents the disease while a diet containing casein as the sole source of protein produces dia- betes in the same animals c several sequence homologies exist between bovine beta casein and beta-cell autoantigens d specific cellular and humoral immune responses toward bovine beta casein are detectable in most T1D patients at the time of diagnosis highly suggestive that this protein may participate in the immune events triggering the disease e casein hydrolysate was shown to be nondiabetogenic in the BB rat and NOD mouse models therefore it was thought that this dietary intervention might be beneficial in humans as well for disease prevention. The rationale behind the use of cow’s milk hydrolysate for primary prevention of T1D is based on several epidemi- ological and in vitro studies indicating that intact cow’s milk if given before three months of age may induce an immune response toward beta cells. The role of vitamin D deficiency Several epidemiological studies have described an intrigu- ing correlation between geographical latitude and the inci- dence of T1D and an inverse correlation between monthly hours of sunshine and the incidence of diabetes. A seasonal pattern of disease onset has also been described for T1D once again suggesting an inverse correlation between sun- light and the disease 10. Vitamin D is an obvious candidate as a mediator of this effect. Dietary vitamin D supplementation is often recom- mended in pregnant women and in children to prevent vitamin D deficiency. Cod liver oil taken during the first year of life reportedly reduced the risk of childhood-onset T1D and a multicentre case-control study also showed an association between vitamin D supplementation in infancy and a decreased risk of T1D. A further study found that an intake of 2000 IU of vitamin D during the first year of life diminished the risk of developing T1D and showed that the incidence of childhood diabetes was three times higher in subjects with suspected rickets 11. It remains to be deter- mined whether these observations are the result of supple- mentation of vitamin D to supraphysiological levels or are simply the result of the prevention of vitamin D deficiency. Observations in animal models suggest the latter since reg- ular supplements of vitamin D in neonatal and early life offered no protection against T1D in non-obese diabetic NOD mice or in BB rats whereas the prevalence of dia- betes is doubled in NOD mice rendered vitamin D-deficient in early life 12. The results of genetic studies investigat- ing a possible relationship between VDR polymorphisms and T1D are inconsistent: a clear correlation exists in some populations whereas no correlation is observed in others. Prediction of T1D as the basis for disease prevention There are different approaches for the identification of indi- viduals at risk for T1D. These approaches are based on fam- ily history of T1D genetic disease markers autoimmune markers or metabolic markers of T1D. These alternatives may also be combined in various ways to improve the pre- dictive characteristics of the screening strategy. The impor- tance of understanding the natural history of immune- mediated prediabetes lies in the development of prevention strategies. Several randomized clinical intervention trials have been concluded and the next generation of such tri- als will rely upon improved and simplified identification of individuals who are at high risk of progression to T1D. This is essential to ensure that trials have sufficient statisti- cal power to detect a given effect of the intervention within the time available for the study. Such understanding is also needed to avoid exposing those who will not develop T1D to the risk of adverse effects of the intervention. Prevention of T1D: current status Although the process by which pancreatic beta cells are destroyed is not well understood several risk factors and immune-related markers are known to accurately identify first-degree relatives of patients with T1D who may develop the disease. Since we now have the ability to predict the development T1D investigators have begun to explore the

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β-cell mass Early diagnosis of type 1 diabetes: Useful or a phyrrhic victory 15 Years Diabetes 100 80 60 40 20 5 10 15 20 FIG 2.2 Strategies to preserve beta-cell mass in T1D. Modified from Reimann M et al. Pharmacology Therapeutics 2009. Genetic analysis PRIMARY PREVENTION SECONDARY PREVENTION TERTIARY PREVENTION use of intervention therapy to halt or even prevent beta-cell destruction in such individuals. The autoimmune patho- TABLE 2.1 Prevention in T1D Study genesis of T1D determines the efforts to prevent it Figure 2.2. Susceptible individuals are identified by searching for evidence of autoimmune activity directed against beta cells. While direct evaluation of T-cell activity might be prefer- able antibody determinations are generally used for screen- ing because these assays are more robust. Antibody titers are often used in combination with an assessment of the genetic susceptibility primarily evaluated by HLA typing. Interventions are generally designed to delay or prevent T1D by impacting some phases of the immune pathogenesis of the disease. As discussed below current trials are attempt- ing to modify the course of disease progress at many points along the presumed pathogenic pathway. Most prevention trials include only relatives of T1D patients a group in which risk prediction strategies are most established. Trials in genetically at-risk infants evaluate whether avoiding one of the putative environmental triggers for T1D can delay or prevent its onset Table 2.1. Primary prevention Secondary prevention Tertiary prevention TRIGR: Casein hydrolysate vs. cow’s milk formula PREVEFIN: Vitamin D supplementation and beta-casein-free diet BABYDIET: Delayed introduction of dietary gluten DIPP: Intranasal insulin ENDIT: Nicotinamide DPT -1: Insulin/oral insulin Cyclosporine Nicotinamide Vitamin D Calcitriol Anti-CD3 Monoclonal antibody GAD DIAPEP277 Anti-IL-1 Primary prevention Primary prevention identifies and attempts to protect indi- viduals at risk from developing T1D. It can therefore reduce both the need for diabetes care and the need to treat diabetes-related complications. T1D is relatively easy to prevent in animal models of the disease and an array of therapies is effective. However the mechanism of prevention is usually poorly defined and there is a lack of surrogate assays of the immune response to define which therapies are likely to prevent diabetes in humans. Inability to define surrogate assays probably results from a fine balance of the immune system so that even with inbred strains of animals only a subset progress to diabetes and thus relatively small changes in immune function may prevent disease. These observations have led to the hypoth- esis that identifying children at a very high genetic risk

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16 Pre-diabetes and the diagnosis of diabetes for diabetes prior to development of measurable beta-cell autoimmunity and treating them at that point may be a more effective means of diabetes prevention. Studies for the primary prevention of T1D i.e. prior to the expres- sion of islet autoantibodies are currently being designed and implemented. These studies target young children at a very high genetic risk for T1D and propose treatments that are very safe. These studies require large-scale screen- ing to identify high-risk subjects and follow-up over a long period of time to observe the outcome of anti-islet autoim- munity as a surrogate marker for the disease and onset of hyperglycemia as the final end point. A large worldwide trial called TRIGR Trial to Reduce IDDM in the Genetically at Risk and a small one in Italy called PREVEFIN aim to answer the question of whether cow’s milk administered in early life is diabetogenic and whether the use of a cow’s milk hydrolysate can protect from the disease. The rationale behind the use of cow’s milk hydrolysate for primary prevention of T1D is based on several epidemiological and in vitro studies indicating that intact cow’s milk if given before 3 months of age may induce an immune response toward beta cells. TRIGR is a randomized double-blind intervention study with the intention to treat as well as statistically analyze the incidence of predictive islet cell autoantibodies vs. the actual occurrence of clinical diabetes in two treatment groups 13. This trial which investigates cow’s milk as an environmental factor has several key features. First it is designed to inter- vene specifically in first-degree relatives of T1D patients. The newborns enrolled must have a genotype with diabeto- genic HLA alleles without protective alleles and a mother father or a sibling who suffers from T1D. Second the sam- ple size is highly significant since previous trials were used to estimate the number of newborns necessary to partici- pate. This is an international trial and recruitment has been carried out during a 2-year period in nine European coun- tries six major centers in the USA 12 centers in Canada and three centers in Australia. Due to statistical consider- ations the frequency of the high-risk HLA genotype con- sent and dropout rates the trial required initial access to 8000 pregnancies that ultimately yielded 5156 infants nec- essary for randomization. Each formula milk used in the two treatment groups is a nutritionally complete infant for- mula. The study formula contains extensively hydrolyzed casein as the protein source vegetable oils as fat source and glucose polymers and modified starch as carbohydrate source. The control formula is a mixture of a standard com- mercial cow’s milk-based formula powder made by the same company plus casein hydrolysate powder in a 4:1 ratio designed to mask the flavor and smell distinctions between the two study formulas. The major outcome for the first phase is the frequency of T1D-associated islet cell autoan- tibodies and/or the development of clinical diabetes by the age of 6 years. The outcome of the second phase will be the manifestation of T1D by the age of 10 years. The mani- fest diabetes outcome will be assessed as the proportion of subjects in each group who develop T1D as well as age at diagnosis. In PREVEFIN the first national preventive trial of T1D in Italy newborns from the general population approx- imately12000 at birth were screened for the presence of the high-risk genotype HLA-DR/ DQ for T1D DRB1 ∗ - DQB1 ∗ 0201/DRB1 ∗ 04- DQB1 ∗ 0302 14. This high-risk genotype has been found to have a frequency of only 0.9 in the general Italian population lower than in other Cau- casian populations thus explaining the low incidence of T1D in continental Italy. Many centers participated in the project that will yield information concerning acceptabil- ity of and compliance with early childhood intervention to prevent T1D. The HLA screening was performed within the first 2 weeks of life so that randomization occurs before 1 month of age. High risk newborns were recruited into two treatment arms from the time mothers have stopped breast- feeding or if they did not breast-feed. Treatment consists of i normal cow’s milk formula with vitamin D supple- mentation 500 IU/day or ii cow’s milk hydrolysate with vitamin D supplementation 500 IU/day continued for up to 1 year. Vitamin D supplementation was included follow- ing recent evidence that administration of this vitamin to newborns can reduce T1D incidence later in life. Detection of islet cell autoantibodies and later devel- opment of diabetes are used as end points. Subjects who participate in a similar project called DIABFIN 15 form the control group where newborns with the same high-risk HLA genotype as in the PREVEFIN trial are being followed for the appearance of islet cell autoantibodies and diabetes. While the proposed trial may not allow all questions to be fully answered this national collaborative network provides safety efficacy and logistic data necessary to design a Phase III trial. Results will be available in 2015. Another pilot study called BABYDIET is currently underway to determine whether primary intervention through delayed introduction of dietary gluten is feasible

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Early diagnosis of type 1 diabetes: Useful or a phyrrhic victory 17 and may reduce the incidence of islet autoimmunity in high-risk first-degree relatives of patients with T1D 16. The study is based on the premise that introduction of foods containing gluten or cereal before the age of 3 months is associated with an increased risk of islet autoimmunity in childhood. Newborn children are eligible if they are younger than 3 months are offspring or siblings of patients with T1D and have HLA genotypes that confer a high T1D risk. Finally the Diabetes Prediction and Prevention Project DIPP Study 17 is a longitudinal study on T1D predic- tion and prevention carried out in the university hospitals of Turku Tampere and Oulu Finland. The aim of the study is to investigate longitudinally the dietary factors in relation to the development of diabetic autoantibodies and clinical T1D. The diet of children is followed up by a struc- tured questionnaire and by 3-day dietary records at various ages. A food frequency questionnaire is applied for studying the dietary intake of pregnant and lactating mothers. The aims of this project are: 1 to identify infants at increased genetic risk for T1D from the general population at birth 2 to monitor such children for the appearance of diabetes-associated autoantibodies so as to identify those at high risk of developing clinical disease and characterize the natural course of T1D 3 to identify the environmen- tal factors inducing the seroconversion to autoantibody- positivity in children at increased genetic risk and 4 to evaluate whether it is possible to delay or prevent progres- sion to clinical T1D by daily administration of intranasal insulin. Whereas the aims given in points 1–4 have been fulfilled and useful information has been obtained the trial with intranasal insulin did not show any beneficial effect of this treatment in preventing the disease. In conclusion since the failure of ENDIT and DPT1 trials see secondary prevention in preventing the onset of T1D in subjects who are beta-cell autoantibody positive interest has switched to prevention trials starting before islet cell autoimmunity has developed. These primary prevention trials of T1D offer an exciting view of how our knowledge of the pathogenesis of this disease can lead to the possibility of intervening at birth. There is still a long way to go however the rationale is sound and the prospects seem good. Secondary prevention Secondary prevention of T1D aims to reduce the incidence of the disease by stopping progression of beta-cell destruc- tion in individuals with signs of such a process. A number of early studies of secondary prevention were carried out in some cases interesting results were obtained as in the case of the gluten-free diet study but the majority of these studies suffered from the limitation of inadequate power or an insufficient follow-up time. T o this end consortia of investigators have been created extended to numerous centers with the objective to gener- ate the required critical mass for the development of studies with sufficient numbers of subjects at risk for T1D. European Nicotinamide Diabetes Intervention Trial ENDIT The ENDIT study conducted predominantly in Europe examined whether nicotinamide could lead to a reduc- tion in the rate of progression to T1D in at-risk relatives of T1D probands. Over 40000 first-degree relatives aged 5–40 years were screened in centers in Europe and North America. The study was designed to recruit at least 422 subjects with ICA titers ≥ 20 JDF units to be random- ized to either a nicotinamide- or a placebo-treated group. With an expected rate of progression to diabetes of 40 in the placebo arm the proposed 5-year observation period should have allowed a 90 power to observe a 35 reduc- tion in the incidence of disease 18. Nicotinamide treatment at the doses used did not show any significant effect on the primary outcome—progression to T1D. A total of 159 participants developed the disease within 5 years of randomization to treatment 82 30 in the active treatment group and 77 28 in the placebo group. The unadjusted Cox proportional hazard estimate showed no difference between the placebo and nicoti- namide groups on an intention-to-treat basis. Nor any dif- ference was found between groups after adjustment for age at baseline glucose concentrations at 2-h glucose in the OGTT and number of islet autoantibodies. The propor- tion of relatives who developed diabetes within 5 years was almost identical in those treated with nicotinamide and those treated with placebo and there was no suggestion of a treatment effect in any of the subgroups defined by well-established markers of additional risk. DPT-1 trials The Diabetes Prevention Trial—Type 1 DPT-1 consisted of two clinical trials that sought to delay or prevent T1D. Nine medical centers and more than 350 clinics in the United States and Canada took part in the two trials of the DPT-1 19 20.

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18 Pre-diabetes and the diagnosis of diabetes Individuals who were eligible for testing were identified as follows: age 3 to 45 years with a brother or sister child or parent with T1D age 3 to 20 years with a cousin uncle or aunt nephew or niece grandparent or half-sibling with T1D. Those who met these criteria had ICA antibodies mea- sured. T o be eligible a subject had to be positive for ICAs. Animal research and small studies indicated that small regular doses of insulin could prevent or delay T1D in subjects at risk. One DPT-1 trial tested whether low-dose insulin injections could prevent or delay the development of T1D in people at high risk for developing T1D within 5 years. First-degree relatives 3 to 45 years of age and second- degree relatives 3 to 20 years of age of patients with T1D were screened for islet-cell antibodies. Those with an islet- cell antibody titer of 10 JDF units or higher were offered staging evaluations. Subjects identified as having a high risk of T1D were eligible for random assignment to the experimental inter- vention parenteral insulin therapy or to a control group that underwent close observation. The results demonstrated that insulin in small doses can indeed be administered safely to persons who are at risk for T1D. The increase in presumed and definite hypo- glycemia among the subjects in the intervention group did not adversely affect cognitive function. In high-risk relatives of patients with diabetes the insulin regimen did not delay or prevent the development of T1D 19. Long-term follow-up to detect any effects on the course of diabetes has begun. There are several potential explanations for the lack of effect observed so far. One is that the intervention took place too late in the disease process to slow down the progression of disease. Studies conducted earlier in the disease process such as the ongo- ing DPT-1 oral-insulin trial in relatives of patients with T1D who have a projected five-year risk of 26 to 50 may be more successful. Moreover oral insulin may have a greater immunologic effect although it does not provide for beta-cell rest. In fact the low-dose insulin used in the trial may have failed to achieve such an effect on beta cells but the dose was limited by the risk of hypoglycemia. With a different dosing scheme or a different regimen insulin or insulin-like peptides might alter the course of development of diabetes. The other study was an oral insulin trial that sought to prevent T1D in subjects with a moderate risk for developing diabetes. First-degree ages 3–45 years and second-degree ages 3–20 years relatives of patients with T1D were screened for ICAs. Those with ICA titer ≥10 JDF units were invited to undergo staging evaluations. Staging confirmed ICA positivity measured insulin autoantibody IAA status assessed first-phase insulin response FPIR to intravenous glucose assessed oral glu- cose tolerance OGT and determined the presence or absence of HLADQA1 ∗ 0102/DQB1 ∗ 0602 a protective hap- lotype that excluded subjects from participation. The study was a double-masked placebo-controlled randomized clinical trial in which participants were assigned to receive capsules of either oral insulin 7.5 mg of recombinant human insulin crystals Eli Lilly Indianapo- lis IN or matched placebo. Subjects consumed the capsule insulin or placebo as a single daily dose before breakfast each day either by taking the capsule or if the subject could not swallow capsules sprinkling its contents in juice or on food. In the primary analysis of relatives selected and ran- domized in DPT-1 oral insulin did not delay or prevent development of diabetes. There was greater variability in the IAA assay for values 39–79 nU/ml than for values ≥80 nU/ml particularly in confirmation of a positive result 98.7 overall confirmation for values ≥80 nU/ml com- pared with 70.6 for values 39–79 nU/ml. This prompted comparison of the rate of evolution of diabetes by entry IAA level. The cohort with confirmed IAA ≥80 nU/ml the original entry IAA criterion progressed to diabetes at a faster rate than those subjects who did not have confirmed IAA ≥80 nU/ml. In addition those with confirmed IAA ≥ 80 nU/ml had other risk characteristics that suggested more rapid evolution to diabetes including younger age greater likelihood of having other antibodies and greater loss of beta-cell function 20. The effect of intervention in each of these two subgroups was further evaluated. The group with confirmed IAA ≥ 80 nU/ml showed a beneficial effect of oral insulin whereas the group who did not have confirmed IAA ≥ 80 nU/ml showed a trend suggesting a detrimental effect of oral insulin 20. This group also had a much lower overall rate of development of diabetes. In conclusion neither low-dose insulin injections in sub- jects at high risk for developing T1D nor insulin capsules taken orally by those at moderate risk for T1D were suc- cessful at preventing or delaying the disease.

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Early diagnosis of type 1 diabetes: Useful or a phyrrhic victory 19 Tertiary prevention T ertiary prevention is aimed at delaying or preventing the development of complications in subjects who already have T1D. A landmark trial investigating patients with T1D showed that good glycemic control can reduce the like- lihood of microvascular complications leading to blind- ness or kidney disease but the trend toward a decrease in macrovascular disease was not statistically significant. Diabetes education of health care professionals and those affected by diabetes plays a key role in the tertiary preven- tion of the disease. T ertiary prevention is identified by the maintenance of the residual beta-cell function present at disease onset and can be realized by immune suppression or immune modulation since the time of clinical diagnosis of T1D. The best results in this field were obtained 20 years ago with the use of cyclosporine 21 subsequently abandoned because of transient benefits and undesired adverse effects. In the following years none of the several treatments that have been proposed has obtained appreciable results but for nicotinamide 22. Recently there has been growing interest in vitamin D and its active metabolites in relation to T1D and its immune pathogenesis. Vitamin D metabolites have been shown to exert several immunomodulatory effects and 125-dihydroxyvitamin D3 125-OH2D3 can either pre- vent or suppress autoimmune encephalomyelitis inflam- matory bowel disease and T1D. Recent data in humans demonstrated that reduction in vitamin D supplementation is associated with a higher risk of the disease whereas its supplementation is associated with a decreased frequency of T1D 23. Based on this rationale an open-label randomized trial was designed to determine whether supplementation with the active form of vitamin D calcitriol at diagnosis of T1D could improve parameters of glycemic control 24. The secretion of C-peptide as an index of residual pan- creatic β-cell function was the primary end point with HbA1c and insulin requirement as secondary end points. The aim of this study was to investigate whether supple- mentation with the active form of vitamin D calcitriol in subjects with recent-onset T1D protects residual pan- creatic beta-cell function and improves glycemic control HbA1c and insulin requirement. In this open-label ran- domized trial 70 subjects with recent-onset T1D mean age 13.6 ± 7.6 years were randomized to calcitriol 0.25 mg on alternate days or nicotinamide 25 mg/kg daily and were followed up for 1 year. Intensive insulin therapy was implemented with three daily injections of regular insulin + NPH insulin at bedtime. No significant differences were observed between calcitriol and nicotinamide groups in respect of baseline/stimulated C-peptide or HbA1c 1 year after diagnosis but the insulin dose at 3 and 6 months was significantly reduced in the calcitriol group. In conclusion at the dosage used calcitriol had a modest effect on residual pancreatic beta-cell function and only temporarily reduced the insulin dose 24. Other strategies for prevention of beta-cell damage with immune intervention at onset of the disease are based on immune tolerance Anti CD3 monoclonal antibody GAD65 Diapep277 Anti-Interleukin1. Only recently experience obtained with the use of the antiCD3 monoclonal antibody in two studies one in the United States and the other in Europe has revitalized the interest in this type of interventions 25 26. The drug a modified form of anti-CD3 antibody that minimizes first- dose side effects was studied by comparing 12 subjects aged 7 to 30 who were treated with the antibody to an equal num- ber of patients in a control group who did not receive the drug. One year after treatment with anti-CD3 the treated patients produced more insulin and needed less insulin therapy than the untreated patients. Those who received the antibody treatment also had better HbA1c levels. The anti-CD3 was designed to act on the immune system’s T cells in a more specific manner than previous attempts at immune intervention in early diabetes. GAD65 the 65 kDa isoform of glutamic acid decarboxy- lase is a human enzyme that has an important role in the nervous system and in several nervous system diseases e.g. Parkinson’s disease and chronic pain. GAD65 is also found in the insulin-producing beta cells of the pancreas although its function at this site is not yet fully established. It is however clear that GAD65 is one of the most important targets when the immune system attacks the insulin-producing beta cells in autoimmune diabetes. Ongoing studies aim to investigate whether rhGAD65 can preserve beta-cell function in recently diagnosed chil- dren and young adults 10–20 years with T1D. This treatment is thought to induce tolerance to GAD65 thereby intervening in the autoimmune attack and pre- serving the capacity to produce insulin in patients with autoimmune diabetes 27. Another study is based on the administration of Heat Shock Protein 60 peptide 277 Diapep 277. This is a 24 amino

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20 Pre-diabetes and the diagnosis of diabetes acids synthetic peptide derived from human heat shock protein Hsp60 and it modulates the immune response by inducing tolerance to a specific peptide present in inflamed beta cells 28. The purpose of the ongoing studies is to determine if DiaPep277 can effectively protect the inter- nal production of insulin in patients newly diagnosed with T1D by stopping the immune destruction of insulin- producing beta-cells in the pancreas. DiaPep277 acts on the immune system and is expected to prevent further destruc- tion of the beta cells by stimulating regulatory responses without causing immunological suppression 29. The aim of using the Anti-interleukin-1 Kineret in newly diagnosed T1D subjects is to test the feasibility safety/tolerability and potential efficacy of anti-IL-1 ther- apy in maintaining or enhancing beta-cell function in peo- ple with new onset T1D. Kineret is already being used in the treatment of patients suffering from rheumatoid arthritis and preclinical studies are now suggesting that it may also be useful for patients with T1D. The active substance is interleukin-1 receptor antagonist a blocker of an immune- signal molecule named interleukin-1 30. A randomized placebo-controlled double-masked par- allel group multicentre trial of IL-1 antagonism in sub- jects with newly diagnosed T1D is ongoing. Patients are instructed to inject 100 mg of Kineret or placebo s.c. once daily for 9 months. Conclusions T oday one of the therapeutic goals in T1D is the preserva- tion of the residual C-peptide secretion that is detected in a significant percentage of patients at diagnosis and which potentially may influence the clinical course of the disease. Several studies have demonstrated that residual C- peptide secretion after T1D diagnosis depends on genetic factors the patient’s age at diagnosis the number of anti- islet antibodies and residual C-peptide secretion. Intensive insulin therapy and immunomodulatory drugs may be use- ful in this regard. The ultimate goal of any therapeutic intervention is to prevent or reverse T1D by abrogation of pathogenic autore- activity and by preservation or restoration of the beta-cell mass and function to physiologically sufficient levels to maintain stable glucose control. Early diagnosis of T1D is crucial if we want to restore and to save beta-cell mass. Different trials using antigen-specific or nonspecific inter- ventions have shown some benefit in modulation of the autoimmune process and in preventing the loss of insulin secretion in the short term after early diagnosis of T1D. Unfortunately there are many limitations to current strategies including a lack of suitable markers to predict and monitor the success of interventions uncertainty about the long-term adverse effects or the duration of treatment effect and the feasibility of restoration of beta-cell mass. Moreover we should remember that T1D is a heteroge- neous disease with an age at onset spanning from childhood to adult age. Ideally the interventions would be specific for T1D free of adverse effects and effective prior to disease onset with long-term and clinically meaningful improvements over standard therapies. The success of these approaches will eventually be evaluated by their impact on glycemic control as this is the definitive determinant of long-term outcome of the disease. In conclusion we can affirm that early diagnosis of T1D is very valuable and is not a phyrrhic victory. Early diagnosis of T1D is more akin to David and Goliath: T1D Goliath could be vanquished with a simple intervention made pos- sible by early diagnosis of the disease Acknowledgments We would like to thank Juvenile Diabetes Research Foun- dation JDRF National Institute of Health NIH Consor- tia Centro Internazionale Studi Diabete CISD Diabete e Metabolismo DEM Foundation and University Campus Bio-Medico that support clinical research on T1D in our University Hospital. References 1. International Diabetes Federation IDF Atlas data. http://www.diabetesatlas.org/. 2. Park Y Eisenbarth GS. Genetic susceptibility factors of type 1 diabetes in Asians. Diabetes Metab Res Rev. 171:2–11 2001. 3. Bennett ST Wilson AJ Cucca F et al. IDDM2-VNTR- encoded susceptibility to type 1 diabetes: dominant pro- tection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun. 9:415–421 1996 4. Ueda H Howson JM Esposito L et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoim- mune disease. Nature. 4236939:506–511 2003.

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Early diagnosis of type 1 diabetes: Useful or a phyrrhic victory 21 5. Ladner MB Bottini N Valdes AM Noble JA. Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. Hum Immunol. 66:60–64 2005. 6. Wasserfall CH Atkinson MA. Autoantibody markers for the diagnosis and prediction of type 1 diabetes. Autoimmun Rev. 5:424–428 2006. 7. Peng H Hagopian W. Environmental factors in the develop- ment of type 1 diabetes. Rev Endocr Metab Disord. 7:149–162 2006. 8. Gamble DR Taylor KW Cumming H. Coxsackie viruses and diabetes mellitus. Br Med J. 4:260–262 1973. 9. Vaarala O. Is type 1 diabetes a disease of the gut immune system triggered by cow’s milk insulin Adv Exp Med Biol. 569:151–156 2005. 10. Chatfield SM Brand C Ebeling PR Russell DM. Vitamin D deficiency in general medical inpatients in summer and winter. Intern Med J. 37:377–382 2007. 11. Hypponen E Laara E Reunanen A Jarvelin MR Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth- cohort study. Lancet. 358:1500–1503 2001. 12. Driver JP Foreman O Mathieu C van Etten E Serreze DV. Comparative therapeutic effects of orally administered 125- dihydroxyvitamin D3 and 1alpha-hydroxyvitamin D3 on type-1 diabetes in non-obese diabetic mice fed a normal- calcaemic diet. Clin Exp Immunol. 151:76–85 2008. 13. TRIGR Study Group. Study design of the Trial to Reduce IDDM in the Genetically at Risk TRIGR. Pediatr Diabetes. 8:117–137 2007. 14. Lorini R Minicucci L Napoli F et al. Screening for type 1 diabetes genetic risk in newborns of continental Italy. Pri- mary prevention Prevefin Italy – preliminary data. Acta Biomed Ateneo Parmense. 76:31–35 2005. 15. Buzzetti R Galgani A Petrone A et al. Genetic prediction of type 1 diabetes in a population with low frequency of HLA risk genotypes and low incidence of the disease the DIABFIN study. Diabetes Metab Res Rev. 20:137–143 2004. 16. Schmid S Buuck D Knopff A Bonifacio E Ziegler AG. BABYDIET a feasibility study to prevent the appearance of islet autoantibodies in relatives of patients with type 1 diabetes by delaying exposure to gluten. Diabetologia. 47:1130–1131 2004. 17. Kupila A Sipila J Keskinen P et al. Intranasally administered insulin intended for prevention of type 1 diabetes–a safety study in healthy adults. Diabetes Metab Res Rev. 19:415–420 2003. 18. Bingley PJ Gale EA European Nicotinamide Diabetes Inter- vention Trial ENDIT Group. Progression to type 1 dia- betes in islet cell antibody-positive relatives in the Euro- pean Nicotinamide Diabetes Intervention Trial: the role of additional immune genetic and metabolic markers of risk. Diabetologia. 49:881–890 2006. 19. Diabetes Prevention Trial Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 346:1685–1691 2002. 20. Skyler JS Krischer JP Wolfsdorf J et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial–Type 1. Diabetes Care. 28:1068–1076 2005. 21. The Canadian-European randomized control trial group. Cyclosporin-induced remission of IDDM after early inter- vention: association of 1 year of cyclosporin treatment with enhanced insulin secretion. Diabetes. 37:1574–1582 1988. 22. Crino A Schiaffini R Ciampalini P et al. IMDIAB Group. A two year observational study of nicotinamide and intensive insulin therapy in patients with recent onset type 1 diabetes mellitus. J Pediatr Endocrinol Metab. 18:749–754 2005. 23. Harris SS. Vitamin D in type 1 diabetes prevention. J Nutr. 135:323–325 2005. 24. Pitocco D Crino ` A Di Stasio E et al. IMDIAB Group. The effects of calcitriol and nicotinamide on residual pancre- atic beta-cell function in patients with recent-onset type 1 diabetes IMDIAB XI. Diabet Med. 23:920–923 2006. 25. Herold KC Hagopian W Auger JA et al. Anti-CD3 mon- oclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 346:1692–1698 2002. 26. Keymeulen B Vandemeulebroucke E Ziegler AG et al. Insulin needs after CD3- antibody therapy in new-onset type 1 diabetes. N Engl J Med. 352:2598–2608 2005. 27. Ludvigsson J. Therapy with GAD in diabetes. Diabetes Metab Res Rev. 254:307–315 2009. 28. Huurman V A van der Meide PE Duinkerken G et al. Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin Exp Immunol. 1523:488–497 2008. 29. Eldor R Kassem S Raz I. Immune modulation in type 1 diabetes mellitus using DiaPep277: a short review and update of recent clinical trial results. Diabetes Metab Res Rev. 254:316–320 2009. 30. Pickersgill LM Mandrup-Poulsen TR. The anti-interleukin- 1 in type 1 diabetes action trial–background and rationale. Diabetes Metab Res Rev. 254:321–324 2009.

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4 How should secondary causes of diabetes be excluded 5 Click Here If You Also Want To Be Free From Diabetes 6 Aonghus O’Loughlin 1 and Sean F . Dinneen 2 1 Specialist Registrar in Endocrinology/Diabetes Mellitus Department of Medicine and Endocrinology/Diabetes Mellitus University College Hospital/National University of Ireland Galway Ireland 2 Senior Lecturer in Medicine Department of Medicine Clinical Science Institute NUI Galway Galway Ireland L E A R N I N G P OIN T S Diabetes clinical practice guidelines do not currently address the issue of population-wide screening for secondary forms of diabetes. Case finding should be undertaken among patients with diabetes and other clinical features of the condition under consideration. Both serum ferritin and transferrin saturation should be used to assess iron stores when screening for hereditary hemochromatosis. When screening for Cushing’ s syndrome the following tests should be considered a 24-hour urinary-free cortisol a 1-mg overnight dexamethasone suppression test a late-night salivary cortisol. Annual oral glucose tolerance testing should be considered in adolescents and adults with cystic fibrosis. Baseline measurement of height weight with calculation of body mass index and laboratory measurement of fasting plasma glucose and fasting lipid profile should be undertaken before commencement of an atypical antipsychotic drug. Introduction In the early 1990s the terminology used to classify diabetes mellitus was based mainly on the approach used to treat the condition the two main forms of the disease were described as “insulin-dependent” and “non-insulin-dependent” dia- betes. The term “other specific types” was used to describe a variety of forms of diabetes for which a cause was clearly identified. Problems arose with this approach because many “non-insulin-dependent” patients ended up being treated with insulin and having the very cumbersome label of “insulin-treated non-insulin-dependent” diabetes. In 1997 an Expert Committee recommended adoption of the terms “type 1” and “type 2 diabetes” to replace “insulin- dependent” and “non-insulin-dependent diabetes” respec- tively 1. The category “other specific types” has remained. It is likely that the terms “type 1” and “type 2 diabetes” represent a bridge between a classification based on treat- ment to a classification based on pathogenesis. We antic- ipate a time when terms like “autoimmune diabetes” and “non-autoimmune diabetes” will be used and when the number of patients currently assigned the label type 2 dia- betes will diminish in favor of an increased number of “other specific types” including genetic forms of diabetes. A recent thought-provoking perspective on the classifica- tion of diabetes suggests that our current system of classi- fication inhibits scientific progress by “lumping” together diverse groups of patients 2. In this chapter we will discuss several forms of diabetes that have a specific etiology. In clinical practice the term “secondary diabetes” is usually applied to these forms of dia- betes. Their recognition is important because of the poten- tial for improvement in or cure of the diabetes through treatment of the underlying cause. The majority of sec- ondary forms of diabetes are rare entities. There is very little mentioned in clinical practice guidelines on when or how to test for secondary diabetes. Even within a group of clinicians it may be difficult to agree on a uniform approach. As well as traditional forms of secondary diabetes we will discuss some of the newer genetic syndromes that have been elucidated in recent years. Although these conditions may Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza

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c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd. 22

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How should secondary causes of diabetes be excluded 23 not be curable their recognition can have a profound effect therapeutic or otherwise on an individual patient and/or their family members. It is worth contrasting the challenge of searching for sec- ondary forms of hypertension with that of searching for secondary forms of diabetes. There are certain “red flags” that most clinicians are alert to in a hypertensive patient that may indicate an underlying secondary cause. These include a young age at onset of hypertension difficult to control blood pressure e.g. requiring three or more antihy- pertensive drugs and the presence of certain clinical e.g. paroxysmal symptoms or biochemical e.g. hypokalemia markers at first presentation. Unfortunately these “red flags” do not easily translate into the diabetes setting. Onset of diabetes at a young age is not unusual and is likely to be classified as type 1 diabetes if the patient is lean or as type 2 if the patient is overweight. The latter is increasingly recog- nized as a feature of the pandemic of obesity and diabetes and is especially common among ethnic minority groups. Similarly diabetes that is difficult to control with tablets would not typically suggest an underlying cause but rather it would lead to the earlier introduction of insulin. The “fail- ure” of oral antihyperglycemic agents is not unusual and does not represent a red flag for secondary causes. It is in the clinical domain that the similarities between approaches to identifying secondary hypertension and secondary diabetes hold up. Indeed several endocrinopathies such as Cushing’s syndrome or Acromegaly are known to lead to both diabetes and hypertension. Because these conditions are so rare in the majority of cases clinical acumen has been the most important factor in identifying secondary diabetes. In this chapter we will address the question “should we be under- taking more systematic case finding among our patients with diabetes” Screening for disease at a population level is an expen- sive endeavor. Within the National Health Service in the United Kingdom the National Screening Committee NSC is charged with providing guidance on conditions for which screening programs should or should not be developed. The criteria by which the NSC adjudicates on the appropriate- ness of introducing a screening program are rigorous. They include questions relating to the condition e.g. does the natural history of the condition include progression from latent to declared disease the test e.g. is it simple safe precise and valid the treatment e.g. is there evidence of early treatment leading to better outcomes than later treat- ment and the screening program itself e.g. is there ran- domized controlled trial evidence that the screening pro- gram itself is cost effective. Only 7 of the 36 adult condi- tions that have been considered by the NSC have been rec- ommended for widespread screening. These include breast bowel and cervical cancer as well as hypertension dia- betic retinopathy abdominal aortic aneurysm and vas- cular risk status. Conditions that have not been recom- mended for population-wide screening include type 2 dia- betes although diabetes screening is recommended as part of a vascular risk assessment and hereditary hemochro- matosis. Although the exercise of searching for secondary forms of diabetes is not strictly speaking screening which by definition is searching for disease in a healthy popu- lation it is a very similar process. We will refer to the NSC criteria in our discussion of secondary causes of dia- betes and we would recommend that anyone interested in the area of screening take a look at the NSC website. The equivalent resource in the United States is the US Preven- tive Services Taskforce which can be accessed through the website of the Agency for Healthcare Research and Quality www.ahrq.gov.. Table 3.1 summarizes the main secondary forms of diabetes mellitus and screening methods available to detect them. Hereditary hemochromatosis Hereditary hemochromatosis is associated with increased and unregulated absorption of iron by enterocytes in the gastrointestinal tract. The disorder is inherited as an auto- somal recessive trait and results from one of several muta- tions in the HFE gene with the commonest being the C282Y mutation. Affected individuals may develop excessive depo- sition of iron in the parenchymal cells of certain organs including liver heart pancreas and skin. The clinical man- ifestations include hepatic fibrosis/cirrhosis cardiomyopa- thy diabetes mellitus and a bronzed appearance to the skin. Joint pains fatigue reduced libido and erectile dysfunction are other potential problems that can occur. The following vignette illustrates a typical patient who developed diabetes secondary to hemochromatosis. Natural history of hemochromatosis In the past hemochromatosis often presented with end- organ damage similar to that described in the case vignette. Although the genetic defect is present from birth the clin- ical manifestations are not usually seen until the sixth or seventh decade. Certain factors can lead to earlier e.g. excessive alcohol consumption or later female gender with regular menses presentation. Prior to 1996 confirmation

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24 Prediabetes and the diagnosis of diabetes TABLE 3.1 Overview of secondary diabetes due to pancreatic disease and hormone excess Condition Screening for condition among people with DM Evidence for benefit from population-wide screening Screening for DM among individuals with the condition Pancreatic Disease Hereditary Hemochromatosis Serum Ferritin Transferrin Saturation Genotyping ++ OGTT/FG CFRD N/A + Annual OGTT Pancreatic cancer Abdominal CT scan +/ − EUS – OGTT Hormone Excess Cushing’ s syndrome 24-hour UFC 1 mg DST + OGTT Late night salivary cortisol Acromegaly Phaeochromocytoma IGF-1 and OGTT with growth hormone Urinary metanephrines catecholamines and plasma fractionated metanephrines ∗ +/ − +/ − OGTT OGTT Abbreviations: EUS: Endoscopic ultrasound DST: Dexamethasone suppression test OGTT: Oral glucose tolerance test IGF-1: Insulin- like growth factor FG: Fasting glucose. ∗ Regional variation. Evidence for benefit from population screening ++ Very strong evidence and improvement of dysglycemia with treatment + Strong evidence +/ − Conflicting evidence – Little evidence. of the diagnosis was undertaken by documenting exces- sive iron stores on biochemistry and measuring hepatic or bone marrow iron levels by quantitative methods. In that year the mutations in the HFE gene which are known to cause hemochromatosis were identified. Confirmation of the diagnosis now involves genetic testing of suspected cases for the commonest mutations C282Y and H63D. The frequency of homozygosity for the C282Y mutation is 4.4 per 1000 in Caucasian populations in the United States. It is less common in Hispanic 0.27 per 1000 African A 43-year-old Caucasian male was referred with a 3-month history of polydipsia polyuria and 4 kg unintentional weight loss. A random blood glucose was 288 mg/dl 16 mmol/L. He was diagnosed with hemochromatosis 12 years before at which time he had a serum ferritin of greater than 4000 ng/mL and hepatic fibrosis on liver biopsy. Regular phlebotomy was instituted but his attendance had become erratic in recent years. His medication included methotrexate and folic acid for hemochromatosis-related arthritis. The patient drank 24 units of alcohol per week. He reported normal libido and erectile function. He had no cardiac symptoms. On examination he had a bronzed appearance. His body mass index was 26 kg/m 2 and his blood pressure was 135/87 mmHg. He had no stigmata of chronic liver disease. The cardiovascular respiratory and gastrointestinal system examinations were normal. His ankles were swollen over the lateral malleoli with scars from previous arthroscopies. He had normal peripheral pulses and no loss of vibration sensation. Biochemical investigations revealed a glycated hemoglobin of 14.3 normal liver chemistries a normal level of alphafetoprotein a serum ferritin of 1340 ng/mL a transferrin saturation of 97 and a normal serum testosterone and gonadotrophins. He was instructed in self-monitoring of blood glucose and reported home readings that were consistently above 15 mmol/L. A multiple daily injection regimen with insulin glargine and aspart was commenced. He received more intensive phlebotomy to maintain his serum ferritin less than 50 ng/mL. Once this was achieved his glycemic control stabilized and his insulin requirements diminished somewhat.

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How should secondary causes of diabetes be excluded 25 American 0.14 per 1000 and Asian American 0.001 per 1000 populations. It has become clear that not every- one homozygous for the C282Y mutation the commonest genetic defect associated with hemochromatosis goes on to develop the full-blown clinical syndrome. In fact pene- trance of the disease has been reported to be as low as 10 in some cohorts 3. In the UK homozygosity for C282Y has been reported in as many as 1 in 300 blood donors and studies on first-degree relatives of probands suggest that penetrance is in the region of 50 for men and 30 for women. These data have huge implications for screening see below. Among the many organ systems that can become involved in the clinical form of the disease liver problems are the commonest occurring in approximately 75 of individuals. Diabetes develops in approximately 50 of cases and results mainly from beta-cell dysfunction iron deposition in pancreatic islets. Reduced insulin action can also play a part in the etiology of glucose intolerance partic- ularly in patients with overt liver disease. The major causes of death in patients with hemochromatosis are complica- tions associated with hepatic cirrhosis including hepatocel- lular carcinoma. Treatment of hemochromatosis involves regular phlebotomy with the goal of achieving a serum fer- ritin level below 50 ng/ml. This may reverse some of the end-organ damage particularly if the phlebotomy is insti- tuted early in the course of the disease. The case for screening In many ways hemochromatosis would appear to be a perfect condition for screening it has an insidious onset over many years there are good biochemical and genetic tests available for detection of cases and a rel- atively safe treatment is available that would appear to be associated with benefit. Despite these consider- ations both the US Preventive Services Taskforce on Screening 3 4 and the UK National Screening Com- mittee http://www.screening.nhs.uk recommend against population-wide screening for hemochromatosis. In the case of the USPSTF the rationale for this decision was based on 1 the full-blown clinical disease is rare in the general population 2 the penetrance of the disease is low among those with a high-risk genotype 3 evidence that early phlebotomy in the screen-detected patient provides additional benefit over phlebotomy in clinically detected patients is lacking and 4 the potential for harm through labeling of homozygous individuals as “diseased” or “high risk” despite the possibility that they may never develop clinical disease. Harm could arise through anxiety denial of life insurance or discrimination through health insur- ance. The UK NSC acknowledged that because the benefits of phlebotomy have been demonstrated through case series it is unlikely that a randomized controlled trial of screen- ing for hemochromatosis will ever be undertaken. It does recommend research to explore these issues further. The case for screening for hemochromatosis among individuals with preexisting diabetes would appear to be stronger than the case for screening in the general popula- tion. This is based on a number of reports of hemochro- matosis prevalence of 5 to 6 times that seen in nondiabetic controls 3 5. However these studies did not use a uniform way of screening for iron overload and some were done in the era prior to the availability of genetic testing for the dis- ease. It is the practice in many diabetes clinics to measure iron stores in patients with newly diagnosed diabetes. This does not really amount to a population-wide approach to screening since not all patients with newly diagnosed dia- betes will be referred to the hospital. It is also common for iron stores to be measured in patients with diabetes and another potential manifestation of hemochromatosis such as abnormal liver function tests or a bronzed appearance to the skin. An important point to remember when mea- suring iron stores is that serum ferritin may be elevated as an acute phase reactant particularly in patients with newly diagnosed diabetes and may not reflect iron overload. A combination of serum ferritin and transferrin saturation is the preferred method of biochemical screening. So where does all of this leave the practicing diabetes clinician In the absence of guidance from the American Diabetes Associa- tion the 2001 Clinical Practice Guideline of the American Association for the Study of Liver Diseases AASLD pro- vides sensible guidance on screening for hemochromatosis in routine clinical practice 6. It emphasizes the measure- ment of iron stores as a first step and targets relatives of individuals known to have the genetic disorder as well as patients with symptoms or manifestations linked to the clinical disorder. The AASLD algorithm is reproduced in Figure 3.1. Cystic fibrosis-related diabetes Cystic fibrosis is the commonest life-threatening autosomal recessive disorder seen in Caucasian populations affecting approximately 1 in 2500 births. It results from a defect in

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Genotype 26 Prediabetes and the diagnosis of diabetes Target population Step 1 Symptomatic Asymptomatic Fasting transferrin saturation and serum ferritin Adult 1st degree relative of HH TS 45 and normal ferritin TS 45 and ferritin elevated Step 2 No further iron evaluation Step 3 Compound heterozygote C282Y/H63D Heterozygote C282Y or non-C282Y Exclude other liver or hematologic disease ± Liver biopsy C282Y/C282Y Age 40 years Ferritin 1000 and Normal ALT/AST ± Therapeutic + Phlebotomy Age 40 years and/or Ferritin 1000 or Elevated ALT/AST Liver biopsy for HIC and histopathology FIG 3.1 Proposed algorithm for screening and treatment of hemochromatosis in diabetic population 6 TS: transferrin saturation HIC: hepatic iron concentration 6. the cystic fibrosis gene which encodes a protein called cys- tic fibrosis transmembrane regulator CFTR. The genetic defect leads to disordered ion transport which in turn affects the function of sweat glands the exocrine pancreas and the gastrointestinal and respiratory tracts. The clas- sical clinical picture of cystic fibrosis is of recurrent pul- monary infections exocrine pancreatic insufficiency mal- nutrition and premature death. In the past two to three decades improvements in the pulmonary antimicrobial and nutritional management of patients with cystic fibrosis means that patients are now living into their third fourth or fifth decades. A major comorbidity that has emerged in older patients is cystic fibrosis-related diabetes CFRD. Natural history of CFRD The primary pathogenetic defect in CFRD is insulin defi- ciency resulting from pancreatic exocrine damage and pan- creatic fibrosis. Glucagon deficiency also occurs and this may explain why ketoacidosis is seldom seen in CFRD. It is uncommon for CFRD to appear in childhood. Various degrees of glucose intolerance become more common as patients get older. A recent North American study from a single center that undertakes annual oral glucose toler- ance testing on its patients reported CFRD rates of 2 in children 19 in adolescents 40 in individuals in their 20s and 45–50 in those aged ≥30 years 7. In the age group of 30–39 years women with CFRD outnumbered men but typically there is no gender difference in preva- lence. The presence of CFRD is associated with reduced survival compared to CF patients without diabetes. This survival difference may be more marked in females. A comparison with other forms of diabetes Table 3.2 compares features of CFRD with the two major forms of diabetes seen in the population at large. Although insulin deficiency is the primary defect in patients with CFRD insulin resistance can also be a factor. This is espe- cially true during periods of intercurrent illness e.g. respi- ratory infections. Autoimmunity does not appear to be a factor in the pathogenesis of CFRD. Low body mass index is associated with premature mortality in cystic fibrosis and this can lead to conflict in the dietary management of patients with CFRD. While calorie restriction is usually recommended in the management of patients with type 2 diabetes this is not the case in CFRD. Instead a liberal diet is recommended and the glucose-lowering therapy usually insulin is adjusted to achieve near normal plasma glu- cose levels. Centers in the United States that have a lot of experience of managing CFRD recommend early use of insulin. As well as achieving and maintaining good glycemic

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How should secondary causes of diabetes be excluded 27 TABLE 3.2 Clinical features of T1DM T2DM and CFRD T1DM T2DM CFRD BMI Usually normal Usually increased Usually decreased Presentation Acute Sub-clinical Sub-clinical Age of onset Childhood and adolescence Adulthood Increasing incidence with age Autoantibodies Yes No Probably no β cell function Insulin action Severely reduced/absent Usually normal Reduced Severely impaired Severely reduced Somewhat impaired ∗ Treatment Insulin Diet glucose-lowering Insulin and nutrition medication including insulin Microvascular complications Yes Yes Reduced Macrovascular complications Yes Yes No Cause of death Cardiovascular disease and Cardiovascular disease Pulmonary disease nephropathy Abbreviations: BMI: body mass index CFRD: cystic fibrosis-related diabetes T1DM: type 1 diabetes mellitus T2DM: type 2 diabetes mellitus. ∗ Insulin sensitivity reduced during acute illness. Adapted from O’Riordan et al. 9. control the anabolic effects of insulin are believed to be advantageous to patients with CFRD. Whereas patients with type 1 and type 2 diabetes require regular surveillance for the microvascular and macrovascular complications of diabetes this is less of an issue for patients with CFRD. Microvascular complications are infrequent and macrovas- cular complications virtually never occur. This is likely to be due at least in part to the shortened lifespan. While most patients with diabetes die as a result of macrovascular dis- ease patients with CFRD most often die from pulmonary complications of their cystic fibrosis. The case for screening It is important to reiterate that screening is not a diagnostic exercise but rather it is an exercise in case finding initi- ating earlier treatment and ideally achieving improved outcomes. It is extremely unlikely that patients with cystic fibrosis would develop diabetes as the first manifestation of their cystic fibrosis. Because of this we will not discuss case finding of cystic fibrosis patients in a general diabetes clinic. Instead we will discuss the case for screening for diabetes among patients with cystic fibrosis. Glucose tolerance status can vary across individuals with cystic fibrosis and within an individual patient. For example at times of severe pul- monary infection or during use of corticosteroid therapy glucose intolerance can develop but may not be permanent. Within the cystic fibrosis literature there was confusion as to how to categorize different states of glucose intolerance. A Consensus Conference report published in 1999 recognized four glucose tolerance categories based on the results of a 1.75 g/kg maximum 75 g oral glucose tolerance test 8. These are still used today and include 1 normal glucose tolerance 2 impaired glucose tolerance 3 CFRD with- out fasting hyperglycemia and 4 CFRD with fasting hyper- glycemia. The literature would suggest that patients with CFRD with fasting hyperglycemia have a worse prognosis than patients with CFRD without fasting hyperglycemia. Because of this early initiation of insulin therapy is gen- erally recommended for patients with CFRD with fasting hyperglycemia. Insulin may be used for patients with CFRD without fasting hyperglycemia although some clinicians would consider using oral glucose-lowering agents in this setting. The case for universal screening is not accepted by everyone. However the most recent guidelines on CFRD management from the International Society for Paediatric and Adolescent Diabetes ISPAD recommend universal screening 9. The guidelines emphasize the importance of undertaking the screening at a time when the patient is at their baseline health status. More intensive monitor- ing of blood glucose through use of reflectance meters or continuous glucose sensors should be considered if hyper- glycemic symptoms develop or at times of acute pulmonary infection. The oral glucose tolerance test is still the means by which the diagnosis is established. It is unlikely that a clinical trial comparing treatment versus no treatment of screen-detected CFRD will be undertaken. In the absence

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28 Prediabetes and the diagnosis of diabetes of such a trial the next best level of evidence comes from well described case series. One such case series was recently reported from the University of Minnesota a unit that has vast experience in management of CFRD. The report high- lights a temporal trend over the past three decades toward improved outcomes and greater longevity in patients with CFRD 7. The authors attribute this to universal screen- ing which they undertake from age 6 earlier recognition of CFRD and more aggressive treatment with insulin and nutritional strategies. Pancreatic-cancer-associated diabetes An association between pancreatic cancer and diabetes has been recognized for a long time but whether the pancreatic cancer caused the diabetes or vice versa has been difficult to ascertain. The truth is that the association is bidirec- tional long-standing diabetes is a recognized risk factor for pancreatic cancer. At the same time pancreatic can- cer can cause new onset diabetes. The latter is likely to be mediated through humoral factors produced by the tumor rather than through destruction of beta cells. Cases have been reported of diabetes disappearing after resection of small early stage pancreatic cancers. Approximately 50 of cases of sporadic pancreatic cancer have diabetes and in nearly half of these the diabetes is diagnosed shortly before or concomitant with the pancreatic cancer. Because the 5-year survival of pancreatic cancer is so dismal it has been suggested that new-onset diabetes may be a marker of early stage cancer and could potentially lead to earlier recognition with a greater chance of cure. In the diabetes literature it has been suggested that age over 50 years a lean body habitus and lack of a family history of type 2 dia- betes are clinical indicators of the potential for underlying pancreatic cancer. However this clinical impression has not been borne out by careful comparison of the characteristics of patients with pancreatic-cancer-associated diabetes and type 2 diabetes. A group at the Mayo Clinic has shown that a similar percentage of patients in both of these groups are overweight and obese and have a positive family history for diabetes 10. In fact as these authors point out obesity itself is a risk factor for pancreatic cancer. In order for new onset diabetes mellitus to be useful as a potential indicator of the presence of underlying pan- creatic cancer it needs to be combined with some tumor biomarker. No such biomarker has yet been identified. The presence of symptoms such as jaundice abdominal pain anorexia and weight loss is problematic because by the time the patient develops symptoms the tumor is almost always unresectable. It is hoped that studies into the patho- genesis of pancreatic-cancer-associated diabetes will lead to the identification of a measurable biomarker which among patients with recent onset diabetes may be used as a screen- ing tool. In the meantime widespread use of abdominal imaging among older patients with new onset diabetes can- not be recommended as a method of searching for occult pancreatic cancer. Diabetes due to hormone excess Several disorders resulting in hormone excess can cause diabetes. These include Cushing’s syndrome due to glu- cocorticoid excess acromegaly due to growth hormone excess pheochromocytoma due to catecholamine excess glucagonoma somatostatinoma and Conn’s syndrome due to aldosterone excess. The latter two conditions cause glucose intolerance by interfering with insulin secretion while the others predominantly affect insulin action. The benefit of identifying one of these conditions in a patient with concomitant diabetes is that cure of the endocrinopa- thy may lead to cure or amelioration of the glucose intol- erance. In the case of acromegaly and pheochromocytoma routine screening among individuals with diabetes is not justified since both conditions are extremely rare and rou- tine screening would very likely be associated with high rates of false positive test results with resultant increased distress and cost from unnecessary testing. Instead case finding should be undertaken when additional clinical fea- tures consistent with the endocrinopathy are present. In the case of acromegaly these would include enlargement of the hands and feet characteristic changes in facial appear- ance headache and increased perspiration. Because these changes are often subtle and take many years to appear they may not be apparent to the patient or even to family members. A comparison of the patient’s current appear- ance with that obtained from old photographs is often very informative. The classical features of pheochromocytoma include paroxysmal hypertension palpitations pallor per- spiration and pain. T able 3.2 includes initial testing that can be undertaken if the clinical suspicion of growth hormone or catecholamine excess is sufficiently high to justify a case- finding exercise. One caveat with acromegaly screening is that poorly controlled diabetes is associated with elevated levels of growth hormone.

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How should secondary causes of diabetes be excluded 29 Cushing’s syndrome merits particular mention because it is by far the commonest endocrine disorder associated with diabetes. This is because of the widespread use of exogenous glucocorticoids in the treatment of a host of inflamma- tory and malignant diseases. A careful medication history should highlight the use of exogenous steroids in a patient with diabetes. Sometimes glucocorticoids may be contained in over-the-counter or herbal preparations or may be taken surreptitiously. In addition use of some steroids such as medroxyprogesterone acetate that are not primarily glu- cocorticoids has been associated with Cushing’s syndrome. The mechanism whereby glucocorticoid excess causes dia- betes is through increased insulin resistance and a failure of the beta cells to respond appropriately to this challenge. If Cushing’s syndrome from exogenous glucocorticoid use is excluded then endogenous Cushing’s syndrome is rare. In population studies its incidence has been reported to be as low as two to three cases per million persons per year. How- ever among populations of patients with diabetes who have undergone screening for Cushing’s syndrome prevalence as high as 3–5 has been reported 11 12. Some authors have advocated screening all patients with newly diagnosed diabetes in a hospital setting while others have suggested that screening for Cushing’s syndrome should be limited to patients with poorly controlled diabetes. Recent guidelines from the Endocrine Society support testing for Cushing’s syndrome among groups of patients with certain “over- lap disorders” i.e. conditions which although common in the community can also be a feature of occult Cushing’s syndrome 13. These include osteoporosis hypertension and diabetes mellitus. The guidelines state that Cushing’s syndrome is more likely when these conditions occur at a young age. Another way of increasing the pre-test proba- bility of Cushing’s syndrome is to limit screening to those patients with diabetes and one or more of the clinical fea- tures associated with tissue glucocorticoid excess. These include but are not limited to facial plethora easy bruis- ing proximal myopathy and striae. The tests recommended by the Endocrine Society are listed in Table 3.2. The choice of which tests to use depends on several factors includ- ing concomitant medication use local laboratory expertise as well as the index of clinical suspicion for severe Cush- ing’s syndrome. Diagnostic criteria that suggest Cushing’s syndrome are a 24-hour urinary-free cortisol above the upper limit of normal for the assay an 08:00 cortisol above 50 nmol/L after administration of dexamethasone 1 mg at midnight and a late-night salivary cortisol above 4 nmol/L. Some authors have advocated using higher cutoff levels as a way of reducing the number of false positives. There is a need for better evidence to support a screening/treatment strategy for Cushing’s syndrome among patients with dia- betes. Whether an opportunistic approach to screening which is likely to be what most clinicians currently prac- tice or whether a more systematic approach at a pop- ulation level should be adopted could be addressed in a randomised controlled trial. Post-transplant diabetes mellitus The term “post-transplant diabetes mellitus” PTDM refers to the recognition of diabetes in recipients of solid organ transplants. Recently the terms “new-onset diabetes mellitus after transplantation” NODAT and “transplant associated hyperglycemia” have been recommended to dif- ferentiate new-onset hyperglycemia from that present prior to transplantation. There is wide variation in the reported incidence of PTDM ranging from as low as 2 to as high as 50. This variation relates in part to varying definitions of hyperglycemia between studies. Risk factors for PTDM include increasing age non-Caucasian ethnicity increas- ing body weight a family history of diabetes and a history of cytomegalovirus or hepatitis C infection. Hepatitis C leads to increased risk of PTDM with either liver or kid- ney transplantation. Treatment with interferon for hepatitis C results in increased insulin resistance. Many immuno- suppressant drugs including tacrolimus and cyclosporin calcineurin inhibitors as well as corticosteroids are dia- betogenic. The latter cause diabetes predominantly through increasing insulin resistance in patients whose beta-cell response is compromised. The mechanism whereby the cal- cineurin inhibitors cause diabetes is less clear but appears to involve toxicity to the beta cell as well as effects on insulin action. Clinical features Weight gain is a common occurrence after transplantation and the risk of developing PTDM increases by a factor of 1.4 for every 10 kg increase in weight over 60 kg 14. Taken with the increasing insulin resistance associated with the immunosuppressant medication the clinical features of PTDM resemble those of type 2 diabetes. The diagnosis of PTDM can be problematic following pancreas transplan- tation for type 1 diabetes as a persistence of autoimmune beta-cell destruction has been reported.

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30 Prediabetes and the diagnosis of diabetes The case for screening Hyperglycemia in the post-transplant period can result in an increased risk of infection graft failure and death from cardiovascular causes. Myocardial infarction was com- moner in the 3 years following transplantation in a group with PTDM compared to nondiabetic transplant recipients. Early recognition of PTDM with the potential to prevent the associated morbidity and mortality has been advocated. The screening tests used are fasting plasma glucose or the oral glucose tolerance test. Management of PTDM involves use of oral antihyperglycemic medication and insulin. The biguanides are contraindicated in the presence of impaired renal function. Modification of the immunosuppressant regimen must be balanced with the risk of graft rejection. Furthermore the benefits of reducing corticosteroid dosage and reducing or substituting calcineurin inhibitors have not been proven fully in clinical trials. A screening pro- gram should involve pre- and post-transplant testing of glu- cose tolerance. A knowledge of pre-transplant risk factors is essential to characterize the subsequent risk of PTDM. The recommended intervals for post-transplant screening initially with a fasting plasma glucose are 4 weeks 3 5 and 12 months and annually thereafter 15. Diabetes associated with atypical antipsychotic drug use Antipsychotic drugs are licensed for use in schizophre- nia and related psychotic disorders. The first-generation antipsychotics were useful for alleviating the positive symp- toms of psychosis such as hallucinations and delusions. They are less efficacious at managing the negative symp- toms of psychosis that include withdrawal poverty of speech and cognitive problems. The introduction of the second-generation or atypical antipsychotics in the early 1990s was greeted with enthusiasm as they were effica- cious against both positive and negative psychotic symp- toms. In addition they were not associated with the often very debilitating extrapyramidal side effects of the first- generation agents. These drugs which include clozapine olanzapine quetiapine and respiridone have transformed the lives of many patients with schizophrenia and have enabled many individuals to live in the community as opposed to being managed as inpatients in psychiatric insti- tutions. The drugs have become very popular among psy- chiatrists and general practitioners and are now prescribed for many psychiatric conditions other than those for which they are licensed. One report published in 2001 estimated that as much as 70 of prescriptions for atypical antipsy- chotics were for off-label use 16. Their side effect profile includes the very rare agranulocytosis associated with cloza- pine and for which regular monitoring of the patient’s full blood count is mandatory to the much commoner metabolic disorders that we will discuss in detail. Natural history The underlying disorders for which the atypical antipsy- chotic drugs are used schizophrenia other psychotic dis- orders major depression etc. are often associated with a sedentary lifestyle and poor dietary habits. Although high- quality cohort studies have been difficult to undertake it is generally accepted that these disorders are associated with an increased risk of obesity dyslipidemia diabetes and resultant increased cardiovascular morbidity. Because of the effect of the underlying disease it has been difficult to tease out the exact contribution of an additional drug effect on top of this. Clinical experience does suggest that many of the atypical antipsychotics are associated with weight gain and metabolic abnormalities. Occasionally use of these agents has been associated with profound metabolic distur- bance including diabetic ketoacidosis DKA. In some case reports the presentation with DKA is followed by subse- quent recovery of beta-cell function akin to the so-called “Flatbush” or “ketosis-prone type 2 diabetes.” More com- monly the metabolic derangement is less profound and associated with weight gain and dyslipidemia. As well as causing new diabetes among individuals not previously rec- ognized as having the disease these drugs can also lead to worsening of preexisting diabetes and a need for intensifi- cation of antihyperglycemic therapy. The case for screening On a background of increasing concern about the metabolic consequences of these drugs a Consensus Conference was convened in late 2003 involving a number of professional organizations including the American Diabetes Associa- tion and the American Psychiatric Association. The report from this conference highlighted a gradation of metabolic risk across drugs in the class with clozapine and olanzapine carrying a higher risk of metabolic side effects than que- tiapine and risperidone 17. The conference participants felt that insufficient experience was available with newer members of the class such as aripiprazole and ziprasidone to classify their risk. The conference called for research into

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How should secondary causes of diabetes be excluded 31 the potential mechanisms whereby these drugs cause dia- betes. The suspicion that the mechanism may not be as simple as weight gain leading to increased central adiposity and insulin resistance was borne out by subsequent studies in which the metabolic effects of the drugs were studied in an animal model. In a series of elegant experiments Dr. Ader and her colleagues showed that the beta-cell response to increasing insulin resistance on exposure to olanzapine was less than that seen with simple diet-induced weight gain of a similar degree 18. This inability of the beta cell to respond to mainly hepatic insulin resistance could be centrally mediated although the mechanism remains speculative. Further work in this area is keenly anticipated and may shed light on some of the complex interplay between the beta cell and insulin action in commoner forms of diabetes. An important message that came from the Consensus Conference report was the need for baseline monitoring of metabolic parameters prior to or as early as possi- ble after commencing long-term prescribing of atypical antipsychotic drugs. At a minimum this should include clinical recording of height and weight and calculation of body mass index waist circumference and blood pres- sure as well as biochemical measurement of fasting glucose and lipid levels. Although these are measured routinely in diabetes clinics around the world they are not undertaken routinely in departments of psychiatry. However if we are to have any chance of stemming the rise in metabolic disor- ders that would appear to be happening with increasing use of these drugs then this is an important first step. The con- sensus group went on to suggest that repeat measurement of fasting glucose and lipids at 12 weeks and then annu- ally thereafter should be undertaken. Several variations on how to screen patients at risk have been published since the report. A recent summary of the various recommendations and a pragmatic approach to screening has been published from a group in the UK 19. Diabetes associated with HIV infection and its treatment Over the past 20 years patients living with human immun- odeficiency virus HIV infection in the developed world have seen a transformation in the disease from one associ- ated with opportunistic infection and premature death to a chronic disease associated with good long-term survival. A consequence of this success story has been the develop- ment in this group of patients of metabolic abnormalities including diabetes dyslipidemia and increased cardiovas- cular event rates 20. Much of the metabolic derangement that occurs in HIV patients is due to the drugs that are used to treat the disease. The use of highly active antiretro- viral therapy HAART has been responsible for much of the benefit but also much of the side effects. Similar to the story with the atypical antipsychotics clinicians prescrib- ing these drugs need to be aware of the risk of metabolic derangement that varies between the different agents 21. Clinicians also need to be aware of the importance of screen- ing their patients for the metabolic consequences of drug use. One aspect of the diabetes that occurs with use of HAART is its frequent association with partial lipodystro- phy. This acquired abnormality in body fat distribution is associated with insulin resistance and has been amenable to treatment with agents from the thiazolidinedione class of antihyperglycemic drugs. A 23-year-old Caucasian male was admitted to hospital with acute urinary retention and renal failure. He had been experiencing progressive thirst polyuria and nocturia over the last eighteen months. He had a past history of diabetes mellitus diagnosed 10 years previously and was managing this with insulin aspart and insulin glargine. He had poor eyesight since childhood and this was attributed to Leber ’s optic atrophy. His mother had type 2 diabetes mellitus and was on insulin. She had a history of gestational diabetes. His father had hypercholesterolemia and was otherwise well. His grandmother had diabetes mellitus and died aged 73 years. His other grandparents died in old age. He had three sisters who were alive and well. On examination he was noted to be very hard of hearing. His blood pressure was 170/95 mmHg and his body mass index was 29.8 kg/m 2 . He had markedly decreased visual acuity. Dilated fundoscopy revealed pale optic disks and scattered retinal hemorrhages. He had no evidence of peripheral neuropathy. Remainder of physical examination was normal. An ultrasound revealed bilateral hydronephrosis. His renal failure resolved with insertion of a suprapubic catheter. An audiogram revealed bilateral sensorineural deafness. A water deprivation test confirmed cranial diabetes insipidus. Genetic testing revealed a complex heterozygote state with c.506G and c.1611 1624del14 mutations in the WFS1 gene on chromosome 4 confirming the clinical impression of Wolfram ’s or DIDMOAD Diabetes Insipidus Diabetes Mellitus Optic Atrophy and Deafness syndrome. Both parents were confirmed to be carriers and the family received genetic counselling on the inheritance of this autosomal recessive disorder.

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32 Prediabetes and the diagnosis of diabetes Genetic forms of diabetes If secondary forms of diabetes are rare then genetic forms of diabetes are rarer again. The main justification for iden- tifying secondary forms of diabetes is the potential for cure through treatment of the underlying condition. This does not apply to genetic forms of diabetes although advances in gene therapy may make this a reality in the future. Instead the justification comes from 1 the ability to provide an individual patient and their family with a more accurate prognosis 2 the potential to better match the treatment regimen to the form of diabetes resulting from the genetic defect and 3 the potential to advance science and our understanding of diabetes in general through elucidation of rare molecular and cellular defects causing diabetes 22. In the case described above the family was not aware of the progressive nature of Wolfram syndrome with almost inevitable death before age 50 most families appreciate the additional knowledge gained through genetic testing and genetic counselling. Examples of the recognition of a genetic form of diabetes resulting in a better fit between the diabetes syndrome and the treatment regimen come from the maturity onset diabetes of the young MODY syndromes. Several different gene defects have been rec- ognized as causing MODY 23. The commonest form of MODY results from a defect in the hepatocyte nuclear factor 1-alpha HNF1A gene and leads to a form of diabetes that can be managed adequately with oral sulfonylurea therapy. Because the diabetes is often diagnosed in childhood or ado- lescence many of these patients are started on insulin on the assumption that they have type 1 diabetes. The ability to rec- ognize previously undiagnosed HNF1A diabetes and poten- tially remove the need for lifelong insulin is a huge bene- fit to the patient. This phenomenon of stopping insulin after many years of use has also been reported in patients with permanent neonatal diabetes due to mutations in the Kir6.2 subunit of the ATP-sensitive potassium channels in the beta cell 24. The cellular mechanism relates to the mutated channels remaining open and resulting in the beta- cell membrane remaining in a hyperpolarized state thereby preventing insulin from being secreted. The sulfonylurea drug leads to closure of the channel thus enabling insulin secretion. Other monogenic forms of diabetes that can be misdi- agnosed as type 1 diabetes if childhood onset or type 2 diabetes if adult onset include that associated with the m.3243AG mutation in mitochondrial DNA as well as lipodystrophic forms of diabetes due to mutations in the LMNA gene causing familial partial lipodystrophy. The phenotypic characteristics that should alert the clinician to the possibility of a monogenic form of diabetes include 1 young age of onset 2 family history demonstrating either a pattern of autosomal dominant inheritance e.g. in MODY kindreds or of maternal transmission e.g. in mitochondrial diabetes 3 association with deafness e.g. mitochondrial diabetes or 4 neurological or neuromus- cular disorders. References 1. Report of the Expert Committee on the Diagnosis and Clas- sification of Diabetes Mellitus. Diabetes Care. 207:1183– 1197 1997. 2. Gale EA. Declassifying diabetes. Diabetologia. 499:1989– 1995 2006. 3. Whitlock EP Garlitz BA Harris EL Beil TL Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 1453:209–223 2006. 4. U.S. Preventive Service Task Force. Screening for hemochro- matosis: recommendation statement. Ann Intern Med. 1453:204–208 2006. 5. O’Brien T Barrett B Murray DM Dinneen S O’Sullivan DJ. Usefulness of biochemical screening of diabetic patients for hemochromatosis. Diabetes Care. 135:532–534 1990. 6. Tavill AS. Diagnosis and management of hemochromatosis. Hepatology. 335:1321–1328 2001. 7. Moran A Dunitz J Nathan B Saeed A Holme B Thomas W. Cystic fibrosis-related diabetes: current trends in prevalence incidence and mortality. Diabetes Care. 329:1626–1631 2009. 8. Moran A Hardin D Rodman D et al. Diagnosis screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report. Diabetes Res Clin Pract. 451: 61–73 1999. 9. O’Riordan SM Robinson PD Donaghue KC Moran A. Management of cystic fibrosis-related diabetes. Pediatr Dia- betes. 94 Pt 1:338–344 2008. 10. Pannala R Basu A Petersen GM Chari ST. New-onset dia- betes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 101:88–95 2009. 11. Reimondo G Pia A Allasino B et al. Screening of Cushing’s syndrome in adult patients with newly diagnosed diabetes mellitus. Clin Endocrinol Oxf 672:225–229 2007.

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How should secondary causes of diabetes be excluded 33 12. Boscaro M Arnaldi G. Approach to the patient with pos- sible Cushing’s syndrome. J Clin Endocrinol Metab. 949: 3121–3131 2009. 13. Nieman L Biller B Findling J et al. The diagnosis of Cush- ing’s syndrome: an endocrine society clinical practice guide- line. J Clin Endocrinol Metab. 93:1526–1540 2008. 14. Cosio FG Pesavento TE Kim S Osei K Henry M Ferguson RM. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int. 624:1440–1446 2002. 15. Bodziak KA Hricik DE. New-onset diabetes mellitus after solid organ transplantation. Transpl Int. 225:519–530 2009. 16. Glick ID Murray SR Vasudevan P et al. Treatment with atyp- ical antipsychotics: new indications and new populations. J Psychiatr Res. 353:187–191 2001. 17. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 272:596–601 2004. 18. Ader M Kim SP Catalano KJ et al. Metabolic dysregulation with atypical antipsychotics occurs in the absence of under- lying disease: a placebo-controlled study of olanzapine and risperidone in dogs. Diabetes. 543:862–871 2005. 19. Churchward S Oxborrow SM Olotu VO Thalitaya MD. Setting standards for physical health monitoring in patients on antipsychotics. Psychiatr Bull. 33: 451–454 2009. 20. Morse CG Kovacs JA. Metabolic and skeletal complica- tions of HIV infection: the price of success. JAMA. 2967: 844–854 2006. 21. De Wit S Sabin CA Weber R et al. Incidence and risk factors for new-onset diabetes in HIV-infected patients: the Data Collection on Adverse Events of Anti-HIV Drugs D:A:D study. Diabetes Care. 316:1224–1229 2008. 22. O’Rahilly S. Human genetics illuminates the paths to metabolic disease. Nature. 4627271:307–314 2009. 23. Fajans SS Bell GI Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 34513:971–980 2001. 24. Hattersley A Bruining J Shield J Njolstad P Donaghue KC. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 10Suppl 12: 33–42 2009.

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4 Screening patients with prediabetes and diabetes for cardiovascular disease To Stop Diabetes In Few Days Click Here Deepika S. Reddy 1 and Vivian Fonseca 2 1 Assistant Professor Department of Endocrinology Scott White Clinic T emple TX USA 2 Professor of Medicine and Pharmacology Tullis Tulane Alumni Chair in Diabetes Chief Section of Endocrinology Tulane University Health Sciences Center New Orleans LA USA L E A R N I N G P OIN T S Patients with dysglycemia are at risk for developing cardiovascular disease before and after they develop frank diabetes. Current guidelines for screening with cardiac imaging have limitations. Assessment of risk factors to stratify a patient’s risk may be helpful. Treating traditional risk factors such as blood pressure elevated LDL cholesterol etc. for cardiovascular disease help reduce the patient’ s risk. When traditional risk factors have been treated normalization of nontraditional risk factors such as highly sensitive C-reactive protein may prove to be useful. The optimal “screening tool” therefore may not be a single imaging study instead it may be a multistep process of assessment and treatment of risk factors to improve cardiovascular outcomes in patients with prediabetes and diabetes. Introduction Patients with diabetes are at increased risk for developing and dying from cardiovascular disease CVD. People with diabetes have been shown to have twice the risk of CVD as the general population 1. Patients with prediabetes in the San Antonio Heart Study had atherogenic risk factors suggesting that risk for CVD may start before the diagnosis of diabetes 2. In a study of Finnish patients with and with- out diabetes followed for seven years the risk of a recurrent event was greatest in diabetic patients with a known history of CVD 3. The risk was similar in patients with diabetes and no history of CVD and patients without diabetes who had a history of known CVD. This gave rise to the notion of “cardiac risk equivalent” and the need to evaluate and treat patients with diabetes in the same way as those with preexisting heart disease. With the worldwide incidence of diabetes rising steadily CVD in patients with diabetes will continue to be a major public health concern requiring a concerted effort to detect those at risk and to intervene early to reduce this risk. The aim of this review is to discuss optimal identification of patients at risk current recommendations for such iden- tification recent developments and possible future direc- tions in such efforts. Current screening guidelines in asymptomatic patients with diabetes In guidelines published in 1998 by the American Diabetes Association 4 ADA a risk factor guided approach was suggested. In the asymptomatic patient presence of two or more risk factors EKG abnormalities or evidence of vascular disease were described as reasons to perform spe- cialized screening for inducible ischemia. In 2004 ADA guidelines 5 recommended cardiac stress testing before initiation of an exercise regimen in all patients with diabetes who were over the age of 40. In those between 35 and 40 years of age pre-exercise stress testing was recommended if other risk factors for cardiovascular disease were present. In 2007 6 an ADA consensus panel recognized that the “risk Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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Screening patients with prediabetes and diabetes for cardiovascular disease 35 Initial DIAD cohort Cardiac imaging No cardiac imaging 22 had abnormal cardiac testing 78 had normal cardiac testing After 3 years 21 continued to have abnormal test 79 had normal test on repeat testing 10 had abnormal test 90 of this group had normal repeat test After 4.8 years FIG 4.1 Composite of data from the three DIAD studies. factor approach” to screening for CVD in the asymptomatic patient had some shortcomings that are listed below. First in the Detection of Ischemia in Asymptomatic Dia- betics DIAD study 7 patients with type 2 diabetes with no symptoms of CVD were randomized to “no imaging” or “cardiac perfusion imaging” groups. Of all the patients who underwent perfusion imaging 22 had abnormal testing. Of these 40 had less than two risk factors for CVD. Three years later when the testing was repeated of those that had a negative test 10 now had a positive test 8. A more striking finding was the resolution of inducible ischemia in 79 of those that had ischemia initially and no interven- ing revascularization procedure. On follow up 4.8 years after the original study the incidence of CV events was low. There was a significant increase in primary prevention efforts in both groups and there was no difference in mor- tality between those that had myocardial perfusion testing and those that did not 9 see Figure 4.1. Thus screen- ing by the guidelines may lead to both false positives and negatives and high-risk patients may be better served by aggressive risk factor modification as suggested by a num- ber of guidelines such as NCEP/ATPIII. Second there is increasing awareness that in patients with stable CVD medical management and percutaneous coronary intervention PCI were equally effective. In the No difference in mortality between those that had cardiac imaging and those that did not COURAGE study 10 patients with CAD were random- ized to just medical care or medical care plus PCI. There was no difference in death or major cardiovascular events between the groups although there was a greater incidence of repeat catheterizations and PCI in those initially assigned to medical management alone. The results were the same in the subset of patients with diabetes. In asymptomatic patients therefore the value of screening with cardiac stress testing is unclear as aggressive risk factor identification and medical management appears to be equally efficacious in reducing the risk of future CV events. Hyperglycemia and the risk of cardiovascular disease Glucose is a continuous variable in the population with an almost linear association with CVD. This is seen even in glucose concentrations below that used to diagnose dia- betes. DECODE an epidemiologic study in Europe looked at over 25000 subjects and demonstrated that mortality was increased not just in patients with diabetes but also in those with impaired glucose tolerance IGT. The study also demonstrated that IGT carries a greater risk than impaired fasting glucose IFG a finding of practical importance as

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36 Prediabetes and the diagnosis of diabetes glucose tolerance testing is often not carried out in patients at possible risk 11. Norhammer et al. demonstrated that in patients with established CAD IGT is common and may be missed 12. This has led to recommendations for more widespread use of GTTs. In the AusDiab study there is a graded increase in both all-cause and cardiovascular mor- tality from normal glucose tolerance to known diabetes 13. Therefore patients at risk for dysglycemia should be screened early and have risk factor management early and those with CVD should be screened for dysglycemia. Similarly the EPIC-Norfolk study demonstrated that HbA1c in the normal range is also associated with increased CVD and mortality 14. The relationship of CVD with HbA1c needs to be studied further given the importance of protein glycation in the pathogenesis of complications. In recent months the use of HbA1c as an initial test for diagnosis of diabetes has been accepted by the American Diabetes Association ADA. Treatment of hyperglycemia in patients with predia- betes may have an impact on the risk for CVD. In the STOP-NIDDM study 15 patients with prediabetes were treated with acarbose. At the end of 3 years patients treated with acarbose had a lower risk of developing diabetes and having a CV event. In patients with known diabetes treatment of hyper- glycemia reduces the risk of CVD. Early prospective studies such as DCCT and UKPDS 16 17 showed improvement in microvascular complications in patients with type 1 and type 2 diabetes respectively. When these patients were fol- lowed a decrease in macrovascular complications was also demonstrated 18 19. The EDIC trial 18 describes long- term follow-up of the patients in the DCCT trial. In EDIC lower HgBA1c while the patients were actively enrolled in the DCCT trial appeared to correlate with improved car- diovascular outcomes. It is important to recognize that the DCCT and UKPDS trials enrolled relatively young patients with a short duration of DM. In addition after the original DCCT and UKPDS trials were terminated the patients no longer maintained their randomization. Despite this there appeared to be an improvement in CVD outcomes in inten- sively treated patients during long-term follow-up. In three recent large studies ACCORD ADV ANCE and V ADT where the patients studied were older than those in UKPDS and had DM for a longer duration tight blood sugar control did not improve CV outcomes in the short term. Those with long-standing DM may have already developed atheroscle- rosis and management of non-glycemic factors takes on more importance. The evidence supports the notion that elevated blood sugars do increase risk for CVD and control of hyper- glycemia does improve that risk. The control of other risk factors also appears to be important especially in those with long-standing type 2 diabetes. What are other risk factors for cardiovascular disease How should they be managed Before the development of type 2 diabetes patients at risk often have evidence of insulin resistance. These patients may be obese with normal glucose levels and hyperinsulinemia or they may have IGT/IFG. In addition other metabolic derangements may be present. These metabolic alterna- tions may help with early identification of these patients. In the San Antonio Heart study 2 over 600 Mexican Ameri- can patients who were hyperinsulinemic were followed for 8 years. Patients that developed diabetes over that period had higher triglycerides lower HDL higher systolic pressures and higher fasting glucose and insulin levels. The investi- gators concluded that these patients were developing CVD even before they developed overt DM. Treating multiple risk factors has resulted in improved risk for CVD. In the STENO-2 study 20 multifacto- rial intervention such as modifying lifestyle reducing total cholesterol LDL 126 mg/dl vs. 83 mg/dl lowering blood pressure systolic blood pressure 146 vs. 131 mmHg and improving glycemic control HbA1c 9.0 vs. 7.9 was studied in patients with type 2 diabetes. At the end of that time intensive treatment of risk factors resulted in reduc- tion in the primary composite end point nonfatal MI car- diovascular death revascularization nonfatal stroke and amputation. The hazard ratio for the intensively treated group was 0.47 p 0.01 How do we “risk stratify” patients The metabolic syndrome MS represents an attempt to capture patients who may have an increased risk for diabetes and cardiovascular disease. Patients with MS may have more than one risk factor that is known to be atherogenic. As the number of risk factors accumulate the risk of CVD increases. There are multiple difficulties with the use of MS as a risk stratification tool. First there are multiple definitions of the syndrome. Second we do not know if the presence of some of the factors results in greater risk than others. The definitions give all risk factors equal weight.

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Screening patients with prediabetes and diabetes for cardiovascular disease 37 Questions raised in evaluation for cardiovascular disease in patients with diabetes and prediabetes 1 Is dysglycemia associated with cardiovascular disease CVD 2 What is the best way to screen for cardiovascular disease Stress testing or risk factor identification and treatment or both 3 If identified do all risk factors carry the same weight Does any combination carry greater risk Patients with diabetes and prediabetes are at increased risk DIAD study raises questions about screening with stress tests. Studies suggest risk factor evaluation and treatment beneficial Unclear FIG 4.2 Clinical questions related to the screening for cardiovascular disease in patients with prediabetes and diabetes. 4 What is the best way to address risk Should we risk stratify and address those at high risk or those early in the course of disease to have greatest impact 5 What is the best method to risk stratify 6 Does early management help Is it cost effective None of the currently used risk engines address risk in all populations. Optimal timing of risk factor reduction not clear Addressing hyperglycemia early helps reduce CVD Unclear if cost effective Third the syndrome is present if three of five risk factors are present. There is no graded estimate of risk based on the number of risk factors present. Finally the definitions do not include well-established risk factors for CVD such as LDL cholesterol. Risk calculators have also been used to stratify patients with CVD risk factors. An early calculator was developed from the Framingham data 21. It is easy to use and widely distributed. Since the number of diabetics in the Framing- ham study was small the risk calculation for diabetics may not reflect true risk in these patients. A risk engine was developed from the UKPDS data 22. It may be helpful for assessing risk in younger patients with a short duration of DM. Its accuracy in those with patients with type 1 DM or those with type 2 diabetes for a longer duration is not clear. All patients with diabetes do not have the same risk for CVD. The early risk engines have been modeled on data that are not inclusive of the range of patients with diabetes that we see in our practice. A new model called ARCHIMEDES may address the limitations of the earlier risk engines 23. It is described by the authors as a mathematical model written at a “deep level of biological clinical and administrative detail.” It attempts to account for a variety of interacting variables that can together affect a patient’s risk for disease. Using data from multiple studies it assesses risk on a continuum as opposed to discrete states. For our current purpose it would take into account the type of diabetes duration presence or absence of risk factors but also what we know about vascular biology in the presence of these risks. It also has the capacity to include clinical features such as adherence to medical regimens etc. It has been validated against clinical trials and has a remarkable degree of concordance of its prediction to the outcomes from the trials. As with a number of issues related to screening for CVD in prediabetes and diabetes there is ongoing evaluation of risk stratification see Figure 4.2. Traditional risk factors Several risk factors have been associated with CVD. The INTERHEART study evaluated a number of these risks and tried to assess the contribution of these risk fac- tors to the presence of CVD 24. It was a multicountry case control study. Over 15000 patients who had acute myocardial infarction and closely matched controls were studied. Nine commonly recognized risk factors smok- ing abnormal lipids apolipoprotein B1/apolipoprotein A1 ratio HTN self-reported diabetes abdominal obesity psychosocial factors were evaluated. The apolipoprotein B1/apolipoprotein A1 ratio was used since apolipoproteins can be checked in non-fasting blood samples unlike low- density lipoprotein levels that would require fasting sam- ples. The authors of the INTERHEART study also cite a paper that shows that this ratio was able to predict CVD events. The percent attributable risk PAR for each risk

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38 Prediabetes and the diagnosis of diabetes factor was calculated. In other words these risks accounted for 90 of the risk for CVD. The vast majority of risk is accounted for by what have come to be termed “traditional risk factors.” Nontraditional risk factors Although the majority of CVD appears to be explained by traditional risk factors there is residual risk that may be due to the presence of other factors. These have been termed “nontraditional” risk factors. These may be useful in deter- mining risk in patients who by history would be at high risk for CVD but have normal values for the traditional risk factors. As our understanding of the mechanisms of CVD in diabetes has improved the role of inflammation in the development of both DM and CVD has been recognized. In addition abnormal fibrinolysis endothelial function alter- ation in adipokine release and vascular wall abnormalities may all play a role in vascular dysfunction in patients with diabetes 25. As these mechanisms are investigated novel risk factors have been identified. A number of interventions we institute for traditional risk factors such as statins and ACE-I appear to improve these nontraditional risk factors. Although promising the nontraditional factors are not ready for routine use in all patients. There are multiple reasons for this such as lack of standardized commercially available tests lack of data on CVD event reduction fol- lowing risk improvement and so on. Of all the novel risks hsCRP and coronary calcium scores may be the only ones that are currently clinically applicable. Highly sensitive C-reactive protein hsCRP As a marker of inflammation hsCRP has been shown in large prospective epidemiologic studies to be associ- ated with an increased incidence of vascular disease and increased mortality. This association was seen in those with and without a known history of CVD and independent of other traditional risk factors. The utility of hsCRP may be in patients at intermediate risk for CVD who have LDL levels at goal. In the Air Force/T exas Coronary Atherosclero- sis Prevention Study 26 6605 patients with dyslipidemia were treated with lovastatin. Patients who had low-density lipoprotein LDL levels above median 159 mg/dl ben- efitted from the statin. In addition those with LDL levels below the median but hsCRP levels above median 1.62 mg/L also benefitted. In contrast those with hsCRP and LDL levels below the median did not appear to benefit from the use of the statin. The recent JUPITER trial 27 conducted in 26 countries evaluated 17000 healthy indi- viduals with no prior history of CVD who had an LDL 130 mg/dl and hsCRP 2 mg/L. They were treated with Rosuvastatin 20 mg a day and followed for occurrence of the combined primary end point of myocardial infarction stroke arterial revascularization hospitalization for unsta- ble angina or death from CVD. The trial was stopped after a median follow up of 1.9 years. The main composite end point was reduced by 44 in the treated group compared to placebo. Interestingly patients traditionally considered low risk non smokers absence of metabolic syndrome Framingham Risk Score of 10 or less benefitted from Rosuvastatin treatment. The JUPITER trial demonstrates that in patients con- sidered low risk by measurement of traditional risk factors but have evidence of low-grade inflammation significant improvement in CVD risk can be achieved by treating with a statin. Coronary Artery Calcium Scoring CAC Another novel risk factor receiving greater attention has been the Coronary Artery Calcium Scoring CAC. Coro- nary calcium is a measure of atherosclerotic plaque devel- opment. The 2007 guidelines by the American Heart Asso- ciation and other groups suggested that the utility of CAC may be greatest in those with intermediate 10-year risk for CVD 28. Calcium scores are higher in patients with dia- betes than in normoglycemic patients with other CVD risk factors. In correlation with clinical findings CAC scores in symptomatic patients with diabetes appear to match scores in patients who do not have diabetes but do have a history of CAD. Raggi et al. have reported on 10000 asymp- tomatic patients of whom about 900 had DM 29. These patients had screening for CAD by CT ordered by the pri- mary care physicians. They were followed for an average of 5 years. The all-cause mortality increased as calcium score increased and for any given score mortality was higher among patients with diabetes. Of particular interest was the finding that the absence of coronary calcium was pre- dictive of low short-term risk of death 1 in 5 years in those with or without a history of DM. The CAC may be used clinically to predict both a positive and negative risk for a CV event.

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Screening patients with prediabetes and diabetes for cardiovascular disease 39 Identify Screen for risk factors Obesity genetic predisposition In future: may use risk engine to identify appropriate patients to treat Evaluate for elevated traditional risk factors: lipids blood pressure blood sugar smoking history and family history If elevated T reatment of risk factors T reat the abnormal risk factors Once traditional risks are treated Risks normal Evaluate for nontraditional risk factors: hsCRP CT calcium scores etc. FIG 4.3 Approach to patient who may be at increased risk for cardiovascular disease. Evaluate efficacy T reat nontraditional risk factors E.g. With statin if CRP high even if LDL normal Evaluate efficacy of treating all these risks and cost considerations Although intriguing prospectively conducted long-term studies will have to be conducted before management of patients with diabetes can be altered based on CAC scores. Summary Patients with diabetes are at increased risk for cardiovas- cular disease. Screening with cardiac imaging in asymp- tomatic individuals may not be as efficacious as “screening” for and treating risk factors. Data regarding evaluation and management of “traditional risk factors” are available for patients with a known history of diabetes but less well estab- lished in those with prediabetes. For those with diabetes screening for and treating traditional risk factors appears to improve outcomes. In patients with diabetes who have normal traditional risk factors consideration can be given to evaluating and treating nontraditional risk factors such as hsCRP although long-term outcomes are not available see Figure 4.3. A number of unanswered questions remain including optimal risk stratification of patients. Although we do know that patients with prediabetes have increased risk of CVD it is not known if early management of risk factors to goals suggested for diabetes will improve outcomes. It is also not clear if all patients with prediabetes should have nontra- ditional risk factors checked although the JUPITER trial seems to suggest that even “healthy” patients with evidence of low-grade inflammation may benefit from treatment. There is not enough data to make specific recommenda- tions at this time. References 1. Buse JB Ginsberg HN Bakris GL et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus:a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 1: 162–172 2007. 2. Haffner SM Stern MP Hazuda HP Mitchell BD Patter- son JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before onset of clinical diabetes JAMA. 26321: 2893–2898 1990. 3. Haffner SM Lehto S Ronnemaa T Pvorala K Laasko M. Mortality from coronary heart disease in subjects with type 2 diabetes mellitus and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 3394: 229–234 1998. 4. ADA. American Diabetes Association: Consensus develop- ment conference on the diagnosis of coronary heart dis- ease in people with diabetes:10–11 February 1998 Miami Florida.. Diabetes Care. 21:1551–1559 1998.

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40 Prediabetes and the diagnosis of diabetes 5. Sigan RJ Kenny GP Wasserman DH Castaneda-Sceppa C. Physical activity/exercise and type 2 diabetes. Diabetes Care. 2710:2518–2539 2004. 6. Bax JJ Young LH Frye RL Bonow RO Steinberg HO Barrett EJ. Screening for coronary artery disease in patients with diabetes. Diabetes Care. 3010:2729–2736 2007. 7. Wackers FJ et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects. The DIAD study. Diabetes Care. 278:1954–1961 2004. 8. Wackers FJ Chyun DA Young LH et al. Resolution of asymptomatic myocardial ischemia in patients with type 2 diabetes in the Detection of Ischemia in Asymptomatic Diabetics DIAD study. Diabetes Care. 3011:2892–2898 2007. 9. Young LH Wackers FJ Chyun DA et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA. 30115:1547–1555. 2009. 10. Boden WE O’Rourke RA T eo KK et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 35615:1503–1516 2007. 11. The Decode Study Group. Is the current definition for dia- betes relevant to mortality risk from all causes and cardiovas- cular and noncardiovascular disease. Diabetes Care. 263: 688–696 2003. 12. Norhammer A T enerz A Nilsson G et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 3599324:2140–2144 2002. 13. Barr EL Zimmet PZ Welborn TA et al. Risk of cardiovas- cular and all-cause mortality in individuals with diabetes mellitus impaired glucose tolerance and impaired glucose tolerance. The Australian Diabetes Obesity and Lifestyle AusDiab. Circulation. 116:151–157 2007. 14. Khaw KT Wareham N Luben R et al. Glycated haemoglobin diabetes and mortality in men in Nor- folk cohort of European Prospective Investigation of Can- cer and Nutrition EPIC-Norfolk. BMJ. 3227277:15–18 2001. 15. Chiasson JL Josse RG Gomis R et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. The STOP- NIDDM trial. JAMA. 2904:486–494 2003. 16. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 32914: 977–986 1993. 17. UK Prospective Diabetes Study UKPDS Group. Intensive blood sugar control with sulphonylureas or insulin com- pared with conventional treatment and risk of complica- tions in Patients with type 2 Diabetes UKPDS 33. Lancet. 352:837–853 1998. 18. The Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Compli- cations DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 35325:2643–2653 2005. 19. Holman RR Paul SK Bethel AM et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 35915:1577–1589 2008. 20. Gaede P Vedel P Larsen N et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 3485:383–393 2003. 21. Stevens RJ Kothari V Adler AI Stratton IM Holman RR. The UKPDS risk engine: a model for the risk of coronary heart disease in type II diabetes UKPDS 56. Clin Sci. 101: 671–679 2001. 22. Wilson PW D’Agostino RB Levy D et al. Prediction of coro- nary heart disease using risk factor categories. Circulation. 97:1837–1847 1998. 23. Eddy DM Schlessinger L. Validation of the archimedes dia- betes model. Diabetes Care. 2611:3102–3110 2003. 24. Yusuf S Hawken S Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries the interheart study: case-control study. Lancet. 3649438:937–952 2004. 25. Fonseca V Desouza C Asnani S Jialal I. Nontraditional risk factors for cardiovascular disease in diabetes. Endocr Rev. 251:153–175 2004. 26. Ridker PM Rifai N Clearfield M et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 34426:1959–1965 2001. 27. Ridker PM Danielson E Fonseca FA et al. Rosuvastatin for vascular prevention in men and women with elevated C-reactive protein. N Engl J Med. 35921:2195–2207 2008. 28. Greenland P et al. ACCF/AHA 2007 clinical expert con- sensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assess- ment and in the evaluation of patients with chest pain. JACC. 493:378–402 2007. 29. Raggi P Shaw LJ Berman DS Callister TQ. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. JACC. 439:1663–1669 2004.

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PART II Initial Evaluation and Management of Diabetes To Cure Diabetes Naturally Click Here

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5 What is the role of self-monitoring in diabetes Is there a role for postprandial glucose monitoring How does continuous glucose monitoring integrate into clinical practice To Get Best Natural Diabetes Treatment Click Here Rami Almokayyad 1 and Robert Cuddihy 2 1 Endocrine Fellow Division of Endocrinology Department of Medicine University of Minnesota Medical School University of Minnesota Minneapolis MN USA 2 Medical Director International Diabetes Center World Health Organization Collaborating Center for Diabetes Education Translation and Computer Technology Minneapolis MN USA L E A R N I N G P OIN T S There is general consensus that the use of SMBG in most individuals with T1DM or those with T2DM treated with insulin is of benefit. The benefit of SMBG in individuals with T2DM not on insulin therapy remains inconclusive and controversial. The role of postprandial glucose monitoring has previously been firmly established in gestational diabetes but remains controversial in T1DM or T2DM. Continuous Glucose Monitoring CGM devices have documented benefit in adults with T1DM on an insulin pump therapy who use the data it provides to modify their therapy. There is a clear need for well-controlled clinical trials to assess the value of SMBG in T2DM for those on other than insulin therapy. The lack of a simple universal output of SMBG and CGM data are an impediment to their appropriate uptake and use in primary care. Self-monitoring of blood glucose Self -monitoring of blood glucose SMBG can be consid- ered one of the bigger advances in diabetes management after the discovery of insulin and oral agents. Bedside measurement of plasma glucose was introduced in the mid-1920s as a necessity after the discovery and use of the first insulin. At that time the only modality to moni- tor diabetes control was qualitative urine glucose measure- ments which only gave patients an estimate of their lev- els over the proceeding 1–2 days revealing hyperglycemia only when serum glucose had exceeded the renal thresh- old ∼200 mg/dl resulting in glycosuria. The procedure of measuring glucose would typically take 20 minutes as described by Maclean in his book Modern Methods in the Diagnosis and Treatment of Glycosuria and Diabetes pub- lished in 1924 1. The use of this method was limited to use by the clinician. By the early 1940s semiquantitative urine glucose mea- surement kits became commercially available for home use and they became the major modality for glucose self- monitoring at home. In the mid-1960s reagent strips were introduced as a semiquantitative method of measuring capillary whole blood glucose a drop of blood was added to these reagents that utilized a glucose oxidase reaction to effect a colori- metric change. The resultant color from the reaction could then be compared with a standard chart and this would give a rough estimate of the blood glucose level. These strips were initially limited to office and hospital use with limited patient access for home use. Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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44 Initial evaluation and management of diabetes By the late 1960s reflectance meters were introduced that utilized the same type of reagent strips where a light source was reflected on the strip instead of reading them manu- ally enabling the reflected light to be read by a photoelectric cell which in turn gave a readout of the estimated glucose using a swinging needle at that time. In the late 1970s meters were developed for patient use. With advances in technology electrochemical meters were introduced and as the technology evolved improvements were made to reduce the size of these meters reduce their reaction and reading times simplify blood sampling techniques and to reduce the discomfort associ- ated with blood sampling 2. T oday glucose meters have a central role in diabetes management with nearly 70 of all patients with diabetes performing some SMBG 3. Long-term follow-up of participants in the Diabetes Complication and Control Trial DCCT as part of the Epi- demiology of Diabetes Interventions and Complications EDIC in type 1 diabetes mellitus T1DM and the 10- year follow-up of the United Kingdom Prospective Dia- betes Study UKPDS in type 2 diabetes mellitus T2DM provide clear evidence that the early and intensive control of hyperglycemia reduces the long-term risks of microvas- cular and macrovascular complications in diabetes. The effect of good glycemic control seems to persist for years to some extent independently of subsequent glycemic control. This phenomenon is referred to as “metabolic memory” or “the legacy effect” 4–6. However tight glycemic control does come at a cost which is a threefold increased risk of severe hypoglycemia seen in the DCCT trial T1DM as well as the Action to Control Cardiovascular Risks in Diabetes ACCORD trial in T2DM 7 8. ACCORD also suggested an increased mortality risk with assignment to a strategy aiming to achieve near normoglycemia. How- ever somewhat surprisingly this risk was inversely propor- tional to the rate of fall in HbA1c being lowest in those individuals who rapidly corrected their HbA1c and high- est in those who lowered their HbA1c slowly or not at all and the highest mortality in both the standard and intensive glycemic control arms of ACCORD occurred in those patients with higher HbA1c publically presented ACCORD data with REF coming out in Diabetes Care online within 1 week—Matt Riddle doi: 10.2337/dc09- 1278 Diabetes Care May 2010 vol. 33 no. 5 983–990. The available evidence would suggest that in most patients with diabetes one should maintain “tight” glycemic control as early in the course of the disease as possible and to con- tinue to maintain this level of control as tightly as possible 9 generally targeting an A1c level 7.0 by ADA guide- lines or 6.5 by IDF or AACE guidelines if this can be accomplished safely without exposing the patient to undue risk of severe hypoglycemia. SMBG therefore can play a pivotal role when used properly as an adjunctive tool to enhance patient self- management of their diabetes. SMBG provides day-to-day data on glycemic control it provides an immediate feedback about the effect of nutrition physical activity and medica- tions on blood glucose. It allows prompt determination of hypoglycemia or hyperglycemia that not only can improve patient safety but also can motivate individuals to make appropriate changes in diet exercise and medications. By shaping meal and activity patterns and providing feedback on medication dosing or titration while simul- taneously providing useful information on the potential occurrence or risks of hypoglycemia the information gleaned from SMBG monitoring can help optimize the delicate balance between the benefits and risks of tight glycemic control. In this section we will discuss the utility of SMBG in diabetes management and we will discuss the evidence behind its use in different patient groups. SMGB in type 1 DM and insulin-requiring T2DM patients The use of SMBG in patients with type 1 diabetes and in those with type 2 diabetes treated with intensive insulin therapies or multiple daily insulin injections MDI appears logical for several reasons is supported by clinical trial data and thus is not controversial. First SMGB will provide day-to-day information that can help adjust insulin dose to optimize the overall glycemic control. Patients on bolus “prandial or meal-related” insulin use the premeal SMBG data to adjust the dose of their prandial insulin correcting it for the amount of carbo- hydrate consumed as well for any variance of the premeal glucose above or below the desired target range so-called corrective dose insulin. While various insulin adjustment methods may differ in their specific titration schemes they all utilize premeal SMBG values as an actionable item aid- ing in appropriately adjusting the insulin dosing before a meal so as to achieve tighter glycemic control. One of the earliest studies that demonstrated the effectiveness of SMBG in improving glycemic control was conducted in 1982 10. This concept was emphasized in the Diabetes Complication and Control Trial in which intensive insulin therapy has shown to improve glycemic

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What is the role of self-monitoring in diabetes 45 control and reduce microvascular complications and this was achieved by intensifying insulin regimens utilizing SMBG 7. Also SMBG is an important safety tool in insulin treated patients to detect hypoglycemia especially in patients with hypoglycemia unawareness. The recommendation from the DCCT was to perform SMBG at least four times per day however observational studies have shown that most patients with type 1 diabetes on intensive physiological insulin regimen fall short of these recommendations 11. SMBG in non-insulin-requiring T2DM Although SMBG is now widely accepted as a part of the management of patients with non-insulin-treated type 2 diabetes its efficacy and rationale is more controversial. Most of the existing data for the efficacy of SMBG in these subjects come from cross-sectional and retrospective stud- ies which slightly favored more frequent SMBG 12–14. Many randomized clinical trials RCTs have been car- ried out in small groups of patients. Participants were not recruited from representative populations in the commu- nity and the strategies for use of the results from SMBG were not clearly defined. The relative benefit in terms of HbA1c reduction typically was modest even in those randomized clinical trials which did show benefit in the range from a one-quarter to two-thirds of 1 and most meta-analysis of various combinations of these RCTs favor SMBG. Epi- demiologic studies utilizing large patient databases have generally noted improved glycemic control in individuals with diabetes who monitor more often but such studies can only implicate an association between more frequent SMBG and improved glycemic control but not a causal relation- ship. Selection biases and other confounding variables may also affect these results 15. Other cross-sectional studies such as the Fremantle Diabetes Study do not show benefit in terms of glycemic control with SMBG 16. The Cochrane Collaborative best-evidence-based review of SMBG use in patients with T2DM on non-insulin ther- apies also appears to favor SMBG but noted that more evidence is needed 17. Recently Farmer and colleagues conducted a random- ized controlled trial Diabetes Glycaemic Education and Monitoring DiGEM study that aimed to test whether SMBG used with or without instruction in incorporat- ing findings into self-care can improve glycemic control in non-insulin-treated diabetes patients compared with stan- dardized usual care 18. A total of 453 patients were indi- vidually randomized to one of three groups: 1 standard- ized usual care with 3-monthly HbA1c control 2 blood glucose self-testing with patient training focused on clini- cian interpretation of results in addition to usual care less intensive self-monitoring or 3 SMBG with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle more intensive self-monitoring. There was no evidence of glycemic benefit between the three groups at the end of 12 months no difference in the primary outcome Hemoglobin A1C. In addition there was no evidence of a significantly different impact of self-monitoring on glycemic control when comparing subgroups of patients defined by duration of diabetes ther- apy and diabetes-related complications. Patients who were in the more intensive SMBG arm detected more hypo- glycemia. The economic analysis suggested that SMBG resulted in extra health care costs and was unlikely to be cost-effective if used routinely. There was an initial nega- tive impact associated with more frequent use of SMBG on the quality of life 19. The potential clinical ramifications from this study have been huge and called into question the utility cost- effectiveness and effect on quality of life of SMBG individ- uals with T2DM who are not on insulin therapy. In an era of tightening financial resources an epidemic of T2DM and attempts to curb health care expenditures in general this and subsequent reports from the DiGEM study had lead to a wide reappraisal of benefits or SMBG in individuals who are not yet treated with insulin. Reappraisal of the need to cover SMBG testing supplies for individuals with T2DM not treated with insulin by payers and national groups such as the National Health Service in the U.K. and the Centers for Medicare and Medicaid Services CMS in the United States have reportedly taken place. Thus a careful look at some of the potential concerns or criticism of the DiGEM study is warranted. This study enrolled individuals with relatively recent onset of diabetes median duration of 3 years treated with diet or oral agents with reasonably good glycemic control mean HbA1c of 7.5 and specifically selected individuals who were either not monitoring SMBG at all or monitoring no more than a single one-time SMBG per week. Thus the study may have inadvertently selected a biased population less geared toward or less compliant with SMBG moni- toring and with potentially less to gain from improvements in glucose control. Of concern is the case that it was in the intensive SMBG cohort that more individuals quit SMBG

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46 Initial evaluation and management of diabetes monitoring than the less intensive cohort. Also for those who were to utilize the SMBG data to modify their lifestyle or medication a delineation of a specified action plan in response to the SMBG data is lacking and not delineated. While there was a minimal decline in HbA1c by 0.17 in this group it was not statistically significant. Of potential concern was the issue that the reduction in HbA1c in this study was far less than those reported from the majority of other RCT evaluating the effect of SMBG. Criticisms aside this study was a careful attempt to get at the issue of the value of SMBG in terms of improvements in glycemic control in such a population of individuals and at least raises the stakes for proponents of SMBG to prove its worth in non-insulin-treated populations. Several groups have formed to attempt to outline the necessary components of a large scale RCT to better evaluate the role and utility of SMBG in T2DM 15 20. From a philosophical standpoint it is of vital importance to understand the use of SMBG as a useful diagnostic tool to enhance patient self-management of diabetes rather than as a direct therapeutic intervention targeting glucose lev- els. As such there are multiple aspects of the use of SMBG that must be in place for the data it generates to be accu- rate beneficial to glycemic control and most importantly used by the patient. Important potential barriers to appro- priate SMBG include proper technique correct coding of glucose meters to match the testing strips correct setting of the time and date of the meter to aid in SMBG review of downloaded meter data and most importantly appropri- ate patient education and understanding of the timing of SMBG and the use of the data derived from it to modify the patient’s self-management. The data can then become an actionable item leading to modification in therapy whether leading to changes in diet or activity through behavioral change or adjustment in medication. Ideally to maxi- mize the impact of SMBG the patients themselves should be educated on how to appropriately use SMBG. Such a tool could be used at various time points to optimize man- agement throughout the day uncovering needed behav- ioral modifications in diet and activity providing feed- back for potential problematic periods of marked hyper- glycemia or hypoglycemia and providing the patient an early detection of worsening overall glycemic control due either to situational factors such as intercurrent illness or steroid usage or the progressive nature of T2DM itself. Such information would indicate the need to titrate ther- apy to reestablish target levels of glycemic control in a timely manner. There is a great need for specific algorithms instructing patients what do in terms of altering their management or therapy in response to their SMBG data. Some early pre- liminary data suggest that patient-driven algorithms based on SMBG can be more effective in helping them reach tar- get than management that relies on the patient’s health care provider or clinician to review the data and recom- mend changes in therapy. For example in the commonly seen patient with good control of AM fasting blood glucose BG but HbA1c’s above target it is likely that BG values are higher at other time points throughout the day. Bergenstal et al showed that utilizing an algorithm for titrating premeal insulin solely based on preprandial SMBG values rather than utilizing strict carbohydrate counting with matching insulin to carbohydrate dosing was equally effective in controlling glycemic levels in insulin-treated individuals with T2DM 21. The technical aspects of glucose meters that serve as bar- riers are the easiest to correct and in fact meters that do not require coding of the meter to match the testing strips are beginning to enter the market. Time and date stamp- ing of SMBG values will become automated. Meal markers are available on some units to aid in interpreting fasting or premeal glucose patterns from postprandial patterns. Many meters can inform the patient if the blood sample is inadequate for an accurate test result. The lack of patient education and training in diabetes self-management including proper use of SMBG remains a significant barrier that requires more effort to correct. In clinical practice one frequently encounters patients treated with lifestyle modification and Metformin monotherapy who have been instructed to perform SMBG and dutifully obtain one fasting blood glucose value each morning. No alternative testing schema is offered if the AM fasting glu- coses are within goal but the HbA1c remains above goal. Clearly rather than obtain seven “normal fasting readings” per week the utility of SMBG would be markedly enhanced if such patients were educated to use these same seven weekly readings in a more dispersed fashion sampling once daily but at alternating times each day. Perhaps obtaining AM fasting blood glucose on Monday 2-hour postprandial BG after breakfast on Tuesday prelunch BG on Wednes- day 2-hour post-lunch BG on Thursday predinner BG on Friday post-dinner BG on Saturday and bedtime BG on Sunday would provide a wealth of actionable information For instance a significant postprandial rise in BG following a specific meal could signal the patient to make modifica- tions in the timing or quantity of carbohydrate consumed

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What is the role of self-monitoring in diabetes 47 during the day or to add more physical activity prior to this meal. If unable to correct this issue with dietary or activity changes such findings could lead the patient to engage their physician to consider the addition of another pharmacologic agent targeting postprandial BGs. The indi- vidual could “learn” from the response of SMBG just how various meals and meal composition affect their BGs and what the affect of various activities are on their BGs acting as a useful tool and reinforcement for beneficial behav- ioral modification. If the postprandial BG rise was more pronounced following one specific meal then the pattern of SMBG monitoring might temporarily change while the individual “works on that particular problem area” per- haps using many of their weekly SMBG determinations before and after that particular meal to assess the result of various attempted interventions returning to a widespread surveillance pattern of SMBG once the “problem is solved” or corrected. This surveillance SMBG would then inform the individual if and where the next issue in fine-tuning glycemic control should occur. If individuals are on agents that can cause hypoglycemia such as a sulfonylurea SU then surveillance SMBG can indicate if there is a problematic period of increased risk of hypoglycemia during the day such as the late afternoon or predinner period or overnight which should ideally lead to corrective intervention to reduce this risk. Utilizing SMBG for continuous surveillance and qual- ity improvement of their diabetes self-management can help counteract the clinical inertia currently seen in our health systems which are not properly designed to man- age non-acute chronic diseases such as diabetes. Brown et al 22 have demonstrated how this inertia can result in patients’ encountering 8–10 years of exposure to signif- icant chronic hyperglycemia with the increased risk for complications that this entails while their medical regimen is very slowly progressed through the different available therapies. Patients should be empowered to contact their health care provider as soon as they encounter problematic hyperglycemia that has not responded to their attempts at correction as medication may need to be advanced. Rather than await their next regularly scheduled 3- to 6-month appointment before advancement in therapy is undertaken the therapies could be quickly optimized until the glycemic goals or treatment targets are achieved. Another barrier to the optimal use of patient derived SMBG data in diabetes management occurs in physician offices. In today’s environment where health care providers have less and less time in which to see their patients they are often forced to complete the entire visit in 15 to 20 minutes. In such a scenario the use of the glucose logbook to look for patterns from which to make therapeutic recommendations is problematic. It is difficult to expect busy providers to visu- ally scan often messy hand-scribbled columns of individual glucose values and try and make some sense of any emerging pattern after flipping through several pages in a standard glucose logbook Figure 5.1. The ability to download glu- cose meter data and present verified aggregate glucose data in an organized fashion with basic statistical summaries is certainly an improvement. However the multitude of dif- fering proprietary software programs needed to download the data from each company’s meter and the slightly differ- ent presentation format of each of these software programs severely inhibit the broad generalizability of this important tool and thus limits its uptake in offices especially in pri- mary care settings. As opposed to another diagnostic tool the electrocardiogram ECG which has the same stan- dardized universal output no such common format and universal output exists for SMBG data. Thus while the stan- dard 12-lead ECG tracing enjoys widespread use in clinical practice SMBG use remains most widely relegated to the use of a handwritten glucose logbook. This is a major gap in our ability to teach glycemic pattern recognition to our patients and fellow clinicians severely impeding the great potential of SMBG to help shape therapeutic interventions and improve overall levels of control. The representation of all SMBG data expressed as a single day over 24 hours was an attempt to have some more common output from the multitude of meters many of which do allow data to also be expressed in this form Figure 5.2. Unfortunately the widespread use of such a modal day output never became commonplace especially in primary care practice where they may be most useful. The many barriers to the proper use of SMBG and the controversy still remaining around the utility of SMBG in patients with T2DM who are not on insulin have given rise to an interesting question. Given that many avail- able therapies including dietary and activity modification or pharmacologic agents such as metformin dipeptidyl peptidase-IV DDP-4 inhibitors glucagon-like peptide -1 GLP-1 receptor agonists and thiazolidinediones TZDs all can improve overall glycemic control and do not result in increased risks for hypoglycemia could many patients use these therapies singly or in combination without the need for any SMBG These patients could be followed by period HbA1c mea- surement to be sure that they are achieving their overall

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48 Initial evaluation and management of diabetes BREAKFAST LUNCH DINNER BEDTIME Date Night BG Med BG BG Med BG BG Med BG BG Med Notes/Ketones SMBG values tranlated in BG mg/dL mg/dL mg/dL mmol/L 2/24 179 199 272 9.9-11.0-15.1 2/25 198 177 189 Shopping 11.0-9.8-10.5 2/26 165 188 182 9.2-10.4-10.1 2/27 195 209 248 10.8-11.6-13.8 2/28 187 225 10.4-12.5 3/1 153 167 288 20 min walk 8.5-9.3-16.0 3/2 182 159 219 10.1-8.9-12.1 3/3 197 155 203 10.9-8.6-11.3 3/4 189 182 199 20 min walk 10.5-10.1-11.1 3/5 210 153 262 20 min walk 11.7-8.5-14.6 3/6 173 9.6 3/7 FIG 5.1 T ypical patient glucose logbook with self-reported data. glycemic targets. The cost savings based on forgoing the need for expensive glucose testing strips one or many times daily as well as the ease of daily self-management of their diabetes and potential perceived improvement in quality of life might justify such an approach Thus there remains an urgent and ongoing need for properly designed well-controlled RCTs to evaluate just what is the benefit of SMBG in those individuals with T2DM treated with non-insulin therapies. This population given their greater numbers likely makes up the lion’s share of the SMBG market and thus this question has enormously important ramifications for general public health care pol- icy in dealing with the growing diabetes epidemic. Postprandial SMBG The role of postprandial SMBG is firmly established in women with gestational diabetes mellitus GDM. Adjusting insulin therapy in mothers with GDM based on postprandial BG resulted in improved HbA1c lower birth weights i.e. less macrosomia less neonatal hypo- glycemia and less need for a cesarean section at delivery 23. Meal-based SMBG is a valuable tool for improving out- comes in pregnancy complicated by diabetes and has been shown to improve fetal perinatal outcomes 24. This is more evident in insulin-treated patients and less clear with diet-controlled patients 25 although such monitoring may be useful in providing feedback for behavioral modifi- cation and surveillance as to the adequacy of glucose control and the need to intensify therapies if not within target. Also it encourages patients to actively participate in their own care. The role of postprandial SMBG in T1DM and espe- cially in T2DM is controversial. The landmark trials such as the DCCT-EDIC and UKPDS and its 10-year follow-up trials clearly showed that improving overall glycemic control thus reducing chronic exposure to hyper- glycemia as measured by the HbA1c reduced the risks of microvascular and macrovascular complications 4–7. Thus the current recommendations by the ADA to tar- get an HbA1c of 7 in most individuals with diabetes 26. These trials did not typically require postprandial SMBG nor compare the effects of targeting fasting and

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Glucose What is the role of self-monitoring in diabetes 49 220 200 180 160 140 120 100 80 60 40 20 0 Time of day Overall target Statistics Glucose average: Within target: of glucose readings: of hypo. readings: Standard deviation: 127 50 16 1 48 Target type: Before meal target: After meal target: Hypoglycemic: Personal 70 –110 90 –140 67 FIG 5.2 Modal Day presentation of downloaded meter with SMBG data. premeal SMBG versus postprandial SMBG in reducing complications. In T1DM it is not uncommon for individuals to mon- itor postprandial SMBG regularly to assess the adequacy of control exerted by their premeal short- or rapid-acting insulin on an MDI program or their bolus if they are on insulin-pump continuous subcutaneous insulin infusion CSII therapy. Monitoring postprandial SMBG provides these individuals with feedback both on insulin dosage and self-management behavior such as carbohydrate count- ing and their insulin to carbohydrate ratio. Nonetheless it remains a common clinical practice for many individuals with either T1DM or T2DM to use their next or following premeal SMBG rather than a 2 hour PPG to gauge the effi- cacy of their previous premeal insulin dose or other therapy directed toward glycemic control. This assumes that if the next premeal SMBG is within target then the postprandial glucose values were likely “acceptable.” While this method does provide a crude indirect estimate of glycemic control over this period it cannot guarantee glucose excursions or overall glycemic exposure are well controlled. Thus while this method is less labor intensive and may be an appropri- ate compromise in terms of “quality of life” for the indi- vidual more intensive SMBG monitoring including PPG should be considered if HbA1c is not within the desired target range. In T2DM the role of postprandial SMBG is even less clear. T2DM usually has a more indolent onset slowly progressing through phases of glucose intolerance to frank diabetes and is closely associated with the metabolic syndrome and the increased cardiovascular risk that this entails. There have been several studies such as the DECODE and others that have found correlations with elevated postprandial glucoses and cardiovascular disease risk extending from impaired glucose tolerance right down into the normal range for glucose and in fact indicate greater association with risks of cardiovascular disease for elevations in postprandial glu- cose PPG than fasting plasma glucose FPG 27 28.

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50 Initial evaluation and management of diabetes Again most of the trials correlated improvement in chronic glucose exposure as measured by HbA1c with decreased risk of long-term complications. Some stud- ies suggest a closer correlation of postprandial or post- challenge glucose with HbA1c and mortality than fasting glucose 29 but this remains controversial and is not seen in yet other studies. Therapies that specifically target PPG such as Acarbose have been shown to reduce CV disease and all-cause mortality in the Stop-NIDDM trial 30 31. Studies by Ceriello and others have provided indirect evi- dence that glycemic variability or excursions typically most marked in the immediate postprandial period directly con- tribute to diabetic complications through oxidative stress and the generation of free radical formation activation of the polyol pathways and generation of PKC β and advanced glycosylation end products AGES 32 33. The role PPG plays in the development of long-term diabetic compli- cations remains very controversial. One often-referenced paper used to support this evidence that PPG plays a role in complications in T1DM noted that in the DCCT trial those individuals in the intensive glycemic treatment arm suffered from less diabetes-related complications than did their counterparts in the standard arm even when matched for HbA1c which is actually incorrect 34. This was actu- ally a hypothesized extrapolation or modeling of the data and not directly representative of the clinical data itself 35. While the controversy continues to rage some groups like the International Diabetes Federation IDF have published guidelines for the control of PPG 36. Given the relative lack of strong RCT data comparing the benefits of postprandial SMBG versus fasting and immedi- ate premeal SMBG measurement why might postprandial SMBG measurement be of importance in individuals with T2DM who are not treated with insulin It may be neces- sary to target PPG to get more of these individuals to their glycemic goal. Monnier et al have shown in a population of individuals with T2DM not treated with insulin that the contribution of PPG to overall glycemic exposure rises pro- gressively the closer one approaches a target HbA1c 7 37. At HbA1c 7.6 the contribution of PPG to over- all glycemic exposure totals approximately 70. This in turn may help to explain why in several RCTs that targeted interventions aimed at achieving an AM fasting blood sugar within a specific goal range typically less than 100 mg/dL many individuals who have achieved this target still have HbA1c that remains above 7. With nearly 40 of the U.S. population not in target in terms of HbA1c more focus on PPG through proper postprandial SMBG monitoring and patient education on what action to take if they are not in target may be necessary As noted the IDF has published a guideline of the targeting of postprandial SMBG 36 and the ADA and AACE guidelines give recommended post- prandial target glucose levels. A reasonable approach may be to recommend targeted PPG or intensification of SMBG in individuals who are either not within their goal range for HbA1c on their sta- bilized maintenance diabetes regimen or in newly treated patients with initially high HbA1c’s as their HbA1c’s are lowered by initial therapies and are approaching 7. The key is to use SMBG when it serves a discreet purpose either as an actionable item to potentially modify therapy or in surveillance to ensure adequate glycemic control is being maintained. Continuous glucose monitoring systems The relatively recent advent of commercially available sub- cutaneous continuous glucose monitoring CGM systems that continuously measure interstitial fluid glucose has added to the armamentarium of tools potentially useful for the self-management of diabetes. Devices from three manu- factures are currently available and licensed as an adjunctive tool for diabetes management most commonly in T1DM for persons on MDI or CSII insulin regimens. The FDA has mandated that these devices not be used for directly calculating an insulin dose based on the most current CGM reading as their accuracy in comparison to those from approved glucose meters measuring capillary venous whole blood has not been firmly established. Rather the data gen- erated from CGM can be useful in guiding necessary SMBG testing by delineating the real-time trending in sequential glucose values either indicating worsening hyperglycemia that may result in the need to confirm with SMBG and potentially take an added supplemental dose of insulin or in indicating rapid glucose lowering that may result in eventual hypoglycemia warranting treatment. These systems also make available alarms that can call one’s atten- tion to developing hyperglycemia or hypoglycemia prompt- ing corrective action. Most studies of CGM to date have utilized this tool in patients with T1DM on MDI or CSII insulin therapies taking advantage of the real-time glucose trending data to fine-tune insulin therapy. Just as with SMBG CGM is but a tool to help guide one’s diabetes self-management and

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What is the role of self-monitoring in diabetes 51 not an antihyperglycemic intervention in and of itself. The effects of CGM on HbA1c have been relatively mild but real. The recent JDRF CGM study 38 showed that the use of CGM in patients with T1DM on CSII did improve HbA1c in adult patients over 25 years of age but not in children and teenagers who had much higher rates of non-adherence with proper CGM use i.e. wearing a sensor or using the provided data for decision making. The Star 1 trial 39 did not demonstrate dramatic HbA1c lowering in individuals with T1DM using CSII who used CGM. It did suggest that in those who used the CGM the increased usage was associated with an increased proba- bility of HbA1c lowering. Many other moderate-sized trials n of 100–200 assessing CGM use have come to similar conclusions i.e. increased use of the CGM devices and the data they provide are associated with higher probability of HbA1c lowering. The soon-to-be completed Star 3 trial is intended to demonstrate that CGM use with CSII is superior to MDI therapy in patients with T1DM. Like almost any intervention there has been a “down- side” occasionally noted in some individuals with T1DM who use a CGM. In some individuals there is a tendency to “overbolus” in response to continuing high readings viewed on the device. This occurs when individuals feel compelled to frequently re-bolus with a short- or rapid-acting insulin when high glucose readings are viewed on the CGM device most of which provide a new reading every 1–5 minutes. This impatience upon frequently viewing high glucose following an intervention that has not yet had adequate time to work can lead to “insulin stacking.” This phe- nomenon occurs where the effect of the most recent insulin dose is in addition to “on top of ” the ongoing insulin effect from the residual insulin on board from the previous injection resulting in hypoglycemia. Proper education and training of individuals as well as careful patient selection is required in choosing individuals who will benefit from CGM. Another effect that has been seen is “sensor burnout” where it becomes difficult to maintain the ongoing effort required to respond to the wealth of data provided by a device in “real time” which may or may not require an action on the individual’s part. In some studies utilizing CGM the HbA1c can be seen to improve over the first 3–9 months only to regress toward the mean after more prolonged follow-up because the information is no longer being used with the same intensity. Currently there is much research attempting to eventu- ally link the continuous data derived from a CGM device to an insulin pump. Such a system might to able to respond to the continuous data communicated to the pump by the CGM device and respond with automated changes in the insulin infusion. Such a “closed loop” device has been the holy grail of diabetes therapies short of an actual cure for the disease. The potential future growth of CGM may well depend largely on its intermittent use for collection and summary of large quantities of glucose data for “glycemic pattern recog- nition” in individuals with T2DM or T1DM. The use of periodic CGM in this way would function as a “diagnos- tic biopsy” providing much more detailed and potentially more useful information than an HbA1c. This glycemic pattern data would aid in targeting appropriate therapeutic changes as well as delineating the optimal and appropriate timing of SMBG once the short period of CGM monitoring is concluded. However just as with SMBG similar barriers are arising with CGM as each company promotes its own proprietary software for data downloading. With no standardized uni- versal output and at least three competing and differing software outputs the widespread adoption of CGM tools in T2DM especially in primary care will face similar bar- riers as the proper use of SMBG. Its use will inevitably be retarded by the increased effort logistical issues and more complicated training and education the widespread use of such varying outputs in the CGM will require of busy physi- cian practices. These issues are made even more complex by the sheer amount of data generated by CGM devices up to 15K glucose values over a 2-week period making even organizing the data as modal day challenging to make clinically relevant sense of Figure 5.3. Future applications of CGM may make graphical organi- zation of this immense amount of data more feasible to be used in the busy office setting perhaps allowing for quick pattern recognition of summarized glycemic data rather than a laborious and time-consuming review of each glu- cose data point. Mazze et al at the International Diabetes Center in Minneapolis have developed a universal out- put from the three currently available commercial CGM devices that has the added advantage of summarizing and smoothing the immense amount of data from such devices in both a quantitative statistical manner as well as in an intu- itive graphic display Figure 5.4. The ambulatory glucose profile AGP readily aids in rapid assessment and pattern

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12:00 AM 2:00 AM 4:00 AM 6:00 AM 8:00 AM 10:00 AM 12:00 PM 2:00 PM 4:00 PM 6:00 PM 8:00 PM 100:00 PM 120:00 AM 52 Initial evaluation and management of diabetes FIG 5.3 Varying outputs from commercially available CGM devices. 350 300 250 200 150 100 50 0 Modal Day FIG 5.4 CGM device output as a Modal Day.

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Glucose mg/dL Glucose mg/dL 12:00 AM 12:00 AM 2:00 AM 2:00 AM 4:00 AM 4:00 AM 6:00 AM 6:00 AM 8:00 AM 8:00 AM 10:00 AM 10:00 AM 12:00 PM 12:00 PM 2:00 PM 2:00 PM 4:00 PM 4:00 PM 6:00 PM 6:00 PM 8:00 PM 8:00 PM 100:00 PM 100:00 PM 120:00 AM 120:00 AM What is the role of self-monitoring in diabetes 53 350 300 250 200 150 100 50 0 AGP without diabetes AGP patient with normal glucose tolerance 350 300 250 200 150 100 50 0 AGP with T2DM 90th 75th median 25th 10th N 3632 TARGETS ABOVE WITHIN BELOW 140 70 43.0 53.1 4.0 MEAN SD MAX MIN AUC DAY 137.3 44.2 279.0 39.0 3213.5 2372 Days 30 Basal Bolus 40 LA 45 RA HbA1c 7.20 10th 25th 50th 75th 90th IQ Range NRM NORM 87.0 107.9 134.0 164.0 198.1 56.0 133.89583 139.52941 FIG 5.5 Universal CGM output as ambulatory glucose profile AGP. A. Subject without diabetes. B. Subject with T2DM recognition of the individual patient’s stable daily glycemic pattern Figure 5.5. Much like the standardized tracings of an EGC the universal graphic output of an AGP may aid in its utility as a tool for the time-pressed primary care physi- cian who is attempting to complete an office visit an assess- ment of multiple medical issues and devise a therapeutic plan for their patients with diabetes within the context of a 15 to 20 minute office visit. In such a scenario the office or practice would own and reuse the CGM device after proper cleaning and disinfection of the device between patient uses. The patient or his or her payer would only pay for a single sensor about 55 and perhaps an interpretation fee much like an ECG. Thus if use of this data to generate an AGP allowed the treating physician to rapidly and more accu- rately assess the patient’s current glycemic control pattern select an appropriate therapy and guide the timing and

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54 Initial evaluation and management of diabetes intensity of targeted SMBG in follow-up it would appear to be time saving. Combine this with the potential ability for this method to allow more rapid and targeted titration of interventions or medication until therapeutic glycemic tar- gets are reached and this future approach may be relatively cost effective. It is important to keep in mind that both SMBG and CGM are but tools to aid in diabetes self-management and to provide actionable data for patients and their caregivers. They are not a therapeutic intervention expected to improve overall glycemic control in and of themselves. T o optimize the benefits of SMBG or CGM it must be used with appropriate understanding of how the information gleaned from these tools is to be used to monitor and if need be alter one’s current therapies. These tools need to be viewed in the larger context of the patient’s knowledge abilities financial resources and desire to utilize these tools appropriately. Current data especially on the use of SMBG in patients with T2DM not utilizing insulin therapy remains fraught with controversy. Opinions are driven by contra- dictory conclusions from multiple small sometimes poorly designed clinical trials as well as various meta-analysis. There remains a real need for well-controlled thought- fully designed randomized clinically controlled trials to help answer these questions. Groups are now attempting to define those important characteristics to be included in such trials 15 20. References 1. MacLean H. Modern Methods in the Diagnosis and Treatment of Glycosuria and Diabetes. Constable London 1924. 2. Dufaitre-Patouraux L Vague P Lassmann-Vague V . History accuracy and precision of SMBG devices. Diabetes Metab. 292 Pt 2:S7–14 2003. 3. Centers for Disease Control and Prevention. MMWR self- monitoring of blood glucose among adults with diabetes — United States 1997—2006. Morb Mortal Wkly Rep. 5643:1133–1137 2007. 4. The Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Compli- cations DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 353:2643–2653 2005. 5. The Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Compli- cations Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy. JAMA. 290: 2159–2167 2003. 6. Holman RR Paul SK Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 359:1577–1589 2008. 7. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complica- tions in insulin-dependent diabetes mellitus. N Engl J Med. 329:977–986 1993. 8. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 dia- betes. N Engl J Med. 358:2545–2559 2008. 9. Del Prato S LaSalle J Matthaei S Bailey CJ on behalf of the Global Partnership for Effective Diabetes Management. Tai- loring treatment to the individual in type 2 diabetes practical guidance from the Global Partnership for Effective Diabetes Management. Int J Clin Pract. 64:295–304 2010. 10. Schiffrin A Belmonte M. Multiple daily self-glucose mon- itoring: its essential role in long-term glucose control in insulin-dependent diabetic patients treated with pump and multiple subcutaneous injections. Diabetes Care. 5:479–484 1982. 11. Hansen MV Pedersen-Bjergaard U Heller SR et al. Fre- quency and motives of blood glucose self-monitoring in type 1 diabetes. Diabetes Res Clin Pract. 852:183–188. Epub 2009 Jun 3 2009. 12. Evans JM Newton RW Ruta DA et al. Frequency of blood glucose monitoring in relation to glycaemic con- trol: observational study with diabetes database. BMJ. 3197202:83–86 1999. 13. Davidson PC Bode BW Steed RD Hebblewhite HR. A cause-and-effect-based mathematical curvilinear model that predicts the effects of self-monitoring of blood glucose frequency on hemoglobin A1c and is suitable for sta- tistical correlations. J Diabetes Sci Technol. 16:850–856 2007. 14. Murata GH Shah JH Hoffman RM et al. Intensified blood glucose monitoring improves glycemic control in sta- ble insulin-treated veterans with type 2 diabetes: the Dia- betes Outcomes in Veterans Study DOVES. Diabetes Care. 266:1759–1763 2003. 15. Klonoff DC Bergenstal R Blonde R et al. Consensus report of the coalition for clinical research – self-monitoring of blood glucose. J Diabetes Sci Technol. 26:1030–1053 2008. 16. Davis W A Bruce DG Davis TME. Does self-monitor of blood glucose improve outcome in type 2 diabetes The Fremantle Study. Diabetologia. 50:510–515 2007. 17. Welschen LMC Bloemendal E Nijpels G et al. Self- monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin. Cochrane

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What is the role of self-monitoring in diabetes 55 Database Syst Rev. 2005 Issue 2. Art. No.: CD005060. DOI: 10.1002/14651858.CD005060.pub2. 18. Farmer A Wade A Goyder E et al. Impact of self monitoring of blood glucose in the management of patients with non- insulin treated diabetes: open parallel group randomized trial. BMJ. 3357611:132 2007. 19. Farmer A Wade A French DP et al. Blood glucose self- monitoring in type 2 diabetes: a randomised controlled trial Health Technol Assess. 1315 2009. 20. Hirsch IB Bode BW Childs BP et al. Self-Monitoring of Blood Glucose SMBG in insulin- and non-insulin- using adults with diabetes: consensus recommendations for improving SMBG accuracy utilization and research. Dia- betes Technol Ther. 106:419–439 2008. 21. Bergenstal R Johnson M Powers M et al. Adjust to target in type 2 diabetes. Diabetes Care. 317:1305–1310 2008. 22. Brown LB Nichols GA Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 27:1535–1540 2004. 23. DeVeciana M Major C Morgan M et al. Postprandial versus preprandial blood glucose monitoring in women with ges- tational diabetes mellitus requiring insulin therapy. N Engl J Med. 33319:1237–1241 1995. 24. Wecher DJ Kaufmann RC Amankwah KS et al. Prevention of neonatal macrosomia in gestational diabetes by the use of intensive dietary therapy and home glucose monitoring. Am J Perinatol. 8:131–134 1991. 25. Homko CJ Sivan E Reece EA. The impact of self-monitoring of blood glucose on self-efficacy and pregnancy outcomes in women with diet-controlled gestational diabetes. Diabetes Educ. 283:435–443 2002. 26. 2010 ADA Clinical Practice Recommendations. 27. The DECODE Study Group. Glucose tolerance and mortal- ity: comparison of WHO and American Diabetes Associa- tion diagnostic criteria. The DECODE study group. Euro- pean Diabetes Epidemiology Group. Diabetes Epidemiol- ogy: Collaborative analysis of Diagnostic criteria in Europe. Lancet. 354:617–621 1999. 28. Ohkubo Y Kishikawa H Araki E et al. Intensive insulin ther- apy prevents the progression of diabetic microvascular com- plications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 28:103–117 1995. 29. Avignon A Radauceanu A Monnier L. Nonfasting plasma glucose is a better marker of diabetic control than fast- ing plasma glucose in type 2 diabetes. Diabetes Care. 20: 1822–1826 1997. 30. Chiasson JL Josse RG Gomis R et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 290:486–494 2003. 31. Hanefeld M Cagatay M Petrowitsch T et al. Acarbose reduces the risk for myocardial infarction in type 2 dia- betic patients: meta-analysis of seven long-term studies. Eur Heart J. 251:10–16 2004. 32. Ceriello A Ihnat M Thorpe J. Clinical review 2: The “metabolic memory”: is more than just tight glucose con- trol necessary to prevent diabetic complications Journal Of Clinical Endocrinology And Metabolism serial on the Inter- net. 942:410–415 2009 cited February 1 2010. Avail- able from: MEDLINE with Full T ext. 33. Brownlee M Hirsch I. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. JAMA serial on the Internet. 29514:1707–1708 2006 cited February 1 2010. Available from: MEDLINE with Full T ext. 34. DCCT Study Group. The relationship of glycemic expo- sure HbA1c to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes. 44:968–983 1995. 35. Lachin JM Genuth S Nathan DM Zinman B Rutledge BN and for the DCCT/EDIC Research Group. Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial—Revisited. Dia- betes. 57:995–1001 2008. 36. Guideline for Management of Postmeal Glucose. International Diabetes Federation www.idf.org 2007. 37. Monnier L Lapinski H Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 26:881–885 2003. 38. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 359:1464–1476 2008. DOI: 10.1056/NEJMoa0805017. 39. Hirsch IB Abelseth J Bode BW et al. Sensor-augmented insulin pump therapy: results of the first randomized treat-to-target study. Diabetes Technol Ther. 10:377–383 2008.

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7 The optimal diet for diabetes is 8 To Get Rid Of Diabetes Permanently Click Here 9 Maria L. Collazo-Clavell Associate Professor of Medicine Division of Endocrinology Diabetes Metabolism Nutrition Mayo Clinic Rochester MN USA L E A R N I N G P OIN T S The goals of medical nutrition therapy MNT are to achieve metabolic goals treat or prevent diabetes related complications minimize other health risks respect personal and cultural preferences. For the individual with a normal BMI 18.5–24.9 kg/m 2 and stable weight no discrete daily calorie amount need be advised. For the individual who is overweight BMI 25–29.9 kg/m 2 or obese BMI 30 kg/m 2 weight loss is advised with a calorie restricted diet. Carbohydrate intake in patients with diabetes should adhere to the following guidelines: the total amount of carbohydrate in meals or snacks has a greater impact on glycemia than source or type of carbohydrates carbohydrate intake should be from whole grains fruits vegetables and low-fat dairy products sucrose and sucrose-containing foods need to be limited to 10 of total calories there is no long-term benefit on weight management by following a low-carbohydrate diet 35 of total calories. Protein intake should represent ≤ 20 of total calories. Protein restriction 0.8–1.0 g/kg or 16 of total calories may be associated with protection of renal function in people with type 1 or 2 diabetes and microalbuminuria and people with type 1 diabetes and macroalbuminuria. Fat intake should focus on healthy fats monounsaturated MUFAs and polyunsaturated fats PUFAs with avoidance of trans-fatty acids restriction of saturated fats to 10 of total calories and restriction of dietary cholesterol intake to 300 mg/day. Weight management should focus on lifestyle changes with calorie restriction through healthy eating habits and regular physical activity. The initial goal should be a weight loss of 5–10 of initial body weight. Many patients would benefit by participating in a comprehensive structured lifestyle program promoting behavioral change. Medical nutrition therapy MNT remains a cornerstone in the management of the patient with diabetes mellitus. Unfortunately many patients seek sources of nutritional information that have little scientific merit while evidence- based nutritional recommendations are ignored or deemed too difficult to implement. Our responsibility as medical practitioners is to remain knowledgeable as to the proven dietary principles that protect the health of our patients with diabetes while being supportive as these changes are being implemented. So what is the optimal diet for the patient with dia- betes In principle MNT should protect the health of our patients by helping them achieve desired metabolic goals treat or prevent diabetes-related complications minimize other health risks while respecting personal and cultural preferences 1. Goals of MNT: Achieve metabolic goals Treat or prevent diabetes-related complications Minimize other health risks Respect personal and cultural preferences Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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The optimal diet for diabetes is 57 TABLE 6.1 Classification of overweight and obesity by Body Mass Index BMI kg/m 2 sure basal metabolic rate whole-room calorimetry or dou- bly labeled water to measure total energy expenditure and Normal 18.5–24.9 heart rate or activity monitors to measure physical activity 3. Instead daily calorie recommendations are often gen- Overweight 25–29.9 Obesity eralized according to sex age and weight. Estimated caloric Class I Class II 30–34.9 35–39.9 needs can also be determined by utilizing various formulas one of the most common being the Harris Benedict equa- Class III 40 Starting with the basics: Calories Calorie recommendations will vary depending on the goals of energy balance: weight maintenance weight loss or weight gain. Weight maintenance would be recommended for individuals that are at a healthy weight range accord- ing to Body Mass Index BMI criteria Table 6.1. Weight loss is desired for those who meet criteria for overweight and obesity in order to minimize the impact of obesity on insulin resistance and lower the risk for other weight-related medical complications 2. Accurate methods for measuring total caloric energy requirements are expensive and not easily incorporated into clinical practice. These include indirect calorimetry to mea- tion HBE Table 6.2. This formula determines resting energy expenditure REE: the number of calories required to maintain current weight at rest. In controlled trials the HBE has been found to be accurate in determining REE amongst groups although there may be inaccuracies when estimating individual REE. An activity factor is added to account for calories spent in activities of daily living and exercise. This activity factor is generally in the order of 30–50 of REE. This activity factor can be an additional source for inaccuracy since patients may often overestimate their activity level. However caloric estimates based on the HBE equation are well accepted 2–4. For the individual with a normal BMI Table 6.1 and whose weight is stable specific calorie amounts need not be recommended. However for the individual who is overweight or obese the recommendation is weight loss through calorie restriction 2 5. A calorie restriction from TABLE 6.2 Dietary recommendations for the patient with diabetes mellitus Calorie recommendations using Harris Benedict equation HBE HBE + 30–50 activity factor kcal/day Men HBE 66 + 13.8weight in kg + 5.0 height in cm – 6.8 age in years Women HBE 655 + 9.5weight in kg + 1.9 height in cm – 4.7age in years Overweight/obesity HBE 1.3 – 250–500 kcal kcal/day Carbohydrate intake 45–55 of total calories Protein intake 20 of total calories Fat intake 25–35 of total calories Saturated fat 10 of total calories Cholesterol 300 mg/day Trans fatty acids 0 mg/day PUFAs 10 of total calories MUFAs Micronutrients Sodium 2400 mg/d Calcium 1000–1500 mg/d Sodium 2400 mg/day Folic acid Reproductive age women 400 mcg/day Alcohol Men 2 alcohol-containing beverages/day Women 1 alcohol-containing beverage/day

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58 Initial evaluation and management of diabetes HBE1.3 of 250–500 kcal can be advised depending on patient preference and motivation. Although greater calo- rie restriction will be associated with greater initial weight loss the patient faces the risk of lower long-term adherence with the greater calorie restriction 1 2. For the individual with a normal BMI 18.5 –24.9 kg/m 2 and stable weight no discrete daily calorie amount need be advised. For the individual who is overweight BMI 25 –29.9 kg/m 2 or obese BMI 30 kg/m 2 weight loss is advised with a calorie-restricted diet Daily caloric intake HBE1.3 – 250 –500 kcal Breaking down calories: Macronutrients Carbohydrates Carbohydrates are the foundation of most diets. This is par- TABLE 6.3 General recommendations for food intake in patients with diabetes Foods to be encouraged MUFAs replacing saturated fats Olive oil and canola oil Used in spreads food preparation and cooking PUFAs Limit to 10 of total calories Oily fish meal 1–2/week Salmon herring halibut trout and tuna Corn sunflower and soybean oils Used in spreads food preparation and cooking High-fiber foods Fruits vegetables legumes and whole grains Foods to be discouraged Trans-fatty acids Hydrogenated vegetable oils Pies pastries biscuits and cakes Saturated fats and cholesterol Animal-based products Butter mayonnaise regular fat milk and lard ticularly true for patients with diabetes. Food carbohydrates can be categorized as sugars starch and fiber. Controver- sies continue regarding the amount of carbohydrates that are optimal for the patient with diabetes. The most recent recommendations by the American Diabetes Association ADA do not provide specific percentages of total calo- ries to be ingested as carbohydrates. Several factors can impact our recommendations for carbohydrate intake to our patient with diabetes e.g. the type of insulin regime activity levels in athletes. However there are many mis- conceptions regarding carbohydrate intake that should be addressed. The medical literature supports the following recommendations for carbohydrate intake: Total amount of carbohydrate in meals or snacks has a greater impact on glycemia than source or type of carbohy- drate 1 2 6 7. Optimal health benefits are observed when carbohydrate intake is from whole grains fruits vegetables and low-fat dairy products 1 2 6 7. Sucrose and sucrose containing foods do not need to be restricted in people with diabetes nor do they affect glycemia differently than an isocaloric amount of starch. They need to be incorporated as part of the overall meal plan but limited to 10 of total calories 1 2 6 7. For weight management calories and not nutrient compo- sition is the most important factor for success. There is no long-term benefit on weight management by following a low-carbohydrate diet 35 of total calories 8 9. Generally in people with diabetes carbohydrates repre- sent 45–55 of total calories recommended. This flexibility can accommodate personal and cultural preferences 1–3. Fiber High intake of fiber-containing foods is preferred in patients with diabetes. High fiber diets have been shown to confer benefits on glycemic control hyperinsulinemia and lipids in patients with both type 1 and type 2 diabetes. How- ever a specific daily amount is not included in the recent recommendations by the ADA 1 7. Intake of high-fiber foods are associated with metabolic health benefits however no specific daily amount is rec- ommended. Protein Recommendations for protein intake in patients with dia- betes are generally based on expert consensus. Some studies suggest a higher protein requirement in patients with both type 1 and type 2 diabetes as a result of increased protein turnover. However this higher protein requirement is eas- ily met by the average protein intake currently reported by most adults of 20 of total calories ingested. Lower pro- tein intakes of less than 20 of total calories have not been

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The optimal diet for diabetes is 59 associated with additional health benefits particularly for the prevalence of nephropathy in patients with diabetes mellitus. The impact of higher protein intake greater than 20 of total calories on the prevalence of nephropathy have not been studied but is generally not recommended. Patients with type 1 or type 2 diabetes and microalbu- minuria may benefit from protein restriction 0.8–1.0 g/kg or 16 of total calories. This degree of protein restric- tion has been shown to improve glomerular filtration rates and reduce albuminuria. Protein restriction has also been shown to reduce the decline in glomerular filtration rates in people with overt nephropathy and type 1 diabetes 1 2. Protein intake should represent ≤ 20 of total calories 1 2 6 7. Protein restriction 0.8 –1.0 g/kg or 16 of total calories may be associated with protection of renal function in people with type 1 or 2 diabetes and microalbuminuria 1 2 6 7. Protein restriction 0.8 g/kg can protect renal function in people with type 1 diabetes and macroalbuminuria 1 2 6 7. Fats The strongest consensus regarding intake of dietary fat for patients with diabetes is no different than that for the gen- eral population and includes: Avoidance of trans-fatty acids Restriction of saturated fats to 10 of total calories Restriction of dietary cholesterol intake to 300 mg/day These recommendations are supported by a large body of evidence supporting the effect of saturated fat/trans-fatty acid intake on LDL cholesterol and risk for cardiovascular events 1 2 6 7. There is controversy regarding the amount of daily calo- ries to be consumed as fat. In the past the recommenda- tion was to restrict the intake of dietary fat to less than 30 of total calories. However this recommendation has been challenged by evidence supporting the potential ben- efits of monounsaturated MUFAs polyunsaturated fatty acids PUFAs: Omega-3 and Omega-6 on lipid profiles and cardiovascular events. Replacing saturated fats by monoun- saturated or polyunsaturated fats instead of carbohydrates is associated with favorable lipid profiles with higher levels of HDL cholesterol and lower serum triglycerides. Omega- 3 fatty acids mainly found in oily fish and fish oils may offer additional cardiovascular benefits. Cardioprotective effects have been reported with dietary consumption of 1–2 serv- ings of fish high in Omega-3 fatty acids per week. A 38 decrease in coronary artery disease CAD mortality has been reported with weekly intakes of fish high in Omega- 3 fatty acids Table 6.2 more than five times per week 10–12. Therefore if adhering to the recommended daily intake of saturated fat and cholesterol a higher intake of “health- ier” fat may not be associated with additional health risk and need not be as strictly restricted as previously recom- mended. Intake of dietary fat of up to 35 of total calories is acceptable 6. Polyunsaturated fat intake should be limited to 10 of total calories. Higher intakes may be associated with lowering of the cardioprotective effects of HDL choles- terol 1 6 7. The only caution to be acknowledged is the caloric density associated with dietary fat even “healthier fats” in the patient who is trying to manage their weight. Restriction of dietary fat is an effective way of limiting caloric intake and should be a strong determinant in the recommendations provided to a patient with diabetes who is trying to manage their weight 1. There is lack of consensus regarding the intake of calories as fat it is generally recommended that it be limited to 35 of total calories. The intake of MUFAs and PUFAs over saturated fats has been shown to provide cardiovascular health benefits. Intake of PUFAs should be limited to 10 of total calories. Micronutrients A well-balanced diet should provide daily requirements for most micronutrients 1 7. The medical literature does not support a clear benefit to multivitamin and mineral supplementation in the general population or in patients with diabetes mellitus 1. However special consideration should be given to the following circumstances: Folic acid supplementation in pregnant women has been shown to lower the risk for neural tube defects. The current recommendation for folic acid intake is 400 mcg/day for all women capable of becoming pregnant 1. This is the amount present in multivitamin preparations. Calcium requirements are frequently not met by most individual’s eating habits. This requirement would be ful- filled by daily intakes of 3–4 servings of a dairy product. As a result most individuals would benefit from addi- tional calcium supplementation. Daily intakes of calcium of 1000–1500 mg are recommended 1.

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60 Initial evaluation and management of diabetes Sodium restriction has been shown to lower blood pres- sure in individuals with and without established hyperten- sion. Current recommendations are to limit sodium intake to 2400 mg/day 1. A daily multivitamin and mineral preparation can be rec- ommended to those individuals following restrictive diets either in their efforts at weight management or special dietary preferences 1. Specific micronutrient recommendations: Folic acid women in reproductive years 400 mcg/day Calcium 1000 –1500/day Sodium 2400 mg/day Alcohol Recommendations for alcohol intake in people with dia- betes are the same as in the general population. For men the recommendation is two alcohol-containing beverages per day and for women one alcohol-containing beverage per day. Abstinence is advised for individuals with med- ical conditions adversely affected by alcohol intake such as severe hypertriglyceridemia. The cardiovascular benefits attributed to alcohol intake are not restricted to specific alcoholic beverage 1 2 6 7. Recommended alcohol intake For men 2 alcohol-containing beverages/day For women 1 alcohol-containing beverage/day Sweeteners Common sweeteners are sucrose fructose and sugar alco- hols. Several studies have confirmed that sucrose consump- tion does not lead to a greater rise in postprandial blood glucose when compared to an isocaloric amount of another carbohydrate. Hence they need not be restricted but should be incorporated as part of the carbohydrate intake in a meal plan. Since there are no nutritive benefits to sucrose intake it should be limited to 10 of total calories 1 2. Compared to sucrose fructose is associated with a lower postprandial glucose rise. Despite this benefit a large intake of fructose can lead to weight gain and unfavorable lipid profiles with elevated fasting triglycerides and LDL choles- terol. There is no proven benefit to the use of fructose over sucrose as a sweetener. However the intake of naturally occurring fructose such as fruits need not be restricted 1 2 6. Sugar alcohols such as sorbitol and xylitol are associated with lower postprandial glucose rise and lower calorie con- tent compared to sucrose. However large amounts of sugar alcohols 30–49 g can be associated with osmotic diarrhea. There have been no proven advantages to the use of sugar alcohols as a sweetener 1 2 6. Nonnutritive sweeteners can provide benefits for indi- viduals trying to follow a calorie-restricted diet. Despite safety concerns several studies have not confirmed any health risk associated to their use 1 2 6 7. Sucrose intake need not be restricted but limited to 10 of total calories. There are no proven benefits to the use of fructose or sugar alcohols over sucrose as sweeteners. Nonnutritive sweeteners can be used safely and be helpful for individuals trying to follow a calorie restricted diet. Hypoglycemia Hypoglycemia is a common complication in the manage- ment of the patient with diabetes. Treatment involves the intake of glucose or carbohydrate-containing food. The severity of hypoglycemia will dictate the amount of glucose or carbohydrate to be ingested to resolve the hypoglycemia. Intakes of 10–20 g of carbohydrate can raise blood glucose levels by 40–60 mg/dl in 30–45 minutes 1 6. In the treatment of hypoglycemia intakes of 10 –20 g of carbohydrate can raise blood glucose levels by 40 –60 mg/dl in 30 –45 minutes. Special considerations Pregnancy Prepregnancy nutrition counseling should focus on indi- vidual meal planning to meet metabolic goals by the time of conception. During pregnancy modification of nutritional therapy is necessary to continue to achieve metabolic goals but also allow for appropriate weight gain and meet addi- tional nutritional requirements. Increased caloric require- ments are noted during the second and third trimester. This is only in the order of an additional 300 kcal/day. Recommended protein intake is 0.75 g/kg per day plus an

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The optimal diet for diabetes is 61 additional 10 g/day. Folic acid supplementation 400 mcg/day is recommended to lower the risk for neural tube defects 1. During pregnancy modification to nutritional therapy includes: Additional 300 kcal/day during the second and third trimester Protein intake of 0.75 g/kg plus 10 g Folate supplementation of 400 mcg/day Children and adolescents Nutrient requirements for children and adolescents with both type 1 and type 2 diabetes are the same as nondiabetic children of the same age. A healthy lifestyle with regular physical activity should be emphasized in both. Determin- ing energy caloric requirements need to take into consid- eration a child’s usual intake as well as daily activity routine. In children with type 1 diabetes meal planning needs to account for insulin regime being used and is best accom- plished with the guidance of a registered dietitian. Intensive insulin regimes can allow flexibility for children and ado- lescents with diabetes allowing for variability in mealtimes and schedules. In children with type 2 diabetes avoidance of excessive weight gain is desirable by promoting healthy eating and regular physical activity 1. Nutrient requirements are not different for children with type 1 and type 2 diabetes compared to similar age children and adolescents. In children and adolescents with type 1 diabetes meal plan- ning must take into consideration insulin regime. In children with type 2 diabetes weight maintenance should be encouraged by promoting a healthy lifestyle. Weight management Weight management with either avoidance of weight gain or weight loss is often a recommendation for people with diabetes and BMI values above 25 kg/m 2 1 2. This can be particularly challenging for the patient with diabetes since glucose-lowering therapy most notable insulin is often associated with weight gain 5. For the patient with type 2 diabetes this is an important consideration for the treat- ing physician as they choose a medication. Another fact to remember is that the process of pursuing weight loss improvement of eating habits and regular physical activity is associated with many health benefits despite only achiev- ing weight maintenance 13. Hence the focus should be on lifestyle changes. An initial weight loss goal is a weight loss of 5–10 of initial body weight 1 5 6 13. This degree of weight loss has been shown to provide many health benefits with improvement in metabolic parameters 13 14. Although initially this degree of weight loss can be easily achieved it is often difficult to maintain 13. Patients pursuing weight management would benefit from ongoing support promot- ing lifestyle changes. Structured lifestyle programs often include frequent visits with a dietitian for MNT physical activity recommendations and educational sessions pro- moting behavioral change toward a healthier lifestyle 1 6 14. Additional interventions such as pharmacotherapy or surgery for weight loss should be considered in the patient meeting accepted criteria 1 5. There has been controversy regarding dietary recom- mendations to prescribe for weight loss. At present the main recommendation is to focus on modest calorie restric- tion 250–500 kcal/day from usual caloric intake 1 2. Activity recommendations include 30 minutes of an aerobic activity most days of the week 13. Achieving this activ- ity recommendation will often involve helping the patient identify obstacles in order to overcome them. Weight management should focus on lifestyle changes with calorie restriction through healthy eating habits and regular physical activity. Initial goal should be a weight loss of 5 –10 of initial body weight. Many patients would benefit by participating in a compre- hensive structured lifestyle program promoting behavioral change. Implementation Putting dietary recommendations into practice is challeng- ing for most patients with diabetes mellitus. Despite the existence of these recommendations for years patients with diabetes have not made progress at improving their eating habits. In fact for those age groups in which the prevalence of diabetes is high 45–65 years higher calorie consump- tion mainly in the form of carbohydrates has been reported 15. The physician plays a central role in the care of the patient with diabetes. It is imperative that he/she be well informed

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62 Initial evaluation and management of diabetes regarding general principles of the nutritional guidelines recommended. They should continually encourage changes in eating habits that have been proven to provide health benefits. The physician should be able to dispel common myths regarding the eating habits for patients with diabetes. For the patient taking insulin especially the patient on an intensive insulin program the physician must recognize how nutritional recommendations will influence insulin dosing. As a result a more detailed nutritional assessment is often required 1 7. This can be provided through an individual MNT session with a registered dietitian or with the dietitian being a member of a DSMT program 16. An MNT visit can help individualize dietary recom- mendations. Areas for potential change in current eating habits can be identified and changes toward recommended guidelines be encouraged while respecting the patient’s cul- tural/dietary preferences 1 16. Other resources to pro- mote dietary change can be discussed such as learning to read food labels use of recipe books and access to online nutritional information for frequently visited food establishments to aid our patients make better choices. A nutritional assessment can also explore the best method for dietary instruction. Patients may be interested in learning more about carbohydrate counting or glycemic index. Carbohydrate counting Carbohydrate counting is a meal planning method focus- ing on the amount of carbohydrate present in foods con- sumed. Although the popularity of carbohydrate counting has increased over the past decade this concept is not new. There are references to carbohydrate counting dating back to the 1920s and it was one of four meal planning techniques used during the Diabetes Control and Complications Trial. Some consider carbohydrate counting a simpler method of meal planning since it focuses on one macronutrient. Patients with all types of diabetes may benefit from using carbohydrate counting in their meal planning but should be selected after a nutritional assessment is completed 17 18. Carbohydrate counting has two main assumptions: car- bohydrate is the main macronutrient affecting postpran- dial glucose rise and carbohydrates are quickly converted to glucose after a meal. Three levels of carbohydrate counting instruction have been proposed. The concept of carbohy- drate counting is introduced in Level 1. Patients learn about the carbohydrate content of foods and may start counting grams of carbohydrates. They learn about the impact of carbohydrate intake on their postprandial glucose levels. They are encouraged to practice consistency in the amount of carbohydrate consumed in meals and snacks in order to achieve metabolic goals. Hence keeping a diet record becomes an important tool in the learning process. The amount of carbohydrate recommended to a patient for meals and snacks is ultimately determined by metabolic goals and patient preferences 17. Level 2 focuses on pattern management. As a result of continued record keeping individuals can learn to recog- nize how their blood glucose is affected by food medica- tions and physical activity. This can guide additional mod- ification to meal planning activity levels and medication to achieve metabolic goals 17. Level 3 is generally for patients on intensive insulin ther- apy via multiple daily injections or insulin infusion via an insulin pump. At this level patients start to use insulin to carbohydrate ratios to match the amount of rapid-acting insulin required before a meal to control postprandial glu- cose rise. In order to succeed patients need to feel confident in their estimation of carbohydrate amount in foods con- sumed. An example for insulin/carbohydrate ratio is 1 unit of rapid-acting insulin per 15 g of carbohydrate. Patients would benefit from continued visits to a registered dietitian as they learn how to estimate the carbohydrate content of foods practice portion control and recognize the need to change carbohydrate to insulin ratio to better control post- prandial glucose levels 17. It is important to remember that although protein and fats are not incorporated in this meal planning tech- nique they are important macronutrients with nutritional and caloric value. Learning appropriate portion control of these macronutrients can help avoid weight gain that can occur when the amount of calories as fat consumed is disregarded. Carbohydrate counting Carbohydrates are the main macronutrient affecting post- prandial glucose rise Carbohydrates are quickly converted to glucose after a meal Level 1: Introduction of basic concepts Level 2: Pattern recognition Level 3: Use of insulin to carbohydrate ratios for premeal insulin dose

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The optimal diet for diabetes is 63 Glycemic index Some patients with diabetes may be interested in the glycemic index GI for their meal planning. The GI quanti- fies the postprandial glycemic response of a food compared to the glycemic response of a standard food 50 g of glucose or a white bread challenge. Low GI foods cause a lower postprandial glucose response compared to a high GI food. Many factors affect the GI value of a food. For example the type of sugar and/or starch in the food food processing cooking and other meal components will affect the GI of a food. Fiber fat and protein content tend to be associ- ated with lower GI indexes. At present there is not enough evidence to support the use of GI principles in the meal planning for all patients with diabetes. Most studies avail- able are short in duration limiting conclusions regarding long-term benefits 1 2 17 18. However the interested patient should be referred to a registered dietitian for fur- ther education. Summary Medical nutrition therapy remains the foundation in the management of the patient with diabetes mellitus. Despite the overwhelming availability of nutritional recommenda- tions it is important that we adhere to the basic nutritional principles that have been shown to benefit our patients. Implementation of these principles is often challenging and we should support our patients in their efforts utilizing resources available. References 1. American Diabetes Association. Nutrition principles and recommendations in diabetes. Diabetes Care. 27Suppl 1: S36–S46 2004. 2. Ha TKK Lean MEJ. T echnical review: recommendations for the nutritional management of patients with diabetes mellitus. Eur J Clin Nutr. 52:467–481 1998. 3. Lin PH Proschan MA Bray GA et al. Estimation of energy requirements in a controlled feeding trial. Am J Clin Nutr. 77:639–645 2003. 4. Kien CL Ugrasbul F. Prediction of daily energy expenditure during a feeding trial using measurements of energy expen- diture fat free mass or Harris Benedict equations. Am J Clin Nutr. 80:876–880 2004. 5. Albu J Rhaja-Khan N. The management of the obese dia- betic patient. Prim Care Clin Off Pract. 30:465–491 2003. 6. Vaughn L. Dietary guidelines for the management of dia- betes. Nurs Stand. 1944:56–64. 7. Choudhary P . Review of dietary recommendations for dia- betes mellitus. Diabetes Res Clin Pract. 65Suppl 1:S9–S15 2004. 8. McAuley KA Hopkins CM Smith KJ et al. Comparison of high-fat and high-protein diets with a high-carbohydrate diet in insulin – resistant women. Diabetologia. 48:8–16 2005. 9. Mann J McAuley K. Carbohydrates: is the advise to eat less justified for diabetes and cardiovascular health Curr Opin Lipidol. 181:9–12 2007. 10. Mozaffarian D Katan MB Ascherio A Stampfer MJ Willett WC. Trans fatty acids and cardiovascular disease. N Engl J Med. 354: 1601 2006. 11. Mata P et al. Effects of long-term monounsaturated vs. polyunsaturated- enriched diets on lipoproteins in healthy men and women. Am J Clin Nutr. 55:846 1992. 12. Jacobson TA. Beyond lipids: the role of Omega-3 fatty acids from fish oil in the prevention of coronary heart disease. Curr Atheroscler Rep. 9:145–153 2007. 13. Tuomilehto J Lindstrom J Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 344: 1343–1350 2001. 14. Franz MJ Warshaw H Daly AE et al. Evolution of dia- betes medical nutrition therapy. Postgrad Med J. 79:30–35 2003. 15. Oza-Frank R Cheng YJN Venkat KM Gregg EW. Trends in nutrient intake among adults with diabetes in the United States: 1988–2004. J Am Diet Assoc. 1097:1173–1178 2009. 16. Daly A Michael P Johnson EQ et al. Diabetes white paper: defining the delivery of nutrition services in medicare medi- cal nutrition therapy vs. medicare diabetes self-management training programs. J Am Diet Assoc. 109:528–539 2009. 17. Gillespie SJ Kulkarni KD Daly AE. Using carbohydrate counting in diabetes clinical practice. J Am Diet Assoc. 988: 897–905 1998. 18. Kelley DE. Sugars and starch in the nutritional management of diabetes mellitus. Am J Clin Nutr. 78Suppl:858S–64S 2003.

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7 How to determine when to pursue lifestyle change alone versus pharmacotherapy at diagnosis To Kill Diabetes Forever Click Here Galina Smushkin 1 and F . John Service 2 1 Fellow Mayo Clinic Division of Endocrinology Rochester MN USA 2 Professor of Medicine Mayo Clinic College of Medicine Rochester MN USA L E A R N I N G P OIN T S Current guidelines list both lifestyle intervention and metformin as core initial therapies but warn that the high rate of weight gain after an initial successful moderate weight loss limits the role of lifestyle modifications in controlling glycemia long term. Pharmacotherapy at diagnosis should be considered when there is a concurrent use of medications known to induce hyperglycemia such as glucocorticoids atypical antipsychotics or immunosuppressants related to organ transplantation. Early pharmacotherapy should be initiated if a patient has symptoms such as weight loss polyuria and polydipsia evidence of microvascular complications at diagnosis or severe concomitant hypertriglyceridemia. Benefits of intentional weight loss caloric restriction and exercise training in type 2 diabetes have been established in a number of trials. A large-scale Look AHEAD trial currently in progress is designed to examine the effect of lifestyle interventions similar to the Diabetes Prevention Program DPP on cardiovascular outcomes in people with type 2 diabetes. Lifestyle modification can be recommended as monotherapy with greater confidence if there is access to a multidisciplinary program either in one’ s own practice by way of an enrollment in a trial or through the community-based initiatives. In a world idealized by evidence-based-medicine aficiona- dos selection of therapy appropriate for each and every medical contingency would be prescriptive and not subject to debate: a specific treatment matched to a unique clinical profile would have been identified from previously con- ducted clinical trials. In actuality such a medical utopia will never be realized for the management of diabetes because no series of studies could possibly encompass the wide range of patient demographics and the permutations and combina- tions of the multiple medications available for the manage- ment of diabetes. In many respects the choice implied in the title is misleading since an accommodation in lifestyle even if it is the minimal effort entailed in taking a tablet once a day is an accompaniment of the presence of dia- betes. The thrust of this debate is the determination that lifestyle change alone in lieu of concomitant medication may be sufficient to control diabetes. Whereas the diagnostic criteria for diabetes appear to undergo convulsive disruption about every 20 years or so the clinical management of diabetes seems to undergo fre- quent changes in recommendations. In contrast to the sit- uation with type 1 diabetes where the selection of therapy is not controversial but its implementation is difficult the reverse is true for type 2 diabetes where the taking of the medication is easy but the selection from the various drugs available is complex. In patients with type 2 diabetes intensive lifestyle mod- ification is a valuable adjunct to pharmacotherapy and in some patients may eliminate the need for pharmacotherapy entirely. Current guidelines from the ADA and the EASD list both lifestyle intervention and metformin as well-validated core initial therapies but warn that the high rate of weight gain after an initial successful moderate weight loss lim- its the role of lifestyle modifications in controlling glycemia long term 1. Metformin on the other hand is an agent that Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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How to determine when to pursue lifestyle 65 has withstood the test of time demonstrating efficacy and relative safety. It improves fasting glycemia by decreasing hepatic glucose production and thereby improves HbA1c by 1.0–2.0 on average. Even greater glycemic improve- ment may be observed in a patient who has been treatment- na¨ ıve. The appeal of metformin is that these results may be achieved without weight gain or hypoglycemia as long as it is not used in patients with significant renal hepatic or gas- trointestinal dysfunction or decompensated heart failure. Such a favorable benefit–risk profile certainly justifies the recommendation to use metformin as a first-line agent but does its initiation right at the diagnosis of type 2 diabetes detract the focus from weight loss efforts At the time of diagnosis how does a clinician select patients for whom it is appropriate to postpone pharmacotherapy in favor of lifestyle changes In some clinical situations the choice of initial management is obvious whereas others present the health care provider with substantial dilemmas. This chap- ter addresses a number of such scenarios. Pharmacotherapy should be considered when there is significant blood glucose elevation from concurrent use of medications known to induce hyperglycemia such as glucocorticoids atypical antipsychotics or immunosup- pressants related to organ transplantation. The odds ratio for developing diabetes on glucocorticoid therapy ranges 1.3–2.3 2–4 and is dose dependent. The hyperglycemia is more severe in the postprandial period and is related to the reduction in insulin sensitivity 5. T o what extent dietary changes and increased physical activity can atten- uate these adverse glycemic effects of glucocorticoids has not been systematically studied. In general the underly- ing medical conditions for which steroids are prescribed present significant barriers to increasing physical activity and the appetite-stimulating effects of steroids make dietary management challenging. For this reason early initiation of pharmacotherapy is appropriate particularly if the dura- tion of steroid use is anticipated to be prolonged or high doses are used. Many of the currently available oral thera- pies for type 2 diabetes have been suggested for the treat- ment of steroid-induced hyperglycemia. However there are scant published data on the efficacy of oral agents in this setting and the concomitant medical conditions in patients requiring glucocorticoid therapy such as renal or liver dys- function represent a contraindication to the use of agents such as metformin or sulfonylureas. In general insulin is a safe and effective treatment for steroid-induced diabetes. In particular NPH insulin can be used successfully as a once- daily injection since it has an action profile that parallels the time course of prednisone effects on glucose peaking at 4–6 hours and lasting approximately 12 hours. There has been debate whether the higher prevalence of diabetes in persons affected by schizophrenia reflects an increased risk from this disease per se the associated lifestyle and family history or the adverse metabolic effects of the antipsychotic medications. Prospective randomized clinical trials are few 6 7 but data from pharmacoepi- demiologic studies suggest that there is an increased risk of diabetes with olanzapine and clozapine compared to typical antipsychotics or other atypical agents such as aripiprazole or risperidone 8. Weight gain related to the use of these agents likely accounts for the majority of cases of new-onset diabetes occurring during treatment. However there may be a substantial proportion of patients in whom rapid dra- matic development of hyperglycemia occurs independent of adiposity likely reflecting direct impairment of the β-cell function by the antipsychotic drug. It has been proposed that this effect may be mediated by antagonistic actions on the M2 muscarinic receptors in the pancreas 9. Given these forces at work early institution of pharmacotherapy should be considered in a patient newly diagnosed with diabetes who is also taking atypical antipsychotics. Com- munication with the patient’s treating psychiatrist is also appropriate as consideration should be given to switching to a different antipsychotic agent. In terms of the choice of initial glucose-lowering therapy for a patient with psy- chiatric comorbidities evidence is limited. A recent sys- tematic review of eight randomized double-blind placebo- controlled trials concluded that metformin will attenuate weight gain in adults and adolescents without diabetes treated with atypical antipsychotics 10. Intuitively one would expect a lower incidence of diabetes to result but the trials were too short in duration to confirm this. The severity of presentation of newly-diagnosed diabetes in a setting of antipsychotic drug use should direct the choice of initial pharmacotherapy used. Thus if there is evidence of extreme hyperglycemia and hyperosmolar state initiation of insulin therapy is imperative. The incidence of new-onset diabetes after solid organ transplantation is increasing and is linked most closely to immunosuppressive therapy with corticosteroids cal- cineurin inhibitors and sirolimus 11. Weight gain is a common predisposing factor but there is evidence of direct β-cell toxicity from calcineurin inhibitors. Animal studies as well as in vitro studies of human pancreatic islets have

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66 Initial evaluation and management of diabetes demonstrated decreased beta-cell volume insulin content and insulin release with cyclosporin treatment 12 13. Tacrolimus and sirolimus may be even more diabetogenic than cyclosporin with some studies showing 70 higher incidence of diabetes in the two years after a kidney trans- plant compared to non-tacrolimus-based immunosup- pression 14. For these reasons post-transplant status requiring immunosuppressive therapy should lower the physician’s threshold for initiation of pharmacotherapy at the time of diagnosis of diabetes. No single choice of therapy has been proven to be more effective in this clinical scenario so the traditional approach of using oral agents as first line is generally used. Depending on the transplanted organ and its function there may be specific contraindications to the use of certain oral agents and thus treatment may require even a greater degree of individualization than in a person with diabetes but without a history of organ transplantation. The degree of glucotoxicity and the extent of β-cell decompensation at the time of diagnosis should be fac- tored into the decision of whether immediate pharmaco- logic intervention is needed. Glucotoxicity refers to the con- cept that continuous elevation of glucose exerts damaging effects on the β-cell further impairing its ability to pro- duce and secrete insulin. There is in vitro evidence from cultured β-cell lines and pancreatic islets that under the conditions of persistent hyperglycemia there is a decrease in insulin mRNA insulin content and release. Mechanisms are likely multiple and have not been completely elucidated 15. It has been proposed that excess glucose is shunted into pathways producing reactive oxygen species which subsequently decrease the activity of insulin gene promoter leading to a decreased expression of the insulin gene. In vitro data from cultured islets and in vivo measurements of oxidative stress markers in subjects with diabetes support this notion but to date the effectiveness of potent antioxi- dants in improving β -cell function in people with diabetes has not been conclusively demonstrated. In vitro exper- iments suggest that the phenomenon of glucotoxicity is at least in part reversible but reversibility is time depen- dent. Prolonged exposure to hyperglycemia triggers the expression of proapoptotic genes and if apoptosis ensues β-cell mass may be lost irreversibly. For this reason the higher the degree of glucotoxicity deemed to be present the more pressing is the need to reverse hyperglycemia and the stronger the argument in favor of pharmacotherapy. Unfor- tunately besides the measurement of plasma glucose there are no other easily quantifiable markers of glucotoxicity. For a given serum glucose level there is likely a significant interindividual variability in the degree of impairment at the level of the β-cell. Nevertheless extremes of glucotoxic- ity are reasonably easily recognized by the presence of symp- toms and measurable profound metabolic disturbances. Symptoms such as polyuria polydipsia and weight loss at the time of diagnosis should prompt initiation of pharmacotherapy. Polyuria develops once the reabsorptive capacity of the kidney is overwhelmed at plasma glucose levels exceeding 180 mg/dl. The osmotic diuretic effect of urinary glucose contributes to dehydration which further exacerbates hyperglycemia. Since calories are lost in the urine weight loss ensues. Engaging in an intense exercise program under these conditions can worsen rather than improve hyperglycemia and increase the likelihood of keto- sis even in type 2 diabetes. Pharmacotherapy along with rehydration interrupts the hyperglycemia-generating forces and establishes conditions where lifestyle modification can be safely implemented. Pharmacotherapy is mandatory when diabetes is diag- nosed with ketoacidosis or hyperosmolar hyperglycemic state requiring management with insulin initially admin- istered intravenously via a drip and subsequently subcuta- neously as multiple daily injections. Similarly severe hyper- triglyceridemia triglycerides greater than 1000 mg/dl at the time of the diagnosis of diabetes warrants immediate initiation of pharmacotherapy which is usually insulin. As the glucotoxicity subsides following the treatment of the acute abnormalities some patients with type 2 diabetes may transition to oral diabetic medications and if aggres- sive lifestyle modification is undertaken and maintained there is evidence that a fraction of patients may be tapered off pharmacotherapy entirely. In a study from China more than 300 patients newly diagnosed with type 2 diabetes were treated with aggressive insulin or oral drug therapy attain- ing euglycemia within 2 weeks of diagnosis and maintaining therapy for 2 weeks before discontinuation of all pharma- cotherapy and initiation of aggressive lifestyle changes 16. On a one-year follow-up 40–50 of the patients initially treated with insulin were maintaining adequate glycemic control with lifestyle interventions alone. Of note patients in this study had significant hyperglycemia at the time of diagnosis with fasting glucose level 200 mg/dl and HgbA1C 9–10 implying a significant degree of glucotoxicity. The presence of microvascular complications at the time of diagnosis constitutes another situation where pharma- cotherapy is favored. In the UKPDS cohort of patients

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How to determine when to pursue lifestyle 67 with type 2 diabetes 37 had retinopathy and 7 had nephropathy in the form of microalbuminuria or protein- uria at the time of the initial diagnosis 17 18. The robust reductions in the rates of progression of these complications seen with intensive management of glycemia support man- agement with pharmacotherapy from the time of diagnosis to ensure a significant glycemic improvement. There has been no randomized clinical trial comparing the effects of intensive lifestyle modification alone versus pharmacother- apy on the progression of preexisting microvascular com- plications in people newly diagnosed with diabetes. It is reasonable to assume that if optimal glycemic control is achieved by diet and exercise alone a similar reduction in the progression of microvascular complications should be expected as with pharmacotherapy initiated at diagno- sis. Given the heterogeneity of results that patients achieve with lifestyle modification clinicians may prefer the greater predictability of glycemic impact associated with pharma- cotherapy in the initial management of such patients. What about patients who are relatively asymptomatic are diagnosed with type 2 diabetes on routine fasting glucose screening and have no evidence of microvascular disease at the time of diagnosis Clinicians often utilize HgbA1C to guide management decisions opting to start pharma- cotherapy if the baseline value is greater than an arbitrarily selected value such as 7. However is this approach too cynical based on an assumption that patients who arrived at this juncture after decades of physical inactivity unhealthy food choices and progressive weight gain are destined to fail at lifestyle modification This view is not unfounded: research suggests that overweight patients with diabetes are less successful at weight loss maintenance than people without diabetes 19 and a meta-analysis of 22 studies of weight loss interventions in patients with type 2 diabetes over 5 years showed minimal improvements in weight 20. Nevertheless in the modern model of patient–physician relationship that is based on joint decision making it is the physician’s obligation to present the patient with specific information about the efficacy of lifestyle modifications and the intensity and the consistency of interventions needed to achieve favorable results. Simultaneously with giving information a physician should elicit information about the patient’s preparedness to embrace lifestyle changes and anticipate possible barriers. In the subsequent pages we will address these aspects with the goal of enabling a clinician to counsel a newly diagnosed patient comprehensively about lifestyle modification. The efficacy of lifestyle modification in primary preven- tion of type 2 diabetes was reported by the Diabetes Pre- vention Program DPP where the incidence of diabetes was reduced by 58 in the lifestyle intervention group compared to placebo after 3 years 21. Early evidence that aggressive lifestyle changes are effective in secondary pre- vention comes from a 6-year Swedish study that included 41 patients with early-stage type 2 diabetes 22 where a combination of dietary intervention and increased physical activity resulted in a 3.7 weight loss and a 52 remission rate. Other studies report more modest glycemic effects but in general changes in HgbA1C correspond to changes in weight 20. Thus interventions that produce a more marked weight loss 10–15 by means of combining a very low calorie diet physical activity and behavior modi- fication result in a more significant HgbA1C improvement 2–2.5 23. Observational studies suggest that weight loss also translates into a meaningful decrease in mortality: a substantial 25 reduction in mortality associated with a mean intentional loss of 11 of body weight 24 lbs was reported in a 12-year observational follow-up of overweight patients with type 2 diabetes 24. There is evidence that significant caloric restriction leads to substantial improvement in plasma glucose levels even before weight loss ensues. Anderson et al. summarized glu- cose and weight response in nine studies of very low energy diets in 192 obese people with type 2 diabetes 25. The glu- cose improvement was more rapid than weight loss with the values improving by 50 within two weeks whereas it took 6 weeks to achieve an approximate 10 weight loss. Additional evidence of the favorable effects of caloric restriction on glucose metabolism comes from the bariatric intervention outcomes. Serum glucose and insulin levels have been reported to drop dramatically within 3 weeks of Roux-en-Y gastric bypass before significant weight loss had occurred 26. In many cases patients with type 2 dia- betes who are on insulin therapy are able to discontinue insulin within several days of the procedure. Similar obser- vations of a rapid resolution of type 2 diabetes have been made with vertical banded gastroplasty and laparoscopic adjustable gastric banding 27 28. These reports empha- size the important role that excess energy intake plays in the pathogenesis of hyperglycemia in people with type 2 dia- betes. Multiple mechanisms have been proposed to explain the drastic improvement in the glucose profile but there are few systematic studies. High ketogenicity of very low energy diets may stimulate insulin secretion improve insulin

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68 Initial evaluation and management of diabetes resistance and directly suppress hepatic gluconeogenesis 29. In the setting of bariatric intervention an interrup- tion of the enteroinsular axis by way of alteration of incretin levels has been suggested as a possible mechanism but con- firmatory studies are largely lacking. Glycemic improvement can also be seen with exercise training alone even in the absence of a significant change in body mass. Molecular mechanisms leading to improved insulin sensitivity with exercise are numerous and are beyond the scope of this chapter. A meta-analysis of 14 clin- ical trials on the effects of exercise in people with type 2 dia- betes demonstrated a statistically significant mean decrease in HgbA1C of 0.7 despite unchanged mean weight 30. However the majority of these clinical trials were relatively short in duration and long-term trials are needed to demon- strate sustained effects of lifestyle modification on mean- ingful outcomes in type 2 diabetes such as microvascular and macrovascular complications. An association between cardiorespiratory fitness CRF and all-cause mortality has been clearly established in peo- ple with type 2 diabetes independent of the BMI. Thus Wei et al. found that in 1263 men with diabetes low CRF and physical inactivity were independent predictors of all-cause mortality with 2.1- and 1.7-fold increased risk respectively 31. More recently a similar association between CRF and all-cause mortality was reported in women with impaired fasting glucose and undiagnosed diabetes 32. Likewise the protective effect of cardiorespiratory fitness held true for subjects with BMI 25. In men with type 2 diabetes mortality from cardiovascular disease has also been shown to be associated with cardiorespiratory fitness. Church et al. demonstrated a hazard ratio of 1.2 for each incremental 1- MET difference in fitness in 2316 men with type 2 diabetes followed for a mean of 16 years 33. Importantly there was no increased CVD risk in the overweight and obese men once their level of fitness was taken into account. In all these studies regular physical activity was a major determi- nant of the level of cardiorespiratory fitness. This evidence underscores the importance of promoting regular physical activity and optimal fitness in patients with type 2 diabetes even if this does not lead to weight loss. The goal of avoiding low-fitness category may be more obtainable and therefore better embraced by individuals who have grown frustrated with prior failures of achieving sustainable weight loss. A large-scale Look AHEAD Action for HEAlth in Dia- betes trial was launched in 2001 and is designed to examine vascular outcomes in people with type 2 diabetes 34. The study cohort includes over 5000 obese patients with a mean HgbA1C of 7.3 some of whom have already had a car- diovascular event. Several lifestyle goals are more rigorous in Look AHEAD than in DPP targeting 10 weight loss 1200–1500 kcal/day diet for initial weights 250 lbs and up to 1800 kcal/day for weights 250 lbs 175 minutes of physical activity per week. The interventions are delivered in groups and individually by professional teams compris- ing of dietitians psychologists and exercise specialists. The interim analysis after 1 year shows a mean 8.6 weight loss and a mean 0.6 decline in HgA1C as well as improve- ments in a number of CVD risk factors including blood pressure and lipid profile 35. The projected duration of the Look AHEAD is 12 years. Setting specific attainable goals improves adherence to a lifestyle modification program 36 and therefore it is imperative that the physician quantitates the intensity of the recommended lifestyle changes. Table 7.1 lists common recommendations 37. The specifics of necessary dietary changes are addressed in a separate chapter. Once weight loss has been achieved intensification of physical activity may be needed to prevent weight regain. Data from the National Weight Control Registry suggest that people who are successful at long-term maintenance of weight loss expend approximately 2800 kcal/week or 60 minutes of brisk walking per day 38. Poor long-term adherence to lifestyle modifications often deters physicians from recommending this as monotherapy. Multiple individual social and economic barriers can affect TABLE 7.1 Commonly recommended lifestyle changes Weight loss Total 5–10 in the first year 0.5–1 kg/week Diet Initial caloric restriction by 500–1000 kcal/day from baseline caloric intake 1000–1200 kcal/day diet to ensure continued weight loss Exercise At least 150 min/week of moderate intensity aerobic activity Or 90-min/week of vigorous aerobic activity T o be distributed over at least 3 days per week No more than 2 consecutive days without activity the effect of lifestyle interventions similar to DPP on cardio-

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How to determine when to pursue lifestyle 69 patients’ motivation and impair their efforts. It is conceiv- able that the multitude and the complexity of these factors is greater than the determinants of compliance with any phar- macotherapy. Interventions employing assessment of the patients’ motivational stage and subsequent individualized counseling approach tailored to the stage of preparedness are generally effective at promoting behavior change 39. Additionally follow-up to provide reinforcement is impor- tant 40. Such comprehensive approach may be beyond the scope of available time and even expertise level of a busy clinician. Therefore lifestyle modification can be rec- ommended with greater confidence if there is access to a multidisciplinary program either in one’s own practice by way of an enrollment in a trial or through the community- based initiatives. References 1. American Diabetes Association ADA. Introduction. Dia- betes Care. 32Suppl 1:S1–S2 2009. 2. Conn JW Fajans SS. Influence of adrenal cortical steroids on carbohydrate metabolism in man. Metabolism. 52: 114–127 1956. 3. Gulliford MC Charlton J Latinovic R. Risk of diabetes asso- ciated with prescribed glucocorticoids in a large population. Diabetes Care. 2912:2728–2729 2006. 4. Owen OE Cahill GF Jr. Metabolic effects of exogenous glu- cocorticoids in fasted man. J Clin Invest. 5210:2596–2605 1973. 5. Rizza RA Mandarino LJ Gerich JE. Cortisol-induced insulin resistance in man: impaired suppression of glucose produc- tion and stimulation of glucose utilization due to a postre- ceptor detect of insulin action. J Clin Endocrinol Metab. 541:131–138 1982. 6. Newcomer JW Haupt DW. The metabolic effects of antipsy- chotic medications. Can J Psychiatry. 518:480–491 2006. 7. Lieberman JA Phillips M Gu H et al. Atypical and conventional antipsychotic drugs in treatment-naive first- episode schizophrenia: a 52-week randomized trial of cloza- pine vs chlorpromazine. Neuropsychopharmacology. 285: 995–1003 2003. 8. Scheen AJ De Hert MA. Abnormal glucose metabolism in patients treated with antipsychotics. Diabetes Metab. 333: 169–175 2007. 9. Johnson DE et al. Inhibitory effects of antipsychotics on carbachol-enhanced insulin secretion from perifused rat islets: role of muscarinic antagonism in antipsychotic- induced diabetes and hyperglycemia. Diabetes. 545:1552– 1558 2005. 10. Miller LJ. Management of atypical antipsychotic drug- induced weight gain: focus on metformin. Pharmacotherapy. 296:725–735 2009. 11. Bodziak KA Hricik DE. New-onset diabetes mellitus after solid organ transplantation. Transpl Int. 225:519–530 2009. 12. Yagisawa T et al. Effects of cyclosporine on glucose metabolism in kidney transplant recipients and rats. Trans- plant Proc. 191 Pt 2:1801–1803 1987. 13. Nielsen JH Mandrup-Poulsen T Nerup J. Direct effects of cyclosporin A on human pancreatic beta-cells. Diabetes. 359:1049–1052 1986. 14. Kasiske BL et al. Diabetes mellitus after kidney transplan- tation in the United States. Am J Transplant. 32:178–185 2003. 15. Poitout V Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev. 293:351–366 2008. 16. Weng J et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diag- nosed type 2 diabetes: a multicentre randomised parallel- group trial. Lancet. 3719626:1753–1760 2008. 17. Kohner EM. Microvascular disease: what does the UKPDS tell us about diabetic retinopathy Diabet Med. 25Suppl 2: 20–24 2008. 18. Bilous R. Microvascular disease: what does the UKPDS tell us about diabetic nephropathy Diabet Med. 25Suppl 2: 25–29 2008. 19. Guare JC Wing RR Grant A. Comparison of obese NIDDM and nondiabetic women: short- and long-term weight loss. Obes Res. 34:329–335 1995. 20. Norris SL et al. Long-term effectiveness of lifestyle and behavioral weight loss interventions in adults with type 2 diabetes: a meta-analysis. Am J Med. 11710:762–774 2004. 21. Knowler WC et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 3466:393–403 2002. 22. Eriksson KF Lindgarde F. Prevention of type 2 non-insulin- dependent diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia. 3412: 891–898 1991. 23. Wing RR et al. Effects of a very-low-calorie diet on long- term glycemic control in obese type 2 diabetic subjects. Arch Intern Med. 1517:1334–1340 1991. 24. Williamson DF et al. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care. 2310:1499–1504 2000. 25. Anderson JW Kendall CW Jenkins DJ. Importance of weight management in type 2 diabetes: review with meta- analysis of clinical studies. J Am Coll Nutr. 225:331–339 2003.

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70 Initial evaluation and management of diabetes 26. Rubino F et al. The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg. 2402:236–242 2004. 27. Deitel M. The early effect of the bariatric operations on diabetes. Obes Surg. 123:349 2002. 28. Segato G et al. W eight loss and changes in use of antidia- betic medication in obese type 2 diabetics after laparoscopic gastric banding. Surg Obes Relat Dis. 62:132–137 2009. 29. Baker S Jerums G Proietto J. Effects and clinical potential of very-low-calorie diets VLCDs in type 2 diabetes. Diabetes Res Clin Pract. 853:235–242 2009. 30. Boule NG et al. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA. 28610:1218–1227 2001. 31. Wei M et al. Low cardiorespiratory fitness and physical inac- tivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med. 1328:605–611 2000. 32. Lyerly GW et al. The association between cardiorespiratory fitness and risk of all-cause mortality among women with impaired fasting glucose or undiagnosed diabetes mellitus. Mayo Clin Proc. 849:780–786 2009. 33. Church TS et al. Cardiorespiratory fitness and body mass index as predictors of cardiovascular disease mortality among men with diabetes. Arch Intern Med. 16518:2114– 2120 2005. 34. Ryan DH et al. Look AHEAD Action for Health in Diabetes: design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials. 245:610–628 2003. 35. Pi-Sunyer X et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one- year results of the look AHEAD trial. Diabetes Care. 306: 1374–1383 2007. 36. Estabrooks PA et al. The frequency and behavioral outcomes of goal choices in the self-management of diabetes. Diabetes Educ. 313:391–400 2005. 37. Sigal RJ et al. Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Associ- ation. Diabetes Care. 296:1433–1438 2006. 38. Hill JO. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr Rev. 277: 750–761 2006. 39. Kirk AF et al. Promoting and maintaining physical activity in people with type 2 diabetes. Am J Prev Med. 274:289–296 2004. 40. Loveman E Frampton GK Clegg AJ. The clinical effective- ness of diabetes education models for type 2 diabetes: a systematic review. Health Technol Assess. 129:1–116 iii 2008.

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8 Insulin sensitizers versus secretagogues as first-line therapy for diabetes: Rationale for clinical choice Click Here For Best Diabetes Treatment Robert J. Richards 1 L. Yvonne Melendez-Ramirez 2 and William T. Cefalu 3 1 Associate Professor of Medicine Joint Program on Diabetes Endocrinology and Metabolism Pennington Biomedical Research Center LSUHSC School of Medicine New Orleans LA and Baton Rouge LA USA 2 Assistant Professor of Medicine Joint Program on Diabetes Endocrinology and Metabolism Pennington Biomedical Research Center LSUHSC School of Medicine New Orleans LA Baton Rouge LA USA 3 Douglas L. Manship Sr. Professor of Diabetes Chief Joint Program on Diabetes Endocrinology and Metabolism Pennington Biomedical Research Center LSUHSC School of Medicine New Orleans LA and Baton Rouge LA USA L E A R N I N G P OIN T S As a rule the secretagogues and sensitizers can potentially lower A1c in the range of 1–2 depending on the baseline A1c. Metformin is mostly weight neutral while thiazolidinediones and insulin secretagogues often lead to weight gain. Metformin and thiazolidinediones are unlikely to cause hypoglycemia. Thiazolidinediones are linked to bone loss in women but the link is not well defined and requires more studies. Concern over the safety of rosiglitazone lead to the FDA severely restricting its use. Introduction The progress made over the recent past in providing new information on the pathophysiology of type 2 diabetes has been nothing short of astounding. It is hard to appreci- ate that within recent memory available choices for treat- ment included only insulin or sulfonylureas. Although the biguanides i.e. metformin had been studied and available in other parts of the world it wasn’t until the last decade of the twentieth century that these agents were available in the United States. However within the last decade new pharmacologic agents have become available that address specific pathophysiologic defects with novel mechanisms of action. As a result clinicians now have a variety of agents from at least seven classes at their disposal to address the pathophysiologic defects that characterize type 2 diabetes i.e. insulin secretory dysfunction insulin resistance and hepatic glucose overproduction. In addition agents are being actively investigated that address other mechanisms to improve glycemia i.e. SGLT2 inhibitors glucose kinase activators inflammatory agents etc. However the down- side of having so many choices is having to decide which drug offers the most advantages to the patient while limiting the untoward side effects. The ultimate choice will depend on factors such as patient phenotype underlying comor- bidities physician experience and cost among others. For the purpose of argument and for this chapter only we will discuss only these two general options: secretagogues sul- fonylureas and meglitinides and sensitizers metformin and thiazolidinediones. Other drugs such as incretin ther- apies that may impact insulin secretion or sensitization are covered elsewhere. There is an ongoing debate whether type 2 diabetes is primarily a disorder of skeletal muscle insulin resistance insulin insufficiency or both. This debate is beyond the scope of this review. However it has been observed for many years that the liver is also a key player in the pathogenesis. Studies also reveal the importance of the gastrointestinal Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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72 Initial evaluation and management of diabetes TABLE 8.1 Comparison of insulin sensitizers and secretagogues with respect to various end-points Secretagogues Sensitizers Issue Sulfonylureas Meglitinides Metformin TZD Glucose HbA1c Fasting glucose mg/dl Postprandial glucose mg/dl ↓1–2 ↓40–50 ↓20–60 ↓1–1.5 ↓20–70 ↓60–110 ↓1–2 ↓40–50 ↓50–140 ↓0.5–1.4 ↓40–60 ↓60–70 Lipids Total cholesterol No effect No effect Small decrease Small decrease 3 LDL No effect No effect Small decrease Small decrease 3 HDL No effect No effect Little effect Small increase 3 Triglycerides No effect No effect Small decrease Small decrease 3 Adverse events Risk of hypoglycemia Significant Less likely Minimal Minimal Body weight Risk of edema ↑2–5 kg Minimal ↑1–4 kg Minimal Overall neutral Minimal ↑2–4 kg Increased risk Bone disease None reported None reported None reported Yes Cancer 1 Increased risk Unknown Decreased risk Increased risk Cardiovascular disease Little impact Unknown Likely protective Being debated Cost/efficacy ratio Per unit drop in A1c 2 5 4 100–200 5 100–250 1 Risk is based on a relatively few number of papers reporting mostly observational data. 2 Relative costs are derived from www.drugstore.com. These reported costs are estimates only. 3 The currently available agents rosiglitazone and pioglitazone exhibit differing effects. 4 Cost used to determine efficacy is based on glipizide and glyburide. tract in the pathophysiology. Thus it is clear that type 2 diabetes is multifactorial. For the purposes as described in this chapter we will primarily focus on the defects of insulin secretion and insulin resistance in providing the rationale as to why a provider should use either class of drugs secretagogues or sensitizers as a first-line choice. Of course the answer is never easy. Each of these classes has advantages and disadvantages. The clinician must balance a host of arguments when selecting a treatment plan. We will attempt to summarize some of the arguments as they pertain to these two classes of agents. This summary is orga- nized by issue rather than agent. A further summarization is presented in Table 8.1. Glucose control There is no single perfect indicator of treatment effec- tiveness but the most accepted and well validated indi- cator is HbA1c. Almost by definition all agents used to treat diabetes have efficacy based on how they lower this indicator—some do so more than others. At least since the mid-1990s the mantra has been to strive for glucose control that is as near to normal as possible but given the recent cardiovascular trials see below less stringent control may be indicated in individuals who are prone to more hypoglycemia have prior cardiovascular events or have other significant comorbidities. Both the ACCORD 1 and ADVANCE 2 studies demonstrated risks involved with aggressive glucose control. The HbA1c lowering for each particular agent is in large part dependent on the baseline value: the higher the initial HbA1c the greater the reduction regardless of the agent used 3. Nevertheless the expected decrease in HbA1c is usually reported to be in the approximate ranges of 1–2 for sulfonylureas 1–1.5 for meglitinides repaglin- ide about 0.5 greater than nateglinide 4 1–2 for metformin and 0.5–1.4 for thiazolidinediones 5. For perspective the estimated drop in HbA1c is 1–2 if lifestyle changes are made and are successful 5. Reductions in fasting glucose are also partially depen- dent upon baseline levels 3 6. Nevertheless one may expect a reduction in fasting glucose levels of about 40–50 mg/dl with sulfonylureas 7. Metformin exhibits similar results 6 though some studies demonstrate a greater

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Sensitizers versus secretagogues 73 improvement 8. The reduction in fasting glucose is sim- ilar with the thiazolidinediones 9 and the meglitinides 10. Glucose levels after meals or after oral glucose load- ing are not widely reported for some agents. Metformin decreases glucose concentrations after an oral glucose load by about 50–60 mg/dl 6 while self-reported postpran- dial glucose drops by about 140 mg/dl 8. The thiazo- lidinediones reduce post-challenge glucose by about 60–70 mg/dl 11. Sulfonylureas decrease postprandial glucose on the order of about 20 mg/dl 12 to 60 mg/dl 13. The main focus of the meglitinides is on postprandial glucose. They reduce it by about 60–110 mg/dl with repaglinide showing greater efficacy 10. However the effectiveness of secre- tagogues versus sensitizers on postprandial control may primarily be based on how well they lower the fasting levels. Essentially by lowering fasting levels the absolute postprandial value may be reduced but the increment between fasting and postprandial peak may not be markedly altered. Newer agents in the incretin class appear to be more effective on postprandial control than traditional agents such as secretagogues or sensitizers 14. Effect on body weight Weight gain is virtually inevitable in the treatment of dia- betes. An increase of 2–5 kg may be commonly observed with sulfonylureas 15 16. Similar weight gain was reported by the UKPDS investigators regarding 750 over- weight subjects treated with sulfonylureas compared to lifestyle intervention 17. The benefit of metformin is that it is mostly weight neutral but favors a mild weight loss 18. Fortunately even a small amount of weight loss can signifi- cantly improve cardiovascular risk 19. A major disadvan- tage of thiazolidinediones and meglitinides is the weight gain 18. Lipid effects The insulin sensitizers are associated with beneficial changes to lipids of varying degrees. A systematic review of randomized controlled trials involving a total of 3000 subjects reported that metformin was associated with small declines in total cholesterol –10 mg/dl LDL –8.5 mg/dl and triglycerides –11.5 mg/dl 20. Most clinicians expect to see small beneficial changes in lipid profiles with met- formin. The two currently available thiazolidinediones appear to have different effects on lipid profiles. In a randomized blinded crossover head-to-head trial of rosiglitazone and pioglitazone that did not utilize a placebo the different effects on lipids 9 were suggested by the authors as likely being due to different PPAR activities. With rosiglitazone the total cholesterol increased by 28 mg/dl LDL increased by 21 mg/dl HDL increased by 2.4 mg/dl and triglycerides increased by 13 mg/dl. With pioglitazone the total choles- terol increased by 9 mg/dl LDL increased by 12 mg/dl HDL increased by 5.2 mg/dl and triglycerides decreased by 52 mg/dl. Taken together as a class the thiazolidinediones raise HDL by a mean of 3–5 mg/dl but raise LDL by a mean of 10 mg/dl 18. The sulfonylureas and meglitinides do not significantly affect lipids 16 18 21. Risk of hypoglycemia A major difference between the insulin sensitizers and secre- tagogues is the rate of hypoglycemia. Secretagogues are well known to put patients at risk for hypoglycemia. The sensi- tizers have much lower rates of symptomatic hypoglycemia. The risk of hypoglycemia when using sulfonylureas has been reported to be about 2–4 16. The meglitinides confer a similar risk of hypoglycemia 18 but are suggested to be less likely to cause nocturnal hypoglycemia due in part to a very short half-life short duration of action and the usual practice of drug administration only at the time of eating. Risk of bone disease A recent concern with the thiazolidinediones is a potential increase in the risk of fractures which has been suggested to be a class effect 22. The ADOPT study of over 4300 sub- jects reported the fracture risk was significantly increased with rosiglitazone compared to metformin and glyburide. This increased risk occurred among women but not men in both the lower and upper limbs 23. Risk of developing cancer Though controversial diabetes has been reported to be a risk factor for development of cancer and for death from cancer. Both type 1 diabetes and type 2 were reported to be associated with an increased cancer risk although the types of cancers are different 24. Several investigators have

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74 Initial evaluation and management of diabetes suggested that treatment modalities may influence cancer risk in patients with type 2 diabetes 24. However this issue if far from settled. Additional work is required before the putative role of treatment is clear. Recently there were reports regarding insulin glargine and increased cancer risk 24 but further discussion is beyond the scope of this review. However the oral drugs are also being studied for possible risks. A retrospective study suggested an increased risk of cancer with sulfonylureas but a protective effect with metformin 25. Another report added more evidence in favor of metformin 26. The reports so far on thiazolidine- diones have been mixed. Little or no information regarding the meglitinides and cancer have yet been reported. Any linkage between glucose-lowering drugs and cancer is sub- ject to many confounders and prospective trials involving all hypoglycemic agents are needed before firm conclu- sions can be made 27. So at this time the association of specific cancer risk and antidiabetic treatment suffers from a paucity of data. Cardiovascular disease Patients with diabetes have a high risk for cardiac events. They exhibit a risk similar to that seen in nondiabetic patients with a prior history of myocardial infarction 28. Patients with diabetes need to be treated similar to patients without diabetes but with known coronary artery disease—a well appreciated high-risk population. This is reflected in the treatment guidelines provided by the Amer- ican Diabetes Association ADA 29 American Associ- ation of Clinical Endocrinologists AACE 30 Ameri- can Heart Association AHA 31and National Cholesterol Education Program NCEP 32. Sulfonylureas The effect of antidiabetic agents on cardiovascular dis- ease CVD has been an area of interest for many years beginning with the controversial University Group Dia- betes Program UGDP. The initial concern regarding a linkage between cardiovascular disease and insulin secreta- gogues has not always borne out. For example a systematic review demonstrated little evidence for such a risk 18 but large retrospective studies recently suggested there may be a small increased risk associated with sulfonylureas when compared to metformin 33. The duration of follow-up is important. It may take many years before the beneficial effect of improved glycemia on the risk of CVD is realized. In the UKPDS subjects were followed for 10 years post-study without intervening in treatment decisions 34. Though UKPDS did not initially demonstrate a statistically signifi- cant reduction in myocardial infarctions 35 the 10-year post-study follow-up did show a reduction 34. Meglitinides No long-term studies have yet been published examining cardiovascular disease with either repaglinide or nateglin- ide. This lack of long-term cardiovascular data provides yet another area requiring additional clinical research. Metformin Metformin has been investigated in many clinical studies sometimes with mixed results. In a subset of subjects all overweight the UKPDS demonstrated that intensive treat- ment with metformin reduced the risk of several end points when compared to conventional treatment primarily diet only. They were myocardial infarction all macrovascular disease and death from cardiovascular disease 17. How- ever the same improvement in risk was seen in overweight subjects assigned to intensive treatment with insulin or sul- fonylureas metformin did not offer an advantage. Other end points in the same study were different. Metformin did prove significantly better than sulfonylurea or insulin for all-cause mortality and the aggregate of any diabetes- related end point micro- or macrovascular. In a different subset of UKPDS defined as subjects of any weight who failed sulfonylurea therapy adding metformin had no benefit on any clinical end point. Quite the contrary adding metformin to these subjects actually increased the risk of diabetes-related death and all-cause mortality 17. The investigators speculated that the increased risk seen with the combination of metformin and sulfonylurea ther- apy may represent “extremes of the play of chance.” When the investigators combined the two subsets the increase in risk was negated. The UKPDS investigators later published a 10-year follow-up of all subjects originally randomized to con- ventional therapy intensive therapy with metformin only overweight subjects were originally randomized into this group and intensive therapy with sulfonylurea-insulin 34. Initial intensive treatment with either sulfonylurea- insulin or metformin overweight subjects only reduced the risk of myocardial infarction death from any cause and several other end points some of which were not

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Sensitizers versus secretagogues 75 significantly different during the intervention phase of UKPDS. Duration of follow-up is key. Though metformin is relatively contraindicated in patients with heart failure there is little worry that met- formin will cause heart failure and it carries only a minimal risk of edema 18. Based on considerable clinical experience metformin is widely used without any overt evidence of danger and continues to be recommended as first-line drug therapy. Thiazolidinediones As recent studies have suggested heart failure is very much a concern with this class. The thiazolidinediones worsen existing heart failure and may induce heart failure in suscep- tible patients. The drug is not approved for use in patients with class 3 or 4 heart failure NYHA. Many clinicians also avoid the drug in patients with class 2 heart failure. The risk of developing heart failure is 1–4 18. In a meta-analysis treatment with rosiglitazone was associated with a significantly increased risk of myocar- dial infarction 36. However the ACCORD and BARI-2D studies did not show increased CV events or mortality with rosiglitazone treatment 1 37. In high-risk type 2 DM patients the addition of pioglitazone reduced the com- posite of all-cause mortality nonfatal MI and stroke 38. Thus studies have supported and refuted findings about rosiglitazone while similar studies involving pioglitazone showed no increased risk but perhaps a small benefit. These issues are outlined in a consensus statement jointly issued by the ADA and the European Association for the Study of Diabetes EASD 5. They recommend “caution.” The thi- azolidinediones remain an important class but clinicians must consider potential cardiovascular risk. More studies are needed. The RECORD study indicated no increase in overall cardiovascular risk with rosiglitazone compared to therapy with metformin and sulfonylureas but the increase in heart failure was significantly higher 39. However in 2010 evidence against rosiglitazone accumulated and the FDA severely restricted its use. This effectively removes it from consideration by clinicians. Overall the effect of antidiabetic agents on CVD disease has been a topic of great debate based on observations to date. As such the Food and Drug Administration FDA has suggested specific guidelines for assessing cardiovas- cular risk for new drugs in development. Specifically any new agent needs to demonstrate that it does not increase cardiovascular risk before it can be considered for approval. Other risks and benefits Beta-cell preservation The UKPDS estimated that about 50 of beta-cell func- tion is lost by the time diabetes is diagnosed 40. ADOPT followed beta-cell function over a period of about five years while treated with glyburide metformin or rosiglitazone 23. During the first six months of treatment beta-cell function increased. This initial increase was much greater with glyburide than with metformin or rosiglitazone. After the initial 6 months all groups lost beta-cell function but the rate of loss was greatest for the secretagogue. Durability More effective beta-cell function may be reflected in dura- bility of effect. UKPDS showed 9-year monotherapy failure rates 41 indicated by fasting glucose 140 mg/dl and HbA1c ≥7 to be quite high for all the modalities i.e. insulin sulfonylureas metformin and diet alone. Clearly these studies were landmark trials in defining the progres- sive nature of the disease. The ADOPT study examined durability of glycemic control with glyburide metformin and rosiglitazone 23. The investigators measured the cumulative monotherapy failure rate at five years defined as fasting glucose 180 mg/dl and found it to be low- est for rosiglitazone 15 intermediate for metformin 21 and highest for glyburide 34. Durability appears to be an advantage of the thiazolidinediones as compared to the other agents. Unfortunately although the thiazolidine- diones appeared to offer some benefits the progression of disease was not halted. Treatment durability is of great inter- est to clinicians. The durability of newer therapies such as incretins is being studied. Some agent specific risks Metformin is associated with an increased risk of lactic aci- dosis. Fortunately this risk is minimal when used appro- priately. Use of the drug is absolutely contraindicated in the presence of renal dysfunction as defined as a serum crea- tinine equal to or greater than 1.5 mg/dl in men and 1.4 mg/dl in women. Administration of nephrotoxic contrast media may cause acute renal failure and metformin must be held until renal function is shown not to be affected. Metformin also has relative contraindications. The patient should exhibit adequate renal function hepatic function and heart function. The thiazolidinediones and insulin sec- retagogues are not as sensitive to renal dysfunction as is

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76 Initial evaluation and management of diabetes metformin. However sulfonylureas exhibit a protracted duration of action in patients with significant renal dis- ease. This is not the case for the meglitinides. The package inserts for repaglinide current as of December 2009 last updated June 2006 and nateglinide current as of Decem- ber 2009 last updated July 2008 indicate approval for use in patients with creatinine clearances as low as 20 mL/min and 15 mL/min respectively. The thiazolidinediones have been associated with edema heart failure and fractures as discussed above. The risk of edema is 2–20 18. This class carries a risk of hepatotox- icity but the risk is minimized when proper liver function is verified. These drugs must be used cautiously if ALT is elevated not initiated if ALT 2.5 times the upper limit of normal ULN and discontinued if ALT 3 times the ULN. The risk of drug-induced pancreatitis is exceedingly low when patients are closely monitored. The anemia seen with this class is only partially explained by dilution but is usually minor when present. Cost-effectiveness Efficacy and cost-effectiveness are important considera- tions when selecting a treatment strategy. The sulfony- lureas and metformin are generic and inexpensive. They provide excellent ratios of cost:efficacy. The estimated cost- effectiveness is less than 5/month per one percentage point drop in HbA1c. In contrast the cost:efficacy ratios are very variable for the meglitinides and thiazolidinediones mainly due to variations in cost. Assuming a monthly cost of 100–200 for meglitinides and 100–250 for thiazo- lidinediones their respective cost:efficacy ratios at the time of this publication are very roughly 60–200/month and 60–500/month per percentage point drop in HbA1c. No medical decision should ever be based solely on cost but unfortunately cost is often a consideration given the eco- nomic burden that diabetes has placed on our population. Most providers observe that patients with few resources are much more likely to be compliant with the less costly treatment alternatives. However the initial cost of a drug is only one consideration. The initial drug chosen may be more expensive but have significant benefits on metabolic factors i.e. glycemia weight and lipids. This benefit may be such that complication rates and other medical expenses are reduced years after diagnosis. Important considerations other than cost need to be factored into the treatment deci- sion. Data on long-term benefits are vitally needed. Conclusions Based on the above rationale there are benefits in choosing a sensitizer over a secretagogue in most clinical situations. In the majority of cases clinicians will choose metformin as the first drug for treatment of type 2 diabetes unless it is contraindicated. Consensus statements and algorithms rec- ommend metformin as the initial drug of choice along with lifestyle intervention 42. Metformin appears to be effec- tive generally well tolerated and has a very low risk for lactic acidosis when used properly. Most algorithms become very nonspecific after metformin. Arguments can be made for all of the other drugs approved for treating type 2 diabetes. Sulfonylureas have been used extensively and are well estab- lished. Unfortunately the weight gain and hypoglycemia remain a concern. Clinicians also have considerable experi- ence with the thiazolidinediones. The advantages are better durability beneficial effect on lipids and good insulin sen- sitizing effect. The disadvantages are weight gain increased risk for heart failure in susceptible populations and other cardiac events. But all glucose-lowering drugs exhibit differ- ent clinical profiles and have roles in the current treatment of diabetes. The choice of treatment is ultimately a decision between the clinician and the patient. As outlined in this review there are many reasons supporting metformin as the initial choice. For purposes of this chapter we primarily focused on the advantages and disadvantages of sensitizers versus secretagogues as requested by the editor. After initi- ating metformin the agent of choice for the next step may include secretagogues or the newer agents in the incretin class or the addition of insulin. These agents are covered in other chapters. References 1. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 dia- betes. N Engl J Med. 35824:2545–2559 2008. 2. The ADV ANCE Collaborative Group. Intensive blood glu- cose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 35824:2560–2572 2008. 3. Bloomgarden ZT Dodis R Viscoli CM Holmboe ES Inzuc- chi SE. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy. Diabetes Care. 299:2137–2139 2006. 4. Raskin P. Comparison of repaglinide and nateglinide in combination with metformin. Diabetes Care. 2612: 3362–3363 2003.

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Sensitizers versus secretagogues 77 5. Nathan DM Buse JB Davidson MB et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 311:173–175 2008. 6. DeFronzo RA Goodman AM The Multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 3339:541–549 1995. 7. Bloomgarden ZT. Approaches to treatment of type 2 dia- betes. Diabetes Care. 318:1697–1703 2008. 8. Kooy A de Jager J Lehert P et al. Long-term effects of met- formin on metabolism and microvascular and macrovascu- lar disease in patients with type 2 diabetes mellitus. Arch Intern Med. 1696:616–625 2009. 9. Goldberg RB Kendall DM Deeg MA et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 287:1547–1554 2005. 10. Rosenstock J Hassman DR Madder RD et al. Repaglin- ide versus nateglinide monotherapy. Diabetes Care. 276: 1265–1270 2004. 11. Miyazaki Y DeFronzo RA. Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab. 1012:1204–1211 2008. 12. Derosa G D’Angelo A Fogari E et al. Nateglinide and gliben- clamide metabolic effects in na¨ ıve type 2 diabetic patients treated with metformin. J Clin Pharm Ther. 341:13–23 2009. 13. Vakkilainen J Mero N Schweizer A Foley JE Taskinen M- R. Effects of nateglinide and glibenclamide on postprandial lipid and glucose metabolism in type 2 diabetes. Diabetes Metab Res Rev. 186:484–490 2002. 14. Cefalu WT Richards RJ Melendez-Ramirez LY. Redefining treatment success in type 2 diabetes mellitus: comprehen- sive targeting of core defects. Cleve Clin J Med. 76Suppl 5:S39–S47 2009. 15. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA. 2873:360–372 2002. 16. Mizuno CS Chittiboyina AG Kurtz TW Pershadsingh HA Avery MA. Type 2 diabetes and oral antihyperglycemic drugs. Curr Med Chem. 151:61–74 2008. 17. UK Prospective Diabetes Study UKPDS Group. Effect of intensive blood-glucose control with metformin on compli- cations in overweight patients with type 2 diabetes UKPDS 34. Lancet. 3529131:854–865 1998. 18. Bolen S Feldman L Vassy J et al. Systematic review: com- parative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 1476:386–399 2007. 19. Hermansen K Mortensen LS. Bodyweight changes associ- ated with antihyperglycaemic agents in type 2 diabetes mel- litus. Drug Saf. 3012:1127–1142 2007. 20. Wulffele ´ MG Kooy A Zeeuw D Stehouwer CDA Gan- sevoort RT. The effect of metformin on blood pressure plasma cholesterol and triglycerides in type 2 diabetes mel- litus: a systematic review. J Intern Med. 2561:1–14 2004. 21. Lund SS Tarnow L Frandsen M et al. Impact of met- formin versus the prandial insulin secretagogue repaglinide on fasting and postprandial glucose and lipid responses in non-obese patients with type 2 diabetes. Eur J Endocrinol. 1581:35–46 2008. 22. Dormuth CR Carney G Carleton B Bassett K Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med. 16915:1395–1402 2009. 23. Kahn SE Haffner SM Heise MA et al. Glycemic durability of rosiglitazone metformin or glyburide monotherapy. N Engl J Med. 35523:2427–2443 2006. 24. Smith U Gale EA. Does diabetes therapy influence the risk of cancer Diabetologia. 529:1699–1708 2009. 25. Currie C Poole C Gale E. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 529:1766–1777 2009. 26. Landman GWD Kleefstra N van Hateren KJJ Groenier KH Gans ROB Bilo HJG. Metformin associated with lower cancer mortality in type 2 diabetes. Diabetes Care. 332:322–326 2010. 27. Gerstein HC. Does insulin therapy promote reduce or have a neutral effect on cancers JAMA. 3035:446–447 2010. 28. Schramm TK Gislason GH Kober L et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation. 11715:1945–1954 2008. 29. American Diabetes Association. Executive summary: stan- dards of medical care in diabetes – 2009. Diabetes Care. 32Suppl 1:S6–S12 2009. 30. Rodbard HW Blonde L Braithwaite SS et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus published correction appears in Endocr Pract 200814:802- 803. Endocr Pract. 13Suppl 1:1–68 2007. 31. Grundy SM Howard B Smith S Jr. Eckel R Redberg R Bonow RO. Prevention Conference VI: Diabetes and Car- diovascular Disease: Executive Summary: Conference Pro- ceeding for Healthcare Professionals From a Special Writ- ing Group of the American Heart Association. Circulation. 10518:2231-2239 2002. 32. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of

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78 Initial evaluation and management of diabetes the third report of the National Cholesterol Education Pro- gram NCEP expert panel on detection evaluation and treatment of high blood cholesterol in adults Adult Treat- ment Panel III. JAMA. 28519:2486–2497 2001. 33. Tzoulaki I Molokhia M Curcin V et al. Risk of cardiovascu- lar disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 339:b4731 2009. 34. Holman RR Paul SK Bethel MA Matthews DR Neil HAW. 10-year follow-up of intensive glucose control in type 2 dia- betes. N Engl J Med. 35915:1577–1589 2008. 35. UK Prospective Diabetes Study UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin com- pared with conventional treatment and risk of complica- tions in patients with type 2 diabetes UKPDS 33. Lancet. 3529131:837–853 1998. 36. Nissen SE Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 35624:2457–2471 2007. 37. The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 36024:2503–2515 2009. 38. Dormandy JA Charbonnel B Eckland DJA et al. Sec- ondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study PROspec- tive pioglitAzone Clinical Trial In macroVascular Events: a randomised controlled trial. Lancet. 3669493:1279–1289 2005. 39. Home PD Pocock SJ Beck-Nielsen H et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combi- nation therapy for type 2 diabetes RECORD: a multicentre randomised open-label trial. Lancet. 3739681:2125–2135 2009. 40. U.K. Prospective Diabetes Study Group. U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 4411:1249–1258 1995. 41. Turner RC Cull CA Frighi V Holman RR for the UK Prospective Diabetes Study Group. Glycemic control with diet sulfonylurea metformin or insulin in patients with type 2 diabetes mellitus: progressive requirement for mul- tiple therapies UKPDS 49. JAMA. 28121:2005–2012 1999. 42. Rodbard HW Jellinger PS Davidson JA et al. State- ment by an American Association of Clinical Endocri- nologists/American College of Endocrinology consen- sus panel on type 2 diabetes mellitus: an algo- rithm for glycemic control. Endocr Pract. 156:540–557 2009.

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10 Are insulin sensitizers useful additions to insulin therapy 11 Want To Diabetes Free Life Click Here 12 John W. Richard III 1 and Philip Raskin 2 1 Endocrinology Fellow Division of Endocrinology Diabetes Nutrition and Metabolism University of T exas Southwestern Medical Center at Dallas Dallas TX USA 2 Professor of Medicine Clifton and Betsy Robinson Chair in Biomedical Research University of Texas Southwestern Medical Center at Dallas Dallas TX USA L E A R N I N G P OIN T S Patients with type 2 diabetes often need higher doses of insulin because of obesity and decreased insulin sensitivity. Insulin sensitizing agents act as useful additions to insulin therapy to combat worsening insulin sensitivity. Metformin suppresses hepatic glucose production gluconeogenesis and increases peripheral tissue insulin sensitivity. Thiazolidinediones increase insulin-stimulated glucose uptake in peripheral tissues hepatic insulin sensitivity and insulin sensitivity in adipose tissue through suppression of fatty acid production. Insulin sensitizing agents have proven effectiveness at improving glucose control and lipid profiles and reducing insulin dose requirements however these agents are not without side effects. Insulin sensitizers Insulin resistance is not a new phenomenon. In the 1930s British physician Harold Percival Himsworth coined the term “insulin insensitivity” to describe patients he observed with resistance to injectable insulin. Fifty years later Dr. Gerald Reaven described metabolic syndrome X a con- dition characterized by decreased insulin sensitivity high insulin levels high triglycerides and low HDL cholesterol leading to type 2 diabetes and cardiovascular disease risk. Considering the role of insulin resistance in the develop- ment of these disease processes insulin action at the tar- get tissue level is an attractive therapeutic target in type 2 diabetes 1. The biguanides i.e. metformin and the thiazolidinediones TZDs act directly to improve insulin sensitivity and so are regarded as insulin sensitizing drugs. Biguanides In Europe Galega officinalis goat’s rue or French lilac was used for centuries to treat diabetes. This guanidine-rich substance later led to the development of several glucose- lowering guanidine derivatives in the 1920s. With the dis- covery of insulin these antidiabetic agents were forgotten until the 1950s when the biguanides: metformin phen- formin and buformin were reintroduced into diabetes treat- ment 1. Phenformin was withdrawn in many countries and from the U.S. market in 1975 because of a high inci- dence of lactic acidosis. Buformin received only limited use in a few countries making metformin the principal biguanide drug used in pharmacotherapy worldwide espe- cially with its improved safety profile and lower cost 1. Mechanism of action The mechanism of action of biguanides i.e. metformin is still not fully understood but this agent is distinctly dif- ferent from oral sulfonylureas. Biguanides do not stimulate pancreatic insulin secretion and only partial suppression of gluconeogenesis occurs in the liver therefore hypoglycemia with monotherapy is rare 2 3. Metformin has a variety of metabolic effects some of which extend beyond glucose lowering Table 9.1. At a cellular level metformin improves insulin sensitivity through a mediated modification of post-receptor signaling in the insulin pathway. Recent data have suggested that a protein adenosine 5 -monophosphate protein kinase AMPK has been identified as a possible Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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80 Initial evaluation and management of diabetes Case A 52-year-old woman with obesity and a 9-year history of type 2 diabetes presents with complaints of fatigue and difficulty losing weight. She denies polyuria polydipsia polyphagia blurred vision or vaginal infections. She states that she has gained an enormous amount of weight since being placed on insulin 6 years ago. Her weight has continued to increase over the past 5 years and she is presently at the highest weight she has ever been. She states that every time she tries to cut down on her eating she has symptoms of shakiness diaphoresis and increased hunger. She does not follow any specific diet and has been so fearful of hypoglycemia that she often eats extra snacks. Her health care practitioners have repeatedly advised weight loss and exercise to improve her health status. She complains that the pain in her knees and ankles makes it difficult to do any exercise. Her blood glucose values on capillary blood glucose testing have been 170–200 mg/d1 before breakfast. Before supper and bedtime values range from 150 mg/dl to 300 mg/dl. Her current insulin regimen is 45 U of NPH plus 10 U of regular insulin before breakfast and 35 U of NPH plus 20 U of regular insulin before supper. This dose was recently increased after her HbA1c was found to be 8.9 goal 7.0 . Past medical history is remarkable for hypertension hypertriglyceridemia and arthritis. Current medications include only insulin lisinopril Prinivil and hydrochlorthiazide Dyazide with triamterene. On physical exam her height is 5’ 1 1 / 2 ” and her weight is 265 lb. Her blood pressure is 160/88 mmHg. The remainder of the physical exam is unremarkable. On laboratory testing chemistries BUN creatinine and liver function tests are normal. Thyroid function tests and urine microalburnin are also normal. After an explanation that the increasing insulin doses were contributing to her weight gain and that she would need to decrease her insulin dose along with her food intake to prevent hypoglycemia the patient agreed to follow a restricted-calorie diet and to decrease her insulin to 30 U of NPH and 10 U of regular insulin twice daily. As she had no contraindications to metformin Glucophage she was also started on 500 mg orally and it was increased to twice daily after one week. She returned to the clinic 3 months later still on the same dose of insulin. She continued to complain of fear of hypoglycemia in the middle of the night and was overeating at night. Despite this she had lost 7 lb. Her blood glucose values were still elevated in a range of 120–275 mg/dl before meals. She was reassured that further insulin reduction would prevent hypoglycemia. Her insulin dosage was decreased to 25 U of NPH and 5 U of regular insulin twice daily and metformin was increased to 500 mg three times daily. Two months later she returned to the clinic with an average blood glucose level of 160 mg/dl. Her weight was now 246 lb and her HbA1c was 7.5. She was feeling much more energetic and was able to start a walking program. Questions 1. Are insulin sensitizers useful additions to insulin therapy TABLE 9.1 Direct and indirect effects of metformin therapy Decreases hyperglycemia Improves diastolic function Decreases total cholesterol levels Decreases very low density lipoprotein cholesterol levels Decreases low-density lipoprotein cholesterol levels Increases high-density lipoprotein cholesterol levels Decreases oxidative stress Improves vascular relaxation Decreases plasminogen activator inhibitor-1 levels Increases tissue plasminogen activator activity Decreases von Willebrand factor levels Decreases platelet aggregation and adhesion target of metformin 1. The mainstay of action of met- formin can be attributed to its hepatic effects. Hepatic sensitivity to insulin is increased by metformin thereby reducing gluconeogenesis Figure 9.1 as well as glycogenol- ysis which contribute to the postprandial plasma glucose lowering effects. Skeletal muscle and adipocytes undergo upregulation of the insulin-sensitive GLUT-4 and GLUT- 1 transporters to the cell membranes thereby increasing glucose uptake 2. Glucose metabolism in the splanch- nic bed also increases through insulin-dependent mecha- nisms. Additional metabolic effects include the suppression of fatty acid oxidation Figure 9.2 as well as a reduction in triglyceride levels in patients with hypertriglyceridemia

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Are insulin sensitizers useful additions to insulin therapy 81 Glycerol Amino Metformin – Ca ++ + Lactate – Pyruvate Metformin – acids – CO Ca ++ 2 OAA ATP ATP+Pi – Glucose PEP Metformin FIG 9.1 Mechanism of action of + GLUT 4 TK Increased glycogen storage Alanine metformin on hepatic glucose production. Glucose Lactate 1 2. Combined the cellular effects of metformin counter insulin resistance and reduce the toxic metabolic effects of glucose toxicity and lipotoxicity in type 2 diabetes. Pharmacokinetics In normal subjects studies demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism or biliary excretion. Because met- formin is not metabolized there is no interference with the metabolism of coadministered drugs. Renal clearance is approximately 3.5 times greater than creatinine clear- ance which suggests that tubular secretion is the main route of metformin elimination. With an oral adminis- tration of metformin patients with normal renal function have a plasma half-life of 2–5 hours and almost 90 of an absorbed dose is eliminated within 12 hours 1. Efficacy of combination therapy Many people with type 2 diabetes are overweight and insulin resistant making high doses of insulin often necessary to achieve adequate glucose control. However insulin therapy is associated with weight gain which could impede any progress in achieving glucose control that would normally be expected. In a double-blind placebo-controlled study where patients were randomly assigned to receive placebo or metformin in combination with insulin for 24 weeks the data showed that adding metformin to an intensified insulin regimen resulted in an 11 reduction in hemoglobin A1c compared to insulin therapy alone. The study also reported improved glucose control using 29 less insulin and a less complicated insulin regimen with no increase in the occurrence of hypoglycemia or weight gain 4. Further studies have verified these findings like this ran- domized trial comparing insulin monotherapy to combined therapy with insulin and metformin which showed clear benefit to using metformin with insulin compared to insulin alone. In this study insulin as a monotherapy resulted in a reduction in HbA1c 8.7 ± 1.6 to 7.0 ± 1.0 with approx- imately 69 more insulin needed from baseline to achieve this effect. Patients in this arm of the study also required a more complicated insulin regimen in approximately 25 of the cases that became time consuming for both the patient and providers. These patients also gained 4.4 kg of weight. In the second arm of this study using insulin in combination with metformin resulted in a reduction in HbA1c of 8.8 ± 1.2 to 7.1± 1.0 which was comparable to the monother- apy arm however these results were achieved without an increase in the total daily dose of insulin. In this arm com- plexity of the insulin regimen was not affected and there was virtually no weight gain or hypoglycemia reported. The only drawbacks were that two-thirds of patients

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82 Initial evaluation and management of diabetes Liver Acyl CoA Krebs Citrate β- cycle – PDH Pyruvate oxidation FA-CoA CPT OAA – PFK G6P Glycolysis – PEP Glucose Glucose Insulin/IGF-1 receptor Metformin Adipose tissues – Glucose transport Glucose – + Pl-3 GLUT 4 P85 PO4 IRS-1 FFA FIG 9.2 Metformin and fatty acids. Kinase – P110 Muscle Cell experienced gastrointestinal side effects but they were mild and transient 5. Because studies have shown that decreasing the required daily dose of exogenous insulin is associated with a decreased risk of cardiovascular disease another placebo- controlled randomized double-blind trial was designed to look at effects on glucose control and insulin require- ments when metformin was added in patients with type 2 diabetes intensively treated with insulin. After 16 weeks of combination therapy the data showed that when met- formin was compared with placebo use there was a statisti- cally significant improvement in glucose control shown by a hemoglobin A1c of 6.9 versus 7.6. The data also showed that the use of metformin was associated with less weight gain –1.6 kg compared with placebo and with a small decrease in LDL cholesterol – 0.19 mmol/l 6. Taken together these data suggest that metformin can be an effective adjunct to insulin therapy. Studies have shown that adding metformin to insulin therapy reduces hemoglobin A1c total daily dose of insulin and reduces or prevents the weight gain associated with intensive insulin treatment. However metformin has gastrointestinal side effects that can hinder titration to its maximum effective dose but these tend to be mild and transient. Additional indications Polycystic ovary syndrome. We now understand that the main feature of polycystic ovary syndrome PCOS as it relates to the use of insulin senitizers is the decreased insulin sensitivity and compensatory hyperinsulinemia that is associated with the condition. Women suffering from PCOS have an increased risk of diabetes later in life and an increased incidence of gestational diabetes if they conceive. The pathophysiology of the disorder is not fully understood but the use of an insulin sensitizer appears to have a pro- found effect on many of the symptoms. In clinical studies

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Are insulin sensitizers useful additions to insulin therapy 83 women with PCOS being treated with insulin sensitizers like metformin saw a reduction in circulating insulin lev- els a reduction in androgen levels improvements in ovar- ian function and improved lipid profiles and severity of hirsutism 7. Contraindications Metformin therapy is contraindicated in patients with liver failure alcoholism and active moderate to severe infec- tion 1 these conditions predispose to development of lactic acidosis either by increased production or decreased metabolism of lactic acid 1. Metformin is also contraindi- cated in people with kidney disorders creatinine levels above 1.4 mg/dl in women and 1.5 mg/dl in men depend- ing on lean body mass 1 according to the package insert and lung disease. Heart failure has long been considered a contraindication for metformin use although a 2007 sys- tematic review showed metformin to be the only antidia- betic drug not associated with harm in people with heart failure 8. Current recommendations suggest that metformin should be temporarily discontinued before any radio- graphic study involving iodinated contrast as contrast dye may temporarily impair kidney function indirectly leading to lactic acidosis by causing retention of metformin in the body 9. Once metformin is withheld hydration should be maintained until preserved kidney function is documented at 24 and 48 hours after the intervention 1. General anes- thesia should be used cautiously to prevent hypotension which leads to renal hypoperfusion and peripheral tissue hypoxia with subsequent lactate accumulation 1. Met- formin should also be used cautiously in the elderly who’s decreased lean body mass leads to reduced serum creati- nine concentrations that often mask impaired glomerular filtration rates 1. Adverse effects Lactic acidosis. Lactic acidosis is a life-threatening compli- cation of biguanide therapy that carries a mortality rate of 30–50 1. The estimated incidence of metformin- associated lactic acidosis is 0.03 cases per 1000 patient- years 1 which is 10 to 20 times lower than that seen with phenformin therapy 1 which was withdrawn because of an increased risk of lactic acidosis up to 60 cases per mil- lion patient-years. Development of lactic acidosis is almost always related to coexistent hypoxic conditions that are probably responsible for the associated high mortality rate. In one report 91 of patients who developed lactic acido- sis while being treated with metformin had a predisposing condition such as congestive heart failure renal insuffi- ciency chronic lung disease with hypoxia or age older than 80 years 1. Therefore patients with impaired renal func- tion or coexistent hypoxic conditions should not be given metformin. Excessive alcohol consumption may also poten- tiate the effect of metformin on lactate metabolism. A care- ful history of alcohol use is therefore important before start- ing metformin therapy 1. Gastrointestinal. Side effects of metformin are mostly lim- ited to digestive tract symptoms such as diarrhea flatu- lence and abdominal discomfort 1 10. Approximately 5 of patients cannot tolerate treatment because of gas- trointestinal side effects 1. The mechanisms of these side effects remain unclear but probably are related to accu- mulation of high amounts of metformin in the intestinal tissue 2 with resultant elevation of local lactate produc- tion. These symptoms are dose dependent and can usually be avoided by slow titration and in some cases reduction of the dose 1. Metformin therapy should be initiated with a single dose of medication usually 500 mg taken with the patient’s largest meal to prevent gastrointestinal symp- toms. These symptoms generally disappear within 2 weeks of treatment 11. Medication doses should be increased in 500-mg increments given after meals every 1 to 2 weeks until a desirable blood glucose level or the maximal effective daily metformin dose of 2000 mg is reached 12. Thiazolidinediones The peroxisome-proliferator–activated receptors PPARs are a subfamily of super-receptors that regulate gene expres- sion in response to ligand binding. 13 Three PPARs identified as PPAR α PPAR δ also known as PPAR β and PPAR γ have been discovered to date. PPARs regulate gene transcription by two mechanisms: transactivation which is DNA-dependent and transrepression which is DNA-independent and may explain the anti-inflammatory actions of PPARs 13. PPAR α is expressed mainly in the liver heart and mus- cle as well as in the vascular wall 2. Fibrates i.e. fenofi- brate act as full or partial PPAR α agonists. In general the activation of PPAR α enhances free fatty acid oxida- tion controls how multiple genes regulate lipoprotein con- centrations and has anti-inflammatory effects Table 9.2.

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84 Initial evaluation and management of diabetes TABLE 9.2 Molecular targets of PPAR γ and PPAR α action Liver Skeletal muscle Adipose tissue Vascular wall PPAR γ Decreased C-reactive protein Increased GLUT4 Increased Increased fatty acid transport protein-1 Decreased intercellular adhesion molecule-1 phosphatidyl 3-kinase Increased acyl–coenzyme A synthetase Decreased vascular-cell adhesion molecule-1 Decreased PDK-4 Increased adiponectin Decreased iNOS Increased LPL Decreased interleukin-6 Increased phosphatidyl 3-kinase Increased GLUT4 PPAR α Decreased C-reactive protein Decreased vascular-cell adhesion molecule-1 Decreased fibrinogen B Decreased cyclooxygenase-2 Decreased TNF α Decreased interleukin-6 Decreased tissue factor Studies have shown that PPAR α agonists can retard or even prevent atherosclerosis in both mice and humans 13. PPAR δ is expressed in several tissue types with the most expression in the skin brain and adipose tissue. PPAR γ is mainly found in adipose tissue but can also be found in pan- creatic beta cells vascular endothelium and macrophages 13. Its expression is low in tissues that express predom- inantly PPAR α such as the liver the heart and skeletal muscle. PPAR γ was discovered as a target for thiazolidine- diones only after testing many agents during multiple large clinical trials. The first thiazolidinedione troglitazone was approved in 1997 for use in treating patients with type 2 diabetes in the United States. This glucose-lowering agent was sub- sequently withdrawn from the market in March 2000 because of cases of hepatotoxicity. In 1999 two γ agonists rosiglitazone and pioglitazone were approved in the United States for use in treating hyperglycemia in type 2 diabetes. Currently studies have linked rosiglitazone to increased risk of cardiovascular events although this is certainly not clear cut 14. Mechanism of action The simulation of PPAR γ is considered a major mechanism through which thiazolidinediones enhance insulin sensitiv- ity. As mentioned previously PPAR γ is mainly found in adi- pose tissue and less concentrated in skeletal muscle and liver. PPAR γ is essential for normal adipocyte differentiation and proliferation as well as fatty acid uptake and storage 13. Because PPAR γ has such a profound effect on adipose tissue it has been postulated that thiazolidinediones achieve their insulin-sensitizing actions through direct means or indi- rectly through altered adipokine release affecting insulin sensitivity beyond the adipose tissue itself. Basically thia- zolidinediones act directly by promoting fatty acid uptake and storage in adipose tissue Figure 9.3. Through this pro- cess there is an increase in adipose-tissue mass and other insulin-sensitive tissues like skeletal muscle the liver and possibly pancreatic beta cells are spared from the harmful effects of high concentrations of free fatty acids 13. There- fore thiazolidinediones keep fat in its proper place. Data from studies of PPAR γ knockout mouse models supports the notion that thiazolidinediones act mainly on adipose tissue as long as normal amounts of adipose tissue exist 13. Although thiazolidinediones keep fat in its proper place in adipose tissue there are still indirect processes that may be responsible for enhancing insulin sensitivity. Stud- ies have shown that select thiazolidinediones i.e. piogli- tazone regulate the expression of more than 100 genes

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Are insulin sensitizers useful additions to insulin therapy 85 Thiazolidinediones Skeletal muscle Adipose tissue Liver triglyceride levels. In a randomized double-blind placebo- controlled study of more than 300 insulin-treated type 2 diabetic patients the addition of troglitazone at doses of 200mg and 600mg daily a reduction in HbA1c level of 0.8 and 1.4 resulted while insulin dose was reduced by 11 and 29 respectively. On the other hand subjects taking insulin and placebo experienced a decrease of 0.1 in HbAlc level ↑ Glucose uptake Adipogenesis ↓ Gluconeogenesis and a 1 increase in insulin dose 16. Subjects random- ↑ Fatty acid uptake ↑ Lipogenesis ↑ Glucose uptake ↓ Plasma free fatty acids ↓ Hyperglycemia FIG 9.3 Effects of thiazolidinediones. 8 and some of the established PPAR γ target genes found in human adipose tissue are listed in Table 9.2. Several adipokines are regulated by PPAR γ but we will focus mainly on adiponectin an adiopocytokine produced exclusively by adipose tissue because it has been shown to increase insulin sensitivity in rodents 13 Whether increases in adiponectin increases hepatic insulin sensitivity in humans is still not clear only rodents have shown this effect of PPAR γ on adiponectin levels. Pharmacokinetics The thiazolidinediones are absorbed completely and rapidly with peak concentrations achieved within 1–2 hours but this may be slightly delayed when taken with food. Both rosiglitazone and pioglitazone are extensively metabolized by the liver. The metabolites of rosiglitazone are weakly active and are excreted mainly in the urine. Pioglitazone produces metabolites that are more active and are excreted mostly in the bile. Both thiazolidinediones are metabolized by the cytochrome P450 system and no clinically significant reduction in plasma concentrations of other drugs has been reported 15. Efficacy of combination therapy Studies have shown that thiazolidinediones used in combi- nation with insulin therapy result in improved blood glu- cose control reduced total daily insulin dose and reduced ized to placebo therapy gained 1.5 kg while those taking the study drug in 200mg and 600mg doses in combina- tion with insulin gained 1.9 and 3.6 kg. T otal cholesterol LDL and HDL cholesterol levels were found to be increased with troglitazone use at 600 mg/day. An open-label study showed that troglitazone had insulin-sparing effects that persisted up to 24 months 17. In a randomized double- blind placebo-controlled study of more than 200 type 2 diabetic patients who were given troglitazone 400mg daily in combination with their baseline insulin dose the results showed a significantly greater reduction in total daily dose of insulin and HbAlc level compared with those patients using insulin and placebo 18. In this study end points were defined as a 50 reduction in injected insulin or either a reduction in blood glucose by 15 and only 7 of patients on insulin and placebo achieved these goals while 22 of patients taking insulin and troglitazone 400 mg daily achieved these goals. Studies using rosiglitazone or pioglitazone in combi- nation with insulin therapy have yielded similar results. In a randomized control study of inadequately controlled insulin-treated type 2 diabetes patients those receiving 26 weeks of treatment with rosiglitazone 4 and 8 mg experi- enced a reduction in HbAlc level of 0.6 and 1.2 respec- tively as compared with virtually no change in the group taking insulin and placebo 19. In this same study insulin doses also decreased by 4.8 and 9.4 in the groups taking insulin plus study drug compared to a decrease of 0.6 in patients taking insulin and placebo. T otal cholesterol HDL and LDL cholesterol levels were found to increase sig- nificantly on treatment with rosiglitazone. Unfortunately significant weight gain occurred in the placebo rosiglita- zone 4mg and rosiglitazone 8mg groups with correspond- ing values of 0.9 kg 4.0 kg and 5.3 kg. In a randomized placebo-controlled study in patients receiving stable insulin therapy when patients assigned to pioglitazone 15 or 30 mg daily in combination with their baseline doses of insulin for 16 weeks HbAlc levels were reduced by 1.0 and 1.3 respectively compared to a reduction of 0.3 in patients

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86 Initial evaluation and management of diabetes on insulin and placebo 13. Those patients on insulin and pioglitazone gained 2.3 and 3.7 kg compared with virtually no change in weight in those using insulin and placebo. This data suggests that thiazolidinediones can be effective adjuncts to insulin therapy. However with growing con- cerns about rosiglitazone and its association with increased myocardial infarction CV-related deaths and poor effect on lipid profile pioglitazone appears to be the only remain- ing TZD to assist in achieving these desired effects of therapy 14. A prospective randomized trial of cardio- vascular outcomes called Prospective Pioglitazone Clinical Trial in Macrovascular Events PROACTIVE has looked at coronary and peripheral vascular events as a primary outcome and myocardial infarction stroke and death as secondary outcomes and the data support pioglitazone as having a favorable effect especially on lipids particularly triglycerides more so than rosiglitazone 20. In contrast to the previous study the Rosiglitazone Evaluated for Car- diac Outcomes and Regulation of Glycemia in Diabetes RECORD trial a long-term multicenter randomized open-label study found conflicting results when looking at cardiovascular outcomes in patients with type 2 dia- betes treated with rosiglitazone plus metformin or sulfony- lurea as compared with the combination of metformin and sulfonylurea. The data showed that the rate of primary end points hospitalization or death from cardiovascular causes was low at 3.1 per year while secondary end points like acute myocardial infarction death from cardiovascu- lar causes or any cause or the composite of cardiovascular death myocardial infarction and stroke showed no statisti- cally significant difference between the rosiglitazone group and the control group 21. However the fact remains that TZDs are still responsible for significant weight gain and increased peripheral edema. Additional indications Nonalcoholic fatty liver disease. Type 2 diabetes has a strong association with nonalcoholic fatty liver disease NAFLD which has a spectrum of liver damage that ranges from simple fatty liver steatosis to irreversible advanced scar- ring of the liver cirrhosis 13. There are an estimated 6.4 million adults in the United States diagnosed with NAFLD which is the most common cause of elevated levels of liver enzymes 13. Elevated levels of alanine amino-transferase ALT have been shown to predict type 2 diabetes indepen- dently of obesity 13. Fatty liver disease is associated with decreased hepatic insulin sensitivity and correlates with insulin requirements during insulin therapy in patients with type 2 diabetes 13. Several recent studies have shown that thiazolidinediones actually reduce fat accumulation in the liver in patients with type 2 diabetes as well as in patients with lipodystrophy associated with the use of highly active antiretroviral ther- apy HAART. Studies have also shown that liver enzymes actually decrease rather than increase during treatment with pioglitazone and rosiglitazone 13. Polycystic ovary syndrome The polycystic ovary syndrome is a disorder that affects approximately 4 of women of reproductive age 13. Women with PCOS frequently develop insulin resistance and hence have an increased risk for type 2 diabetes 13. Hyperinsulinemia which accompanies insulin resistance is thought to contribute to the hyperandrogenism that is seen in patients with PCOS 13. Interventions with the role of reducing insulin levels like weight loss and medi- cations i.e. metformin can decrease hyperandrogenism and reduce insulin resistance 13. A large-scale placebo- controlled trial of 410 women showed that the use of trogli- tazone showed significant improvements in ovulatory func- tion hirsutism hyperandrogenism and insulin resistance 13. A more recent small placebo-controlled study that randomized women to either rosiglitazone and placebo or to rosiglitazone and clomiphene has shown similar results. This study demonstrated that 56 of women previously resistant to clomiphene were able to ovulate 13. Although metformin is considered safe for women who become preg- nant rosiglitazone and pioglitazone are classified as preg- nancy category C which indicates toxic effects in studies in animal models but the results in human studies are inad- equate. If these agents are used during pregnancy then the potential benefit must justify the potential risk to the fetus. Polycystic ovary syndrome is currently not an approved indication for the use of TZDs. Lipid lowering Studies have shown that low-density lipoprotein LDL cholesterol levels have remained unchanged when monotherapy with pioglitazone or combination therapy with pioglitazone and sulfonylurea metformin or insulin has been used. However some studies have shown increases in LDL cholesterol levels between 8 to 16 higher with rosiglitazone use. Studies have also shown an approx- imate 10 increase in high-density lipoprotein HDL

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Are insulin sensitizers useful additions to insulin therapy 87 cholesterol levels with the use of both drugs. The effects of TZDs on triglycerides have been more variable with decreases in triglyceride levels having been observed more often with pioglitazone than with rosiglitazone 13. In a direct comparison of rosiglitazone and pioglitazone one study of 127 patients previously treated with troglitazone supports the notion that both drugs have similar effects on glucose levels and body weight 13. This same study supported the notion that pioglitazone is more effective than rosiglitazone at lowering LDL cholesterol and serum triglyceride levels. The difference in efficacy of these two drugs on lipids cannot be attributed to the effect they have on serum free fatty acid concentrations which decreases by approximately 20 to 30 in both 13. Pioglitazone appears to be a partial agonist of PPAR α in vitro and rosiglitazone appears to be a pure PPAR γ agonist 13. So far however the data on mechanisms underlying the effects of the TZDs on lipids in humans is quite limited. Lipodystrophies The most common form of lipodystrophy is that associated with highly active antiretroviral therapy use in patients with human immunodeficiency virus HIV disease. After only 12 to 18 months of therapy with HAART approximately half of patients develop a lipodystrophy-related symptom like facial lipoatrophy 13. Facial lipoatrophy can be disfig- uring and stigmatizing especially since there is no pharma- cologic therapy for this condition which is usually accom- panied by marked insulin resistance. Thiazolidinediones would seem to be a wonderful solution to insulin resis- tance and lipoatrophy caused by HAART because these drugs increase both insulin sensitivity and subcutaneous fat mass. Unfortunately there has been only one placebo- controlled trial in which patients with HAART-associated lipodystrophy were treated with rosiglitazone 8 mg per day for six months and there was no increase in adipose tissue or body weight in contrast to studies in patients with type 2 diabetes 13. Carotid intima-media thickness. Carotid IMT is a well- established surrogate marker for cardiovascular risk. A thickened carotid intima-media layer not only correlates with increased cardiovascular risk but also with the risk of future macrovascular events like myocardial infarction and stroke 22. Several studies using multiple agents i.e. ACE inhibitors calcium channel blockers β-blockers and statins have shown a reduction or even regression of carotid IMT in patients without diabetes 22. However carotid IMT appears to be more significant in patients with type 2 diabetes reflecting a more dramatic cardiovascular risk in this patient population 22. Limited data currently exists about the effect of intervention in type 2 diabetes on carotid IMT. However a recent randomized control study of 192 patients showed that treatment with pioglitazone for 24 weeks led to a significant decrease in carotid IMT in patients with type 2 diabetes and this was found to be independent of glucose control 22. Contraindications In patients with diabetes hypertension and coronary artery disease occur frequently. These conditions are risk factors for the development of congestive heart failure CHF 23. Diabetes can affect cardiac structure and systolic or diastolic function independent of other established risk factors for CHF because of diabetic cardiomyopathy 23. This phe- nomenon makes diabetes an independent risk factor for CHF which was supported by an analysis of 9591 people with type 2 diabetes in the Kaiser Permanente Northwest Division that demonstrated that 11.8 of diabetic subjects had CHF at baseline and an additional 7.7 developed CHF during a 30-month follow-up period 23. This sug- gests that CHF may be present prior to physicians beginning therapy with TZDs or that this condition may develop dur- ing the course of treatment. TZDs can still be used in patients with underlying asymp- tomatic heart disease although its safety has not been fully established. The package inserts for both rosiglitazone and pioglitazone indicate that patients with more advanced heart disease NYHA class III or IV were excluded in pre- marketing clinical trials and hence these drugs are not rec- ommended in such patients. Currently there are no guide- lines on the use of TZDs in patients with diabetes who have any degree of heart disease or for those already on a TZD who develop CHF. What makes this clinical dilemma more perplexing is the more common side effect of peripheral edema associated with TZDs which makes the origin of the development of edema or weight gain more difficult to decipher. Physicians should be cautious before prescribing TZDs to patients with diabetes who have been previously diag- nosed with a condition that increases risk of bone frac- tures i.e. osteoporosis hyperparathyroidism Paget’s dis- ease etc.. Recent studies have shown a correlation between TZD use and an increased risk of bone fractures. In fact

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88 Initial evaluation and management of diabetes according to data taken from the ADOPT study group and others the relative risk of fractures with thiazolidine- diones remained consistently elevated irrespective of age or menopausal status of women 24. In addition a recent meta-analysis showed that the long-term use of thiazo- lidinediones rosiglitazone pioglitazone or troglitazone doubles the risk of fractures among women with type 2 diabetes and the overall use of thiazolidinediones signifi- cantly increased the risk of fractures among patients with type 2 diabetes. Also identified in this meta-analysis was that thiazolidinedione use was also associated with signif- icant changes in bone mineral density at the lumbar spine and the hip 24. Adverse effects A recent paper looked at multiple studies correlating weight gain and glycosylated hemoglobin with thiazolidinedione use and the paper showed that TZDs lead to an increase in body weight of 2 to 3 kg for every 1 decrease in glycosy- lated hemoglobin values. This increase in body weight was found to be the same irrespective of TZD use as a monother- apy or in combination with insulin or metformin in patients with type 2 diabetes. One of the mechanisms proposed to explain this phenomenon is that the increase in body weight is attributed to expansion of the subcutaneous fat depot and in some patients to edema whereas the mass of visceral fat remains unchanged or even decreases 13. The use of TZDs is not only associated with weight gain but some patients experience fluid retention and plasma volume expansion which lead to the development of peripheral edema. The development of peripheral edema has been reported in 4 to 6 of patients undergoing treat- ment with TZDs as compared with 1 to 2 of those receiv- ing placebo or other hypoglycemic therapies. Edema devel- opment appears to occur most when either of the TZDs is used in combination with insulin. Studies have shown that the use of rosiglitazone 4 or 8 mg per day in combination with insulin was associated with a 13.1 and 16.2 inci- dence of edema respectively compared with 4.7 in those taking insulin alone 19 and with pioglitazone used at 15 mg or 30 mg daily in combination with insulin resulted in a combined 15.3 incidence of edema compared with 7.0 for insulin alone 23. Edema appears to occur at a higher incidence when either of the TZDs is combined with insulin as opposed to when TZDs are used in combi- nation therapy with other oral hypoglycemic agents. This increase in body weight and edema has been associated with an increase in the incidence of congestive heart failure in patients treated with TZDs and insulin. As a result the Food and Drug Administration added a warning in the drug packet information for those patients taking rosiglitazone and pioglitazone. The European Agency for the Evaluation of Medicinal Products actually considers insulin therapy a contraindication to the use of TZDs. According to the data this agency presents the frequency of CHF was 2.5 times greater in combination therapy of insulin and thiazolidine- diones than with insulin alone. However the cause for this result remains unclear. In a meta-analysis of 42 trials containing more than 27000 patients over 15000 of them on treatment with rosiglitazone the data showed an overall odds ratio of 1.43 for myocardial infarction MI and 1.64 for death from car- diovascular cause. From this meta-analysis compared with placebo or with other hypoglycemic agents treatment with rosiglitazone was associated with a significant increase in the risk of MI and with an increase in the risk of death from cardiovascular causes that was of borderline significance 14. A recent study suggests an elevated risk of fracture asso- ciated with TZDs compared with other oral hypoglycemic agents. The risk of fracture with TZD use was present at multiple anatomic sites and these results were potentially clinically significant 25. This suggests that caution should be taken when considering treatment of type 2 diabetic patients with TZDs who have an increased risk for frac- tures. Discussion So the question remains “Are insulin sensitizers useful addi- tions to insulin therapy” Currently the data suggest that metformin is a feasible option in all patients with type 2 diabetes and should be initiated at the onset of insulin ther- apy unless a specific contraindication to metformin use exists. The benefits of metformin therapy in these patients is an improvement in hemoglobin A1c a reduction in total daily dose of insulin and most importantly a reduction in weight gain despite intensive insulin regimens 4–6. The only potential disadvantage to metformin therapy is its side effect profile. This medication is contraindicated in patients with impaired renal function due to risk of lactic acidosis but renal impairment can be a common condition in those with a prolonged diabetes course 1 9. The other disad- vantage to metformin therapy relates to its gastrointestinal

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Are insulin sensitizers useful additions to insulin therapy 89 side effects which may impede titration to its maximal effective dose. However these side effects are often mild and transient and usually can be avoided by slow titration and in some cases reduction of the dose 1. Therefore metformin appears to be an appropriate choice when con- sidering adding an inexpensive insulin sensitizer with few side effects to all patients with type 2 diabetes currently on insulin therapy or planning its initiation. Similarly studies have shown that thiazolidinediones used in combination with insulin therapy result in improved blood glucose control reduced total daily insulin dose and reduced triglyceride levels 16–19. However the side effects of these agents can prove to significantly reduce any benefit that may have been gained from their use. In studies rosiglitazone has been associated with a significant increase in the risk of MI and with an increase in the risk of death from cardiovascular causes 14. Rosiglitazone has also been found to significantly increase total cholesterol HDL and LDL cholesterol levels 13. This data suggests that extreme caution should be used when treating patients with this medication and likely even avoided. In addition recent studies have suggested that TZDs have an elevated risk of bone fracture at multiple anatomic sites compared with other oral hypoglycemic agents 25. Studies of piogli- tazone have shown more favorable outcomes than rosigli- tazone with less risk of myocardial infarction and other cardiovascular-related deaths as well as a better lipid pro- file response especially with triglycerides 14 20. However a better track record still does not excuse the fact that each of these medications still causes significant weight gain and peripheral edema 13 19. With increased weight comes decreased insulin sensitivity a hindrance to any benefit that this drug may afford the patient and peripheral edema has its own disadvantages to maintaining medication compli- ance. With dual therapy including insulin plus metformin or insulin plus thiazolidinediones significant reductions have been shown in hemoglobin A1c total daily dose of insulin and weight gain. These results would suggest that triple therapy including insulin plus metformin and TZDs would produce an even more profound effect and select stud- ies have considered these combinations. For example in this randomized study of 28 type 2 patients with diabetes using insulin monotherapy 4 months of triple therapy was initiated by adding metformin to insulin then troglita- zone TGZ versus adding TGZ to insulin then metformin. Researchers found that hemoglobin A1c decreased with dual therapy but improved more during triple therapy insulin + metformin 7.0 insulin + TGZ 6.2 insulin + metformin adding TGZ 6.1 insulin + TGZ adding met- formin 5.8. T otal daily dose of insulin was significantly reduced in the insulin + TGZ group –14.1 units insulin + TGZ adding metformin –13.7 units and the insulin + metformin adding TGZ –17.3 units but not in the insulin + metformin group –3.2 units. However patients in the insulin + TGZ group experienced significant weight gain 4.4 kg and those in the insulin + metformin insulin + metformin adding TGZ and insulin + TGZ adding metformin saw no weight gain. Thus the order in which metformin and TZDs are added to the treatment regimen is important especially as it relates to weight gain. Adding a TZD to a patient who is already on metformin seems to protect the patient from TZD-induced weight gain 26. Ultimately metformin is an excellent choice for all indi- viduals with type 2 diabetes seeking to reach glucose and weight targets and in fact should always be used in combi- nation with insulin unless there is some specific contraindi- cation to its use. Thiazolidinediones however appear to be more problematic. References 1. Krentz AJ Bailey CJ. Oral antidiabetic agents current role in type 2 diabetes mellitus. Drugs. 65 2005. 2. Klip A Leiter LA. Cellular mechanism of action of met- formin. Diabetes Care. 136:696–704 1990. 3. Kirpichnikov D McFarlane SI Sowers JR. Metformin: an update. Ann Intern Med. 137:25–33 2002. 4. Aviles-Santa ML Sinding J Raskin P. Effects of metformin in patients with poorly controlled insulin-treated type 2 diabetes mellitus. Ann Intern Med. 131:182–188 1999. 5. Strowig SM Aviles-Santa ML Raskin P. Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and troglitazone in type 2 diabetes. Diabetes Care. 25:1691–1698 2002. 6. Strowig SM Raskin P. Combination therapy using met- formin or thiazolidinediones and insulin in the treatment of diabetes mellitus. Diabetes Obes Metabol. 7:633–641 2005. 7. Muth S Norman J Sattar N Fleming R. Women with poly- cystic ovary syndrome PCOS often undergo protracted treatment with metformin and are disinclined to stop: indi- cations for a change in licensing arrangements Hum Reprod. 19:2718–2720 2004. 8. Eurich DT McAlister FA Blackburn DF et al. Bene- fits and harms of antidiabetic agents in patients with

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90 Initial evaluation and management of diabetes diabetes and heart failure: systematic review. BMJ. 335:497 2007. 9. Weir J. Guidelines with regard to metformin-induced lactic acidosis and X-ray contrast medium agents. R Coll Radiol. 54:29–33 1999. 10. Garber AJ Duncan TG Goodman AM Mills DJ Rohlf JL. Efficacy of metformin in type II diabetes: results of a double- blind placebo-controlled dose response trial. Am J Med. 103:491–497 1997. 11. Haupt E Knick B Koschinsky T Liebermeister H Schneider J Hirche H. Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabetes Metab. 17:224–231 1991. 12. DeFronzo RA Goodman AM. Efficacy of metformin in patients with noninsulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. NEJM. 333:541–549 1995. 13. Yki-Jarvinen H. Thiazolidinediones. NEJM. 351: 1106–1118 2004. 14. Nissen SE Nissen SE Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. NEJM. 356:2457–2471 2007. 15. Baldwin SJ Clarke SE Chenery RJ. Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol. 48: 424–432 1999. 16. Schwartz S Raskin P Fonseca V Graveline JF. Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. NEJM. 338:861–866 1998. 17. Fonseca V Foyt HL Shen K Whitcomb R. Long-term effects of troglitazone: open-label extension studies in type 2 dia- betic patients. Diabetes Care. 23:354–359 2000. 18. Buse JB Gumbiner B Mathias NP Nelson DM Faja BW Whitcomb RW. Troglitazone use in insulin-treated type 2 diabetic patients. The Troglitazone Insulin Study Group. Diabetes Care. 21:1455–1461 1998. 19. Raskin P Rendell M Riddle MC Dole JF Freed MI Rosenstock J. A randomized trial of rosiglitazone ther- apy in patients with inadequately controlled insulin- treated type 2 diabetes. Diabetes Care. 24:1226–1232 2001. 20. Dormandy JA Charbonnel B Eckland DJ et al. Sec- ondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study PROspec- tive pioglitAzone Clinical Trial In macroVascular Events: a randomized controlled trial. Lancet. 366:1279–1289 2005. 21. Home PD Pocock SJ Beck-Nielson H et al. Rosiglitazone evaluated for cardiovascular outcomes – an interim analysis. NEJM. 357:28–38 2007. 22. Langenfeld MR Forst T Hohberg C et al. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation. 111:2525–2531 2005. 23. Nesto RW Bell D Bonow RO et al. Thiazolidinedione use fluid retention and congestive heart failure. Diabetes Care. 271:256–263 2004. 24. Loke YK Singh S Furberg CD. Long-term use of thiazo- lidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 180:32–39 2009. 25. Solomon DH Cadarette SM Choudhry NK Canning C Levin R Sturmer T. A cohort study of thiazolidinediones and fractures in older adults with diabetes. JCEM. 94:2792–2798 2009. 26. Strowig SM Aviles-Santa ML Raskin P. Improved glycemic control without weight gain using triple therapy in type 2 diabetes. Diabetes Care. 27:1577–1583 2004.

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10 Is there a role for incretin-based therapy in combination with insulin Click Here If You Also Want To Be Free From Diabetes Matheni Sathananthan 1 and Adrian Vella 2 1 Endocrinology Fellow Division of Endocrinology Diabetes Nutrition and Metabolism Mayo Clinic Rochester MN USA 2 Associate Professor of Medicine Department of Endocrinology Mayo Clinic Rochester MN USA L E A R N I N G P OIN T S Glucagon-like peptide-1 GLP-1 receptor agonists such as exenatide and liraglutide are powerful insulin secretagogues that also enhance satiety delay gastric emptying and produce some weight loss. Dipeptidyl peptidase-4 DPP-4 inhibitors raise concentrations of endogenous GLP-1 but do not affect gastrointestinal function. They are less powerful insulin secretagogues than GLP-1 receptor agonists. Few studies have examined the use of incretin-based therapy in combination with insulin. A challenge to future clinical use of these combinations is the identification of patients who will benefit from these secretagogues despite requiring insulin therapy. Diabetes is a complex metabolic disorder characterized by chronic hyperglycemia arising because of a relative or abso- lute deficiency of insulin. Established type 2 diabetes is characterized by defective and delayed insulin secretion as well as abnormal postprandial suppression of glucagon. These two defects contribute to the defective suppression of endogenous glucose production after meal ingestion leading to postprandial hyperglycemia. Additional contrib- utors to postprandial hyperglycemia include an impaired ability of glucose and insulin to suppress endogenous glu- cose production and to stimulate glucose uptake. The islets of people with long-standing type 2 diabetes have a characteristic appearance with prominent amyloid deposition and a decrease in functional β-cells 1. These anatomical defects explain the decrease in insulin secre- tion although defects in insulin secretion arise early in the pathogenesis of diabetes and likely precede any visible anatomic changes. Furthermore common genetic variation that affects β-cell function and therefore insulin secretion in quantifiable ways increases the risk of progression from glucose intolerance to type 2 diabetes 2. The defects in insulin action also arise early in the course of disease development and contribute to its pathogene- sis 3. Moreover with progressive worsening of glucose tolerance the impairment in insulin secretion worsens in concert with worsening defects in insulin action. Although a multitude of mechanisms have been invoked in the patho- genesis of impaired insulin action in prediabetes a unifying mechanism remains elusive. Lifestyle and dietary changes underpin the treatment of type 2 diabetes. Initiation of pharmacologic treatment is usually sequential metformin is often first-line pharma- cotherapy with a sulfonylurea added if glycemic goals are not achieved or maintained. The reasons for adopting such therapies include their relative safety known efficacy and the fact that they are inexpensive. What has become less clear is what medications to use as third-line therapy when combination therapy with metformin and sulfonylureas is failing. Thiazolidinediones such as rosiglitazone and pioglita- zone are selective ligands of the peroxisome-proliferator- activated receptor gamma 4. Thiazolidinediones improve insulin action in adipose tissue skeletal muscle and also the liver 5. A major side effect of this class of drug is weight gain due to fluid retention as well as increased adipose tissue mass 5. In addition thiazolidine- diones are contraindicated in those with New Y ork Heart Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza

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c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd. 91

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92 Initial evaluation and management of diabetes Association class III or IV heart failure. There has been considerable controversy regarding an increased risk of coronary events associated with rosiglitazone use—perhaps arising from its unfavorable effects on cholesterol concen- trations. Moreover there is an increased risk of fractures associated with thiazolidinedione use 6. Incretin-based therapy is another potential adjunct to established therapies. Incretin hormones such as glucagon-like peptide-1 GLP-1 and glucose-dependent insulinotropic polypeptide GIP are secreted by the enteroendocrine cells in response to meal ingestion and stimulate postprandial insulin secretion 7. GLP-1 sup- presses glucagon secretion and stimulates insulin secretion even after sulfonylureas are no longer effective 8. More- over it decreases food intake and delays gastric empty- ing. However it is rapidly inactivated in the circulation by an enzyme with wide distribution—dipeptidyl peptidase- 4 DPP-4—so that its half-life is measured in minutes. Because of this the hormone would need to be infused continuously for GLP-1 to be an effective therapy. Alter- native approaches have focused on inhibition of DPP-4 to decrease clearance of endogenous GLP-1 or to develop GLP-1 receptor agonists that are resistant to degradation by DPP-4. Exenatide was the first GLP-1 receptor agonist to be approved by the U.S. Food and Drug Administration FDA 9. Exenatide is administered subcutaneously twice daily in doses of 5 or 10 µg 10. Recently Liraglutide a once- daily GLP-1 receptor agonist has also been approved. There are several other GLP-1 receptor agonists currently under development including Albiglutide and Taspoglutide 10. GLP-1 receptor agonists stimulate insulin secretion and inhibit glucagon secretion 11. These actions are glucose- dependent therefore minimizing the risk of hypoglycemia unless used in conjunction with a sulfonylurea 11. Since their use is associated with a significant incidence of gas- trointestinal side effects including nausea many patients treated with these medications experience weight loss—at least in the short term 11. In contrast DPP-4 inhibitors such as sitagliptin and saxagliptin raise concentrations of endogenous GLP-1. Their effects on HbA1c lowering are less pronounced than that observed with GLP-1 receptor agonists. Moreover their use does not cause weight loss. Whether this is due to the absence of gastrointestinal side effects or any dis- cernible effect on gastric emptying and accommodation is unknown. Another important adjunct to the treatment of patients who are failing first- and second-line therapy is insulin. Use of this intervention requires appropriate education and lifestyle intervention if hypoglycemia and/or weight gain are to be avoided. In such situations it is often used in conjunc- tion with metformin. Usually simple regimens of “basal” insulin are utilized first. However there are certain circum- stances where more elaborate “basal-bolus” regimens are utilized. These significantly increase the patient’s partici- pation in his or her care with more frequent monitoring and daily adjustment/ supplementation. Utilizing insulin in combination with incretin-based therapy raises the pos- sibility that simpler regimens can avoid meal-dosed insulin therapy and perhaps mitigate the weight gain associated with the initiation of insulin treatment. A “basal” insulin regimen is often used in the treat- ment of people with type 2 diabetes. This often involves twice-daily injection of NPH insulin or the use of a sin- gle dose of long-acting insulin analogue. Insulin dosing is subsequently adjusted to ensure that appropriate control of fasting glucose concentrations is achieved. However such regimens are limited by their ability to adequately control postprandial hyperglycemia and are unlikely to be effective in situations where dietary intake is unrestricted and / or β-cell function is severely impaired 12. In patients failing metformin and sulfonylurea combination therapy a GLP- 1 receptor agonist appears to be an attractive alternative given the effects on postprandial glycemic control as well as weight. In a 26-week study where patients failing oral therapy were randomized to exenatide 10 µg twice daily or once-daily insulin glargine titrated to maintain fasting blood glucose levels less than 100 both therapies reduced HbA1c by 1.11. Patients receiving exenatide experienced greater reduction in postprandial glucose excursions and in weight compared to the glargine-treated group who experienced a greater reduction in fasting glucose con- centrations 12. Nevertheless there was a significant inci- dence of gastrointestinal side effects in the exenatide-treated group. DPP-4 inhibitors exhibit synergistic actions with met- formin and are effective in combination. They can reduce fasting and postprandial glucose concentrations with no significant increase in adverse effects such as hypo- glycemia. In a study of patients on metformin who were randomly assigned to receive sitagliptin 100 mg daily or placebo results showed that sitagliptin treatment resulted in a reduction in hemoglobin A1c by 0.65 compared to

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Is there a role for incretin-based therapy in combination with insulin 93 placebo 13. The utility of combination therapy with DPP- 4 inhibitors and sulfonylureas is less clear with conflicting data as to the magnitude of HbA1c lowering when com- pared to the placebo arm. There is also uncertainty as to whether the combination is associated with increased risk of hypoglycemia and weight gain 14. Although GLP-1 infusion has been shown to produce an insulin secretory response in patients who have experienced secondary failure of conventional oral therapy it is possi- ble that glycemic benefit observed in some patients arises more from the effects on gastric emptying and glucagon secretion than effects on insulin secretion. In these cir- cumstances where β-cell function is significantly impaired little additional benefit can be expected from therapy with a DPP-4 inhibitor since there is no significant effect on delaying gastric emptying or on weight. Although GLP-1 receptor agonists and DPP-4 inhibitors improve β-cell func- tion after cessation of treatments β-cell function returns to pretreatment levels 15. Pramlintide is a synthetic analog of the peptide hor- mone amylin 16. Amylin is co-secreted with insulin from pancreatic β-cells 17. Type 2 diabetics have a relative defi- ciency in amylin while type I diabetics have essentially none 16. Pramlintide is currently indicated as adjunctive ther- apy in the treatment of type 1 and type 2 diabetes 17. It enhances satiety and reduces postprandial glucose fluctu- ations 17. A study was done to assess the effect of meal- time pramlintide on weight control and long-term glycemic control in type 1 diabetics 18. Patients were randomized to receive either placebo or pramlintide four times daily in addition to existing insulin regimens. Patients treated with pramlintide had a mean reduction in hemoglobin A1c of 0.67 compared to placebo 0.16 reduction after 13 weeks of treatment. There was also a significant placebo-corrected treatment difference in hemoglobin A1c that was sustained through week 52 18. Both pramlin- tide and rapid-acting insulin analogs decrease postprandial hyperglycemia but the side-effect profile is different for both 19. Pramlintide may be associated with nausea and weight loss whereas rapid-acting insulin analogs have the added expense of risk of hypoglycemia and weight gain 19. A 24-week open-label multicenter study was conducted in which patients were randomly assigned to either mealtime pramlintide or a titrated rapid-acting insulin analog with basal insulin and prior oral antihyperglycemic medications 19. The primary end point was the proportion of patients achieving a hemoglobin A1c of less than or equal to 7.0 without weight gain or severe hypoglycemia 19. This was achieved more in the pramlintide-treated group 19. Nei- ther group experienced severe hypoglycemia which was defined as an event requiring administration of glucagon or IV glucose or requiring the assistance of another person 19. There are a limited number of studies evaluating com- bination therapy with insulin and GLP-1 receptor agonists. In one instance the electronic medical records of three pri- vate practice endocrinologists who prescribed insulin and exenatide in patients with type 2 diabetes were reviewed 20. Exenatide use resulted in a reduction of hemoglobin A1c despite a reduction or discontinuation of premeal insulin use 20. However in this study 36 of patients discontinued exenatide due to adverse side effects namely gastrointestinal intolerance. In addition 10 of patients experienced hypoglycemia 20. A retrospective review of patients with diabetes mellitus type 2 treated in the outpa- tient setting revealed reductions in weight hemoglobin A1c and prandial insulin requirements in patients who received exenatide in addition to insulin-based therapy 21. In a retrospective analysis of obese type 2 diabetics treated with exenatide 5 mcg/day and insulin therapy it was found that insulin requirements were decreased in those who were on split-mixed insulin as well as those on short-acting insulin 22. The dosages of those on glargine or NPH insulin did not change significantly. Those treated with exenatide and insulin therapy experienced a reduction in hemoglobin A1c levels triglycerides and systolic blood pressure with the combination therapy 22. Similarly there are few studies assessing the use of DPP- 4 inhibitors in combination with insulin therapy. A study in people with type 2 diabetes evaluating the efficacy of the addition of sitagliptin to insulin therapy alone or in combination with metformin showed a statistically signif- icant reduction in hemoglobin A1c with the addition of sitagliptin to both treatment groups. However there was an increased incidence of hypoglycemia in those treated with sitagliptin compared to placebo 23. The treatment of diabetes is complex and with the avail- ability of various treatment options health care providers are faced with the difficult task of treating patients effec- tively while minimizing side effects that could not only cause harm but also prevent compliance with the ther- apy being prescribed. The place of incretin-based therapy in the conventional treatment algorithm is still the subject of considerable debate. Metformin is often considered to

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94 Initial evaluation and management of diabetes be first-line therapy for people with type 2 diabetes how- ever DPP-4 inhibitors are often considered to be suitable adjuncts to metformin monotherapy. Their role in combi- nation with a sulfonylurea is less certain. On the other hand GLP-1 receptor agonists are often considered as second or third-line agents in part because parenteral administration is a significant inconvenience to most patients. Better identification of patients who might benefit from early therapy with such agents is needed. The data supporting combination therapy with insulin is sparse and at the present time in the absence of significant obesity/overeating and the presence of maintained insulin secretory capacity unlikely to be of significant benefit in most patients on insulin. However this is a rapidly evolving field and improved recognition of patients likely to benefit from such combination therapy may result in increased use in selected patients. References 1. Hayden MR Sowers JR. Isletopathy in type 2 diabetes mel- litus: implications of islet RAS islet fibrosis islet amy- loid remodeling and oxidative stress. Antioxid Redox Signal. 97:891–910 2007. 2. Florez JC Jablonski KA Bayley N et al. TCF7L2 polymor- phisms and progression to diabetes in the Diabetes Preven- tion Program. N Engl J Med. 3553:241–250 2006. 3. Bock G Dalla Man C Campioni M et al. Pathogenesis of pre-diabetes: mechanisms of fasting and postprandial hyper- glycemia in people with impaired fasting glucose and/or impaired glucose tolerance. Diabetes. 5512:3536–3549 2006. 4. Solomon DH Cadarette SM Choudhry NK Canning C Levin R Sturmer T. A cohort study of thiazolidinediones and fractures in older adults with diabetes. J Clin Endocrinol Metab. 948:2792–2798 2009. 5. Rodbard HW Jellinger PS Davidson JA et al. State- ment by an American Association of Clinical Endocrinol- ogists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic con- trol. Endocr Pract. 156:540–559 2009. 6. Dormuth CR Carney G Carleton B Bassett K Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med. 16915:1395–1402 2009. 7. Krentz AJ Patel MB Bailey CJ. New drugs for type 2 diabetes mellitus: what is their place in therapy Drugs. 6815:2131–2162 2008. 8. Drucker DJ Nauck MA. The incretin system: glucagon- like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 3689548:1696–1705 2006. 9. Amori RE Lau J Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta- analysis. JAMA. 2982:194–206 2007. 10. Davidson JA. Advances in therapy for type 2 diabetes: GLP-1 receptor agonists and DPP-4 inhibitors. Cleve Clin J Med. 76Suppl 5:S28–S38 2009. 11. Drucker DJ Sherman SI Gorelick FS Bergenstal RM Sher- win RS Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. 332:428–433 2010. 12. Heine RJ Van Gaal LF Johns D Mihm MJ Widel MH Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 1438:559–569 2005. 13. Charbonnel B Karasik A Liu J Wu M Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2912:2638–2643 2006. 14. Garber AJ Foley JE Banerji MA et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inad- equately controlled with a sulphonylurea. Diabetes Obes Metab. 1011:1047–1056 2008. 15. Bunck MC Diamant M Corner A et al. One-year treat- ment with exenatide improves beta-cell function compared with insulin glargine in metformin-treated type 2 dia- betic patients: a randomized controlled trial. Diabetes Care. 325:762–768 2009. 16. Edelman S Maier H Wilhelm K. Pramlintide in the treat- ment of diabetes mellitus. BioDrugs. 226:375–386 2008. 17. Marrero DG Crean J Zhang B et al. Effect of adjunctive pramlintide treatment on treatment satisfaction in patients with type 1 diabetes. Diabetes Care. 302:210–216 2007. 18. Whitehouse F Kruger DF Fineman M et al. A randomized study and open-label extension evaluating the long-term effi- cacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care. 254:724–730 2002. 19. Riddle M Pencek R Charenkavanich S Lutz K Wilhelm K Porter L. Randomized comparison of pramlintide or meal- time insulin added to basal insulin treatment for patients with type 2 diabetes. Diabetes Care. 329:1577–1582 2009. 20. Sheffield CA Kane MP Busch RS Bakst G Abelseth JM Hamilton RA. Safety and efficacy of exenatide in combination with insulin in patients with type 2 diabetes mellitus. Endocr Pract. 143:285–292 2008. 21. Yoon NM Cavaghan MK Brunelle RL Roach P. Exenatide added to insulin therapy: a retrospective review of clinical practice over two years in an academic endocrinology out- patient setting. Clin Ther. 317:1511–1523 2009.

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Is there a role for incretin-based therapy in combination with insulin 95 22. Viswanathan P Chaudhuri A Bhatia R Al-Atrash F Mohanty P Dandona P. Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin. Endocr Pract. 135:444–450 2007. 23. Vilsboll T Rosenstock J Yki-Jarvinen H et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 122:167–177 2010.

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11 HbA1c: Is it the most important therapeutic target in outpatient management of diabetes To Stop Diabetes In Few Days Click Here Steven A. Smith Associate Professor of Medicine Medical Director Mayo Patient Education Consultant in Endocrinology Diabetes Nutrition and Metabolism Health Care Policy Research Mayo Clinic Rochester MN USA L E A R N I N G P OIN T S HbA1c is the best clinical measure of glycemic exposure. HbA1c is only one of the several measures of glycemic control and does not accurately assess glycemic variation or hypoglycemia. HbA1c maybe valuable in predicting vacular complications and risk independent of its association with measures of blood glucose and other measures of glycemic control. Similar to other laboratory tests it is important to realize that there are limitations in the interpretation of HbA1c values. There are plausible biological and physiological explanations as well as evidence from observation/epidemiological studies controlled trials and meta-analysis that support the hypothesis that treatment of hyperglycemia will reduce microvascular complications of diabetes. There is an uncertain treatment effect for reducing macrovascular events. For over 70 years the relationship between the level of hyperglycemia and the development of long-term vascular complications has remained a primary hypothesis Glucose Hypothesis in the management of the complex metabolic disorders in diabetes. For this reason clinical measures to assess an individual’s degree of glucose exposure fasting glucose urinary glucose glucose challenge tests and glyco- sylated protein assays and risk of diabetes complications have been the holy grail in the clinical management of peo- ple with diabetes. In 1962 Huisman and Dozy reported a fast-moving elec- trophoretic band on hemoglobin electrophoresis in four patients taking tolbutamide for diabetes and attributed this to the medication’s reaction with hemoglobin 1. Six years later Samuel Rahbar clarified the more spe- cific association of this observation with diabetes observ- ing a two- to threefold increase in the red cells of dia- betic patients 1. Structurally glycosylated hemoglobins are closely related to adult hemoglobin and are irreversibly formed from the nonenzymatic condensation of glucose or other reducing sugars with hemoglobin A. Cellulose acetate electrophoresis high performance liquid boronate affinity chromatography as well as immunoassays have used charge and/or structure to separate the glycated forms of hemoglobin 2. Because the concentration of glycated hemoglobin is determined by blood glucose the life span of the red blood cell RBC and membrane permeabil- ity of glucose or glycation gap it has become the stan- dard for assessing integrated glucose exposure and glycemic control. As a clinical standard the measure of glycosylated hemoglobin has served as the primary outcome for the Glucose Hypoth- esis and has been used to predict the impact of long- term glycemic control and risks for diabetes. Is it the most important therapeutic target in the management of dia- betes To address this question we ask is HbA1c the best measure of an individual ’s glycemic exposure glucose con- trol and risk Secondly we examine the evidence for the importance of glucose control in managing the risks of diabetes. Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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Is HbA1c the most important therapeutic target in outpatient management of diabetes 97 Is HbA1c the best measure for glycemic exposure glucose control and risk Prior to 1975 patients with both type 1 and type 2 diabetes monitored urine glucose and ketones to adjust medication to minimize glycosuria and symptoms. This was accompanied by the occasional blood glucose determina- tion during visits with their physicians. Treating day-to-day symptoms required levels of glucose below renal threshold and was easily determined by the monitoring of urine sug- ars. Managing patients to lower target levels of glucose as opposed to symptom relief was made possible with the advent of home glucose monitoring HBGM. This tech- nology evolved rapidly as a standard of care such that by the time of the Diabetes Control and Complication trial DCCT 3 patients in the usual control group initially restricted to urine testing were allowed to monitor their own blood glucose levels. HbA1c standardization The DCCT the United Kingdom Prospective Diabetes Study UKPDS and the Kumamoto Study were the first to provide evidence for the relationship between the con- trol of glucose HbA1c and risk for diabetes complications 3–5. From the DCCT trial it was recognized that there was a direct relationship between HbA1c and mean blood glucose over the preceding 8–12 weeks. Based largely on these findings the National Glycohemoglobin Standard- ization Program NGSP in 1993 established a program for certification of clinical laboratories providing physicians and patients with measures of HbA1c linked to the DCCT reference method 6. By 2002 laboratories reporting to the NGSP had a coefficient of variation of less than 5 6 and as of 2009 97 of laboratories in the United States reported HbA1c that was NGSP certified. Despite this sys- tematic biases drifts in analytic performance over time and inter-method variability have been observed among NGSP-certified HbA1c methods. This variability has been a potential source of inaccuracy interpreting HbA1c results relative to clinical decision thresholds 7. Relationship of HbA1c to average glucose With the advent of continuous glucose monitoring sys- tems CGMS it has become easier to estimate a patient’s mean blood glucose with greater accuracy. A recent inter- national study was completed to determine if HbA1c could serve as a reliable estimate of average glucose eAG for TABLE 11.1 Relationship of HbA1c and the estimate of average blood glucose mgm/dl adapted from 8 Estimate of average blood HbA1c glucose mgm/dl 5 97 6 126 7 154 8 183 9 212 10 240 11 269 12 298 individuals with and without diabetes 8. A total of 587 patients 268 type 1 159 type 2 and 80 without diabetes used CGMS for 48 hours on 4 different occasions over a 3-month period 8 point self glucose monitoring during CGMS days 7 point self-glucose monitoring at least 3 days per week of the study and monthly HbA1c assay that was DCCT referenced and performed in a central lab. Despite attempts to have a broad ethnic representation the study participants were mainly non-Hispanic white 83 His- panic Black and Asian American participants combined accounted for 16 of the total group. In addition as a first attempt in using CGMS to assess the association of HbA1c and eAG the study included only patients with stable glycemic control and excluded children pregnant women and individuals with renal impairment. Despite these limitations 90 of patients had average glucose val- ues that were within +/– 15 the predetermined minimal standard for data acceptability. Using the derived regres- sion equation eAG mgm 28.7 × HgbA1c – 46.7 the authors report HgbA1c derived specific eAGs Table 11.1. While a specific eAG may seem to be more meaningful to patients and physicians taking into account the confidence intervals interpretation demonstrates a significant analytic and clinical imprecision. For example a HbA1c of 7 could have an eAG of 123–185 mgm which could have a HbA1c range of 6.7–9.2. Despite the endorsement for the concept of eAG by major consensus groups e.g. American Diabetes Association International Diabetes Federation and Euro- pean Association for the Study of Diabetes its impact in clinical care is still uncertain and its use has not been uni- versally accepted 2 9.

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98 Initial evaluation and management of diabetes Other limitations for the measurement of HbA1c HbA1c is not the complete expression of glycemic control and is not a reliable measure of pre- and postprandial glycemic variation as well as hypoglycemia 10. In addition other clinical conditions where HbA1c may not accurately reflect glucose control are based on abnor- malities in RBC production and half-life and include hemolysis hemoglobinopathies severe anemias and recent transfusion. It is often recognized that some patients have discrepant HbA1c values compared to their clinical presentation HBGM or other measures of glycated proteins i.e. fructosamine. This has been hypothesized to be due to age race and other genetic factors determining differences in glycation rates RBC life span and membrane permeability 2. Other considerations for the measurement of HbA1c Somogyi was the first to report that for healthy individuals without diabetes the ratio of serum to intracellular RBC glucose could range from 0.66 to 0.95 11. Since that time there have been a number of reports that emphasize the potential implications regarding HbA1c as a measure of RBC intracellular glycation and differences in membrane permeability for circulating glucose. Consistent with this from 4 to 12 of apparently healthy individuals have been found to have elevation in HbA1c without an association with glycemic control glucose intolerance caloric intake or activity 12 13. In addition the fact that there could be sub- stantial interindividual variation in RBC glucose exposure could help explain discordance in the measures of blood glucose and other glycated circulating protein such as albu- min 14. The observed association of HbA1c and tobacco use aging and atherosclerosis without other abnormali- ties in our traditional measures of glycemic control could suggest a unifying hypothesis for the contribution of intra- cellular hyperglycemia to risks for complications 12. Con- sistent with these epidemiologic observations expert pan- els have made recommendations that HbA1c be used for screening and diagnosis of glucose abnormalities and risk in individuals 15. Why HbA1c is the best measure for glycemic exposure glucose control and risk 1 At present HbA1c is the best clinical measure of glycemic exposure. 2 HbA1c is only one of the several measures of glycemic control and does not accurately assess glycemic variation or hypoglycemia. 3 HbA1c may be valuable in predicting vascular complica- tions and risk independent of its association with mea- sures of blood glucose and other measures of glycemic control. 4 Similar to other laboratory tests it is important to realize that there are limitations in the interpretation of HbA1c values. What is the evidence for glucose control in managing the risks of complications of diabetes In order to answer the question regarding the importance of HbA1c in the outpatient management of diabetes we need to understand the importance of glycemia and the efficacy effectiveness and value of our current therapeutic options in glucose control for patient-important outcomes of morbidity mortality and quality of life. Efficacy: What are the plausible arguments that glucose control can reduce risk Physiologic studies Glucose reacts with many different proteins circulating and tissue which result in advanced glycation end products increased protein kinase signaling altered arterial struc- ture/distensibility plaque formation and endothelial dys- function 16–19. It is proposed that these processes are cumulative and often result in subsequent atherosclerosis from decades of exposure to hyperglycemia. Epidemiology and observational studies From epidemiologic studies we know that diabetes is asso- ciated with high rates of complications related to microvas- cular e.g. nephropathy retinopathy and neuropathy and macrovascular e.g. cardio- and cerebrovascular disease 20 while observational studies demonstrate a strong asso- ciation of chronic hyperglycemia with microvascular com- plications 21 22 cognitive impairment 23 and evidence that patients with microvascular disease such as retinopa- thy are also at increased risk for myocardial infractions and cardiovascular morbidity and mortality 24. In addition to the association of vascular events with glycemic con- trol it has long been recognized that associated metabolic

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Is HbA1c the most important therapeutic target in outpatient management of diabetes 99 abnormalities e.g. hypertension hyperlipidemia are also important contributors to the risk of complications 25. Randomized controlled trials In randomized trials improving glucose control signifi- cantly reduces the risk of microvascular disease in peo- ple with diabetes 3 5 26. Alternatively regarding macrovascular complications clinical trials have histori- cally depended on surrogate intermediate outcomes such as HbA1c because of being underpowered for hard cardio- vascular outcomes having insufficient follow-up to detect moderate cardiovascular risk reduction and having insuf- ficient follow-up to provide measurable feedback concern- ing the long-term success for interventions to improve glycemic control. While glycemic outcomes e.g. HbA1c values are important to providers and patients Montori and others have emphasized that studies often lack other patient-important outcomes 27. Recently three very large randomized trials have tried to address the value of inter- ventions for glycemic control the relationship of HbA1c and important cardiovascular events 28–30. While point estimates for hazard ratios for primary outcomes non- fatal MI nonfatal stroke CVD death and hospitalization for CHF revascularization showed a favorable trend these studies were collectively unable to show a significant asso- ciation with aggressive glycemic control Table 11.2. In addition the intensive glycemic control arm of the ACCORD trial was stopped early because of risk of death hazard ratio HR 95 CI 1.22 1.01–1.46 29. Meta-analysis Several meta-analyses including observational studies have suggested that chronic hyperglycemia as measured by HbA1c is associated with an increased risk for cardiovas- cular disease in people with diabetes 31. Meta-analysis and pooled estimates for the recent large randomized trials suggest that intensive glucose control can reduce the risk for nonfatal myocardial infarction but not cardiovascular or all-cause mortality 32. Effectiveness: What is the evidence that glucose control is effective in reducing risk and adds value What are the risks of glucose control hypoglycemia The risks of severe hypoglycemia during randomized trials have been reported to be up to 2–3 times greater for patients intensively treated for hyperglycemia 3 4 29 30 but not found to be statistically different for patients in other stud- ies 33 34 where intensive treatment regimens were left up to the judgment of health care provider and patient. In addi- tion to the immediate risks associated with hypoglycemia an episode of severe hypoglycemia within 3 months has been reported to be the strongest predictor of a first pri- mary outcome HR 2.062 1.132 3.756 30. This time- dependent covariate raises the question of interaction with other significant predictors of first primary events i.e. age HR 1.33 1.191 1.492 and duration of diabetes HR 1.019 1.007 1.030 and has lead to the hypothesis that the adverse risk of death in intensive intervention could be explained by the aggressiveness of treatment in an elderly population with longer duration of diabetes and established coronary disease. As compared to the ADVANCE trial where treat- ment goals median A1c achieved of 6.4 occurred over 12–18 months most individuals in ACCORD achieved this target A1c within 6 months 29 30. T o confirm or exclude the diagnosis of hypoglycemia clinical trials will need to include more accurate measurement of the circulating glu- cose levels than HbA1c. What are the risks of glucose control weight gain More individuals in the intensive arm of the ACCORD trial gained 10+ kg from baseline 29 vs. 14 p 0.001 29 while differences in weight at study end for ADVANCE were more favorable for standard intervention attributed to ∼1 kg weight loss compared to weight neutrality for the intensively treated group 30. The large weight gain seen TABLE 11.2 Effect of intensive glucose control and primary outcomes ACCORD ADVANCE VADT Primary outcome Nonfatal MI nonfatal stroke CVD death Hospitalization for CHF and revascularization Nonfatal MI nonfatal stroke CVD death Nonfatal MI nonfatal stroke CVD death Hazard ratio 95 CI 0.87 0.73–1.04 0.90 0.78–1.04 0.94 0.84–1.06

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100 Initial evaluation and management of diabetes in individuals in the ACCORD study has been attributed to the greater use of thiazolidinediones TZD in the intensive arm. No differences in weight gain were reported for the UKPDS follow-up or Steno 2 study 33 34. What are the benefits of glucose control microvascular In clinical practice management of hyperglycemia in patients with diabetes is in concert with other manage- ment strategies for risk reduction e.g. lipids blood pres- sure. In the Steno 2 study an example of a multifactorial intervention initiative at the end of trial 7.8 years and at the end of follow-up 13.3 years there was a relative risk reduction 95 CI of 0.44 0.25 0.77 for nephropa- thy one patient in the intensive therapy group progress- ing to dialysis as compared to six patients in the conven- tional therapy group p 0.04. Relative risk for progres- sion of retinopathy 0.57 0.37 0.88 laser treatment for proliferative retinopathy 0.45 0.23 0.86 and blindness 0.51 0.17 1.53 also favored the intensive intervention group 33. What are the benefits of glucose control macrovascular Point estimates for hazard ratios for primary outcomes nonfatal MI nonfatal stroke death from cardiovascu- lar causes and hospitalization for CHF revascularization for the Action to Control Cardiovascular Risk in Dia- betes ACCORD Action in Diabetes and Vascular Dis- ease Preterax and Diamicron MR Controlled Evaluation ADV ANCE and Veterans Administration Diabetes Trial V ADT trials showed favorable trends with significantly less events but collectively were unable to show a signifi- cant association Table 11.2. An observation that has been consistently observed in the Steno 2 and United Kingdom Prospective Diabetes Study UKPDS follow-up studies is the suggestion of a legacy effect of early management of hyperglycemia for macrovascular events. For example the relative risk reduction for myocardial infarction for ear- lier glycemic control was 15 p 0.014 median 8.5 years posttrial follow-up in UKPDS 34 while the absolute risk reduction seen in Steno 2 was 29 median follow-up 13.3 years 33. What are glycemic treatment goals for hyperglycemia Guidelines for glycemic goals have used HbA1c values and are as a low of 6 in Latin America and up to 7.5 in the United Kingdom see Figure 11.1. Table 11.3 summarizes the median HbA1c values achieved in recent trials intervention versus standard as well as those seen in posttrial follow-up. Based on these studies to reduce cardiovascular events a conservative HbA1c goal of 8 would seem appropriate as an accountability measure that could apply to all patients. Otherwise it appears prudent to individualize treatment goals based on expected risks/benefits of treatment. For example a goal of 7 to reduce the risks of microvascular FIG 11.1 International HbA1c goals.

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Is HbA1c the most important therapeutic target in outpatient management of diabetes 101 TABLE 11.3 Summary of intervention and follow-up studies for glycemic control Duration of follow-up Median A1c achieved median/years Intervention Standard ACCORD 3.5 6.4 7.5 ADVANCE 5 6.4 7.0 VADT 6 6.9 8.4 UKPDS follow-up 8.5 7.8 7.8 Steno 2 follow-up 13.33 7.8 7.8 complications should be balanced against the risks for occurrence of hypoglycemia. What is the value of glucose control Diabetes is an expensive illness to manage but it is more expensive not managed. In the United States diabetes is reported to be associated with an annual direct medical expenditure of 91.8 billion while the per capita cost totals 13243 for individuals with diabetes compared to 2560 for those without 35. In the Steno 2 follow-up study while a large part of the increased costs for care for people with diabetes was pharmacy and consultation incremental costs for all complications and interventions were less for intensive compared to conservative treatment despite the fact that patients lived longer 1.7 quality-adjusted life years with intensive treatment. The incremental cost-effectiveness ratio was favorable € 3927 6682 USA per life year gained 35 and was likely related to a comprehensive approach to patient management and not solely glycemic control. What is a patient’s risk for micro- and macrovascular events In order to assess the value of glucose control it is necessary to assess an individual’s risks. T o do this a clinician can turn to a number of statistical e.g. UKPDS and Framing- ham and simulation e.g. Archimedes models that have reduction with improvement in LDL cholesterol to 100 mgm or systolic blood pressure to 120. In contrast he has a projected 21 risk of kidney failure in 30 years for which the models predict can be significantly reduced with glycemic control. In addition and consistent with the importance of both bio and psychosocial measures atten- tion to other outcomes measures e.g. weight loss reg- ular foot exams can have a similar impact as glycemic control. TABLE 11.4 Diabetes risk according to Archemedes PhD Simulation 37 Case: A 54-year-old Caucasian male with a family history of diabetes has had type 2 diabetes for 8 years. He is taking Metformin Glimepiride Aspirin Simvastatin and Lisinopril has a blood pressure of 138/90 a BMI of 31 kg/m 2 and symptoms-signs of peripheral neuropathy. His HbA1c is 7.8 cholesterol 235 mgm HDL 35 mgm and triglycerides are 280 mgm. Risk 10 year 30 year Myocardial infarction HbA1c 7.8 1 2 14.3 HbA1c 7.0 12.4 HbA1c 6.5 11.0 Kidney failure HbA1c 7.8 3 21.0 HbA1c 7.0 6.0 Foot problem HbA1c 7.8 4 20.0 HbA1c 7.0 13.0 been validated against large clinical trials and other popula- tions and are available to predict micro- and macrovascular complications for type 2 diabetes patients. As an example the patient described in Table 11.4 has a 10-year risk of myocardial infarction MI of 14 25 and 14 for Archimedes UKPDS and Framingham respec- tively. With improvement in HbA1c to 7 his risk drops by 13 while there is a projected 50 or greater risk 10-year risk 30-year risk 1 UKPDS 38 25.2 Framingham 39 14.0 2 and LDL 100 mgm 9.2 or Systolic blood pressure 120 9.5 or Weight loss 11.8 3 and Systolic blood pressure 120 LDL 100 mgm 5.1 4 and regular foot exams 14.0

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102 Initial evaluation and management of diabetes ● Decision Making Analytic Stage ● Action ● Deliberation ● Emotion Past Experiences ● Information Exchange ● Uncertainty ● Biomedical ● Psycho Social ● Morbidity ● Mortality ● Physiologic ● Clinical Markers Proximate Outcomes ● Functional Status ● pain emotions vitality ● Behavioral ● Adherence ● Acceptance Self-Care Social Support ● Technology Intervention ● Pharmaceuticals ● Behavioral Intervention ● Knowledge patient/provider ● Concordance Trust ● Self-Efficacy Motivation FIG 11.2 Process for decision making from 36. What is the Evidence for Glucose Control in Managing the Risks of Complications of Diabetes 1 There are plausible biological and physiological explanations as well as evidence from observa- tion/epidemiological studies controlled trials and meta- analysis that support the hypothesis that treatment of hyperglycemia will reduce microvascular complications of diabetes. 2 There is an uncertain treatment effect for reducing macrovascular events. T o reduce macrovascular events the benefit of early treatment of hyperglycemia and/or conservative treatment regimens that minimize hypo- glycemia seem prudent but require further study. What can we conclude Is HbA1c the most important therapeutic target in outpatient management of diabetes Summary HbA1c the current best measurement of glucose control is one of the important therapeutic targets in the out- patient management of diabetes. Similar to the model of clinical decision making by Charles and Gaffini 36 Fig- ure 11.2 decision making in the management of diabetes is currently determined by guidelines and public policy that has uncertainty and as a consequence often there are strong emotions about the importance of glycemic control and HbA1c levels. Additional important therapeutic targets include lipid hypertension and behavioral outcomes. Because it is unlikely that all “what if ” questions will be effectively addressed by head-to-head comparisons in large well powered randomized trials more effective modeling of outcomes with the inclusion of both biomedical e.g. HbA1c and psychosocial outcomes important to patients will be essential for comparative evaluation. Until that time one can conclude that there is not a “most important” but many important outcomes in the care of people with diabetes. References 1. Rahbar S. The discovery of glycated hemoglobin: a major event in the study of nonenzymatic chemistry in biological systems. Ann N Y Acad Sci. 1043:9–19 2005. 2. Little RR Sacks DB. HbA1c: how do we measure it and what does it mean Curr Opin Endocrinol Diabetes Obes. 162:113–118 2009. 3. Anonymous. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.see comment. N Engl J Med. 32914:977–986 1993.

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Is HbA1c the most important therapeutic target in outpatient management of diabetes 103 4. Anonymous. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS 34. UK Prospective Diabetes Study UKPDS Group. see commenterratum appears in Lancet 1998 Nov73529139:1557. Lancet. 3529131:854–865 1998. 5. Shichiri M Kishikawa H Ohkubo Y Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 23Suppl 2:B21–B29 2000. 6. Little RR. Glycated hemoglobin standardization–National Glycohemoglobin Standardization Program NGSP per- spective. Clin Chem Lab Med. 419:1191–1198 2003. 7. Holmes EW Ersahin C Augustine GJ et al. Analytic bias among certified methods for the measurement of hemoglobin A1c: a cause for concern see comment. Am J Clin Pathol. 1294:540–547 2008. 8. Nathan DM Kuenen J Borg R et al. Translating the A1C assay into estimated average glucose values. see comment. Diabetes Care. 318:1473–1478 2008. 9. Brick JC Derr RL Saudek CD. A randomized comparison of the terms estimated average glucose versus hemoglobin A1C. Diabetes Educ. 354:596–602 2009. 10. Cox DJ Gonder-Frederick L Ritterband L Clarke W Kovatchev BP. Prediction of severe hypoglycemia. Diabetes Care. 306:1370–1373 2007. 11. Somogyi M. The distribution of sugar in blood. J Biol Chem. 781:117–127 1928. 12. Bloomgarden ZT. Cardiovascular disease neuropathy and retinopathy. Diabetes Care. 326:e64–e68 2009. 13. Selvin E Zhu H Brancati FL. Elevated A1C in adults without a history of diabetes in the U.S. Diabetes Care. 325:828–833 2009. 14. Khera PK Joiner CH Carruthers A et al. Evidence for interindividual heterogeneity in the glucose gradient across the human red blood cell membrane and its relationship to hemoglobin glycation. Diabetes. 579:2445–2452 2008. 15. Fonseca V Inzucchi SE Ferrannini E. Redefining the diag- nosis of diabetes using glycated hemoglobin. comment. Diabetes Care. 327:1344–1345 2009. 16. Feener EP King GL. Vascular dysfunction in diabetes melli- tus. Lancet. 350Suppl 1:SI9–SI13 1997. 17. Schmidt AM Yan SD Wautier JL Stern D. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res. 845:489–497 1999. 18. Sheetz MJ King GL. Molecular understanding of hyper- glycemia’s adverse effects for diabetic complications. see comment. JAMA. 28820:2579–2588 2002. 19. Srivastava AK. High glucose-induced activation of protein kinase signaling pathways in vascular smooth muscle cells: a potential role in the pathogenesis of vascular dysfunction in diabetes review. Int J Mol Med. 91:85–89 2002. 20. Harris MI. Diabetes in America: epidemiology and scope of the problem. see comment. Diabetes Care. 21Suppl 3:C11–C114 1998. 21. Gaster B Hirsch IB. The effects of improved glycemic con- trol on complications in type 2 diabetes. Arch Intern Med. 1582:134–140 1998. 22. Klein R Klein BE Moss SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1241 Pt 2:90–96 1996. 23. Cukierman-Yaffe T Gerstein HC Williamson JD et al. Rela- tionship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other car- diovascular risk factors: the action to control cardiovascular risk in diabetes-memory in diabetes ACCORD-MIND trial. Diabetes Care. 322:221–226 2009. 24. Reaven PD Emanuele N Moritz T et al. Proliferative dia- betic retinopathy in type 2 diabetes is related to coronary artery calcium in the Veterans Affairs Diabetes Trial VADT. Diabetes Care. 315:952–957 2008. 25. Poulter NR. Blood pressure and glucose control in subjects with diabetes: new analyses from ADV ANCE. J Hypertens. 27Suppl 1:S3–S8 2009. 26. Anonymous. Intensive blood-glucose control with sulpho- nylureas or insulin compared with conventional treat- ment and risk of complications in patients with type 2 diabetes UKPDS 33. UK Prospective Diabetes Study UKPDS Group.see commenterratum appears in Lancet 1999 Aug143549178:602. Lancet. 3529131:837–853 1998. 27. Montori VM Fernandez-Balsells M. Glycemic control in type 2 diabetes: time for an evidence-based about-face Ann Intern Med. 15011:803–808 2009. 28. Duckworth W Abraira C Moritz T et al. Glucose con- trol and vascular complications in veterans with type 2 diabetes.see commenterratum appears in N Engl J Med. 2009 Sep336110:1024-5 PMID: 19726779. N Engl J Med. 3602:129–139 2009. 29. Action to Control Cardiovascular Risk in Diabetes Study G Gerstein HC Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. see comment. N Engl J Med. 35824:2545–2559 2008. 30. Group AC Patel A MacMahon S et al. Intensive blood glu- cose control and vascular outcomes in patients with type 2 diabetes. see comment. N Engl J Med. 35824:2560–2572 2008. 31. Selvin E Marinopoulos S Berkenblit G et al. Meta- analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. see comment. Ann Intern Med. 1416:421–431 2004.

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104 Initial evaluation and management of diabetes 32. Kelly TN Bazzano LA Fonseca VA Thethi TK Reynolds K He J. Systematic review: glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med. 1516:394–403 2009. 33. Gaede P Lund-Andersen H Parving HH Pedersen O. Effect of a multifactorial intervention on mortality in type 2 dia- betes. see comment. N Engl J Med. 3586:580–591 2008. 34. Holman RR Paul SK Bethel MA Matthews DR Neil HA. 10- year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 359:1577–1589 2008. 35. Gaede P Valentine WJ Palmer AJ et al. Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study. Diabetes Care. 318:1510–1515 2008. 36. Charles C Whelan T Gafni A. What do we mean by partnership in making decisions about treatment BMJ. 3197212:780–782 1999. 37. Association AD. Archimedes PhD Available from: http://www.diabetes.org/diabetesphd/default.jsp ed. 38. Oxford DU. UKPDS Risk Engine Available from: http:// www.dtu.ox.ac.uk/index.phpmaindoc/riskengine/ down- load.php ed. 39. Institute NHLB. Framingham Risk Calculator Available from: http://hp2010.nhlbihin.net/atpiii/calculator.asp ed.

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P A R T III Management of Associated Risk Factors and Disease To Cure Diabetes Naturally Click Here

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13 Primary therapy for obesity as the treatment of type 2 diabetes 14 To Get Best Natural Diabetes Treatment Click Here 15 Manpreet S. Mundi 1 and Michael D. Jensen 2 1 Senior Associate Consultant Division of Endocrinology Mayo Clinic Rochester MN USA 2 T omas J. Watson Jr. Professor in Honor of Dr. Robert L. Frye Mayo Foundation Rochester MN USA L E A R N I N G P OIN T S The treatment of obesity is an important part of the therapy of type 2 diabetes and may require oral agents as well as surgical intervention. Weight gain is a common side effect of the treatment of type 2 diabetes. Weight loss alone improves the metabolic status of patients with type 2 diabetes. The obesity epidemic is escalating the incidence of dia- betes in adults and children requiring health care providers to reassess treatment options to best suit the obese patient. Obesity has long been recognized as the major risk fac- tor for type 2 diabetes. Nearly 90 of type 2 diabetics in the United States are overweight or obese 1. The associ- ation between obesity and the prevalence of diabetes in a population has been well documented. For example data from the Nurses’ Health Study 84941 women followed for 20 years indicated that body mass index BMI was the most important diabetes risk factor 2. In that popula- tion the risk of diabetes was ∼39 times greater in women with BMI of 35 kg/m 2 or greater and ∼20 times greater for women with BMI between 30.0 and 34.9 kg/m 2 compared to women with BMI of less than 23.0 kg/m 2 . Similarly the prevalence of diabetes was found to be 2.5 times greater in overweight men BMI 25–29.9 and 3 times higher in overweight women compared to the normal weight group in the NHANES III study 3. From these studies it seems evident that the prevalence of diabetes increases as weight increases. This chapter will present cases highlighting the pharmacologic dietary and surgical options for treating the obese diabetic patient. A 40-year-old male presents after routine preemployment blood tests revealed fasting plasma glucose of 132 mg/dL. He currently has no complaints and reports that he has not seen a physician for over 20 years. He is well appearing and has a BMI of 31.4 kg/m 2 . His blood pressure is 154/87 with a heart rate of 94. Other than obesity the physical examination is within normal limits. Repeat blood work reveals fasting blood glucose of 128 mg/dL and total cholesterol of 224 mg/dL with triglycerides of 314 mg/dL HDL of 28 mg/dL and LDL of 114 mg/dL. This case highlights the fact that in addition to the increased risk of diabetes obesity complicates treatment by exacerbating metabolic complications such as hyperten- sion and dyslipidemia 2–6. Obesity itself may account for approximately 78 and 65 of essential hypertension in men and women respectively 7 with progressive increases in systolic blood pressure as BMI increases 8. A similar relationship has also been noted between increasing obe- sity and hyperlipidemia. The NHANES III survey revealed approximately a 1.5 times higher prevalence of high choles- terol in obese men and women when compared to the nor- mal weigh cohort 3. The combination of diabetes and obesity especially cen- tral obesity is also strongly associated with insulin resis- tance and a pro-atherogenic lipid profile consisting of increased triglyceride and apolipoprotein B concentrations an increased proportion of small dense LDL particles and a low HDL cholesterol. This high-risk combination is often Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza

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c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd. 107

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108 Management of associated risk factors and disease accompanied by a prothrombotic and a proinflammatory profile which significantly worsens an individual’s risk of cardiovascular disease and overall mortality 9. Compared with normal-weight individuals with diabetes mortality is 2.5 to 3.3 times higher in diabetics with body weights that are 20–30 greater than ideal weight and 5.2 to 7.9 times higher for those with body weights 40 above the ideal 10. We suggest that this exponential increase in risk attributed to obesity indicates that weight management should be the first target for overweight/obese patients at presentation. Although many physicians seem pessimistic about the likelihood that lifestyle modification can result in long-term benefit results of the Diabetes Prevention Pro- gram clearly show that this approach is feasible given the proper support 11. Furthermore an effect on prevention of T2DM seems to be detectable as many as 10 years after beginning the intervention 12. For physicians with a large number of obese patients with or at risk for T2DM we believe that efforts to identify or develop successful lifestyle programs will improve practice outcomes. Reduced energy diets increased physical activity and the accompanying weight loss have a positive effect on almost every risk factor associated with diabetes and obesity. Newly diagnosed type 2 diabetics in the UKPDS cohort who were treated successfully with dietary therapy experienced a sub- stantial decrease in fasting blood glucose concentrations from an average of 205 down to 146 mg/dL in the first 3 months 13. This was accompanied by a decrease in fasting insulin concentrations 14 an increase in insulin sensitiv- ity 15 and an improvement in beta-cell function 15. Similar improvements were also noted in coexisting condi- tions such as hypertension and dyslipidemia. In the first few days of caloric restriction VLDL and triglyceride concen- trations decrease and LDL particle size increases 16. With longer duration of therapy a decrease in LDL concentration and an increase in HDL particle numbers occurs. Although the improvements in metabolic characteristics are generally greater in patients who lose the most weight modest weight loss can also produce significant benefit. The findings of a retrospective review of the medical records of 263 patients with type 2 diabetes treated at the Aberdeen Diabetic Clinic suggested that the lifestyle changes required for weight loss were associated with a three- to four-month prolonged survival for each 1 kg decrease in weight 17. The investigators estimated that lifestyle changes required to maintain a 10-kg weight loss would eliminate 35 of the expected reduction in life expectancy seen with type 2 diabetes. Despite the numerous benefits of weight loss in type 2 diabetes it is often quite difficult for obese individuals to initially lose the desired weight and then maintain the weight loss. Even when patients achieve their goal of weight reduction with calorie restriction they commonly regain most if not all of the weight that was lost 18. Long- term follow-up has shown that repeated episodes of weight loss and gain also known as weight cycling are common and can have more negative health impact than weight- stable obesity. Sub-analysis of the Framingham Heart Study Cohort examined the effects of weight fluctuations on total mortality morbidity and mortality from coronary heart disease and mortality from cancer 19. Even after account- ing for an individual’s current weight and other confound- ing factors weight variability was significantly positively associated with total and coronary heart disease mortal- ity in both men and women. Because the relative risks attributable to fluctuations in weight were comparable in magnitude to the risks attributable to being overweight we suggest that physicians place a high value on interventions that are more likely to result in permanent reductions in weight. Although rapid weight loss due to severe calorie restric- tion can rapidly lower blood glucose in patients with type 2 diabetes these diets can also have adverse metabolic con- sequences 20. Very low calorie/liquid protein diets are associated with decreased thyroid hormone T3 concen- trations elevated ketone bodies and a rise in serum uric acid concentrations 21. An average of 38 of rapid weight loss in the first 12 days of these diets consists of fluid 21 loss of lean body mass accounts for only approximately 10 of the initial weight loss. Electrolyte imbalances and excess fluid losses may occur and may be problematic managing in patients with multiple underlying comorbidities. We suggest that physicians emphasize a more modest goal for rates of weight loss that will carry less risk and encourage patients to develop long-term healthy lifestyle patterns. Weight loss of about 0.4 to 0.6 kg/week with an initial goal of 5–10 of body weight lost appears to be safe and effective at improving metabolic control. The published literature suggests that this moderate caloric restriction in combination with mild exercise can result in an average weight loss of 4.4 ± 2.7 kg over 12 months see Table 12.1. If the individual is able to achieve and maintain this loss further weight reduction can then be attempted. Diet changes should be focused on helping patients to reduce energy intake in a manner that is consistent with long-term adherence rather than single-mindedly focusing

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TABLE 12.1 Summary of selected clinical trials enrolling type 2 diabetic subjects Treatment Patients/ characteristics Trials number of subjects Average duration of treatment months Mean weight change kg Mean change in HgbA1c Side effects Lifestyle modifications diet and exercise Newly diagnosed type 2 diabetics 22 1870 12.4 ± 17 –4.4 ± 4.2 0.25 ± 0.40 Metformin alone NIDDM 14 8842 14.6 ± 14 –2.35 ± 0.52 –0.87 ± 0.76 Common: nausea vomiting Metformin plus diet/exercise NIDDM 5 624 7.2 ± 2.7 –1.41 ± 2.51 –0.40 ± 1.07 bloating and diarrhea Metformin plus insulin Secretagogues sulfonylureas NIDDM 6 1602 13.9 ± 8.3 0.35 ± 1.03 –0.95 ± 0.51 Rarely can lead to lactic acidosis. Contraindicated in elderly and and meglinitides patients with renal insufficiency liver Metformin plus thiazolinedione NIDDM 3 952 6.0 ± 0.0 1.68 ± 0.31 –0.78 ± 0.31 disease and congestive heart failure Thiazolinediones NIDDM 11 3595 12.1 ± 12.9 3.15 ± 1.62 –0.72 ± 0.51 Water retention and contraindicated in patients with decreased ventricular function Sulfonylureas NIDDM 7 5425 13.8 ± 15.8 1.68 ± 0.65 –1.00 ± 0.98 Hypoglycemia Contraindicated in pregnancy teratogenic and liver/kidney impairment Exenatide plus sulfonylurea NIDDM on sulfonylurea 2 254 7.5 ± 0.0 –1.30 ± 0.30 –0.70 ± 0.20 Nausea vomiting bloating diarrhea Exenatide plus metformin NIDDM on metformin 2 223 7.5 ± 0.0 –2.20 ± 0.60 –0.60 ± 0.20 headache and decreased appetite Exenatide plus metformin/TZD NIDDM on 1 121 4 –1.8 –0.9 Rarely can cause pancreatitis metformin/TZD Exenatide plus metformin/sulfonylurea NIDDM on metfromin/ sulfonylurea 5 1548 13.9 ± 12.5 –3.13 ± 1.59 –0.92 ± 0.17 Continued

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TABLE 12.1 Continued Average duration of Patients/ Trials number of treatment Mean weight Mean change in Treatment characteristics subjects months change kg HgbA1c Side effects DPP-4 inhibitors NIDDM 10 2779 6.6 ± 1.9 –0.25 ± 0.51 –0.99 ± 0.25 Nasopharyngitis diarrhea contact DPP-4 inhibitor plus TZD NIDDM 3 441 6.0 ± 0.0 1.77 ± 0.35 –1.50 ± 0.53 dermatitis and osteoarthritis DPP-4 inhibitor plus sulfonylurea NIDDM on sulfonylurea 3 445 5.3 ± 1.2 0.72 ± 0.79 –0.53 ± 0.16 Note that long term safety outcomes pending DPP-4 inhibitor plus metformin NIDDM on metformin 8 2468 6.9 ± 2.1 –0.92 ± 0.70 –0.87 ± 0.81 Sibutramine Obese NIDDM 8 483 7.3 ± 3.0 –6.00 ± 3.32 –0.47 ± 0.78 Insomnia dry mouth constipation Sibutramine plus sulfonylurea NIDDM on sulfoyulurea 1 44 12 –4.1 0.6 nausea and elevation in blood pressure Orlistat Obese NIDDM 10 1048 7.7 ± 2.8 –5.13 ± 1.37 –0.99 ± 1.00 Fecal urgency oily stool increased Orlistat plus metformin NIDDM on metformin 1 250 12 –4.7 ± 0.3 –0.75 ± 0.08 defecations and fecal incontinence Orlistat plus sulfonylurea NIDDM on sulfonylurea 1 139 12 –6.2 ± 0.5 –0.28 ± 0.09 Orlistat plus Metformin/sulfonylurea NIDDM on metformin and sulfonylurea 2 141 8.0 ± 5.7 –4.28 ± 1.31 –1.23 ± 0.35 Orlistat plus insulin Type 2 diabetic on insulin 1 274 12 –4.0 ± 0.3 –0.62 ± 0.08 Bariatric surgery overall Obese diabetics 9 452 Variable –40.55 ± 11.36 –2.13 ± 0.50 Initially associated with surgical risk diarrhea nausea vomiting and Gastric banding Obese diabetics 3 23 Variable –17.28 ± 9.36 –1.40 ± 1.00 dumping syndrome Gastric bypass Obese diabetics 3 161 Variable –42.65 ± 8.29 –2.18 ± 0.53 Long-term associated with vitamin Biliopancreatic Diversion/duodenal switc Obese diabetics 3 268 Variable –56.30 ± 10.11 N/A and mineral deficiencies Data are presented as weighted means ± weighted standard deviations about the mean 39.

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Primary therapy for obesity as the treatment of type 2 diabetes 111 on a specific diet composition. Despite the plethora of diets and dieting guides available head-to-head compar- isons of the various diets have revealed that weight loss is similar between diets with varying macronutrient compo- sition provided that dietary adherence is comparable 22. In one study comparing high carbohydrate high mono- unsaturated fat and high saturated fat diets the partici- pants lost an average of 6.6 kg in each of the three groups after 12 weeks. As expected the participants in the high sat- urated fat group had the worst lipid profile. This supports the recommendation by the American Diabetes Association that saturated fats be limited to less than 7 of the total energy intake 23. In summary this patient with newly diagnosed T2DM deserves an aggressive trial of lifestyle modification if he is willing to attempt changes with or without pharmacother- apy as needed. Even though long-term success may not occur in the majority of patients this approach is virtually risk-free. We suggest that not considering this approach will deprive the subset of patients who are “lifestyle respon- ders” of a treatment that improves a host of metabolic abnormalities. A 52-year-old asymptomatic female was diagnosed with diabetes 4 years ago and has been treated with glyburide and pioglitazone for the last two years. She is referred for consultation because of suboptimal glycemic control HbA1c of 8.6. Her BMI is 36 kg/m 2 and her blood pressure is 138/86 with a heart rate of 88. This patient would benefit from aggressive weight loss therapy however because she is on a sulfonylurea this should be done with caution due to the increased risk for hypoglycemia while she is actively losing weight. Pharma- cotherapy may need to be altered to avoid agents that cause hypoglycemia. Furthermore agents that are associated with weight gain insulin sulfonylureas and thiazolidinediones TZDs see Table 12.1 are counterproductive in this set- ting. Biguanides of which metformin is the sole approved agent are not associated with significant weight gain and are recommended as first-line pharmacotherapy by most treatment guidelines. Metformin enhances insulin sensi- tivity thus inducing greater peripheral glucose uptake and decreasing hepatic glucose output 24. The effect of met- formin on body weight in large randomized controlled tri- als has been variable depending on the addition of other hypoglycemic agents 25. The United Kingdom Prospective Diabetes Study UKPDS randomized 753 overweight newly diagnosed diabetics to conventional therapy diet only versus inten- sive glucose control with metformin glibenclamide or insulin. After a 10-year follow-up period the change in bodyweight was similar in the metformin and conventional treatment groups with a ∼1.5 and ∼1.9 kg net weight gain. However this was significantly less than the weight gain seen in the sulfonylurea or insulin-treated groups who experi- enced ∼3.7 and ∼6.0 kg weight gains respectively 26. In addition to the lack of significant weight gain metformin resulted in fewer hypoglycemic episodes than sulfonylurea or insulin therapy and achieved similar improvements in HbA1c. A Diabetes Outcome Progression Trial ADOPT showed significant weight loss associated with metformin treatment 27. This 4-year double-blind randomized con- trol trial assigned 4360 newly diagnosed type 2 diabetics to receive metformin glyburide or rosiglitazone. Over the duration of the trial weight decreased in the metformin group by 2.9 ± 0.6 kg see Table 12.1 while rosiglitazone was associated with a weight gain of 4.8 ± 0.5 kg. Gly- buride was associated with a 1.6 ± 0.6 kg weight gain in the first year with the weight remaining stable afterward. The weight gain noted with both glyburide and rosiglita- zone was associated with an increase in the waist and hip circumferences. Metformin however resulted in a reduc- tion in both hip and waist circumferences. These beneficial changes in fat distribution have been quantified in a ran- domized study comparing the effects of metformin and rosiglitazone monotherapy for 26 weeks 28. They noted that metformin significantly decreased body weight by an average of 2.0 kg while placebo and rosiglitazone groups remained weight stable. Metformin also resulted in a sig- nificant decrease in both abdominal subcutaneous from 5.3 ± 0.6 to 4.9 ± 0.5 kg and intra-abdominal fat masses from 2.5 ± 0.3 to 2.2 ± 0.2 kg. The weight benefits of metformin have also been found when it is used in combination with other antidiabetic agents see Table 12.1. In patients with type 2 diabetes who were suboptimally controlled on a sulphonylurea adding metformin improved HbA1c to the same extent as adding pioglitazone 29. However patients receiving the sulphonylurea-pioglitazone combination gained 2.8 kg in one year whereas the sulphonylurea-metformin group lost an average of 1.0 kg. Although other studies noted

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112 Management of associated risk factors and disease less weight benefit the addition of metformin to sulfony- lurea did significantly lessen weight gain when compared to the use of sulfonylureas alone 0.35 ± 0.94 vs. 1.68 ± 0.58 respectively. Similar results have been noted with the addition of metformin to TZDs or insulin 25. Another class of medications the “incretins” is reported to be weight neutral or display weight loss properties. These compounds are either glucagon-like peptide-1 GLP- 1 receptor agonists or prevent GLP-1 breakdown through inhibition of dipeptidyl peptidase-4 DPP-4 the enzyme responsible for the rapid clearance of GLP-1 from the circu- lation. Numerous clinical trials have reported on the efficacy of exenatide as adjuvant therapy in type 2 diabetics who fail to achieve adequate glycemic control with standard oral hypoglycemic agents. With a maximum dose of 10 µg twice daily exenatide allowed 32–62 of patients to achieve a HbA1c of 7 or less 30. These trials also reported weight loss averaging 1.3 ± 0.3 kg after 30–52 weeks of treatment see Table 12.1. T otal weight loss of 5.3 ± 0.4 kg was found during an open label extension trial with 46 of subjects achieving and maintaining a HbA1c of less than 7 with 3 years of treatment 31. The caveat is that only responders stayed in the open label extension so these results are likely not representative of “average” results. Liraglutide a long-acting GLP-1 analog also produces significant weight reductions both as mono- and adjuvant- therapy. A 14-week trial comparing various dosages of liraglutide 0.65 mg 1.25 mg 1.90 mg daily versus placebo noted a significant average weight loss of 2.9 kg at the high- est dose 32. This weight loss was accompanied by a 1.5 reduction in HbA1c and 46 of patients achieved a HbA1c of less than 7 in the highest dose group. In a 5-week dose escalation study of 144 type 2 diabetics the addition of liraglutide to metformin produced a 70 mg/dl reduc- tion in fasting glucose a 0.8 reduction in HbA1c and an additional 2.9 ± 0.7 kg weight loss 33. Weight loss associated with the DDP-4 inhibitors sitagliptin and vildagliptin is not as remarkable and this class of drug is best characterized as weight neutral. Mul- tiple studies utilizing sitagliptin and vildagliptin as both mono- and adjuvant therapeutic agents have revealed min- imal to no significant weight loss or gain see Table 12.1 30. Combination therapy with sulfonylureas and TZDs has been shown to result in small weight gain 30. Overall the incretin class of drugs is effective in reducing HbA1c and has not been shown to result in significant weight gain. For the obese patient with T2DM these agents offer a chance to avoid the weight gain side effects of sulfonylureas and TZDs and should be utilized early on in patients such as those presented above. A 49-year-old female with T2DM is referred by her primary care physician after failing multiple attempts at weight loss. She has had T2DM for 5 years and has been successfully treated with metformin and glipizide her current HbA1c is 7.2. Over the last ten years she has tried numerous times to lose weight through diet and exercise but has been unsuccessful. She reports only minor success with dieting but has usually rapidly regained the weight. Her BMI is 33 kg/m 2 and her blood pressure is 132/82 and heart rate is 78. Diet and exercise along with an adjustment in the hypo- glycemic medications may not be sufficient for a signifi- cant number of obese patients who may require additional weight loss therapy. For patients who have a BMI of 27 kg/m 2 or higher and have failed to achieve weight loss after at least 6 months of treatment with diet exercise and behavioral therapy the use of obesity pharmacother- apy may be considered. Sibutramine one of two currently approved drugs for long-term use acts as an inhibitor of norepinephrine and serotonin reuptake in the CNS result- ing in a reduction in food intake through increased satiety. In a multicenter 12-month randomized double-blind trial sibutramine produced significant weight loss with both 15 mg/day 5.5 ± 0.6 kg and 20 mg/day 8.0 ± 0.9 kg doses after 12 months of follow-up see Table 12.1 34. Of note weight loss of greater or equal to 10 was achieved by 14 and 27 of subjects receiving 15 and 20 mg respectively but by none given placebo. Subjects who experienced a weight loss of ≥10 also showed significant decreases in HbA1c 1.2 ± 0.4 as well as fasting plasma glucose 32 mg/dl. The most common side effects reported with sibutramine use are insomnia headache dry mouth constipation and nausea. Cardiovascular side effects have also been reported. Treatment with 15 mg/d sibutramine raised diastolic blood pressure by ≥5 mmHg in 43 of subjects versus 25 in the placebo group 34. Pulse rate increased by ≥10 bpm in 42 of treated patients versus 17 with placebo. Of note an ongoing study the Sibutramine Cardiovascular Outcome Trial SCOUT is currently being conducted to address the efficacy and safety of sibutramine in high-risk subjects with increased risk of cardiovascular events.

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Primary therapy for obesity as the treatment of type 2 diabetes 113 Orlistat the remaining approved long-term weight loss compound acts as an inhibitor of gastric and pancreatic lipases. The weight loss is believed to largely result from fat malabsorption and as might be expected the most common side effects are gastrointestinal symptoms such as fecal urgency oily stool increased defecation and fecal incontinence 1. Orlistat has also been more thoroughly studied than sibutramine with over 15 randomized placebo- controlled trials in obese subjects with type 2 diabetes see Table 12.1 35. One such multicenter trial randomized 391 sulfonylurea-treated patients to either orlistat 120 mg tid or placebo in addition to a low calory diet 36. After 1 year of treatment the orlistat group lost 6.2 ± 0.5 of initial body weight versus 4.3 ± 0.5 in the placebo group and twice as many subjects receiving orlistat lost ≥5 of their initial body weight 48.8 vs. 22.6 p 0.001. Orli- stat treated patients also achieved greater improvements in glycemic control than placebo HbA1c change of –0.28 vs. +0.18 respectively resulting in a significant decrease in sulfonylurea dosage 23 vs. 9 respectively. Fasting glucose –0.02 mmol/L vs. +0.54 mmol/L respectively as well as fasting insulin –5.2 vs. +4.3 respectively also improved signifi- cantly in the orlistat group versus placebo. Similar results were also noted in patients who were previously being treated with metformin 37 or insulin 1. The plethora of data available as well as the lack of cardiovascular and systemic side effects makes orlistat a reasonable therapeutic option in obese type 2 diabetics such as the patient illus- trated in the case above. A 51-year-old female with a long-standing history of diabetes is referred for consultation for diabetes management. She reports that she was diagnosed with diabetes in her mid-thirties was initially treated with oral hypoglycemic agents and then started on insulin therapy 2 years ago. She reports that over the last 10 years she has gained over 100 lbs despite trying various diet and exercise programs. She is currently unable to exercise due to severe pain in both knees. On exam BMI is 42 kg/m 2 and her blood pressure is 152/88 and pulse is 94. She has acanthosis nigricans in her axillae and neck. Bilateral nonproliferative retinopathy is present and deep tendon reflexes in the ankles are absent. Bariatric surgery may be another option in individuals who fail to have adequate weight loss with pharmacologic therapies and lifestyle changes and who have a BMI of 40 or a BMI ≥ 35 kg/m 2 in the presence of multiple severe medical complications such as the case described above. Numerous techniques fall under this category rang- ing from gastric banding to the Roux-en-Y gastric bypass. The later procedure is more complex involving the exclu- sion of the majority of the stomach and anastamosis of a small gastric remnant to an enteric limb carrying food. The remainder of the stomach duodenum and jejunum carry- ing the bilio-pancreatic secretions are anastamosed to the nutrient-carrying portion of the intestine at variable dis- tances from the ileocolonic junction to allow digestion and absorption of food. A review of studies published between 1990 and 2006 revealed a total weight loss of 38.5 kg or 56 of excess body weight in patients with an average presurgery BMI of 47.9 kg/m 2 38. For patients with diabetes the total weight loss with all procedures was 40.6 kg 64 of excess body weight. This weight loss appears to persist for at least 2 years as trials with follow-up of greater than 2 years note a weight loss of 42.9 kg 58 of excess body weight. Overall 78 of patients had a complete resolution and 87 experienced an improvement or resolution of the clin- ical and laboratory manifestations of diabetes with a mean decline in HbA1c of 2.1 a fall in fasting glucose of 79 mg/dl and reduction in fasting insulin of 98 µU/mL. The resolution of diabetes was least following the gastric band- ing procedure 56.7 and greatest with the Roux-en-Y gastric bypass—95. Other studies have also revealed an improvement in both morbidity and mortality in type 2 diabetics after bariatric surgery 38. Despite the impres- sive benefits associated with bariatric surgery it is associated with significant long- and short-term complications such as malabsorption vitamin deficiencies and anemia which have not been fully studied in long-term trials 10 years of follow-up. Therefore candidates for bariatric surgery should be well informed of these risks and benefits and be chosen carefully to ensure adequate follow-up. The treatment of type 2 diabetes is quite taxing for both the patient as well as health care workers and requires significant resources. Currently the obesity epidemic has made this situation even more difficult both in terms of the prevalence of diabetes and a worsening of its prognosis. Thus it is paramount for health care professionals caring for patients with type 2 diabetes to focus on treatment of obesity as even moderate amounts of weight loss can pro- duce significant benefits. An ideal approach can address this issue through many different methods focusing on patient

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114 Management of associated risk factors and disease education diet exercise and a tailoring of hypoglycemic therapy toward weight loss. If these techniques are unsuc- cessful in producing the desired effects focus can shift toward assessing other methods such as weight loss drugs or even surgery in the appropriate candidates. Due to the diversity of the disease and the factors that have created it a multifaceted approach armed with an equally diverse set of tools can better yield a successful and sustainable weight loss along with a reversal of the morbid complications of obesity. References 1. Maggio CA Pi-Sunyer FX. Obesity and type 2 diabetes. Endocrinol Metab Clin North Am. 324:805–822 viii 2003. 2. Hu FB Manson JE Stampfer MJ et al. Diet lifestyle and the risk of type 2 diabetes mellitus in women. N Engl J Med. 34511:790–797 2001. 3. Must A Spadano J Coakley EH Field AE Colditz G Dietz WH. The disease burden associated with overweight and obesity. JAMA. 28216:1523–1529 1999. 4. Allison DB Fontaine KR Manson JE Stevens J VanItallie TB. Annual deaths attributable to obesity in the United States. JAMA. 28216:1530–1538 1999. 5. Despres JP Fong BS Julien P Jimenez J Angel A. Regional variation in HDL metabolism in human fat cells: effect of cell size. Am J Physiol Endocrinol Metab. 2525:E654–E659 1987. 6. Kissebah AH Alfarsi S Adams PW Wynn V. Role of insulin resistance in adipose tissue and liver in the pathogenesis of endogenous hypertriglyceridaemia in man. Diabetologia. 126:563–571 1976. 7. Kannel WB Garrison RJ Dannenberg AL. Secular blood pressure trends in normotensive persons: the Framingham Study. Am Heart J. 1254:1154–1158 1993. 8. Kissebah AH Krakower GR. Regional adiposity and morbid- ity. Physiol Rev. 744:761–811 1994. 9. Despres J Lemieux I Bergeron J et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol. 286:1039–1049 2008. 10. Blackburn GL Read JL. Benefits of reducing–revisited. Post- grad Med J. 60Suppl 3:13–18 1984. 11. Knowler WC Barrett-Connor E Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 3466:393–403 2002. 12. Knowler WC Fowler SE Hamman RF et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 3749702:1677–1686 2009. 13. UK prospective diabetes study 7: Response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients. Metabolism. 399:905–912 1990. 14. Henry RR Gumbiner B. Benefits and limitations of very- low-calorie diet therapy in obese NIDDM. Diabetes Care. 149:802–823 1991. 15. Henry RR Wallace P Olefsky JM. Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin- dependent diabetes mellitus. Diabetes. 359:990–998 1986. 16. Markovic TP Campbell LV Balasubramanian S et al. Bene- ficial effect on average lipid levels from energy restriction and fat loss in obese individuals with or without type 2 diabetes. Diabetes Care. 215:695–700 1998. 17. Lean ME Powrie JK Anderson AS Garthwaite PH. Obesity weight loss and prognosis in type 2 diabetes. Diabet Med. 73:228–233 1990. 18. Wadden TA Foster GD Letizia KA. One-year behavioral treatment of obesity: comparison of moderate and severe caloric restriction and the effects of weight maintenance ther- apy. J Consult Clin Psychol. 621:165–171 1994. 19. Lissner L Odell PM D’Agostino RB et al. Variability of body weight and health outcomes in the Framingham population. N Engl J Med. 32426:1839–1844 1991. 20. Isner JM Sours HE Paris AL Ferrans VJ Roberts WC. Sudden unexpected death in avid dieters using the liquid- protein-modified-fast diet. Observations in 17 patients and the role of the prolonged QT interval. Circulation. 606:1401–1412 1979. 21. Henry RR Wiest-Kent TA Scheaffer L Kolterman OG Olef- sky JM. Metabolic consequences of very-low-calorie diet therapy in obese non-insulin-dependent diabetic and non- diabetic subjects. Diabetes. 352:155–164 1986. 22. Heilbronn LK Noakes M Clifton PM. Effect of energy restriction weight loss and diet composition on plasma lipids and glucose in patients with type 2 diabetes. Diabetes Care. 226:889–895 1999. 23. Executive Summary: Standards of Medical Care in Diabetes–2009 Internet. Diabetes Care. 2009 Jan 1 cited 2009 Apr 24 Available from: http://care. diabetesjournals. org. 24. Cusi K Consoli A DeFronzo R. Metabolic effects of met- formin on glucose and lactate metabolism in noninsulin- dependent diabetes mellitus. J Clin Endocrinol Metab. 8111:4059–4067 1996. 25. Golay A. Metformin and body weight. Int J Obes. 321:61–72 2007. 26. UKPDS. Effect of intensive blood-glucose control with met- formin on complications in overweight patients with type 2 diabetes UKPDS 34. Lancet. 3529131:854–865 1998.

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Primary therapy for obesity as the treatment of type 2 diabetes 115 27. Kahn SE Haffner SM Heise MA et al. Glycemic durability of rosiglitazone metformin or glyburide monotherapy. N Engl J Med. 35523:2427–2443 2006. 28. Virtanen KA Hallsten K Parkkola R et al. Differential effects of rosiglitazone and metformin on adipose tissue distribu- tion and glucose uptake in type 2 diabetic subjects. Diabetes. 522:283–290 2003. 29. Hanefeld M Brunetti P Schernthaner GH Matthews DR Charbonnel BH. One-year glycemic control with a sul- fonylurea plus pioglitazone versus a sulfonylurea plus met- formin in patients with type 2 diabetes. Diabetes Care. 271:141–147 2004. 30. Chia CW Egan JM. Incretin-based therapies in type 2 dia- betes mellitus. J Clin Endocrinol Metab. 9310:3703–3716 2008. 31. Klonoff DC Buse JB Nielsen LL et al. Exenatide effects on diabetes obesity cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 241:275–286 2008. 32. Vilsboll T Zdravkovic M Le-Thi T et al. Liraglutide a long-acting human glucagon-like peptide-1 analog given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 306:1608–1610 2007. 33. Nauck MA Hompesch M Filipczak R Le TDT Zdravkovic M Gumprecht J. Five weeks of treatment with the GLP-1 ana- logue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes. 1148:417–423 2006. 34. McNulty SJ Ur E Williams G. A randomized trial of sibu- tramine in the management of obese type 2 diabetic patients treated with metformin. Diabetes Care. 261:125–131 2003. 35. Choussein S Makri AA Frangos CC Petridou ET Daskalopoulou SS. Effect of antiobesity medications in patients with type 2 diabetes mellitus. Diabetes Obes Metab Internet. 2009 Feb 18 cited 2009 Apr 24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19236442. 36. Hollander PA Elbein SC Hirsch IB et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care. 218:1288–1294 1998. 37. Miles JM Leiter L Hollander P et al. Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin. Diabetes care. 257:1123–1128 2002. 38. Buchwald H Estok R Fahrbach K et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta- analysis. Am J Med. 1223:248–256.e5 2009. 39. Bland JM Kerry SM. W eighted comparison of means. BMJ. 3167125:129 1998.

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13 Are statins the optimal therapy for cardiovascular risk in patients with diabetes Are triglycerides an important independent risk factor for diabetes To Get Rid Of Diabetes Permanently Click Here Michael O’Reilly 1 and Timothy O’Brien 2 1 Specialist Registrar in Endocrinology/Diabetes Mellitus Department of Medicine and Endocrinology/Diabetes Mellitus University College Hospital/National University of Ireland Galway Ireland 2 Professor of Medicine Consultant Endocrinologist/Director of REMEDI Department of Medicine and Endocrinology/Diabetes Mellitus University College Hospital/National University of Ireland Galway Galway Ireland L E A R N I N G P OIN T S Dyslipidemia is part of the adverse cardiovascular risk profile in type 2 diabetes mellitus. Syndrome X the metabolic syndrome refers to a constellation of abnormalities that frequently cluster together in type 2 diabetes. Therapy with statins is an important part of primary and secondary cardiovascular disease prevention in diabetes. Hypertriglyceridemia is an independent risk fact for cardiovascular disease in diabetes. Dyslipidemia in type 2 diabetes Type 2 diabetes mellitus T2DM is associated with a two- to fourfold increase in the risk of coronary heart disease com- pared to the nondiabetic population 1. Dyslipidemia is the best-characterized risk factor for atherosclerosis in patients with T2DM. A number of features of dyslipidemia are char- acteristically associated with diabetes mellitus increasing the predisposition to atherosclerosis. The most common derangement of lipid profile in diabetes mellitus is elevated triglycerides and decreased HDL cholesterol levels associ- ated with increased circulating concentrations of remnant particles and a preponderance of dense LDL cholesterol particles 2. Although LDL cholesterol levels in T2DM are not significantly different from the nondiabetic population qualitative abnormalities of this lipid fraction exist 2. For instance patients with diabetes mellitus typically have smaller denser LDL particles with likely increased atherogenicity even if the total LDL concentration is not increased. In addition studies have shown that the ratio of esterified to free cholesterol is increased in the LDL particle in diabetes mellitus 3. This leads to increased oxidation of LDL particles which increases the delivery of cholesterol to atherosclerotic plaques via macrophage uptake. Oxidized LDL is also known to be increased in T2DM 4. Glycation of LDL is also believed to increase the atherogenicity of the particle by increasing the susceptibility to oxidation and also increasing free radical production. Levels of the cardioprotective lipid fraction HDL choles- terol are decreased in patients with diabetes mellitus. HDL particles are known to protect LDL from oxidation through paraoxonase activity. HDL composition is also altered in subjects with elevated plasma triglycerides 5. Hypertriglyceridemia is the most common lipoprotein abnormality found in poorly controlled diabetes mellitus. The pathophysiology underlying hypertriglyceridaemia in T2DM is complex and is caused by disturbances in fatty acid metabolism. The key feature of diabetic dyslipidemia appears to be an increase in production of very low density lipoprotein VLDL by the liver in response to elevations Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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Use of statins in both primary and secondary prevention of cardiovascular disease 117 Renal degradation ApoA1 FFAs glycerol X and glucose Insulin Lipoprotein or Hepatic lipase X ↑ ApoB ↑ Triglyceride Cholesterol esters Hepatic lipase Triglycerides Dense LDL LDL VLDL HDL Triglycerides Cholesterol esters FIG 13.1 Insulin resistance and dyslipidemia. The suppression of lipoprotein lipase and very-low-density lipoprotein VLDL production by insulin is defective in insulin resistance leading to increased free fatty acid FFA flux to the liver and increased VLDL production which results in increased circulating triglyceride concentrations. The triglycerides are transferred to low-density lipoprotein LDL and high-density liporotein HDL and the VLDL particle gains cholesterol esters by the action of the cholesterol ester transter protein CETP. This leads to increased catabolism of HDL particles by the liver and loss of apolipoprotein Apo A resulting in low HDL concentrations. The triglyceride-rich LDL particle is stripped of the triglycerides resulting in the accumulation of atherogenic small dense LDL particles. Copyright © 2008 by Saunders an imprint of Elsevier Inc. All rights reserved in free fatty acids FFAs. Insulin suppresses lipolysis and mediates uptake of FFAs by striated muscle. Insulin resis- tance leads to derangements in this process with increasing levels of FFAs available to the liver. This disorder is charac- terized by the accumulation of apo-B-containing lipopro- teins which are proatherogenic in the plasma. In fact fasting nonesterified free fatty acid NEFA levels are an independent predictor of insulin sensitivity 6 and ele- vations are the first lipid abnormality in impaired glucose tolerance. In addition insulin-dependent lipoprotein lipase activity is defective in T2DM. This leads to an accumula- tion of triglyceride-rich lipoproteins in the plasma and a delay in the clearance of chylomicrons and VLDL with a consequent increase in remnant particles Figure 13.1. It is important to bear in mind however that as in non- diabetic individuals lipids levels can be deranged inde- pendently of hyperglycemia or defective insulin action. Secondary causes of dyslipidemia such as renal disease hypothyroidism and genetically determined lipoprotein disorders e.g. familial combined hyperlipidemia and familial hypertriglyceridemia must be taken into consider- ation. Furthermore alcohol oestrogen and antiretroviral agents may induce abnormalities of plasma lipids. Syndrome X or the metabolic syndrome refers to a con- stellation of metabolic derangements frequently found in T2DM that are individually and continually associated with an increased risk of cardiovascular disease. These include low HDL cholesterol elevated triglycerides small easily oxidized LDL molecules and elevated serum uric acid con- centration 7. Central obesity and hypertension are usually clinically manifest. There is a strong association between the metabolic syndrome and incidence and mortality of cardiovascular disease. A Finnish Prospective cohort study showed the age-adjusted relative risk RR for coronary heart disease CHD mortality was 2.96 95 CI 1.31–3.21 8. Hyperinsulinemia is likely the underlying link between hyperglycemia and CVD in these patients several studies have shown elevated fasting insulin levels to be an indepen- dent predictor of CVD risk 9. There are different sets of diagnostic criteria for the metabolic syndrome that have been published by the National Cholesterol Education Program NCEP Adult

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Absolute event rate per 5 years PROVE-IT: per 2 years 5 118 Management of associated risk factors and disease Bo x 1 3 . 1 . NCEP guidelines for d iagnosis of the metabolic syndr ome Presence of three of the following five risk factors: Abdominal obesity waist circumference 40 inches in men 35 inches in women Plasma triglycerides ≥150 mg/dl 1.7 mmol/L Plasma HDL cholesterol ≤ 40mg/dl in men 1.02 mmol/L and ≤50 mg/dl in women 1.27 mmol/L Blood pressure 130/85 mmHg Fasting plasma glucose 110 mg/dl 6.1 mmol/L Treatment Panel III ATP III see Box 13.1 the World Health Organisation WHO and the International Dia- betes Federation IDF. It is important to remember that risk is conferred by the underlying risk factors and the defi- nition of metabolic syndrome is an arbitrary aggregation of risk factors whose presence or absence is defined by discrete cut points. In practice risk is conferred continuously. Treatment of dyslipidemia in patients with diabetes mellitus Evidence for treatment of dyslipidemia in T2DM for pri- mary and secondary prevention of cardiovascular disease is well established Figure 13.2. Hydroxymethylglutaryl coenzyme A reductase inhibitors statins have a partic- ularly strong evidence base in several large trials in diabetic patients with and without CHD. In 1997 the Scandinavian Simvastatin Survival Study 4S looked at 202 diabetic and 4242 nondiabetic subjects with known CHD treated with simvastatin or placebo for 5 years 10. The RR of major CHD events nonfatal myocardial infarction or revascular- ization and mortality was 0.45 and 0.57 respectively. Sub- sequently in the Cholesterol and Recurrent Events CARE trial pravastatin use in diabetes patients with established CHD had a significant 25 reduction in the incidence of CHD death nonfatal myocardial infarction MI coronary artery bypass graft CABG surgery and revascularization procedures 11. Subgroup analysis of diabetes patients in the Long-term Intervention with Pravastatin in Ischemic Disease LIPID study showed a 19 reduction in major 30 25 LDL-C: Placebo Pravastatin Atorvastatin Simvastatin Gemfibrozil 131 93 mg/dL 20 15 180 122 139 97 150 113 95 62 101 131 104 81 113 113 10 20 mg 63 40 40 mg 40 mg 37 mg 0 40 40 80 mg mg mg 10 80 mg mg 20 mg 77 40 mg 80 23 mg 1.2 g Relative risk HPS 4S CARE LIPID PROVE IT TNT IDEAL VA HIT reduction 27 34 24 24 16 20 11 22 Simvastatin Pravastatin Atorvastatin Gemfibrozil FIG 13.2 Rates of fatal and nonfatal myocardial infarction on recent major lipid-lowering trials conducted in patients with CHD or CHD-equivalent disorders. In all trials lower LDL-C levels were associated with lower event rates. The relative risk reductions were 11 to 34. Absolute event rates approached 10 per 5 years 2 per year for all patients in all trials irrespective of treatment. In PROVE-IT Pravastatin or Atorvastatin Evaluation and Infection Therapy the only trial of patients with acute coronary syndrome the 2-year event rate was 8.3 despite average on-treatment LDL-C 1.61 mM/L62 mg/dL. 4S Scandinavian simvastatin survival study CARE cholesterol and recurrent events IDEAL incremental decrease in endpoints through aggressive lipid lowering LIPID long-term intervention with pravastatin in ischemic disease TNT treating to new targets VA-HIT Veterans Administration HDL intervention trial. Copyright © 2008 by Saunders an imprint of Elsevier Inc. All rights reserved

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Use of statins in both primary and secondary prevention of cardiovascular disease 119 CHD fatal and nonfatal myocardial infarction 12. Haf- fer et al. studied simvastatin therapy across a range of glu- cose tolerance from normal to diabetes treatment signif- icantly reduced major adverse cardiovascular events and revascularization procedures in patients with diabetes mel- litus. In the subgroup with impaired glucose tolerance sim- vastatin treatment was also associated with a significant reduction in total and coronary mortality 13. The Heart Protection Study HPS published in the Lancet in 2002 was a large randomized placebo-controlled trial that examined the use of simvastatin 40 mg in 20536 high-risk patients over 5 years 14. Of this large num- ber of study participants 29 had T2DM. Treatment with simvastatin resulted in a significant reduction in major vascular events in patients with T2DM who had previ- ous MI or other coronary artery disease 33.4 vs. 37.8 in simvastatin- and placebo-treated patients respectively. This benefit extended to patients with T2DM who had no previous CHD 13.8 vs. 18.6 and in both groups com- bined 20.2 vs. 25.1. The HPS also demonstrated a sig- nificant 12 relative risk reduction in all-cause mortality and an 18 relative risk reduction in coronary mortality in all patients in the simvastatin group. This study suggested that the benefit of statins was also seen in patients with “normal” LDL cholesterol implying that all patients with diabetes mellitus should be treated with a statin regardless of LDL cholesterol levels. The most recent large-scale intervention study for pri- mary prevention in T2DM the Collaborative Atorvastatin Diabetes Study CARDS demonstrated that 10 mg ator- vastatin was beneficial 15. This was a large n 2838 randomized placebo-controlled trial that assessed the ben- efit of atorvastatin 10 mg od in the prevention of acute coronary heart disease events coronary revascularization or stroke in patients with T2DM with no previous history of CVD and plasma LDL 160 mg/dL 4.08 mmol/L. This study was terminated two years early after prespecified efficacy criteria were met. Patients treated with atorvastatin had a relative risk reduction of 37 of first cardiovascu- lar events after a median of 3.9 years 95 CI –52 –17 p 0.001 compared with placebo-treated patients. Acute coronary heart disease-related events were reduced by 36 coronary revascularization by 31 and stroke by 48. Ben- efit emerged within one year of initiating therapy. The Treating to New Targets TNT study published in the Lancet in 2006 was an international multicentre double-blind trial that randomized 10003 with clinically evident CHD who also met NCEP criteria for diagnosis of the metabolic syndrome to treatment with 10 mg or 80 mg of atorvastatin for a period of 4.9 years 16. The study included 778 patients with T2DM 22 of study population. Treatment with 80 mg of atorvastatin was sig- nificantly more effective in reducing major cardiovascular events than the 10 mg dose HR 0.71 95 CI 0.61–0.84 p 0.0001. This is presumably due to the significantly greater reduction in LDL cholesterol in the aggressive treat- ment group. The relative risk of stroke alone in the 80 mg atorvastatin was 23 lower at the end of the study. There was also a 26 drop in risk of hospitalization for conges- tive cardiac failure in the aggressive treatment group. This was the first randomized trial to demonstrate the benefits of lowering LDL cholesterol below 2.6 mmol/L in patients with stable coronary artery disease. These benefits included a 22 reduced risk of cardiovascular events and a 25 reduction in the risk of stroke. Both of these benefits were achieved without additional significant safety risks in the high-dose group. When the percentage of patients with new CHD events was plotted against the average achieved LDL cholesterol in the TNT study compared with other major secondary prevention statin trials the relationship remained linear indicating that levelling of the effect of LDL cholesterol lowering did not occur in TNT. In other words the LDL level below which vascular events ceased was not reached in this study. Based on the literature at the time of writing all patients with T2DM should be on statin therapy regardless of LDL cholesterol. As the TNT demonstrated a lower LDL level below which vascular events no longer occur has not been reached. While target LDL cholesterol has traditionally been below 2.6 mmol/L the TNT suggests that a target of ≤ 1.8 mmol/L may be reasonable. The ATP III guidelines have been updated to reflect this point and suggest that the latter target may be very appropriate for those high-risk patients with T2DM and established CHD. However aggressive pharmacotherapy with high-dose statins is not without side effects and the likelihood of adverse events such as hepa- totoxicity or myositis increases in a dose-dependent man- ner. Current ADA guidelines suggest an LDL cholesterol target of below 100 mg/dl 2.6 mmol/L in patients both with and without CHD. Desirable HDL cholesterol levels are above 40 mg/dl 1.02 mmol/L. However the lower the LDL cholesterol that can be achieved the greater the reduction in vascular risk. This must be balanced against potential adverse effects of lipid-lowering therapy and the

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120 Management of associated risk factors and disease clinician must thus target the lowest LDL possible with the maximum tolerated lipid-lowering agent. The above literature refers almost exclusively to the management of dyslipidemia in patients with type 2 diabetes mellitus. Indeed there is a paucity of evidence on the benefits of statin therapy in primary prevention in type 1 diabetes mellitus T1DM. This group does have an increased incidence of CHD than nondiabetic patients but diabetes is usually diagnosed at a young age when the absolute incidence of CHD is negligible. The benefit of statin therapy in T1DM has not been proven given the very small numbers of these patients included in statin trials. A small number of patients with T1DM were included in HPS. Although they received a similar benefit to the diabetic group as a whole this failed to reach statistical significance due to the small size of the group. It remains uncertain when to initiate statin therapy in people with T1DM nevertheless it seems reasonable to extrapolate the trial data from type 2 to type 1 diabetes. While there is now a very large evidence base supporting the use of statins in T2DM even in patients with “normal” LDL cholesterol levels there still exists a significant increase in adverse outcomes related to coronary artery disease in statin-treated patients. This fact has been referred to as the residual risk. Attention is now focusing on how the resid- ual risk may be further reduced in patients with diabetes mellitus and whether additional attention to CVD risk fac- tors such as hypertriglyceridemia may be therapeutically beneficial. Evidence linking hypertriglyceridemia to CHD risk in diabetes mellitus Elevated LDL cholesterol is well established as a risk fac- tor for cardiovascular disease in patients with normal and abnormal glucose metabolism. But what evidence do we have that elevated triglycerides the most common lipid abnormality in T2DM poses a cardiovascular risk indepen- dently of hyperglycaemia elevated LDL and low HDL Is there evidence in the literature that lowering serum triglyc- erides reduces CHD risk and clinical outcomes Grow- ing evidence indicates that hypertriglyceridemia may be an independent risk factor for CAD in type 2 DM 17. However whether the atherogenicity is due to triglyceride particles per se or to their metabolic consequences is a matter of debate. In 1996 a Finnish group calculated that serum triglycerides were the major determinant of LDL size in both diabetic and nondiabetic subjects 18. They con- cluded that serum triglyceride levels should be kept as low as possible in subjects with T2DM to prevent atherogenic changes in LDL. Indeed there is growing epidemiological evidence to suggest that hypertriglyceridemia is a strong risk factor for CHD. The Paris Prospective Study in 1989 looked at 943 men with diabetes or impaired glucose toler- ance and found that elevated triglycerides were a risk factor for CHD but did not find that this risk was independent of cholesterol 19. During a mean follow-up of 11 years 26 of these 943 patients with abnormal glucose metabolism died from CHD. The distribution of plasma triglyceride level was clearly higher for the subjects who died from CHD compared to those who did not die from this cause or were alive at the end of follow-up. More recently the Hoorn study has shown hypertriglyc- eridemia to be an independent risk factor in patients with abnormal glucose metabolism 20. In this population- based cohort study which began in 1989 869 men and 948 women had participated. The aim of the study was to inves- tigate the association of triglyceride and non-HDL choles- terol concentration with cardiovascular disease in subjects with and without abnormal glucose metabolism. After 10 years the age and sex-adjusted hazard ratios for cardiovas- cular disease were 1.35 1.11–1.64 and 1.71 1.40–2.08 for high triglycerides and high non-HDL cholesterol respectively. After adjustment for abnormalities in glucose metabolism the hazard ratios for non-HDL cholesterol were 1.71 1.31–2.21 in normal glucose metabolism and 1.56 1.12–2.18 in abnormal glucose metabolism. Triglyc- erides were not a risk factor for cardiovascular disease in subjects with normal glucose metabolism HR 0.94 CI 0.73–1.22 however in patients with abnormal glucose metabolism the hazard ratio for cardiovascular disease was 1.54 1.07–1.22. In subjects with abnormal glucose metabolism the hazard ratio for the combined presence of high triglycerides and non-HDL cholesterol was 2.12 1.35–3.34 Table 13.1. There is a large body of evidence that implicates hyper- triglyceridemia as a risk factor for cardiovascular disease in both diabetic and nondiabetic patients 21 22. A large 1996 meta-analysis of 17 prospective trials with 57000 patients also concluded that elevated triglycerides are a risk factor for CHD in nondiabetic subjects also 23. There are several possible explanations for the discrepancy in contribution of hypertriglyceridemia to CHD risk in euglycemic and dysg- lycemic subjects. High fasting and in particular postpran- dial triglyceride levels in patients with abnormal glucose metabolism are due to defective insulin action in the liver

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TABLE 13.1 Hazard ratios 95 CI of cardiovascular disease CVD for medians of triglycerides TG and non-HDL-cholesterol stratified for glucose metabolism from 20. Normal glucose metabolism Abnormal glucose metabolism n Cases CVD n Cases CVD Dichotomised Age- and sex-adjusted High TG a 547 112 1.10 0.86–1.41 314 111 1.67 1.16–2.39 High non-HDL b 647 153 1.67 1.30–2.15 260 95 1.67 1.20–2.33 Mutually adjusted c High TG 547 112 0.94 0.73–1.22 d 314 111 1.54 1.07–2.22 d High non-HDL 647 153 1.70 1.31–2.21 d 260 95 1.56 1.12–2.18 d Multivariate model e High TG 529 105 0.70 0.53–0.92 303 106 1.48 1.00–2.20 High non-HDL 629 144 1.54 1.17–2.03 253 90 1.20 0.84–1.71 Combined categories Age- and sex-adjusted Low non-HDL low TG 509 75 1 107 25 1 Low non-HDL high TG 181 28 0.96 0.62–1.48 113 32 1.03 0.55–1.93 High non-HDL low TG 281 69 1.711.23–2.37 59 16 1.13 0.67–1.91 High non-HDL high TG 366 84 1.60 1.17–2.19 201 79 2.12 1.35–3.34 Multivariate model e Low non-HDL low TG 497 72 1 105 24 1 Low nonHDL high TG 173 25 0.69 0.44–1.10 109 32 1.38 0.79–2.41 High non-HDL low TG 273 64 1.54 1.09–2.16 59 16 1.09 0.57–2.07 High non-HDL high TG 356 80 1.07 0.77–1.50 194 74 1.73 1.06–2.81 a Cut-off points for triglycerides are 1.4 mmol/l in men and 1.3 mmol/l in women medians b Cut-off points for non-HDL-cholesterol are 5.2 mmol/l in men and 5.3 mmol/l in women medians c Age- and sex-adjusted d Interaction between triglyceride ∗ non-HDL-cholesterol ∗ glucose metabolism status p 0.14 e Adjusted for age sex waist-to-hip ratio hypertension prevalent cardiovascular disease smoking and alcohol consumption

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122 Management of associated risk factors and disease and peripheral tissues. This results in impaired suppression of hepatic VLDL production reduced lipoprotein lipase activity and impaired clearance of triglyceride-rich particles due to competition for the same pathways. The net effect of this is the persistence of atherogenic triglyceride-rich par- ticles in the circulation in patients with abnormal glucose metabolism. These particles last longer than in patients with normal glucose metabolism and have increased athero- genicity. Many epidemiological studies have reported on asso- ciations between high triglycerides and the risk of CHD. Sarwar et al. reported primary data on triglyceride concen- trations from two prospective cohort studies in Circulation in 2007: the Rejkavik study and the European Prospec- tive Investigation of Cancer EPIC–Norfolk study which in total comprised 44237 Western middle-aged men and women predominantly Caucasian and a total of 3582 inci- dent cases of CHD including 1089 female cases 24. In addition previous meta-analyses were updated with a further 12 studies providing information from a total of 10000 CHD cases from 29 Western studies involving a total of 260000 participants. After adjustment for baseline values of several established risk factors odds ratio for CHD was 1.76 95 CI 1.39–2.21 in the Rejkavik study and 1.57 95 CI 1.10–2.24 in the EPIC-Norfolk study in a com- parison of individuals in the top third with those in the bot- tom third of the usual log-triglyceride values. Similar overall findings adjusted odds ratio 1.72 95 CI 1.56–1.90 were observed in the updated meta-analysis involving a total of 10158 cases of incident CHD from 262525 participants in 29 studies Figure 13.3. Although these data were not adjusted for normal and abnormal glucose metabolism they indicate consistent moderate and highly significant associations between triglyceride and CHD risk. Nordestgaard et al. examined the hypothesis that very high levels of nonfasting triglycerides were predictors of myocardial infarction ischemic heart disease and death 25. This was a prospective cohort study of 7587 women and 6394 men from the general Danish population followed from 1976 to 2004. Baseline nonfasting triglycerides were stratified into categories of increasing severity of hyper- triglyceridemia and compared to triglyceride levels of less than 88.5 mg/dl 1 mmol/L. Nonfasting triglyceride levels of 5 mmol/L or more ≥442.5 mg/dl were found to be pre- dictive of CHD. This study also supported the concept that nonfasting triglyceride levels more strongly predict CHD risk than levels measured after a 12- to 14-hour fast. Post- prandial lipoproteins are generally triglyceride-rich and if an individual has a predisposition to small dense LDL cholesterol or has insulin resistance then clearance of these Risk ratio 95 Cls top third vs. bottom third a Uncorrected for b Corrected for Western European and North American Populations Reykjavik Study No. of CHD cases 2459 within-individual triglycerides variations within-individual triglycerides variations EPIC-Norfolk Study Studies published between 1995 and 2005 Studies published before 1995 1123 3785 2791 Asian and Pacific Populations APCSC 850 1 2 1 2 FIG 13.3 Available prospective studies of triglycerides and CHD in essentially general populations. APCSC indicates Asian and Pacific Cohort Studies Collaboration. Includes three studies that were published before 1995 but were not included in the previous review from 24.

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Use of statins in both primary and secondary prevention of cardiovascular disease 123 lipoprotein particles can be delayed for up to 12 hours. The authors thus postulate that prolonged exposure of the endothelium to triglyceride-rich atherogenic remnant par- ticles or the associated states in which atherogenic lipopro- tein particles occur such as obesity or the metabolic syn- drome may explain why nonfasting triglycerides are more predictive of CHD risk. Data from this study also suggested that women have greater risk associated with hypertriglyc- eridemia than men. The risk for atherosclerosis-related events is significantly increased when triglyceride levels are between 150 mg/dl and 1000 mg/dl 1.7–11.3 mmol/L but whether this is the cause or effect remains unclear. Most pre- vious studies on triglycerides have focused on fasting levels that exclude remnant lipoproteins. However a previous Norwegian study found that nonfasting triglyceride levels of 3.5 mmol/L or more ≥309.7 mg/dl versus less than 1.5 mmol/L 132.7 mg/dl was associated with a fivefold risk of death from coronary heart disease and a twofold risk of total death in women. Again it should be emphasized that these data were not adjusted for normal and abnormal glu- cose metabolism however studies to date indicate that if anything the predictive value of triglycerides as a risk factor for CHD is even stronger in the setting of dysglycemia as demonstrated in the Hoorn study. There is strong epidemiological evidence to date that hypertriglyceridemia in an independent risk factor for CHD. Prospective randomized controlled trials examining this link are difficult given the large number of patients with diabetes who are already on statin treatment which modestly lower triglycerides and the presence of other lipoprotein and metabolic derangements that may con- found results. The data summarized above however sug- gest a consistent link between elevated plasma triglycerides and cardiovascular disease and that this effect is more pro- nounced in patients with abnormal glucose tolerance. Evidence that treating hypertriglyceridemia will reduce CV risk in DM Pharmacological interventions for hypertriglyceridemia include fibrates niacin nicotinic acid and omega-3 fish oils. The Fenofibrate Intervention and Event Lowering in Diabetes FIELD study assessed the effect of long-term fenofibrate therapy on cardiovascular events in patients with T2DM 26. Patients were randomized to receive either micronized fenofibrate 200 mg qd n 4895 or placebo n 4900. Marked hypertriglyceridemia ≥2.3 mmol/L was associated with a higher CVD risk than merely meeting criteria for the metabolic syndrome independent of HDL cholesterol. Multivariate modeling confirmed the indepen- dent contributions of HDL cholesterol triglyceride levels and blood pressure to CVD risk. This supports a contin- uous positive relationship between triglyceride concentra- tions and CVD. After 5 years of follow-up coronary events were observed in 5.9 of placebo patients and 5.2 of fenofibrate-treated patients but this difference was not sta- tistically significant. However fenofibrate treatment did significantly reduce total CVD events HR 0.89 95 CI 0.75–1.05 p 0.035 coronary revascularization progres- sion of albuminuria and the need for laser treatment of retinopathy. There was a significant 24 reduction in non- fatal MI outcome of first MI or CHD death. The secondary outcome of total cardiovascular disease events the compos- ite of cardiovascular disease death myocardial infarction stroke and coronary and carotid revascularization was significantly reduced by fenofibrate. It is possible that sta- tistical significance was not reached for the primary end point due to the fact that by the end of the study 17 of the placebo patients were taking lipid-lowering agents nonstudy drug e.g. statins compared with 8 in the fenofibrate group thus masking the treatment effect. The effect of fibrates is to lower triglycerides by 25. Individ- uals with elevated triglycerides thus appear to obtain the greatest benefits from fibrates in the study. In the Bezafibrate Infarction Prevention BIP 3090 patients with a previous myocardial infarction or stable angina total cholesterol of 180 to 250 mg/dl HDL choles- terol 45 mg/dl triglycerides 300 mg/dl and LDL choles- terol 180 mg/dl were randomized to receive either 400 mg of bezafibrate daily or placebo and followed for a mean of 6.2 years 27. Bezafibrate reduced triglycerides by 21 and raised HDL cholesterol by 18. No difference was apparent in the all-cause and cardiac mortality between the bezafibrate and placebo groups. However on post hoc analysis there was a significant reduction in the primary end point in 459 patients with high baseline triglycerides ≥200 mg/dl or 2.26 mmol/L. The reduction in the cumu- lative probability of the primary end point by bezafibrate was 39.5 p 0.02. Bezafibrate may thus have a promi- nent role in the management of dyslipidemia and CHD when targeted to a subgroup of patients with CHD. This supports the evidence from meta-analyses and epidemio- logical studies that triglycerides are indeed an independent

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124 Management of associated risk factors and disease risk factor for CHD in patients with both normal and abnormal glucose metabolism. The authors subsequently evaluated the effect of bezafibrate on the incidence of MI in patients enrolled in the BIP study who met the crite- ria for the metabolic syndrome 28. The study sample for this post hoc subgroup analysis comprised 1470 patients aged 42 to 74 years who were randomly assigned to receive bezafibrate 400 mg daily 740 patients or placebo 730 patients. The follow-up period was 6.2 years for events and 8.1 years for mortality data. New myocardial infarc- tion was recorded in 82 patients from the bezafibrate group 11.1 and 111 patients 15.2 from the placebo group p 0.02. Bezafibrate was associated with a reduced risk of any MI and nonfatal MI with hazard ratios of 0.71 95 CI 0.54–0.95 and 0.67 95 CI 0.49–0.91 respectively. The cardiac mortality risk tended to be lower in patients taking bezafibrate HR 0.74 95 CI 0.54–1.03. However post hoc analysis on the effect on MI risk of specifically low- ering triglycerides within this group with metabolic syn- drome was not performed. The primary prevention trial the Helsinki Heart study also showed that treatment with the fibric acid derivative gemfibrozil significantly reduced major cardiovascular events. The Diabetes Atherosclerosis Intervention Study DAIS demonstrated that reduction of triglycerides with fibrates has coronary angiographic benefit 29. This study was designed to assess the effects of correcting lipoprotein abnormalities with fenofibrate on coronary atherosclerosis in T2DM. DAIS took place in 11 clinical centres in Canada Finland France and Sweden. In this study 731 men and women with T2DM were screened by metabolic and angio- graphic criteria of these 418 were randomly assigned to receive fenofibrate 200 mg daily or placebo for at least 3 years. Half of the participants had a clinical history of coro- nary disease making this a primary and secondary preven- tion trial. T otal plasma cholesterol HDL cholesterol LDL cholesterol and triglyceride concentrations all changed sig- nificantly more than baseline in the fenofibrate group n 207 than in the placebo group n 211. The fenofi- brate group showed a significantly smaller increase in per- centage diameter stenosis on coronary angiogram than the placebo group mean 2.11 vs. 3.65 p 0.02. Although the trial was not powered to examine clinical end points there were fewer in the fenofibrate than placebo group 38 vs. 50. Although there was angiographic benefit in the set- ting of reduction of hypertriglyceridemia as in most trials on triglycerides it is difficult to deduce if this is a direct triglyceride-lowering effect or the result of correction of other lipoprotein abnormalities. Other agents effective at lowering triglycerides include niacin nicotinic acid and fish oils. However the evidence for these agents in T2DM is relatively sparse and most tri- als focus on elevation of HDL cholesterol and cardiac end points rather than the effects of lower serum triglycerides. The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol ARBITER was a random- ized double-blind study in which patients were assigned to receive extended-release niacin 500 mg titrated to 1000 mg qid n 87 or placebo n 80 on a background statin therapy 30. The primary end point of the study was change in carotid intima media thickness CIMT after 1 year of niacin treatment. Despite a significant 21 increase in HDL cholesterol levels in patients receiving niacin the overall difference in CIMT progression between the niacin- and placebo-treated groups only tended toward significance p 0.08. No studies on niacin have been conducted in diabetes due to concerns with regard to worsening of hyper- glycemia. However although niacin at a dose of 2.5 g/day increases fasting glucose by 4–5 and HbA1C by ∼0.3 these increases are modest transient and reversible and typically amenable to adjustments in oral hypoglycemic regimens without discontinuing niacin. Two large trials on the addition of niacin to statin therapy that include patients with diabetes mellitus—AIM-HIGH and HPS2- THRIVE—are currently underway. These are primarily tar- geted at increasing HDL cholesterol in patients at target LDL but will provide useful information. Discussion Hypertriglyceridemia is associated with a constellation of metabolic abnormalities most notably those that comprise the metabolic syndrome. While the metabolic syndrome and fasting hyperinsulinemia are recognized as indepen- dent risk factors for CHD whether elevated triglycerides represent an independent marker of cardiovascular risk remains controversial. The approach to diabetic patients with LDL cholesterol at or below target but who have elevated plasma triglycerides and low HDL cholesterol is equally a matter of some debate. However a mounting body of epidemiological evidence including several meta- analyses over the past 20 years as reviewed above suggests that hypertriglyceridemia may confer additional risk and that this risk may be greater in patients with abnormal

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Use of statins in both primary and secondary prevention of cardiovascular disease 125 glucose metabolism. Post hoc analysis of several large prospective trials mentioned above has also pointed toward an increased CHD risk with elevated plasma triglycerides. More recent interventional and intention-to-treat trials have shown varying degrees of clinical benefit in treat- ing hypertriglyceridemia in diabetes mellitus. Such clin- ical outcomes range from improved CHD mortality and improved outcomes to angiographic benefit and coronary plaque regression. Ongoing studies such as ACCORD will provide additional information. We suggest that all patients with T2DM should be on a statin to lower LDL cholesterol and thus reduce cardio- vascular risk. The ADA currently recommends initiating a statin for primary prevention when LDL cholesterol is above 3.36 mmol/L 130 mg/dl with the goal of reducing LDL to less than 2.57 mmol/L 100 mg/dl. Target LDL cholesterol on current guidelines is less than 2.6 mmol/L we recommend the lowest possible LDL based on trial data from TNT. ATP III would suggest that a target of LDL cholesterol 70 mg/dl 1.8 mmol/L may be reasonable in patients with T2DM and CHD. This however must be taken in the context of increased risk of adverse events related to statin-lowering therapy on larger doses of these agents. Optimal HDL-cholesterol levels are 40 mg/dl 1.02 mmol/L in men a higher target may be more desirable in women 50 mg/dl or 1.28 mmol/L based on physiolog- ically higher HDL levels in the female population. Raising HDL levels pharmacologically in patients with diabetes is very difficult since the most effective agent increasing HDL is nicotinic acid which is relatively contraindicated in dia- betes mellitus. The evidence is lacking in patients with T1DM but it is reasonable to extrapolate much of this data to this cate- gory of patient in particular those with microalbuminuria. Patients with T1DM are typically younger and therefore clinical experience and intuition is required in this group with regard to initiation of statin therapy. One approach is to commence patients with T1DM on statin therapy above the age of 30 years or once micro- or macrovascular com- plications have developed. We agree with current ADA guidelines that triglycerides are a recognized target for intervention in diabetes and that optimal triglyceride levels are 150 mg/dl 1.7 mmol/L. Initial therapeutic intervention for hypertriglyceridemia is behavioural modification with weight loss increased physical activity and moderation of alcohol consumption. Improving glycemic control will also lower triglycerides. When LDL cholesterol is at or below target but triglyc- erides are elevated and HDL cholesterol suboptimal as in the introductory case to this chapter the physician may consider adding a fibrate niacin or fish oil therapy. For more modest hypertriglyceridemia 1.7–3.0 mmol/L fibrates such as fenofibrate gemfibrozil or bezafibrate can be considered as an adjunct to statin therapy. Nicotinic acid may also be used in combination with statins but must be used with caution in diabetes as the combination may worsen hyperglycemia which would require adjustment of glycemic treatment. There are also issues surrounding tol- erability due to facial flushing although a new formulation is now available containing laropiprant a novel flushing pathway inhibitor. High doses of niacin 3 g/day should generally be avoided in people with T2DM although lower doses may effectively treat diabetic dyslipidemia without significantly worsening hyperglycemia. References 1. Laasko M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes. 48:937–942 1993. 2. Owens D Maher V Collins P Johnson A T omkin GH. Cellu- lar cholesterol regulation: a defect in the type 2 non-insulin- dependent patient diabetic patient in poor metabolic con- trol. Diabetologia. 33:93–99 1990. 3. Bowie A Owens D Collins P Johnson A T omkin GH. Gly- cosylated low-density lipoprotein is more sensitive to oxi- dation. Implications for the diabetic patient. Atherosclerosis. 102 63–67 1993. 4. Schaefer PG T eerlink T Heine RJ. Clinical significance of physiochemical properties in diabetes. Diabetologia. 48:808–816 2005. 5. Mastorikou M Mackness M Mackness B. Defective metabolism of oxidised phospholipids by HDL from peo- ple with type 2 diabetes. Diabetes. 55:3099–3013 2006. 6. Haber EP Procopio J Carvalho CR Carpinelle AR New- sholme P Curi R. New insights into fatty acid modulation of pancreatic beta cell function. Int Rev Cytol. 248 1–41 2006. 7. Kahn R Buse J Ferrannini E et al. The metabolic syndrome: time for a critical appraisal: joint statement from the Amer- ican Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 289: 2289–2304 2005. 8. Lakka H-M Laaksonen DE Lakka TA et al. The metabolic syndrome and total cardiovascular disease mortality in middle-aged men. JAMA. 288:2709–2716 2002. 9. Howard G O’Leary DH Zaccaro D et al. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study IRAS Investigators. Circulation. 93:1809–1817 1996.

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126 Management of associated risk factors and disease 10. Pyorala K Pedersen TR Kjekshus J Fraergeman O Ols- son AG Thorgeirsson G. The Scandinavian Simvastatin Sur- vival Study 4S Group. Cholesterol-lowering with simvas- tatin improves prognosis of diabetic patients with heart dis- ease. Diabetes Care. 20:614–620 1997. 11. Goldberg RB Mellies MJ Sacks FM et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with aver- age cholesterol levels: subgroup analyses in the cholesterol and recurrent events CARE trial. The Care Investigators. Circulation. 98:2513–2519 1998. 12. The Long-term Intervention with Pravastatin in Ischaemic Disease LIPID Study Group. Prevention of cardiovascular events and death in pravastatin patients with coronary heart disease and a broad range of initial cholesterol levels. N Eng J Med. 339:1349–1357 1998. 13. Haffner SM Alexander CM Cook TJ et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired glucose levels. Arch Intern Med. 159:2661–2667 1999. 14. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvas- tatin in 20536 high-risk individuals: a randomized placebo- controlled study. Lancet. 360:7–22 2002. 15. Calhoun HM Betteridge DJ Durrington PN et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study CARDS: multi-centre randomised placebo-controlled trial. Lancet. 364:685–696 2004. 16. Deedwania P Barter P Carmena R et al. Reduction of low-density lipoprotein cholesterol in patients with coro- nary heart disease and metabolic syndrome: analysis of the treating to new targets study. Lancet. 368:919–928 2006. 17. Assmann G Schulte H Funke H von Eckardstein. The emer- gence of triglycerides as a significant independent risk fac- tor in coronary artery disease. Eur Heart J. 19Suppl M: M8–M14 1998. 18. Lahdenpera S Syvanne M Kahri J et al. Regulation of low- density lipoprotein particle size distribution in NIDDM and coronary disease: importance of serum triglycerides. Dia- betologia. 39:453–446 1996. 19. Fontbonne Eschweg E Cambien F et al. Hypertriglcy- eridemia as a risk factor of coronary heart disease mortal- ity in subjects with impaired glucose tolerance or diabetes. Diabetologia. 32:300–304 1989. 20. Bos G Dekker JM Nijpels G et al. A combination of high concentrations of serum triglyceride and non-HDL choles- terol is a risk factor for cardiovascular disease in subjects with abnormal glucose metabolism: The Hoorn study. Diabetolo- gia. 46:910–916 2003. 21. Ballantyne CM Olsson AG Cook TJ Mercuri MF Peder- sen TR Kjekshus J. Influence of low high-density lipopro- tein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 104 3046–3051 2001. 22. Despres JP Lemiieux I Dagenais GR Cantin B Lamarche B. HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study. Atherosclerosis. 153 263–272 2000. 23. Hokanson JE Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population- based prospective studies. J Cardiovasc Risk. 3:213–219 1996. 24. Sarwar N Danesh J Eiriksdottir G et al. Triglycerides and the risk of coronary heart disease: 10158 incident cases among 262525 participants in 29 western prospective studies. Cir- culation. 115 450–458 2007. 25. Nordestgaard BG Benn M Schnohr P et al. Nonfasting triglycerides and risk of myocardial infarction ischemic heart disease and death in men and women. JAMA. 2983: 299–308 2007. 26. Scott R O’Brien R Fulcher G et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9795 individuals with type 2 diabetes and various components of the metabolic syndrome. The Fenofibrate Intervention and Event Lowering in Diabetes FIELD study. Diabetes Care. 32:493–498 2009. 27. Secondary prevention by raising HDL cholesterol and reduc- ing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention BIP study. Circulation. 102 21–27 2000. 28. T enenbaum A Motro M Enrique Z et al. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med. 165 1154–1160 2005. 29. Effect of fenofibrate on progression of coronary-artery dis- ease in type 2 diabetes: the Diabetes Atherosclerosis Interven- tion Study DAIS a randomised study. Lancet. 357:905–910 2001. 30. Taylor AJ Sullenberger LE Lee HJ et al. Arterial Biology for the Investigation of the Treatment Effects of Reduc- ing Cholesterol ARBITER 2: a double-blind placebo- controlled study of extended-release niacin on atherosclero- sis progression in secondary prevention patients treated with statins. Circulation. 11023: 3512–3517 2004. Erratum in Circulation. 11023: 3615 2004. Circulation. 11124: e446 2005.

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14 The role of bariatric surgery in obese patients with diabetes: Primary or rescue therapy To Kill Diabetes Forever Click Here Praveena Gandikota 1 and Blandine Laferre ` re 2 1 Endocrine Fellow Endocrine Diabetes and Nutrition Division Department of Medicine St Luke’s Roosevelt Hospital New Y ork NY USA 2 Assistant Professor of Medicine Division of Endocrinology Diabetes and Nutrition Obesity Research Center Department of Medicine St Luke’s Roosevelt Hospital Center Columbia University College of Physicians and Surgeons New Y ork NY USA L E A R N I N G P OIN T S Obesity and type 2 diabetes mellitus T2DM are major public health issues that are closely related. Lifestyle modifications LSM with diet and exercise leading to weight loss are cornerstones of T2DM management along with pharmacologic therapy. Limitations are cost effectiveness and short-term effect for LSM and compliance cost and side effects for medications. Newer medications may help preserve beta-cell function over time. Bariatric surgery is increasingly becoming popular for management of morbid obesity and its related comorbidities including T2DM. Diabetes control improves for most patients after bariatric surgery with full remission in over 50 of patients. The mechanisms of remission include but are not limited to caloric restriction with weight loss and changes of the incretins particularly after gastric bypass GBP. Although bariatric surgery is approved for diabetic patients with BMI ≥ 35 kg/m 2 the use of surgery to treat diabetes in less obese individuals is currently proposed. Limitations to this approach are lack of high quality data on short and long term complications of the surgery and long-term data on diabetes remission and cost analysis. Emerging new endoscopic techniques may be an option in the future. Introduction The prevalence of type 2 diabetes mellitus T2DM and obe- sity is increasing worldwide and represents a considerable public health burden. Approximately half of patients with diabetes in the United States are obese. Medical therapy for patients with diabetes combines costly and often inefficient lifestyle modifications LSM with various medications some of them inducing unwanted weight gain and/or hypo- glycemia. However in the last few years management and prognosis of T2DM have changed considerably. Novel phar- macotherapies have emerged with not only the capability to preserve beta-cell function such as thiazolidinediones TZDs or incretin based therapies but also to decrease body weight incretins and amylin analogs. In addition full remission of diabetes is achieved in 40–80 of cases by various types of bariatric surgeries. T2DM a chronic disease leading to progressive beta-cell death and vascular compli- cations is now a curable disease after weight loss surgery and can go into remission 1 2. In view of the spectacular effect of bariatric surgery on T2DM it is understandable that bariatric surgery be proposed as treatment of T2DM independently of the beneficial weight loss effect i.e. in patients with body mass index BMI 35 kg/m 2 . This could be a particularly attractive alternative in some ethnic groups like Asians who have a high risk of T2DM at lower BMI compared to Caucasians. Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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128 Management of associated risk factors and disease The objective of this chapter is to discuss whether bariatric surgery should be offered as first-line therapy or as rescue therapy when medical options have failed to con- trol diabetes. In addition hypotheses on mechanisms of action of bariatric surgery on glucose homeostasis the role of bariatric surgery in treatment of patients with T2DM with BMI 35 kg/m 2 risks and benefits of different types of bariatric surgery and future techniques will be discussed. Possible mechanisms by which bariatric surgery improves T2DM Effect of weight loss T2DM is a very complex disorder with insulin resistance in the muscle and the liver impaired beta- and alpha-cell function impaired incretin effect and alteration of glu- cose homeostasis in the kidney and the brain. A significant degree of beta-cell failure and vascular complications are often present at the time of diagnosis of T2DM. Reduced calorie intake and increased physical activity are essential for the management of T2DM. Multiple studies have shown the effectiveness of LSM in preventing T2DM with a risk reduction up to 58. Sim- ilarly weight loss and LSM in patients with established T2DM are beneficial 3. A modest 10 weight loss is associated with significant improvement in diabetes and other obesity-related comorbidities such as hypertension and dyslipidemia. Contrary to LSM that result in weight loss of small magnitude and short duration 4 bariatric surgery results in weight loss of greater magnitude 40–50 excess weight loss EWL sustained over time up to 14 years 1 5. Weight loss is a key factor in the improvement of T2DM after bariatric surgery. Effect of incretins Resolution of T2DM after bypass procedures has been described within days of the surgery suggesting that factors other than weight loss could be responsible for the diabetes improvement. The change in incretins may explain part of diabetes remission after GBP . The two main incretins are glucagon like peptide 1 GLP1 and glucose- dependent insulinotropic peptide GIP produced by the L and K cells respectively. T ogether they are responsible for the “incretin effect” or the greater insulin response after oral glucose compared to intravenous glucose. The incretins play a key role in postprandial glucose-mediated insulin secretion. In addition GLP-1 decreases glucagon induces weight loss and in animal models decreased apoptosis and increased beta-cell mass. The incretin effect is blunted in T2DM. Both incretin levels and effect increase after GBP 6 7 but not after diet 8 or purely restrictive procedures 9. Levels of GLP-1 increase as early as 2 days 10 and persist up to 20 years 11. The mechanisms of increased incretin levels after GBP are not fully understood. The rapid delivery of nutrients to the lower intestine after bypass surgeries or after vertical sleeve gastrectomy VSG 12 may increase the production of GLP-1 by direct nutrient exposure of the L cells. This hypothesis has been fueled by results of ileal transposition in rodents 13. The foregut exclusion hypothesis emphasizes the role of exclusion of the proximal part of the gut from nutrients 14 suggesting the presence of a would-be anti-incretin factor secreted by the proximal small intestine. This hypothesis is the basis for the current trials with endoluminal sleeves see below. It is possible that both mechanisms play a role in the changes of incretin release and glucose homeostasis after GBP . Other possible mechanisms of successful weight loss and metabolic improvement after bariatric surgery include changes in ghrelin and PYY 9 15 bile acids 16 changes in taste patterns inflammatory markers gastric emptying and intestinal transit time 7 and possibly in gut flora 17. Role of bariatric surgery in T2DM: First-line therapy or rescue therapy when medical options fail Of the multiple pharmacological agents targeting phys- iopathological defects in diabetes the insulin sensitizer thi- azolidinediones TZD and incretin derived therapies have opened new perspectives for management of T2DM as they both have the potential to preserve beta-cell function. Pharmacological agents used to treat T2DM 18 are not without risks and side effects. Weight gain and/or the risk of hypoglycemia especially with sulfonylureas and insulin is a major hindrance in the management of the already obese patients. Additionally challenges occur in patients with associated conditions like renal failure or heart failure. However in spite of the various excellent pharmacologi- cal agents available in the United States 43 of patients with T2DM fail medical therapy and do not achieve the HbA1C target of 7 19. In a study by Holman et al only 31.9–44.7 of patients achieved an HbA1c 6.5 at 3 years with different insulin regimen 20. None of the medical clinical trials report diabetes remission.

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The role of bariatric surgery in obese patients with diabetes 129 Nearly 30 of patients who undergo bariatric surgery have T2DM 1 although about a third of these patients are undiagnosed 21. In the Buchwald meta-analysis 22 criteria used to define diabetes resolution was fasting blood glucose 100 mg/dl and/or HbA1c 6 off diabetes medications. The percentage of diabetes remission varies according to surgery: 95 after BPD/duodenal switch 80 after RYGBPP 80 with gastroplasty and 57–73 after gas- tric banding GB. The greater the malabsorption BPD and weight loss the more likely the patient will achieve diabetes remission. Significant improvement in T2DM has also been shown in the Swedish Obesity Study SOS a long-term observational prospective study that compared surgical versus nonsurgical groups 5. The surgical group fared better at both 2 years’ and 10 years’ follow-up with respect to decrease in glucose and insulin levels incidence as well as recovery from T2DM. In a randomized con- trolled trial RCT Dixon et al. showed that GB resulted in a 73 diabetes remission rate at two years compared to conventional medical interventions 13 23. The ben- efit of bariatric surgery include not only a ∼40 weight loss but the resolution and/or significant improvement of diabetes and most obesity-related comorbidities like hyper- lipidemia 70 hypertension 61.7 and of obstructive sleep apnea 85.7 22. Recent studies have shown a decreased mortality 24 particularly the mortality related to diabetes after bariatric surgery. Would patients failing medical treatment who tend to be older with longer duration of diabetes with less opti- mal access to care respond to bariatric surgery Which bariatric surgery is more likely to help patients achieve their blood glucose target and/or go into remission Should obese patients with BMI ≥ 35 kg/m 2 with T2DM be offered bariatric surgery as a first-line therapy It is difficult to answer these questions as the data are scarce and the qual- ity of surgical studies thus far is poor with a high attrition rate. Available surgical studies on diabetes remission often do not report data on diabetes control and/or duration 25. Diabetes duration when provided is short 23 26 and few patients 0.5 23 to 39 27 are insulin treated. The study by Schauer et al. 26 is the only one that pro- vides outcome data analyzed according to preoperative dia- betes status and duration. Patients with less severe disease had significantly better fasting plasma glucose and HbA1c post surgery compared with insulin-requiring patients with more severe disease. Additionally the longer the duration of diabetes the more likely patients were to remain on medi- cations and/or insulin. However the preoperative duration of T2DM did not result in significant differences in post- operative glucose control among the groups 26. Another issue in interpreting published data is the definition used for diabetes remission. As diabetes remission is indeed a novel concept 2 no uniform definition was used in previous surgical studies 22 23. The recent consensus statement proposed to define complete remission of T2DM as “normal glycemic measures HbA1c in the normal range fasting glu- cose 100 mg/dl for at least 1 year duration in the absence of active pharmacologic therapy or ongoing procedures” 2. Whether this clinical definition of diabetes remission is accompanied by reversal of the pathophysiological defects seen with diabetes remains to be demonstrated. According to the current guidelines bariatric surgery is approved for patients with BMI ≥ 40 kg/m 2 or BMI ≥ 35 kg/m 2 in the presence of any comorbidity. Less than 3 of the patients who qualify for bariatric surgery undergo this treatment of their obesity and over 200000 surgeries are performed yearly in the United States. As morbidly obese patients gain significant health and quality of life benefits from bariatric surgery an effort to increase the number of surgeries on patients with higher BMI 45 kg/m 2 is a rea- sonable approach 28. According to the latest ADA 2010 guidelines 18 bariatric surgery should be considered for adults with BMI ≥ 35 kg/m 2 and T2DM especially if dia- betes or other comorbidities are difficult to control with lifestyle and pharmacologic therapy. What defines “diffi- cult to control” and for how long a patient has to be failing medical therapy prior to being offered bariatric surgery is unclear. Identifying preoperative predictors of diabetes res- olution is critical not only for patient selection but also for determining which type of surgery would be the best. The amount of weight loss is clearly a major determinant. This is particularly true after GB when diabetes remission is directly proportional to the degree of weight loss 23. The duration of diabetes and/or preoperative insulin use decreases the chances of diabetes remission 26 27. This implies that the less the deterioration of beta-cell function at the time of surgery the higher the chances of diabetes remission. However even if patients do not go into remis- sion after bariatric surgery most of them will experience significant improvement of their disease and achieve glu- cose control on less medications 26. There are no data from RCT comparing aggressive medical treatment with bariatric surgery in morbidly obese persons. Even with the best medical scenario however results of bariatric surgery will be likely hard to match at least in the first 5–10 years after surgery.

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130 Management of associated risk factors and disease Gastric banding or gastric bypass There are three main categories of bariatric surgery. Restric- tive procedures with or without gastrectomy aim to reduce gastric volume in order to limit food intake and induce weight loss. These procedures include laparoscopic adjustable gastric banding GB vertical banded gastro- plasty VBG rarely performed now and vertical sleeve gas- trectomy VSG. The Roux-en-Y gastric bypass RYGBP surgery combines gastric restriction with some malab- sorption and is the most commonly performed proce- dure in the United States. Finally biliopancreatic diversion BPD is a procedure with significant malabsorption with Figure 14.1 or without gastric restriction. Although A Bypassed segment B Adjustable band Port C New stomach pouch Gastric sleeve D Part of stomach removed Stomach removed Bypassed segment FIG 14.1 Bariatric surgeries. A Laparoscopic adjustable gastric banding GB B Roux-en-Y gastric bypass RYGBP C biliopancreatic diversion BPD with duodenal switch D vertical sleeve gastrectomy VSG. http://www.mayoclinic.org/ bariatric-surgery/bariatric-procedures.html Figure used by permission of Mayo Foundation for Medical Education and Research. All rights reserved.

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The role of bariatric surgery in obese patients with diabetes 131 surgeons empirically tend to perform malabsorptive pro- cedures in patients with BMI 50 kg/m 2 rather than GB there is no data and/or guidelines determining the best surgery for a particular patient. The choice of the type of surgery should not be based on surgeons’ preference and/or on early 6–12 months weight loss outcome but rather on short- and long-term data generated by RCT comparing various surgical procedures. Collecting long-term data is essential to learn about the effect of bariatric surgery on weight loss resolution of comorbidities as well as compli- cations such as nutritional deficiencies. Data about nutri- tional deficiencies weight regain comorbidities resolution and overall morbidity are essentially poorly known as loss to follow-up is notably high for this patient population. In a recent review 29 only five studies were identified with data on nutritional deficiencies with at least 12 month follow-up and the data were suboptimal. Morbid obesity is associated with an increased mortal- ity. The mortality rate associated with bariatric surgery has been reported to be 0.1–1.1 22. In a recent prospec- tive multicenter observational study 28 the 30-day death rate was 0 after laparoscopic GB 0.2 after laparoscopic RYGBP and 2.1 after open RYGBP . These rates are compa- rable to the 90-day mortality rate of 1 seen after cholecys- tectomy. Both prospective e.g. SOS 24 and retrospec- tive studies 30 have shown decreased overall mortality after bariatric surgery. Specifically cause-specific mortality in the RYGBP surgery group decreased by 92 for dia- betes 30. Bariatric surgery is associated with early post- operative complications such as thromboembolism wound complications like infection/dehiscence pulmonary com- plications like atelectasis and late postoperative compli- cations like anastomotic stricture intestinal obstruction incisional hernias and gastrogastric fistula. In addition dumping syndrome can be disabling. Long-term metabolic and nutritional complications related to altered micronu- trient and vitamin absorption are frequently observed after malabsorptive surgeries 29 and need to be aggressively treated often for a lifetime. Vitamin D deficiency may require weekly doses of ergocalciferol 50000 units weekly or a few times a week and iron and B12 often are needed parenterally. Deficiencies need to be carefully monitored at least twice yearly for a lifetime. At present there are no established guidelines for mineral and vitamin supplemen- tation after bariatric surgery. Hyperinsulinemic hypoglycemia associated with histo- logical appearances of nesidioblastosis in pancreatectomy specimen is rare. It usually occurs 2 years or more after RYGBP 31. Patients present with severe postprandial neu- roglycopenic symptoms in the presence of elevated endoge- nous hyperinsulinemia. Dietary management with or without glucosidase inhibitors octreotide and other phar- macological treatment should always be tried first prior to performing partial pancreatectomy. The mechanism of nesidioblastosis is at present unknown. Bariatric surgery is the treatment of choice for morbid obesity with the additional benefit of diabetes improve- ment and/or remission in over 80 of cases. As all morbid obese individuals will greatly benefit from bariatric surgery long duration and/or poor control of diabetes should not be contraindications to the surgery. Long-term high-quality data 10 years on weight loss safety and nutritional complications are essential. These long-term studies will help establish predictors of success delineate the choice of surgery and help implement guidelines for vitamin supple- mentation. As the number of bariatric surgeries increases the number of patients in need of lifetime bariatric care will grow exponentially. Primary care physicians and/or endocrinologists need to be trained appropriately to opti- mize patient management both preoperatively and postop- eratively. Role of weight loss surgery in the treatment of patients with T2DM and BMI 35 kg/m 2 There are currently few studies of bariatric surgery on patients with T2DM and BMI35 kg/m 2 . In the RCT by Dixon et al. 23 patients with well-controlled T2DM of 2 years duration mean BMI of 37.1 kg/m 2 went into diabetes remission in 73 of cases after GB at 2 years the dropout rate was low versus 13 in the diet group 23. The studies from De Paula et al. with complicated surgeries including ileal transposition report high remission rate but a nonnegligible mortality at least in the initial report 32. A study reports remission of diabetes and improvement of insulin sensitivity 18 months after BPD in five patients with BMI 35 kg/m 2 33. A recent nonrandomized study by Shah et al. in Asian Indians reported 100 remission rate in 15 patients 3 months after GBP surgery. Preoperatively 80 of the patients were insulin treated diabetes control was poor with HbA1C ∼10 and diabetes duration was 9 years 34. The RCT by Dixon et al. provides the best evidence-based data to suggest the use of GB in patients

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132 Management of associated risk factors and disease with diabetes and lower BMI 23. The diabetes remission was directly related to the amount of weight loss and the preoperative HbA1C levels. Participants had fairly mild dia- betes. Whether these results can be achieved in a more severe diabetic population different ethnic groups and with a dif- ferent health care system is unknown. There is currently not enough evidence to suggest that bariatric surgery par- ticularly bypass should be indicated for patients with BMI 35 kg/m 2 . As for more invasive surgeries bypass ± ileal transposition it is unclear whether the risk they represent is worth their use in clinical practice outside of very well controlled research RCT. New techniques that can be an option in the future Endoluminal duodenal sleeve either in lean diabetic rats 14 or in rats with diet-induced obesity 35 improves glu- cose metabolism and induces weight loss. The human trials of endoluminal treatments of obesity are limited to restric- tive interventions such as intragastric balloons transoral gastroplasty and endoluminal vertical gastroplasty. More recently the duodenojejunal bypass sleeve the only endolu- minal sleeve studied in humans has been shown to promote weight loss and seems to improve glucose metabolism. This device aims to mimic the duodenal bypass effects of Roux- en-Y GBP without the need for intestinal anastomoses and may offer novel outpatient therapeutic modalities for obese patients with T2DM. Early data in humans are encouraging but long-term efficacy and safety data are lacking. In conclusion bariatric surgery should be the treatment of choice for patients with morbid obesity complicated by T2DM and with high metabolic and cardiovascular risks. The surgery has been proven to not only improve quality of life but also prolong life in these high-risk patients. In morbidly obese patients with T2DM even with poor con- trol bariatric surgery can result in remission in about 50 of cases an effect unmatched by medical treatment. There is not enough evidence to perform invasive bariatric surg- eries and/or to experiment with new surgical procedures in patients with lower BMI and/or with milder diabetes outside of well-controlled RCT. Optimizing chronic care after GB a noninvasive procedure to ensure proper weight loss and diabetes remission is important. Multidisciplinary teams including surgeons endocrinologists gastroenterol- ogists psychiatrists nutritionists and primary care are needed to follow up these patients. Bariatric surgery offers a unique model to understand the complexity of T2DM and help develop new treatments for this chronic disease. References 1. Pories WJ Swanson MS MacDonald KG et al. Who would have thought it An operation proves to be the most effec- tive therapy for adult-onset diabetes mellitus. Ann Surg. 2223:339–350 1995. 2. Buse JB Caprio S Cefalu WT et al. How do we define cure of diabetes Diabetes Care. 3211:2133–2135 2009. 3. Pi-Sunyer X Blackburn G Brancati FL et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care. 306:1374–1383 2007. 4. Wadden TA Sternberg JA Letizia KA Stunkard AJ Foster GD. Treatment of obesity by very low calorie diet behavior therapy and their combination: a five-year perspective. Int J Obes. 13Suppl 2:39–46 1989. 5. Sjostrom L Lindroos AK Peltonen M et al. Lifestyle dia- betes and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 35126:2683–2693 2004. 6. Laferre ` re B Heshka S Wang K et al. Incretin levels and effect are markedly enhanced 1 month after Roux-en-Y gas- tric bypass surgery in obese patients with type 2 diabetes. Diabetes Care. 307:1709–1716 2007. 7. Morinigo R Moize V Musri M et al. Glucagon-like peptide- 1 peptide YY hunger and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 915:1735–1740 2006. 8. Laferre ` re B Teixeira J McGinty J et al. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. J Clin Endocrinol Metab. 937:2479–2485 2008. 9. Bose M Machineni S Olivan B et al. Superior appetite hormone profile after equivalent weight loss by gastric bypass compared to gastric banding. Obesity Silver Spring. 186:1085–1091 2010. 10. le Roux CW Welbourn R Werling M et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg. 2465:780–785 2007. 11. Naslund E Gryback P Hellstrom PM et al. Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity. Int J Obes Relat Metab Disord. 215:387–392 1997. 12. Vidal J Ibarzabal A Nicolau J et al. Short-term effects of sleeve gastrectomy on type 2 diabetes mellitus in severely obese subjects. Obes Surg. 178:1069–1074 2007. 13. Strader AD Vahl TP Jandacek RJ Woods SC D’Alessio DA Seeley RJ. Weight loss through ileal transposition is accom- panied by increased ileal hormone secretion and synthesis

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The role of bariatric surgery in obese patients with diabetes 133 in rats. Am J Physiol Endocrinol Metab. 2882:E447–E453 2005. 14. Rubino F Forgione A Cummings DE et al. The mecha- nism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the patho- physiology of type 2 diabetes. Ann Surg. 2445:741–749 2006. 15. Olivan B T eixeira J Bose M et al. Effect of weight loss by diet or gastric bypass surgery on peptide YY3-36 levels. Ann Surg. 2496:948–953 2009. 16. Patti ME Houten SM Bianco AC et al. Serum bile acids are higher in humans with prior gastric bypass: potential con- tribution to improved glucose and lipid metabolism. Obesity Silver Spring. 179:1671–1677 2009. 17. Zhang H Dlbalse J Zuccolo A et al. Human gut microbiota in obesity and after gastric bypass. PNAS. 1067:2364–2370 2009. 18. American Diabetes Association. Diabetes Care. 33Suppl 1:S1–S2 2010. 19. Cheung BM Ong KL Cherny SS Sham PC Tso A W Lam KS. Diabetes prevalence and therapeutic target achievement in the United States 1999 to 2006. Am J Med. 1225:443–453 2009. 20. Holman RR Farmer AJ Davies MJ et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 36118:1736–1747 2009. 21. Residori L Garcia-Lorda P Flancbaum L Pi-Sunyer FX Laferre ` re B. Prevalence of co-morbidities in obese patients before bariatric surgery: effect of race. Obes Surg. 133:333–340 2003. 22. Buchwald H Avidor Y Braunwald E et al. Bariatric surgery: a systematic review and meta-analysis. JAMA. 29214:1724–1737 2004. 23. Dixon JB O’Brien PE Playfair J et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a ran- domized controlled trial. JAMA. 2993:316–323 2008. 24. Sjostrom L Narbro K Sjostrom CD et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 3578:741–752 2007. 25. Vetter ML Cardillo S Rickels MR Iqbal N. Narrative review: effect of bariatric surgery on type 2 diabetes mellitus. Ann Intern Med. 1502:94–103 2009. 26. Schauer PR Burguera B Ikramuddin S et al. Effect of laparo- scopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2384:467–784 2003. 27. Sugerman HJ Wolfe LG Sica DA Clore JN. Diabetes and hypertension in severe obesity and effects of gastric bypass- induced weight loss. Ann Surg. 2376:751–756 2003. 28. Purnell JQ Flum DR. Bariatric surgery and diabetes: who should be offered the option of remission JAMA. 30115:1593–1595 2009. 29. Shah M Simha V Garg A. Review: long-term impact of bariatric surgery on body weight comorbidities and nutri- tional status. J Clin Endocrinol Metab. 9111:4223–4231 2006. 30. Adams TD Gress RE Smith SC et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 3578:753–761 2007. 31. Service GJ Thompson GB Service FJ et al. Hyperinsuline- mic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 3533:249–254 2005. 32. Depaula AL Macedo AL Mota BR Schraibman V. Laparo- scopic ileal interposition associated to a diverted sleeve gas- trectomy is an effective operation for the treatment of type 2 diabetes mellitus patients with BMI 21-29. Surg Endosc. 236:1313–1320 2009. 33. Chiellini C Rubino F Castagneto M Nanni G Min- grone G. The effect of bilio-pancreatic diversion on type 2 diabetes in patients with BMI 35 kg/m2. Diabetologia. 526:1027–1030 2009. 34. Shah SS T odkar JS Shah PS Cummings DE. Diabetes remis- sion and reduced cardiovascular risk after gastric bypass in Asian Indians with body mass index 35 kg/m 2 . Surg Obes Relat Dis. 64:332–338 2010. 35. Aguirre V Stylopoulos N Grinbaum R Kaplan LM. An endo- luminal sleeve induces substantial weight loss and normalizes glucose homeostasis in rats with diet-induced obesity. Obe- sity Silver Spring. 1612:2585–2592 2008.

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16 Hyperglycemia should be avoided in critical illness and the postoperative period 17 Click Here For Best Diabetes Treatment 18 Kalpana Muthusamy 1 and John M. Miles 2 1 Clinical Fellow Division of Endocrinology Mayo Clinic Rochester MN USA 2 Professor of Medicine Endocrine Research Unit Mayo Clinic Rochester MN USA L E A R N I N G P OIN T S T o discuss evidence for and against the use of insulin infusion to control hyperglycemia in the critically ill. T o consider the role of hypoglycemia in the disparate results of large clinical trials investigating the use of intensive insulin therapy in the critically ill. T o review the use of nutrition and its potential influence on insulin requirements and outcomes in the critically ill. T o discuss mechanisms by which insulin infusion may modulate outcomes when used in critically ill patients. Introduction Hyperglycemia is a frequent finding in acute care hospitals with a prevalence rate in excess of one-third of all inpatients 1 2. Among patients with hyperglycemia admission glu- cose 7 mmol/L or random glucose 11.1 mmol/L only two-thirds are known to have diabetes the remainder either have newly diagnosed diabetes or temporary “stress” hyperglycemia. Hyperglycemia has been identified as an independent predictor for higher infection rates 3 4 and increased mortality 5 6 in critically ill and postopera- tive patients. A number of large clinical trials have been conducted over the past 15 years to address the question of whether intravenous infusion of insulin could improve morbidity and mortality in the critically ill. One of these trials 7 led to a consensus conference convened in 2004 by the American College of Endocrinology and cosponsored by the American Diabetes Association the American Heart Association the American Society of Anesthesiologists the Endocrine Society the Society of Critical Care Medicine and the Society of Thoracic and Cardiovascular Surgeons 8. The consensus conference concluded again on the basis of a single clinical trial 7 that blood glucoses should be maintained 6.1 mmol/L in critically ill patients and that insulin infusion was the means to achieve that goal. The conference also recommended that a preprandial glucose target 6.1 mmol/L in patients who are eating on general medical-surgical wards should be adopted. This latter rec- ommendation which in our view had and has very little evidence to support it is not the subject of this chapter and will not be discussed further. Instead we will address mech- anisms of hyperglycemia-related morbidity and mortality in the critically ill and will undertake a detailed review of the evidence supporting the use of insulin infusion in the ICU with emphasis on ten large clinical trials. We will also dis- cuss the importance of hypoglycemia nutritional support and imprecision in blood glucose testing in interpreting the results of these trials. We conclude that there is strong evidence to support the use of insulin infusion to control hyperglycemia in the critically ill but very little evidence to indicate what the blood glucose target should be. Mechanisms mediating adverse effects of hyperglycemia during critical illness During acute illness hyperglycemia is exacerbated in peo- ple with diabetes as a consequence of the release of counter- regulatory hormones and cytokines 9. The same mech- anisms along with subtle defects in insulin secretion contribute to stress or temporary hyperglycemia in some nondiabetic individuals. The exact mechanisms by which Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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Hyperglycemia should be avoided in critical illness and the postoperative period 135 hyperglycemia mediates adverse outcomes such as infection and increased mortality are not fully understood how- ever nor are the mechanisms responsible for improved outcomes resulting from correction of hyperglycemia. Several interesting hypotheses have been proposed involv- ing both metabolic and non-metabolic pathways 10. Hyperglycemia can cause direct cellular damage as well as indirect effects via increased generation of reactive oxy- gen species. Although the normal protective response of cells to hyperglycemia is to downregulate glucose trans- port expression and localization of GLUT-1 and GLUT-3 in several cell types has been shown to be increased by elevated levels of cytokines growth factors and hypoxia which often occur together in the critically ill potentially leading to cellular glucose overload 11. Increased sub- strate availability for glycolysis results in excess superoxide formation that can overwhelm the normal detoxification process leading to mitochondrial dysfunction 11. Inten- sive insulin therapy has been shown to reverse or prevent hepatic mitochondrial abnormalities noted with critical ill- ness 12. There is also evidence showing improvement in the phagocytic and bactericidal activities of polymor- phonuclear leukocytes with improved glycemic control in diabetic subjects thus enhancing immunity 13. Glucotox- icity can also impair β-cell secretory function potentially initiating a vicious cycle of relative insulin insufficiency and further increases in glucose levels 14. The pleiotrophic effects of insulin independent of its glucose-lowering effect have attracted considerable atten- tion as a contributor to clinical benefits. Insulin has been shown to have anti-inflammatory properties producing a decrease in concentration of acute phase reactants. Reduced mortality and organ failure in critically ill patients treated with insulin infusion is associated with decreased high sen- sitivity C-reactive protein levels suggesting but not prov- ing a role for reduced inflammation in improved out- comes 15. Modulation of nitric oxide synthase expres- sion and activity by insulin therapy mitigates the increased nitric oxide levels seen during stress thus protecting against endothelial damage 16. Endothelial adhesion molecules such as ICAM-1 and E-selectin despite being compa- rably elevated at admission are lower during intensive insulin therapy indicating reduced endothelial activation 16. These factors in combination likely help maintain the integrity of the microvasculature leading to less organ damage and providing survival benefits. There is also evidence that insulin therapy may favor- ably influence outcomes by improving altered lipid home- ostasis. Plasma free fatty acids FFA are elevated in the critically ill in spite of hyperinsulinemia due to resistance to insulin’s antilipolytic effects in adipocytes 17. This is of potential importance because elevated FFA contribute to acute endothelial dysfunction 18 have pressor effects 19 and can contribute to the dyslipidemia of critical ill- ness by driving hepatic VLDL production 20. Mesotten et al. in a post hoc analysis of a large clinical trial found that intensive insulin therapy in the critically ill produced sub- stantially lower triglyceride levels 21. There was a four- to fivefold increase in mortality over a range of triglyceride levels although in a multivariate analysis HDL cholesterol had the strongest association with mortality. The mecha- nism for increased morbidity and mortality related to dys- lipidemia is not known but could involve impairment of reticuloendothelial function as discussed elsewhere 22. Other proposed mechanisms of benefit are insulin-induced increase in expression of adiponectin 23 and a potential role in enhancing innate immunity 24. Collectively the evidence supports a role for nonglycemic effects of insulin therapy in improving outcomes in critical illness although the relative contribution of these factors is an important area for future research. Large intervention studies Background As recently as a decade ago at a time when hyperglycemia was recognized as a predictor of adverse outcomes elevated blood glucose in the critically ill was often ignored. How- ever since that time the results of large clinical trials have forced a reconsideration of this attitude of indifference. These results have produced wide swings in the pendulum of expert opinion. Initially the changes were subtle pro- posed glucose targets were quite liberal and in fact were based more on associations than on harder evidence blood glucose levels of 12.2 mmol/L were considered by some to be optimal as they were associated with improved post- operative infection rates 25. In 2004 an expert committee declared that a glucose target of 6.1 mmol/L was appropriate for most criti- cally ill patients 8. As recently as January 2009 the ADA stated in a position paper that “Critically ill surgical patients’ blood glucose levels should be kept as close to 110 mg/dl 6.1 mmol/L as possible . . .” 26. Four months later in a joint statement with the American Association of Clin- ical Endocrinologists the ADA declared that “a glucose

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136 Management of associated risk factors and disease range of 140 to 180 mg/dl 7.8 to 10.0 mmol/L is rec- ommended for the majority of critically ill patients.” 27. What is the explanation for these wide shifts in prevailing views In 2001 Van den Berghe and colleagues published a landmark study hereafter referred to as “Leuven 1” of more than 1500 patients in a surgical ICU. In this study they aimed for and achieved a target blood glucose of 4.4–6.1 mmol/L in an intensive control group and 10–11.1 mmol/L in a conventional treatment group 7. The in- hospital mortality was significantly lower in the intensive group at 7.2 compared to 10.9 in the conventional arm. They also reported a reduction in mortality during intensive care from 8 in the conventional group to 4.6 in the intensive group 42 relative reduction. Most of these benefits were observed in the patients who stayed in the intensive care unit ICU longer than 5 days. There was significant improvement in morbidity related to fewer days on mechanical ventilation shorter ICU stay reduced infection acute renal failure critical-illness polyneuropa- thy and fewer blood transfusions. These overwhelmingly positive results were the sole basis for the target recom- mended in the 2004 consensus statement and obviously the driving force behind the January 2009 ADA recommenda- tion. A recently published survey revealed that the majority of intensivists prefer a target blood glucose of 6.1 mmol/L 28. Although there was little published disagreement with the guidelines it is not clear that they penetrated to the local level a 2008–2009 informal poll of over 30 medium-sized hospitals in the United States most of which did not have a critical care service revealed that whereas there was a general recognition of the value of insulin infusion in the critically ill virtually none were strictly adhering to the 6.1 mmol/L benchmark JMM unpublished observations. In March 2009 the results of the NICE-SUGAR trial were published demonstrating that excessively tight control tar- get 6.0 mmol/L average glucose 6.4 mmol/L might actually be harmful compared to a less stringent target 10 mmol/L average glucose 8.0 mmol/L 29. The odds ratio for death in the intensive arm of this study was 1.14 p 0.02. The ADA-AACE consensus statement relaxing the guidelines was published less than two months later. Where does this leave us The results of meta-analyses 30 31 conclude that intensive insulin therapy does not reduce mortality in critically ill patients and increases the risk of hypoglycemia although one report 31 acknowl- edges it might benefit surgical patients. Taken at face value it could be argued that these studies provide a rationale for abandoning intensive treatment with insulin infusion altogether. The fact that the authors of the ADA-AACE con- sensus statement still endorse intensive treatment albeit in a less aggressive form 26 indicates that they must see merit in the several studies that have reported benefit from this treatment. For this chapter we will review in detail the results of ten large clinical trials that have produced disparate difficult-to-reconcile results 7 29 32–39. We included all trials of 500 patients in which glycemic tar- gets were part of the study design but we excluded studies in which glucose infusion was employed in one group but not the other for the purpose of allowing infusion of insulin at higher rates than would otherwise be necessary to control hyperglycemia 40. Our purpose is to attempt to identify features of the studies that might explain divergent findings leading to conflicting conclusions and recommendations. Specifically we hoped to determine whether variables such as acuity of illness in the study population hypoglycemia blood glucose testing methodology and nutritional support might explain differences among studies. General findings Tables 15.1 and 15.2 Table 15.1 shows the ten studies in chronological order and provides details on trial design and study populations together with glucose targets and levels achieved. Eight of the studies were randomized controlled trials two used his- torical controls. Diabetes mellitus was an entry criterion for two of the studies in the other eight the majority of patients did not have diabetes. Patients were receiving nutritional support in eight of the studies but did not receive artificial nutrition in two 32 33. Table 15.2 provides information on severity of illness APACHE II scores and mortality. We believe that the first five studies should be con- sidered to indicate benefit from intensive insulin therapy whereas the second five studies should be considered neg- ative. Certainly this interpretation could be questioned. The DIGAMI study was likely underpowered and showed benefit in the whole cohort only with long-term follow-up. However in-hospital mortality was significantly improved with intensive therapy in the diabetic patients who were lower risk and not previously treated with insulin 32. The Portland and Stamford studies utilized historical controls an inherently weaker design but both had the strength of a large sample size. The Leuven 2 study has been interpreted as unequivocally negative by some authors because there was no difference in the primary end point i.e. mortal- ity in the aggregate cohort 35. However in the subset of individuals who were in the ICU for ≥3 days mortality

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Study Type of study Patient population Number of patients Diabetes intensive conventional intensive conventional DIGAMI 1997 32 RCT multicenter Coronary care unit 620 100 7.0–10.9 Usual care 9.6 11.7 Leuven-1 2001 7 RCT single-center Surgical ICU 1548 13 4.4–6.1 10–11.1 5.7 8.5 Furnary 2003 33 Historical controls single-center CABG 3554 100 variable 11.1 9.8 11.9 Krinsley 2004 34 Historical controls single-center Medical-surgical ICU 1600 17 7.8 Usual care 7.3 8.4 Leuven-2 2006 35 RCT single-center Medical-surgical ICU 1200 17 4.4–6.1 10–11.1 5.8 8.6 De La Rosa 2008 36 RCT single-center Medical-surgical ICU 504 29–32 4.4–6.1 10–11.1 6.5 8.2 VISEP 2008 37 RCT multicenter Medical-surgical ICU 537 30 4.4–6.1 10–11.1 6.2 8.4 Arabi 2008 38 RCT single-center Medical-surgical ICU 523 32–48 4.4–6.1 10-11.1 6.4 9.5 NICE-SUGAR 2009 29 RCT multicenter Medical-surgical ICU 6104 20 4.5–6.1 10 6.4 8.0 Glucontrol 2009 39 RCT multicenter Medical-surgical ICU 1078 16–21 4.4–6.1 7.8–10 6.5 8.0 TABLE 15.1 Trial design patient characteristics Mean blood glucose target mmoI/L Mean blood glucose achieved mmoI/L

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138 Management of associated risk factors and disease TABLE 15.2 APACHE scores and mortality data Mortality Relative Basis for difference reduction in in mortality v Study APACHE score Intensive Conventional mortality controls DIGAMI 1997 32 NR 19 at 1 year 26 30 NR followup Leuven-1 2001 7 9 median 7.2 in-hospital 10.9 34 ↓sepsis MOF Furnary 2003 33 NR 2.5 in-hospital 5.3 47 Cardiac related Krinsley 2004 34 15 median 14.8 20.9 20.9 ↓in subpopulation with septic shock neurological or surgical diagnosis Leuven-2 2006 35 23 mean 37.3 43 for 3 ICU days in- 40 52.5 for 3 ICU days NS 18P0.05 ∗ Multiple hospital De La Rosa 2008 36 16 mean 36.6 in-hospital 32.4 NS – VISEP 2008 37 20 mean 39.7 90 day 35.4 NS – Arabi 2008 38 23 mean 13.5 17.1 NS – NICE-SUGAR 2009 21 mean 27.5 24.9 Increased by 14 Increases in cardiovas- 29 cular death Glucontrol 2009 39 15 mean 15.3 17.2 NS – NR Not reported NS Not significant MOF multiple organ failure ∗ long-stayers 3 ICU days only. was significantly reduced with intensive therapy. This delay in apparent benefit was also observed to a lesser extent in the surgical ICU study from the same investigators 7. The benefit in the long-stayers in ICU in Leuven 2 was least apparent in patients in the highest quartile of APACHE II scores 35. The mortality data in Table 15.2 clearly indicate the Leuven 2 patients to be the sickest of those in any of the ten studies. It has been pointed out that a failure of benefit with short-term therapy could dilute to insignificance an effect in patients with longer ICU stays 41. The last five of the studies found no benefit of inten- sive insulin therapy and the NICE-SUGAR study actually reported higher mortality in intensively treated patients 29. Three of the five studies were smaller and perhaps underpowered. Furthermore in two of the five studies the glucose target range in the control group was lower than the Leuven trials. The threshold for initiating insulin infusion a higher value than the actual target range in many studies in the control group was lower than in the Leuven studies in two of the trials 29 37 and not stated in two others 38 39. It is therefore not surprising that the average glu- cose in the control group of four of the five negative studies was lower or equal to the average glucose in the control group of all of the positive studies. Mesotten and van den Berghe suggest that this is due to the strong influence of the positive studies on the design of the subsequent negative studies and could have minimized differences in mortality between groups 42. Role of hypoglycemia in interpretation of study results Table 15.3 Hypoglycemia defined as a blood glucose ≤2.2 mmol/L or 40 mg/dl was reported in the landmark van den Berghe study of surgical patients as more common in patients receiving intensive treatment than in the control group but not leading to hemodynamic deterioration or convul- sions. It was not discussed further. The frequency of hypo- glycemia was remarkably low in the Krinsley study of med- ical ICU patients especially considering that a more liberal definition of hypoglycemia 3.3 mmol/L was employed. The Leuven 2 study was the first of the trials to indicate that hypoglycemia might be responsible for mortality in some patients. In three of the five subsequent negative studies there was an association between hypoglycemia and mortality 37–39. An association between hypo- glycemia and mortality was confirmed in the NICE-SUGAR study and the authors speculated that hypoglycemia could be partly responsible for adverse effects observed with intensive therapy 29. Thus there is substantial evidence that hypoglycemia could have material harmful effects on

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Definition of Study hypoglycemia mmoI/L Hyperglycemia should be avoided in critical illness and the postoperative period TABLE 15.3 Hypoglycemia data 139 Incidence of hypoglycemia Association between Intensive Conventional hypoglycemia and mortality DIGAMI 1997 32 3.0 15.0 0.0 NR Leuven-1 2001 7 Furnary 2003 33 ≤2.2 NR 5.1 NR 0.8 NR No NR Krinsley 2004 34 3.3 1.4 0.9 No Leuven-2 2006 35 ≤2.2 18.7 3.1 Yes De La Rosa 2008 36 ≤2.2 8.3 0.8 NR VISEP 2008 37 ≤2.2 12.1 2.1 Yes Arabi 2008 38 ≤2.2 28.6 3.1 Yes NICE-SUGAR 2009 29 ≤2.2 6.8 0.5 No Glucontrol 2009 39 ≤2.2 8.7 2.7 Yes outcomes in patients receiving intensive treatment with insulin infusion. It is noteworthy that hypoglycemia is conventionally defined in the critical care literature as a value ≤2.2 mmol/L 7 29 35–39. It appears that this definition is used because of a prevailing view that less severe hypoglycemia is not clin- ically important. In fact a recent survey of adult intensivists showed that over 40 thought hyperglycemia was more dangerous than hypoglycemia and a majority preferred a target of 6.1 mmol/L 28. Ironically in the same survey the median value for blood glucose that was considered to be the hypoglycemic threshold was 3.33 mmol/L. In fact severe symptoms of hypoglycemia can occur at glucose con- centrations much higher than 2.2 mmol/L and the coun- terregulatory response including sympathoadrenal activa- tion routinely occurs as glucose levels descend through the 3.6–3.8 mmol/L range 43. Moreover defective counter- regulation 41 and lack of clinical cues of hypoglycemia may make hypoglycemia more difficult to identify but not necessarily less threatening. For this reason hypoglycemia experts have argued that the threshold for clinical important hypoglycemia lies in the 3.5 mmol/L 44 to 3.9 mmol/L 45 range. It is therefore simply not reasonable to dismiss glucose levels of 2.3–3.8 mmol/L as clinically unimpor- tant in patients who are intubated 7 receiving propo- fol or other sedatives 36 38 or both. Most of the stud- ies reviewed here are encumbered by the limitation that clinically important hypoglycemia may have been excluded from consideration by an inappropriately narrow definition of hypoglycemia. A rather high incidence of hypoglycemia 15 was reported in the intensive arm of the DIGAMI study 32 but this is likely because a liberal definition 3.0 mmol/L of hypoglycemia was used. The incidence of “severe” 2.2 mmol/L hypoglycemia in the DIGAMI study is not known. In summary it is clear that hypoglycemia is a potentially serious limitation to the pursuit of near-euglycemia with intensive insulin therapy in the critically ill. It is possible even likely that hypoglycemia mitigated beneficial effects of intensive insulin therapy in negative 29 35–39 and equiv- ocal 35 studies. Failure to consider less severe 2.3–3.8 mmol/L hypoglycemia is a serious limitation of these stud- ies. A recent retrospective analysis of hypoglycemia in 1109 patients from two Australian ICUs demonstrated a step- wise and significant increase in mortality associated with increasingly severe hypoglycemia including patients with glucose values of 4.0–4.5 mmol/L 46. This indicates that even very mild hypoglycemia may have significant effects on survival in the critically ill. Methodology for glucose testing The observation that glucose values 4.0–4.5 mmol/L not considered to be in the hypoglycemic range by even the most liberal definition of hypoglycemia could be associ- ated with increased mortality is difficult to understand. In people with diabetes there may be a shift upward in the glycemic threshold for the sympathoadrenal response 47. Another possible explanation would apply to nondiabetic as well as diabetic patients and relates to the methods used to measure glucose in the critically ill. Point-of care POC blood glucose testing was used in a number of the studies and it has been shown to be very inaccurate and imprecise

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140 Management of associated risk factors and disease especially during hypoglycemia. CLIA defines inaccuracy with POC glucose devices as values 20 different from the laboratory value except in the case of hypoglycemia where values 0.83 mmol/L different are considered inac- curate. Thus a true glucose level of 4.0 mmol/L could be reported as 3.2 mmol/L or a true level of 2.8 could be reported as 3.6 mmol/L and both values would be con- sidered to be accurate. Critchell et al. reported that POC devices when used by trained laboratory technicians were inaccurate in 19 of samples 48. Kanji et al. found the agreement of POC measurements with a central laboratory to be 56 and only 26 in hypoglycemia samples 49. The potential for error when POC devices are used is thus readily apparent. POC devices may also systematically over- estimate true glucose 48. Among the large clinical trials reviewed here a bedside meter was used exclusively in two of the negative studies 36 38. NICE-SUGAR used both a blood gas machine which has excellent precision and accu- racy 50 and a POC device. When a POC device was used in NICE-SUGAR laboratory confirmation was obtained only 60 of the time. Even when hypoglycemic values were confirmed it should be recognized that the antecedent glu- cose level was unconfirmed and thus could have dictated an inappropriate decision about insulin infusion rate that led to the subsequent hypoglycemic episode. The Leuven 1 study used a blood gas instrument and Leuven 2 used the Hemocue a POC device that is designed for clinical use not for self-monitoring. The VISEP study utilized both a blood gas device and the Hemocue 37. Thus the tech- niques used for blood glucose measurement in several of the studies may have contributed to hypoglycemia failed to identify hypoglycemia and even overcalled hypoglycemia. The role of nutritional support in results of trials A physician so the story goes once gave 1 mg of thyroxine daily to an elderly frail woman who complained of fatigue. When the patient developed acute atrial fibrillation and died the physician concluded that death was to be expected from thyroxine administration and that it should never be used again. This kind of reasoning has been attributed to the “Chagrin Factor” which derives from aversion to a course of action that has produced an unexpected poor outcome 51. Nutrition support is often used in the care of the criti- cally ill affecting glucose levels and insulin requirements. In two of the ten large trials 32 33 nutrition was given to very few patients 22. Enteral nutrition was used almost exclusively in the study of Krinsley J Krinsley personal communication to JMM . Enteral nutrition was used pri- marily in four studies 29 36 38 39 whereas enteral and parenteral nutrition were used equally in the VISEP study 37. In the two Leuven studies the majority of nutritional support was parenteral at least for the first 7 days in the ICU. This has an impact on interpretation of the data from the Leuven 1 study since parenteral nutrition is known to increase infection rates 52 and differences in infection especially sepsis accounted for most of the differences in mortality between the intensive and control groups in Leu- ven 1 22 53. Enteral feeding does not appear to confer the same risk of infection 53 although control data on this issue are not available. In contrast the differences in mortality in the NICE-SUGAR study were based primar- ily on cardiovascular outcomes which may be influenced adversely by hypoglycemia 54. In addition to the route of nutrition the amount of nutrition given may influence the results of studies of glycemic control in the critically ill. We calculated energy supply in the Leuven 1 trial in relation to estimated basal energy expenditure and thus basal energy requirements using the Harris-Benedict equation 22. This can be done for any study in which the calories given are reported and height and weight are provided. In the absence of height and weight data the calculation can be made from body mass index and estimated height 22. We therefore calculated energy given in relation to energy requirements in five of the reports where adequate information was available 7 29 35–37 using data on the intensively treated arm of the studies. Height was estimated from online information e.g. http://forums.interbasket.net/ f10/average-male-height-by-country-updated-9287/ and http://en.wikipedia.org/wiki/Human height. Including protein in the energy calculation estimated to be 1.0 g/kg per day when not provided the values used for daily feeding rate were 27 kcal/kg for Leuven 1 22 25 kcal/kg for Leuven 2 35 25.5 kcal/kg for De La Rosa 36 1236 kcal/day for VISEP 37 from online appendix and 1624 kcal for NICE-SUGAR 29 from online appendix. In several of the studies 7 29 37 the average energy intake on days 3–5 was used. Energy intake in the Arabi study was provided only as an average given over the first 7 days and was much lower than expected based on the method for feeding described by the authors—using the Harris-Benedict equation and adjusting for stress factors

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Energy supply BEE Energy supply BEE Hyperglycemia should be avoided in critical illness and the postoperative period 141 140 130 120 110 100 90 80 70 Leuven 1 Leuven 2 De La Rosa VISEP NICE- SUGAR FIG 15.1 Energy supply expressed as a percentage of estimated basal energy expenditure BEE calculated from the Harris-Benedict equation in five studies. 38 for this reason we excluded the Arabi study from the analysis. Energy intake expressed as a percentage of estimated basal energy requirements is shown in Figure 15.1. The feeding rates among the various studies are surprisingly different. The amount of nutrition given in the Leuven studies although within published guidelines is greater than probable energy requirements in the critically ill 55 and may account for the rather high insulin requirements in the intensively treated groups in those studies especially noteworthy considering that very few of the participants had diabetes. In contrast studies that relied primarily on enteral feedings such as the NICE-SUGAR study provided energy more in line with probably energy requirements 55. This may be in part because tube feeding intolerance tends to limit infusion rate of enteral formulae. The relationship between amount of feeding and insulin infusion rate for the intensive groups of five studies is shown in Figure 15.2. As can be seen there was a strong correlation between feeding rate and insulin requirement particularly impressive since the modes of feeding were heterogenous among the studies and when energy supply is controlled for insulin requirements related to intravenous feeding are greater than requirements during enteral feeding 56. The data 150 LEUVEN 1 130 DE LA ROSA LEUVEN 2 110 90 VISEP NICE-SUGAR y 1.4169x + 34.752 R 2 0.923 70 30 40 50 60 70 80 Insulin infusion rate U/day FIG 15.2 Energy supply versus insulin infusion rate in five studies.

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142 Management of associated risk factors and disease shown in the figures are admittedly estimates but do serve to illustrate how variable approaches to nutrition support can impact insulin requirements in the critically ill. This is an important point as it is common to invoke “stress” as the cause of temporary hyperglycemia in critically ill nondiabetic patients without sufficient attention to the role of overfeeding 55. A recently published meta-analysis concluded that there is no evidence to support the use of intensive insulin therapy in general medical-surgical patients who are fed according to current guidelines 57. The study was unusual in that it attempted to assess the role of nutritional support in the outcomes of some of the same clinical trials reviewed here. It found that there was a high incidence of hypoglycemia and increased risk of death in patients on intensive insulin therapy not receiving parenteral nutrition 29 36 38 39. Unfortunately the authors did not consider the impact of how hypoglycemia is defined or the methodology used for blood glucose testing on frequency of hypoglycemia and did not consider the possibility that 1 hypoglycemia could be avoided that 2 selection of more reasonable glucose targets and use of better glucose testing techniques could facilitate avoidance of hypoglycemia and like the physician who gave up on thyroxine rather than consider a different dose that 3 successful avoidance of hypoglycemia might completely change study outcomes and conclusions. Conclusions Available data concerning intensive therapy of hyper- glycemia in the critically ill is inconsistent and confusing. However much of the contradictory data is likely related to differences in experimental design that result in differ- ent frequency and severity of hypoglycemia. In most of the studies reviewed here hypoglycemia was poorly defined and insufficiently respected. It should be emphasized that hypoglycemia may exert adverse effects of its own mask- ing beneficial effects of glycemic control. Problems with the accuracy and precision of available blood glucose testing methodology impose considerable limitations on interpre- tation of data and contribute to safety concerns. Nutri- tional support may also confound the interpretation of large clinical trials although avoidance of overfeeding 55 should minimize concerns in that regard. Based on avail- able data we believe that intensive insulin therapy has a role in the management of the critically ill although it is unclear what the optimal target range should be. Pending further research and in the interest of minimizing hypo- glycemia we believe that the current ADA/AACE guidelines for treatment of hyperglycemia on the critically ill which recommend insulin infusion with a blood glucose target of 7.8–10 mmol/L are appropriate. Robust and carefully standardized methods for blood glucose testing should be used staff should be well trained and hypoglycemia should be appropriately defined and assiduously avoided. Acknowledgments This work was supported in part by the USPHS HL67933 and the Mayo Foundation. We thank P . E. Cryer for helpful comments on the manuscript. References 1. Umpierrez GE Isaacs SD Bazargan N You X Thaler LM Kitabchi AE. Hyperglycemia: an independent marker of in- hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 87:978–982 2002. 2. Cook CB Kongable GL Potter DJ Abad VJ Leija DE Ander- son M. Inpatient glucose control: a glycemic survey of 126 U.S. hospitals. J Hosp Med. 4:E7–E14 2009. 3. Golden SH Peart-Vigilance C Kao WH Brancati FL. Peri- operative glycemic control and the risk of infectious com- plications in a cohort of adults with diabetes. Diabetes Care 22:1408–1414 1999. 4. Zerr KJ Furnary AP Grunkemeier GL Bookin S Kanhere V Starr A. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg 63:356–361 1997. 5. Weir CJ Murray GD Dyker AG Lees KR. Is hypergly- caemia an independent predictor of poor outcome after acute stroke Results of a long-term follow up study. BMJ. 314:1303–1306 1997. 6. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous popula- tion of critically ill patients. Mayo Clin Proc. 78:1471–1478 2003. 7. van den Berghe G W outers P Weekers F et al. Inten- sive insulin therapy in critically ill patients. N Engl J Med. 345:1359–1367 2001. 8. Garber AJ Moghissi ES Bransome ED Jr. et al. ACE posi- tion statement. Endocr Pract 10:5–9 2004. 9. McCowen KC Malhotra A Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin. 17:107–124 2001. 10. Andreelli F Jacquier D Troy S. Molecular aspects of insulin therapy in critically ill patients. Curr Opin Clin Nutr Metab Care. 9:124–130 2006.

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Hyperglycemia should be avoided in critical illness and the postoperative period 143 11. van den Berghe G. How does blood glucose control with insulin save lives in intensive care J Clin Invest. 114:1187–1195 2004. 12. Vanhorebeek I De Vos R Mesotten D Wouters PJ De Wolf- Peeters C Van Den Berghe G. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet. 365:53–59 2005. 13. Bagdade JD Stewart M Walters E. Impaired granulocyte adherence. A reversible defect in host defense in patients with poorly controlled diabetes. Diabetes. 27:677–681 1978. 14. Poitout V Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocrine Rev. 29:351–366 2008. 15. Hansen TK Thiel S Wouters PJ Christiansen JS Van den Berghe G. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab. 88:1082–1088 2003. 16. Langouche L Vanhorebeek I Vlasselaers D et al. Inten- sive insulin therapy protects the endothelium of critically ill patients. J Clin Invest. 115:2277–2286 2005. 17. Stoner HB Little RA Frayn KN Elebute AE Tresadern J Gross E. The effect of sepsis on the oxidation of carbohydrate and fat. Br J Surg. 70:32–35 1983. 18. Steinberg HO Tarshoby M Monestel R et al. Elevated circu- lating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 100:1230–1239 1997. 19. Stojiljkovic MP Zhang D Lopes HF Lee CG Goodfriend TL Egan BM. Hemodynamic effects of lipids in humans. Am J Physiol. 280:R1674–R1679 2001. 20. Lewis GF Uffelman KD Szeto LW Weller B Steiner G. Inter- action between free fatty acids and insulin in the acute con- trol of very low density lipoprotein production in humans. J Clin Invest. 95:158–166 1995. 21. Mesotten D Swinnen JV Vanderhoydonc F W outers PJ Van Den Berghe G. Contribution of circulating lipids to the improved outcome of critical illness by glycemic con- trol with intensive insulin therapy. J Clin Endocrinol Metab. 89:219–226 2004. 22. Miles JM McMagon MM Isley WL. For debate: no the glycemic target in the critically ill should not be 6.1 mmol/L. Diabetologia. 51:916–920 2008. 23. Langouche L Vander Perre S Wouters PJ D’Hoore A Hansen TK Van Den Berghe G. Effect of intensive insulin therapy on insulin sensitivity in the critically ill. J Clin Endocrinol Metab. 92:3890–3897 2007. 24. W eekers F Van Herck E Coopmans W et al. A novel in vivo rabbit model of hypercatabolic critical illness reveals a biphasic neuroendocrine stress response. Endocrinology. 143:764–774 2002. 25. Pomposelli JJ Baxter JK 3rd Babineau TJ et al. Early post- operative glucose control predicts nosocomial infection rate in diabetic patients. JPEN: J Parenter Enteral Nutr. 22:77–81 1998. 26. ADA: Standards of Medical Care in Diabetes—2009. Dia- betes Care 32:S41 2009. 27. Moghissi ES Korytkowski MT DiNardo M et al. American Association of Clinical Endocrinologists and American Dia- betes Association consensus statement on inpatient glycemic control. Diabetes Care. 32:1119–1131 2009. 28. Hirshberg E Lacroix J Sward K Willson D Morris AH. Blood glucose control in critically ill adults and children: a survey on stated practice. Chest 133:1328–1335 2008. 29. Investigators N-SS Finfer S Chittock DR et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 360:1283–1297 2009. 30. Wiener RS Wiener DC Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. Erratum appeared in JAMA. 2009 Mar43019:936. JAMA. 300:933–944 2008. 31. Griesdale DEG de Souza RJ van Dam RM et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 180:821–827 2009. 32. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocar- dial infarction in patients with diabetes mellitus. DIGAMI Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction Study Group. BMJ. 314:1512–1515 1997. 33. Furnary AP Gao G Grunkemeier GL et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Car- diovasc Surg. 125:1007–1021 2003. 34. Krinsley JS. Effect of an intensive glucose management pro- tocol on the mortality of critically ill adult patients. Mayo Clin Proc. 79:992–1000 2004. 35. Van den Berghe G Wilmer A Hermans G et al. Inten- sive insulin therapy in the medical ICU. N Engl J Med. 354:449–461 2006. 36. De La Rosa GDC Donado JH Restrepo AH et al. Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial. Crit Care London England. 12:R120 2008. 37. Brunkhorst FM Engel C Bloos F et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 358:125–139 2008. 38. Arabi YM Dabbagh OC Tamim HM et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med. 36:3190–3197 2008.

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144 Management of associated risk factors and disease 39. Preiser J-C Devos P Ruiz-Santana S et al. A prospective ran- domised multi-centre controlled trial on tight glucose con- trol by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 35:1738–1748 2009. 40. Gray CS Hildreth AJ Sandercock PA et al. Glucose- potassium-insulin infusions in the management of post- stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial GIST-UK. Lancet Neurol. 6:397–406 2007. 41. Cryer PE. Hypoglycaemia: the limiting factor in the gly- caemic management of the critically ill Diabetologia. 49:1722–1725 2006. 42. Mesotten D Van den Berghe G. Clinical benefits of tight gly- caemic control: focus on the intensive care unit. Best Practice Research Clinical Anaesthesiology. 23:421–429 2009. 43. Cryer PE. Hierarchy of physiological responses to hypo- glycemia: relevance to clinical hypoglycemia in type I insulin dependent diabetes mellitus. Horm Metab Res. 29:92–96 1997. 44. Frier BM. Defining hypoglycaemia: what level has clinical relevance Diabetologia. 52:31–34 2009. 45. Cryer PE. Preventing hypoglycaemia: what is the appropriate glucose alert value Diabetologia. 52:35–37 2009. 46. Egi M Bellomo R Stachowski E et al. Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc. 85:217–224. 47. Boyle PJ Schwartz NS Shah SD Clutter WE Cryer PE. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med. 318:1487–1492 1988. 48. Critchell CD Savarese V Callahan A Aboud C Jabbour S Marik P. Accuracy of bedside capillary blood glucose measurements in critically ill patients. Intens Care Med. 33:2079–2084 2007. 49. Kanji S Buffie J Hutton B et al. Reliability of point-of-care testing for glucose measurement in critically ill adults. Crit Care Med. 33:2778–2785 2005. 50. Beneteau-Burnat B Bocque M-C Lorin A Martin C Vaubourdolle M. Evaluation of the blood gas analyzer Gem PREMIER 3000. Clin Chem Lab Med. 42:96–101 2004. 51. Feinstein AR. The ‘chagrin factor’ and quantitative decision analysis. Arch Int Med. 145:1257–1259 1985. 52. Perioperative total parenteral nutrition in surgical patients. The Veterans Affairs T otal Parenteral Nutrition Cooperative Study Group. N Engl J Med. 325:525–532 1991. 53. Braunschweig CL Levy P Sheean PM Wang X. Enteral com- pared with parenteral nutrition: a meta-analysis. Am J Clin Nutr. 74:534–542 2001. 54. Adler GK Bonyhay I Failing H Waring E Dotson S Free- man R. Antecedent hypoglycemia impairs autonomic car- diovascular function: implications for rigorous glycemic control. Diabetes. 58:360–366 2009. 55. Miles JM. Energy expenditure in hospitalized patients: impli- cations for nutritional support. Mayo Clin Proc. 81:809–816 2006. 56. van den Berghe G Wouters PJ Bouillon R et al. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med. 31:359–366 2003. 57. Marik PE Preiser J-C. Toward understanding tight glycemic control in the ICU: a systematic review and metaanalysis. Chest. 137:544–551 2010.

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16 Is there an optimal revascularization strategy in diabetic patients with ischemic heart disease Want To Diabetes Free Life Click Here Stephen H. McKellar 1 Morgan L. Brown 2 and Robert L. Frye 3 1 Resident Division of Cardiovascular Surgery Mayo Clinic Rochester MN USA 2 Resident University of Alberta Edmonton AB Canada 3 Professor of Medicine Division of Cardiovascular Diseases Mayo Clinic Rochester MN USA L E A R N I N G P OIN T S Coronary artery disease is a leading cause of death among patients with diabetes. Outcomes after coronary events/interventions are worse among patients with DM compared to those without DM. Patients with no or mild stable symptoms may have extensive multivessel CAD. Risk stratification is essential. Control of symptoms and reduction in risk of death and MI are reasons for invasive intervention. Choice of CABG or PCI depends on individual patient characteristics with CABG preferred for those with the most extensive disease. Introduction Coronary heart disease CHD is the leading cause of death among adults with diabetes mellitus 1. While a major decline in CHD mortality has been observed since the 1960s in the general population those with DM partic- ularly women have not experienced the same decline 2. Moreover there are striking health disparities in the bur- den of disease and poor outcomes among specific minority ethnic and disadvantaged populations 3. Also of con- cern is the rising obesity and type 2 DM epidemic and its likely impact on cardiovascular disease. Recent data suggest a leveling off of the reduction of CHD mortality in younger patients as a result of the metabolic consequences of obesity and DM 4. These findings call for a careful assessment of how we manage CHD in the setting of DM. Advances in understanding the basic pathophysiologic mechanisms that account for the more aggressive vascular disease in DM are important when considering the optimal strategy for coronary revascularization 5. While percu- taneous coronary intervention PCI has the advantage of being less invasive the hostile metabolic milieu of DM may alter the response to injury of the arterial wall inherent in such interventions 6 and fails to anticipate new dis- ease that may develop in untreated segments 7. Coronary artery bypass grafting CABG has the inherent risks of major surgery with a more prolonged recovery time but provides more complete revascularization. T o help clin- icians decide which revascularization strategy is best for diabetic patients this chapter will focus on: 1 the indi- cations for coronary revascularization 2 selection of PCI or CABG if revascularization is needed and 3 the impor- tance of aggressive medical management regardless of the specific revascularization procedure. Screening for CHD in patients with diabetes is discussed in Chapter 4. Coronary revascularization The optimal revascularization strategy for patients with diabetes depends on the following: clinical characteristics of the individual patient severity extent and location of anatomic coronary artery disease CAD Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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146 Management of associated risk factors and disease TABLE 16.1 Class I indications for CABG For asymptomatic patients with left main disease or left main equivalent and triple-vessel disease For patients with stable angina with left main disease or TABLE 16.3 Diabetes and coronary revascularization Euroepan Society of Cardiology and European Association for the Study of Diabetes Recommendation Class a Level b left main equivalent triple-vessel disease two-vessel disease with LVEF 50 two-vessel disease without proximal left main disease if large territory is at risk and Treatment decisions regarding revascularization in patients with diabetes should favor coronary artery IIa A for refractory disabling angina For patients with unstable angina/NSTEMI with left main bypass surgery over percutaneous intervention or left main equivalent disease and ongoing refractory Glycoprotein IIb/IIIa inhibitors are I B ischemia indicated in elective PCI in a diabetic For patients with STEMI who have failed PCI or unsuitable patient PCI anatomy mechanical complications of myocardial infarction MI cardiogenic shock and life-threatening arrhythmias with left main or triple-vessel disease When PCI with stent implantation is performed in a diabetic patient drug-eluting stents DES should be used IIIa B For patients with left ventricular dysfunction with left Mechanical reperfusion by means of I A main or left main equivalent disease and multivessel primary PCI is the revascularization disease mode of choice in a diabetic patient with acute MI physiologic consequences of the CAD documentation of ischemia and patient comorbidities and preferences. The ACC/AHA 8–10 and European Society of Cardiol- ogy 11 Guidelines are essential references for a detailed set of recommendations for coronary revascularization. The latter provides extensive data for the broad management of cardiovascular disease. The Class 1 recommendations for all patients are listed in Table 16.1 CABG and Table 16.2 PCI from the ACC/AHA document. The recommenda- tions that are specific for the patient with DM and CAD TABLE 16.2 Class I recommendations for PCI For patients with unstable angina/NSTEMI with at least one of the following high-risk features: refractory ischemic or heart failure symptoms elevated biochemical markers of ischemia new ST -segment depression L V dysfunction with or without hemodynamic instability prior PCI or CABG For patients with STEMI with new MI or left bundle branch block ∗ For patients with STEMI who develop shock within 36 hours of acute MI ∗∗ For patients with STEMI with severe heart failure and/or pulmonary edema ∗ ∗ must be performed within 12 hours of symptom onset. ∗∗ must be within 36 hours of symptom onset a Class of recommendation b Level of evidence from European Heart Journal 200728:88–136. are included in the European Society Guidelines Table 16.3. Our goal is to provide a clinical overview on the approach to individual patients based on existing guidelines for 1 selecting patients who need coronary revascularization and 2 selection of the specific procedure for an individual patient while emphasizing the importance of careful med- ical management for all patients regardless of the invasive procedure. There are two basic reasons to consider an invasive coronary revascularization procedure PCI or CABG in a patient with CHD regardless of the presence of DM: 1 for control of symptoms due to myocardial ischemia in spite of optimal medical therapy and 2 to reduce morality and subsequent nonfatal myocardial infarction in high-risk patients regardless of symptoms. These are not mutually exclusive as highly symptomatic patients may also have clear survival and survival-free-of-MI benefits from revas- cularization. It is now clear from recent trials that patients with less severe but definite anatomic CAD may usually be managed first with medical therapy and with revascu- larization later if the disease progresses. We will review the rationale and justification for recommending invasive coronary revascularization in each setting noting specific findings in patients with DM when available as most of the trials included a majority of patients without DM.

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Revascularization strategy in diabetic patients with ischemic heart disease 147 Control of symptoms in spite of optimal medical therapy stable patients Rationale The placebo effect for any intervention to control symp- toms such as angina is well recognized and calls for carefully controlled studies 12. Considerable skepticism regarding surgery for CHD developed in the era of ligation of the internal thoracic artery ITA for angina and later implantation of the ITA in the myocardium after sham pro- cedures demonstrated no therapeutic effectiveness of such procedures 13. However it is now clear from multiple studies in patients with and without diabetes that coronary revascularization improves symptoms and quality of life compared to medical therapy alone both with CABG and PCI. 1415 An advantage of CABG compared to PCI in duration of benefit in relief of angina without need for a repeat procedure has been shown by multiple studies. A practical challenge for practitioners is in assessing the nature of symptoms that may be disabling and raise the necessity of coronary revascularization This includes deal- ing with the possibility that patients with DM may not perceive the classic symptoms of myocardial ischemia dys- pnea is a frequent angina equivalent. Moreover because of the widespread use of noninvasive CT coronary angiogra- phy many patients are found to have evidence of anatomic coronary artery disease and it may be difficult to determine if the symptoms truly relate to the physiologic consequences of the anatomic findings. Such a dilemma is evident also with invasive angiography and the finding of borderline lesions in terms of luminal diameter narrowing. It is quite clear from studies of CABG 16 and PCI that pre-intervention 17 documentation of ischemia increases the probability of symptom relief after either intervention. The final resolution of the significance of flow limitation in borderline lesions 50–75 narrowing calls for fractional flow measurement and/or intracoronary ultrasound imag- ing at the time of the diagnostic study. Unless the free flow ratio FFR is less than 0.75 across lesions with moderate narrowing the likelihood of symptomatic improvement is reduced 17. Gould has emphasized the need for care- ful consideration of physiologic factors in coronary flow dynamics and avoiding fixation on angiographic findings. Selecting PCI or CABG patients with DM for symptom control Having determined the presence of ischemia producing poorly controlled symptoms and coronary anatomy suit- able for PCI or CABG what is the basis for choosing one procedure over the other with the primary goal of reduc- ing symptoms In patients with single-vessel disease PCI is the preferred strategy unless there is an anatomic rea- son to consider CABG regardless of the presence of DM. Some have erroneously concluded from the original BARI Bypass Angioplasty Revascularization Investigation trial that PCI is inappropriate for any patient with DM. This is a serious error in generalizing results of a randomized clinical trial as there were no patients with single-vessel disease in BARI-l. Thus it is quite appropriate for PCI to be the first choice for revascularization in a patient with DM and single-vessel disease with angina not responding to medical therapy presuming the anatomy is suitable for PCI. In DM patients and single-vessel disease not suitable for PCI CABG with an arterial graft is an alternative. In such a setting it is important to ensure medical therapy is intense as it is best to defer CABG if possible until there is multivessel involvement. The bottom line for patients with severe multivessel disease is clearly articulated by the SYNTAX Synergy between PCI with Taxus and Cardiac Surgery investigators: “CABG remains the standard of care for patients with three-vessel or left main coronary artery disease since the use of CABG as compared with PCI resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year” 18. For less extensive multivessel disease PCI may have a role particularly if comorbidities call for the less invasive strategy. In the original BARI Registry where decisions were made by choosing the presumed optimal procedure it was demonstrated that physicians could select the patients with DM and multivessel disease who would likely do well with PTCA 19. This was based on selecting those for PTCA with less extensive disease. In the BARI 2D trial which included only patients with type 2 DM and in whom PCI or CABG was chosen most patients with single-vessel disease were selected for PCI and those with more extensive disease for CABG 20. Thus one may intervene in patients with less severe disease to control symptoms without affecting survival. Acute coronary syndromes Acute coronary syndromes include unstable angina non- ST-segment elevation myocardial infarction NTEMI and ST elevation myocardial infarction STEMI. Prompt PCI is the preferred treatment for patients with STEMI regardless of the presence or absence of DM. Emphasis on reduc- ing/eliminating delays to the cath lab for prompt treatment of the infarct-related artery provides real benefit. In patients

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148 Management of associated risk factors and disease with the most extensive anatomic disease CABG is the pre- ferred invasive revascularization strategy. The Global Reg- istry of Acute Coronary Events has documented that one in four patients presenting to a participating hospital with ACS have DM 21 and are at increased risk for heart fail- ure renal failure cardiogenic shock and death compared to those without DM. Also noted were differences between those with and without DM in terms of use of PCI and specific drugs such as beta-blockers and aspirin. Of partic- ular importance was a much greater delay in seeking care in the setting of ACS among those with DM. This is a par- ticular issue for primary providers in counseling patients to present promptly to an emergency room with symptoms suggesting ACS. It was noted in this observational experi- ence that more patients with DM and STEMI went to CABG than those without DM reflecting more extensive disease. However it is clear that patients with DM benefit from early revascularization in the setting of STEMI combined with aggressive medical management. For patients with unstable angina and NSTEMI there is also evidence that early coronary revascularization is of benefit in reducing death and MI. The advantage of prompt coronary revascularization is well established by several prospective randomized trials and extends to patients with DM based upon post hoc analysis of the DM subgroups. The Framingham and Fast Revascularization During Insta- bility in Coronary Artery Disease FRISC II trial has also focused on experience with diabetic patients in the setting of unstable CAD 22. The benefit in long-term outcomes death MI among those with DM randomized to early invasive therapy was actually greater than among patients without DM the number needed to treat to reduce death and MI was 11 for those with DM as opposed to 32 for those without DM 11. Coronary revascularization for prolonging life and preventing subsequent MI in stable patients Clinical trials —Coronary artery revascularization Studies demonstrating a survival benefit from coronary revascularization began with trials comparing coronary artery bypass grafting CABG to best medical therapy in the 1970s and 1980s 24–27. These trials showed the most benefit was derived from revascularization in patients with the greatest disease burden multivessel disease as well as specific anatomic lesions such as left main or proxi- mal left anterior descending with two-vessel disease and in patients with decreased left ventricular function 28–30. These findings have been also been noted in observational studies and meta-analyses. In contrast no trial has shown a survival benefit for stable mildly symptomatic patients for coronary revascularization via PCI compared to medical therapy. Though unproven in randomized trials the pres- ence of a critical proximal LAD lesion amenable to PCI is thought to be of enough risk to justify invasive treatment regardless of the presence of DM. Pooling of data from the original CABG trials was the basis of a careful meta-analysis by Yusuf confirming a survival benefit with CABG overall but also demonstrating the importance of risk stratifica- tion. Those at high risk noted improved survival those at low risk did not benefit in terms of survival or may have been harmed. A significant limitation in the early CABG trials relates to the absence of modern medical therapy. The studies however clearly demonstrated the gradient of risk in relation to the extent of disease and LV function. Recent observational data have demonstrated improved survival with CABG in stable asymptomatic patients with DM who were identified as being at high risk by nuclear stress imaging. Several more trials are of interest in considering the reduction of risk for subsequent cardiac events. The Ran- domized Intervention Treatment of Angina RITA 2 trial randomized stable patients to PTCA or medical therapy and demonstrated an advantage of PTCA in reducing symptoms but there was more frequent MI in the PTCA group 15. The Angioplasty Compared to Medical Therapy ACME trial also demonstrated better symptom control but no effect on event rates. Two other trials the Medicine Angioplasty of Surgery Study MASS and Trial of Invasive versus Medical Therapy in Elderly Patients with Chronic Symptomatic Coronary-Artery Disease TIME failed to demonstrate improved survival. The TIME trial which included highly symptomatic patients showed reduced cardiac event rates and improved symptoms in the revas- cularization group. The most currently relevant trial in the general population is the Clinical Outcomes Uti- lizing Revascularization and Aggressive Drug Evaluation COURAGE trial which recently reported with no advan- tage of early revascularization for stable angina. About a third of the patients had DM. Based on these data the indications for coronary revascularization to reduce risk of death or subsequent MI regardless of the presence of DM have been established. In stable patients with high-risk anatomy a survival benefit for coronary revascularization

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Revascularization strategy in diabetic patients with ischemic heart disease 149 has been demonstrated. Less severe disease can usually be managed medically regardless of the presence or absence of DM Table 16.1 and 16.2. Class I indications exist for both PCI and CABG and are shown in the table. In all of these trials it must be emphasized that strict long-term treatment comparisons were not possible. Thus patients randomized to an initial strategy of medical therapy might “cross over” to have revascularization. Thus the medical therapy groups undoubtedly benefitted from subsequent revascularization if they became unstable. It is important to note however that these guidelines and Class I indications were derived from studies of patient cohorts where the majority of patients did not have diabetes. It is thus important to look at subgroups of patients with DM and also the few trials comprised only of patients with type 2 DM. Diabetes subgroup analysis The BARI trial was the first to observe a survival benefit at 5 years for patients with treated diabetes undergoing CABG with at least one internal thoracic artery ITA as a conduit compared to patients treated with PTCA. This observation in patients with treated diabetes was not a pre- defined end point but had been selected by the study’s data safety and monitoring board to monitor for safety. Sub- sequent reports from the BARI trial with longer follow-up confirm the initial observation of improved survival among patients revascularized with CABG vs. PCI 76 vs. 56 at 7 years. This difference is due in part to poorer out- comes among diabetic patients randomized to PTCA with a subsequent Q-wave MI resulting in a tenfold higher 30- day mortality compared to patients experiencing Q-wave MI subsequent to CABG. A recent meta-analysis of 7812 patients based upon pooled data from ten clinical trials found improved survival for patients with diabetes under- going CABG n 615 compared to PCI n 618 HR 0.7 95 CI 0.56–0.87 but no difference in survival among nondiabetics. Comparable conclusions were reached in the New Y ork State Registry 23. Although drug eluting stents have reduced restenosis rates they remain higher in those with DM than those without DM and furthermore it seems unlikely that mortality is linked to restenosis. Is coronary artery disease different in patients with diabetes It is estimated CAD accounts for nearly 3 times as many deaths among diabetic compared to nondiabetic patients 1. Are diabetic patients adequately represented in ran- domized clinical trials and large registry data In Hlatky’s meta-analysis of 7812 patients patients with diabetes com- prised only 16 of the total patient sample range 6–28. The impact of diabetes remained even after adjustment for other risk factors and excluding patients from the BARI trial. Since diabetic patients have been under-represented in earlier clinical trials conclusions about patients with dia- betes have been drawn from subgroup analyses with all its inherent biases. Fortunately the BARI-2D trial has stud- ied coronary revascularization in an exclusively diabetic population. BARI 2D trial BARI 2D was designed to test treatment strategies in patients with type 2 DM and angiographically documented CAD to determine if in mildly symptomatic patients not requiring revascularization to control symptoms or insta- bility prompt revascularization would reduce mortality or subsequent MI compared to an initial strategy of opti- mal medical therapy with delayed or no revascularization. An insulin-sensitizing strategy was also compared to an insulin-providing strategy to achieve target glycemia con- trol levels. The randomization was stratified by the proce- dure determined to be optimal for the individual patients i.e. PCI or CABG. No difference in mortality/MI/stroke was observed for either treatment strategy. However when analyzed by prespecified strata there was a significant reduc- tion in the combined end point of death MI and stroke for patients having prompt CABG. Furthermore there was some evidence that insulin-sensitizing therapy may enhance the benefit of CABG. About 40 of the patients randomized to initial medical therapy alone had subse- quent revascularization. The benefit of CABG was observed only in the patients with the most extensive disease high myocardial jeopardy scores. Therefore for asymptomatic or mildly symptomatic patients with type 2 DM with less extensive disease no advantage was seen with prompt revascularization and waiting until symptoms develop is a safe and reasonable option. In contrast among patients with extensive dis- ease with high myocardial jeopardy scores a reduction in death/MI/stroke compared to medical therapy was shown with revascularization using CABG. Since the majority of patients presented with mild or no symptoms identify- ing those with high-risk anatomy in the clinical practice of managing patients with type 2 DM remains a challenge.

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150 Management of associated risk factors and disease Why is CAD different in patients with diabetes Brown- lee et al. have suggested that damage to vascular endothe- lial cells in diabetes is predominantly caused by oxidative stress secondary to intracellular hyperglycemia. Vascular endothelial cells cannot reduce glucose transport into the cell rendering them unable to regulate intracellular hyper- glycemia. This in turn leads to overproduction of oxida- tive species from a dysfunctioning mitochondrial electron transport chain. Excessive oxidative species leads to cellu- lar damage through modification of intracellular proteins involved in gene transcription and regulation cell signal- ing dysfunction and increased production of inflamma- tory cytokines 5. Predictably patients with diabetes often present with a more diffuse pattern of coronary disease rather than isolated culprit lesions given the damaging intracellular milieu found throughout all vascular endothe- lial cells. Such a pattern of disease is best suited for a revas- cularization strategy using CABG as available data shows improved outcomes compared to PCI. This is likely due to the ability of CABG to offer more complete revasculariza- tion instead of revascularization of a single culprit lesion. Long-term studies demonstrate a survival advantage when arterial conduits are used for surgical revasculariza- tion. The BARI study demonstrated survival benefit only for diabetic patients in whom the ITA was used as conduit to revascularize the LAD. Since then long-term survival has also been demonstrated in large surgical series using ITA to LAD revascularization. Moreover data from the Cleve- land Clinic at 10- and 20-year follow-up suggest a survival advantage with revascularization using bilateral ITA con- duits compared to one ITA conduit despite an increased risk of deep sternal wound infections. It is important to note that the majority of these patients nearly 70 had advanced two- or three-vessel disease. More recent obser- vational studies from that group also demonstrate that use of the contralateral ITA as a second conduit is beneficial regardless of whether it is used to revascularize the right coronary or circumflex coronary artery. Risk factor modification Secondary prevention of ischemic events is critical follow- ing coronary revascularization and is a critical part of decid- ing on optimal revascularization. The benefits of any inva- sive procedure may be compromised by continued smoking and lack of attention to all the details of medical man- agement. The combined efforts of the European Society of Cardiology and the European Association for Diabetes Guidelines provide in-depth review of all aspects of medical management in patients with CAD and diabetes. Lifestyle modification such as complete smoking cessation exer- cise and weight management coupled with controlling metabolic risk factors can reduce mortality. Clinical tri- als have demonstrated the benefits of reducing hyperten- sion and hyperlipidemia. Additionally antiplatelet therapy is also beneficial following revascularization. For patients treated with PCI and if drug-eluting stents were used clopi- dogrel is mandatory to prevent in-stent thrombosis in the postprocedure setting and often becomes lifelong in an attempt to prevent in-stent restenosis or thrombosis. Life- long aspirin therapy however is sufficient in most patients following CABG. Angiotensin converting enzyme ACE inhibitor and beta-blockade therapies are recommended for most patients following revascularization. Starting an ACE inhibitor early for patients following MI is impor- tant and should be continued indefinitely for patients with LV dysfunction to prevent adverse ventricular remodel- ing. Similarly beta-blockade should be initiated in high- risk patients following infarction and likewise is usually continued indefinitely. In addition to their lipid-lowering effects HMG-CoA reductase inhibitors or statins have also been shown to strengthen atherosclerotic plaques and reduce myocardial events and should be part of the program for each patient unless there is lack of tolerance because of side effects. Glycemic control is essential and more com- plicated given the results of the Action to Control Cardio- vascular Risk in Diabetes ACCORD study. Current ADA guidelines should be observed. Intensive insulin therapy in patients following cardiac surgery is controversial and may lead to worse outcomes. Van den Berghe reported the results of a randomized con- trolled trial in patients mechanically ventilated in a surgical ICU. They observed a survival benefit among patients with receiving intensive insulin control who stayed in ICU for 5 or more days and those with sepsis. Furnary has been a strong proponent of continuous insulin infusions during the perioperative period of CABG. However in randomized studies of cardiac surgery patients intensive insulin ther- apy showed no benefit and potential harm. It should also be noted that glycemic control at the time of PCI may influence outcomes though there is evidence to the contrary. Regardless of the impact of perioperative glycemic control on mortality a growing body of evidence shows improved outcomes with aggressive long-term

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Revascularization strategy in diabetic patients with ischemic heart disease 151 multifactorial interventions among patients with diabetes. The Steno-2 trial has shown a nearly 50 reduction in car- diovascular and microvascular events as well as a reduction in all-cause and cardiovascular-related mortality by imple- menting a multifactorial approach to risk factor modifica- tion in patients with diabetes. This prospective randomized observational study randomized patients to receive conven- tional risk factor modification compared to multifactorial intervention consisting of treatments aimed at diabetic and concomitant risk factor management reduction similar to published guidelines by the American Diabetic Association. Patients were treated for nearly 8 years then followed for another 5 years. The hazard ratio for death was 0.54 95 CI 0.32 0.89 p 0.02 and cardiovascular-related mortality was 0.41 0.25 0.67 p 0.001 demonstrating significant reduction in death from all causes with intensive multifac- torial interventions. Conclusions Coronary revascularization can be highly beneficial in selected patients with DM and CAD. While many patients with mild symptoms and documented CAD that is not severe may be managed without invasive intervention for many years it must be recognized that there are high-risk patients with extensive CAD who present with mild symp- toms and risk stratification is important as BARI 2D has demonstrated selected patients with extensive CAD may benefit from early CABG. Patient preferences are frequently strong and must be considered though with a frank discus- sion of potential adverse outcomes. In general CABG is the preferred procedure in the diabetic patient with the most extensive disease. However many patients with less exten- sive disease but severe symptoms may benefit from PCI but there is no evidence in those patients that survival or sur- vival free of MI is enhanced. The critical role of aggressive medical management of all aspects of the patient’s risk fac- tors and metabolic consequences of DM cannot be overem- phasized. Insulin sensitization needs further study in reduc- ing event rates after coronary revascularization. Regardless of PCI or CABG aggressive and continued medical man- agement is critical. References 1. Diabetes in American 2nd edition Available from: http:// diabetes.niddk.nih.gov/dm/pubs/America/pdf p. 221 233. 2. Gregg EW Gu O Cheng YI Narayan KMV Cowie CC. Mortality trends in men and women with diabetes 1971 to 2000. Ann Intern Med. 1473:149–155 2007. 3. Ford ES Capewell S. Coronary heart disease mortality among young adults in the U.S. from 1980 through 2002: concealed leveling of mortality rates. J Am Coll Cardiol. 50:2128–2132 2007. 4. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 546:1615–1625 2005. 5. Cutlip DE Chhabra AG Baim DS et al. Beyond restenosis: five-year clinical outcomes from second-generation coro- nary stent trials. Circulation. 110:1226–1230 2004. 6. Eagle KA et al. ACC/AHA 2004 guideline update for coro- nary artery bypass graft surgery: a report of the Ameri- can College of Cardiology/American Heart Association Task Force on Practice Guidelines committee to update the 1999 guidelines for coronary artery bypass graft surgery. Circu- lation. 11014:e340–e437 2004. 7. Eagle KA et al. ACC/AHA guidelines for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on prac- tice guidelines committee to revise the 1991 guidelines for coronary artery bypass graft surgery. American College of Cardiology/American Heart Association. J Am Coll Cardiol. 344:1262–1347 1999. 8. Smith SC Jr. et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention – sum- mary article: a report of the American College of Cardi- ology/American Heart Association Task Force on practice guidelines ACC/AHA/SCAI writing committee to update the 2001 guidelines for percutaneous coronary intervention Circulation. 1131:156–175 2006. 9. Ryden L Standl E et al. Guidelines on diabetes pre-diabetes and cardiovascular disease: executive summary. Eur Heart J. 28:88–136 2007. 10. Cobb LA et al. An evaluation of internal mammary ligation by a double blind technic. NEJM. 260:1115–1118 1959. 11. CASS PRINCIPAL INVESTIGATORS AND THEIR ASSO- CIATES. Coronary Artery Surgery Study CASS: A random- ized trial of coronary artery bypass surgery Quality of life in patients randomly assigned to treatment groups. Circulation. 68:951–960 1983. 12. Jones RH. Floyd RD. Austin EH. Sabiston DC Jr. The role of radionuclide angiocardiography in the preoperative prediction of pain relief and prolonged survival following coronary artery bypass grafting. Ann Surg. 1976:743–754 1983. 13. Bech GIW De Bruyne B Pijls NHJ et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis. A randomized trial. Circulation. 103:2928–2934 2001.

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152 Management of associated risk factors and disease 14. Serruys PW et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 36010:961–972 2009. 15. Feit F et al. Coronary revascularization in diabetic patients: a comparison of the randomized and observational compo- nents of the Bypass Angioplasty Revascularization Investi- gation BARI. 995:633–640 1999. 16. Lagervist B Husted S Kontny F et al. A long-term per- spective on the protective effects of an early invasive strat- egy in unstable coronary artery disease the FRISC II Investigator two-year follow-up of the FRISC-II invasive study. J Am Coll Cardiol. 43:585–591 2004 doi:10.1016/ j.jacc.2003.08.05. 17. Yusuf S et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet. 3448922:563–570 1994. 18. Sorajja P Chareonthaitawee P Rajagopalan P et al. Improved survival in asymptomatic diabetic patients with high-risk Spect imaging treated with coronary artery bypass grafting. Circulation. 1129 Suppl:I311–I316 2005. 19. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease TIME: a randomised trial. Lancet. 3589286:951–957 2001. 20. Boden WE O’Rourke RA Teo KK et al. Optimal medi- cal therapy with or without PCI for stable coronary artery disease. NEJM 356:1503–1516 2007. 21. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascular- ization Investigation BARI. Circulation. 966:1761–1769 1997. 22. Hlatky MA et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet. 3739670:1190–1197 2009. 23. Hannan EL Racz MJ Walford et al. Long-term outcomes of coronary-artery bypass grafting versus stent implantation. NEJM. 352:2174 2005. 24. BARI 2D investigators. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 36024:2503–2015 2009. 25. Sabik JF 3rd et al. Does location of the second inter- nal thoracic artery graft influence outcome of coronary artery bypass grafting Circulation. 11814:S210–S215 2008. 26. Accord 53 van den Berghe G et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 34519:1359–1367 2001. 27. Furnay 55 Gandhi GY et al. Intensive intraoperative insulin therapy versus conventional glucose management dur- ing cardiac surgery: a randomized trial. Ann Intern Med. 1464:233–243 2007. 28. Corpus RA George PB et al. Optimal glycemic control is associated with a lower rate of target vessel revascularization in treated type II diabetic patients undergoing elective percu- taneous coronary intervention. J Am Coll Cardiol. 43:8–14 2004. 29. Gaede P. et al. Multifactorial intervention and cardiovascu- lar disease in patients with type 2 diabetes. N Engl J Med. 3485:383–393 2003. 30. American Diabetes Association. Standards of medical care in diabetes–2007. Diabetes Care. 301:S4–S41 2007.

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Index To Kill Diabetes Forever Click Here Note: Page numbers with italicized f ’s and t ’s refer to figures and tables. A Diabetes Outcome Progression Trial ADOPT 111 Aberdeen Diabetic Clinic 108 acarbose 7 acromegaly 24t 28 Action to Control Cardiovascular Risks in Diabetes ACCORD 44 100 150 acute coronary syndromes 147–8 adenosine 5 -monophosphate protein kinase AMPK 79–80 adolescents with diabetes continuous glucose monitoring in 51 cystic fibrosis-related diabetes 26 diet 61 environmental factors 15–17 type 1 diabetes 11 ADOPT trial 7 ADVANCE study 100 Air Force/T exas Coronary Atherosclerosis Prevention Study 38 alanine amino transferase 86 albiglutide 92 ambulatory glucose profile AGP 51–2 52f amylin 93 Angioplasty Compared to Medical Therapy ACME trial 148 angiotensin converting enzyme ACE inhibitor 150 antiCD3 monoclonal antibody 19 anti-interleukin-1 20 antipsychotic drugs 30–31 65 apolipoproteins 37 ARBITER study 124 ARCHIMEDES 36–7 ariprizole 65 atherosclerosis 5 116 123 Atherosclerosis Risk in Communities Study ARIC 5 atorvastatin 118f 119 AusDiab study 5 autoantibodies 12 autoimmune diabetes 22 average glucose 97 BABYDIET study 16–17 Baltimore Longitudinal Study of Aging 6 BARI 2D trial 149–50 bariatric surgery 127–32. See also obesity revascularization gastric banding 130–31 gastric bypass 130–31 incretin effect of 128 side effects 110t for type 2 diabetes 128–9 weight loss and 113 128 basal energy expenditure 141f beta casein 13–14 beta lactoglobulin 14 beta-cell function 6 15f 65–6 75 bezafibrate 123–4 Bezafibrate Infarction Prevention BIP 123–4 biguanides 79–83 111. See also insulin sensitizers efficacy of combination therapy 81–2 mechanism of action 79–81 pharmacokinetics 81 polycystic ovary syndrome 82–3 thiazolidinediones 83–8 bilio-pancreatic diversion BPD 130–31 blood glucose 135–6 capillary 4 80 carbohydrate counting 62 control. See glucose control estimate of average glucose 97t fasting 129 HbA1c and 97 hyperglycemia 135–6 hypoglycemia 60 metformin and 83 pharmacotherapy 65 self-monitoring 43–54 testing 139–40 thiazolidinediones and 85 body mass index BMI 57t 107 131–2. See also obesity body weight 73 bone disease 73 bovine beta casein 13–14 buformin 79 C282Y mutation 23–5 calcineurin inhibitors 29 65 calcitriol 19 calcium 59–60 Clinical Dilemmas in Diabetes First Edition. Edited by Adrian Vella and Robert A. Rizza c 2011 Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.

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154 Index caloric restriction 67 calories 57–8 cancer 73–4 carbohydrate counting 62 carbohydrates 58 cardiac risk equivalent 34 cardiorespiratory fitness CRF 68 cardiovascular disease 34–9. See also coronary heart disease CHD obesity glucose metabolism and 121t highly sensitive C-reactive protein 38 hyperglycemia and 35–6 insulin sensitizers and 74–5 meglitinides and 74 metabolic syndrome 36–7 metformin and 74–5 nontraditional risk factors 38 risk factors 36–8 risk stratification 36–7 sulfonylureas and 74 thiazolidinediones and 75 carotid intima-media thickness CIMT 87 casein 13–14 children with diabetes continuous glucose monitoring in 51 cystic fibrosis-related diabetes 26 diet 17 61 environmental factors 13 identification 15–17 type 1 diabetes 11–12 vitamin D deficiency in 14 weight maintenance in 61 cholesterol 38 58t 59 73 86–7 116 117f Cholesterol and Recurrent Events CARE trial 118 cirrhosis 23 25 86 clozapine 30 65 cod liver oil 14 Collaborative Atorvastatin Diabetes Study CARDS 119 congenital rubella 13 congestive heart failure CHF 87–8 continuous glucose monitoring GCM 50–54. See also self-monitoring of blood glucose SMBG closed-loop system 51 commercial devices 52f estimate of average glucose 97 HbA1c measurement 97 outputs 52–3f sensor burnout 51 continuous subcutaneous insulin infusion CSII 49 coronary artery bypass grafting CABG 145–51. See also percutaneous coronary intervention PCI in acute coronary syndromes 147–8 class I indications for 146t clinical trials 148–50 vs. percutaneous coronary intervention 147 rationale for 147 risk factor modification 150–51 Coronary Artery Calcium Scoring CAC 38–9 coronary artery disease CAD 59 74 87 119–20 149 coronary heart disease CHD 145. See also cardiovascular disease dyslipidemia and 118–20 hypertriglyceridemia and 120–23 metabolic syndrome and 117 nonfasting triglyceride level and 123 prevention of 119 risk for 4 type 2 diabetes and 116 weight fluctuations and 108 coronary revascularization 145–51 for myocardial infarction 148–50 for prolonging life 148–50 recommendations for 145–6 risk factor modification 150–51 for symptom control 147–8 corticosteroids 65 COURAGE trial 35 148 cow’s milk 13–14 Coxsackievirus B serotypes 13 C-reactive protein CRP 38 Cushing’s syndrome 24t 28–9. See also secondary diabetes cyclosporin 19 29 66 119–20 cystic fibrosis transmembrane regulator CFTR 26 cystic fibrosis-related diabetes CFRD 25–8. See also secondary diabetes clinical features 27t vs. other forms of diabetes 26–7 screening 27–8 treatment algorithm 26f cytomegalovirus 13 cytotoxic T lymphocyte antigen 4 CTLA-4 12 Da Qing IGT and Diabetes Study 6 DECODE study 5 35 Detection of Ischemia in Asymptomatic Diabetics DIAD 35 Diabetes Atherosclerosis Intervention Study DAIS 124 Diabetes Control and Complications Trial DCCT 44 97 Diabetes Glycaemic Education and Monitoring DiGem study 45 diabetes mellitus 22 body mass index and 107 cardiovascular disease and 34–9 continuous glucose monitoring 50–54 coronary revascularization in 145–51 flatbush diabetes 30 genetic forms 32 HbA1c and 96–102 incretin-based therapy 91–4 lifestyle changes vs. pharmacotherapy 64–9 medical nutrition therapy 56–63 post-transplant 29–30 secondary 22–32 antipsychotic drugs and 30–31 cystic fibrosis-related diabetes CFRD 25–8 definition of 22 hematochromatosis 23–5 HIV infection 31 hormone excess 24t 28–9 pancreatic disease 24t pancreatic- cancer-associated diabetes 28 post-transplant diabetes mellitus 29–30 self-monitoring of blood glucose 43–50 type 1 diabetes 11–20 119–20 beta-cell mass preserving 15f clinical features 27t cow’s milk and 13–14 defined 22 early diagnosis of 11–20 incidence of 11 pathogenesis of 12–13 prediction of 14

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Index 155 prevalence of 11 prevention of 14–20 15f 15t self-monitoring of blood glucose 44–5 vitamin D deficiency and 14 type 2 diabetes 22 bariatric surgery for 127–32 clinical features 27t dyslipidemia in 116–18 insulin-requiring 44–5 non-insulin-requiring 45–8 obesity and 107–14 self-monitoring of blood glucose 44–8 Diabetes Prediction and Prevention Project DIPP 17 Diabetes Prediction and Prevention Trial-Type 1 DPT-1 17–18 Diabetes Prevention Program 7 67 diabetic ketoacidosis 30 DIABFIN study 16 DiaPep277 19–20 diet 56–63 alcohol 60 calories 57–8 carbohydrate counting 62 carbohydrates 58 for children/adolescents with diabetes 61 fiber 58t glycemic index 63 hypoglycemia and 60 implementation 61–2 vs. intensive glucose control 112 lifestyle changes and 68t macronutrients 59 micronutrients 59–60 obesity and 108–11 pregnancy and 60–61 proteins 58–9 recommendations 57t sweeteners 60 weight management and 61 dipeptidyl peptidase-4 DPP-4 47 92 110t 112 DR15-DQ6 HLA haplotype 12 DR3-DQ2 HLA haplotype 12 DR4-DQ8 HLA haplotype 12 DREAM trial 7 dyslipidemia 116–20. See also hypertriglyceridemia insulin resistance and 117f secondary causes of 117 treatment of 118–20 in type 2 diabetes 116–18 Enterovirus 13 EPIC-Norfolk study 36 Epidemiology of Diabetes Interventions and Complications EDIC 44 estimate of average glucose eAG 97 European Nicotinamide Diabetes Intervention Trial ENDIT 17 exenatide 92–3 109t exercise 34 66–8 68t 112 fats/fatty acids 58t 59. See also medical nutrition therapy MNT free 117 135 metformin and 82f monounsaturated 58t 59 nonesterified free 117 omega-3 59 polyunsaturated 58t 59 saturated 58t 59 trans 58t fenofibrate 123 Fenofibrate Intervention and Event Lowering in Diabetes FIELD 123 fiber 58. See also medical nutrition therapy MNT fibrates 123–4 Finnish Diabetes Prevention Study 6 flatbush diabetes 30 folic acid 59–60 fractures risk of 73 Framingham Heart Study Cohort 108 free fatty acids FFAs 117 135 French lilac 79 FRISC II trial 148 fructose 60 GAD65 19 Galega officinalis 79 gastric banding 110t 130–31 gastric bypass surgery 67 110t 130–31 gemfibrozil 118f gestational diabetes mellitus 48 glargine 24 31 74 92 Global Registry of Acute Coronary Events 148 glucagon-like peptide GLP-1 47 92–4 112 128 glucocorticoids 29 65 glucose control. See also self-monitoring of blood glucose SMBG benefits of 100 epidemiologic studies 98–9 evidence for 102 hazard ratio 99t hyperglycemia and 100–101 hypoglycemia and 99 insulin sensitizers 72–3 international goals 100f macrovascular effects of 100 meglitinides 72–3 meta-analysis 99 metformin 72–3 microvascular effects of 100 observational studies 98–9 physiologic studies 98 primary outcome 99t randomized controlled trials 99 risks 99–101 secretagogues 72–3 sensitizers insulin 72–3 sulfonylureas 72–3 thiazolidinediones 72–3 value of 101 weight gain and 99–100 glucose hypothesis 96 glucose-dependent insulinotropic polypeptide GIP 92 128 glucotoxicity 66 GLUT-1 transporters 80 GLUT-4 transporters 80 glyburide 75 glycated hemoglobin. See HbA1c glycated hemoglobin glycemic index 63 glycosuria 97 goat’s rue 79 Harris Benedict equation HBE 57–8 HbA1c glycated hemoglobin 96–102. See also self-monitoring of blood glucose SMBG average glucose and 97 cardiovascular disease and 36 glucose control 98–102 glycemic exposure 98 lifestyle modification and 67

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156 Index HbA1c glycated hemoglobin cont. measurement of 98 self-monitoring of blood glucose 45–6 standardization 97 weight loss and 112 Heart Protection Study HPS 119 heat shock protein 19–20 hemochromatosis 23–5. See also secondary diabetes natural history 23–5 screening 24t 25 hepatitis C 29 hepatocyte nuclear factor 1-alpha HNF1A 32 hereditary hemochromatosis 23–5 natural history 23–5 screening 24t 25 high-density lipoprotein HDL cholesterol 59 73 86–7 116 117f highly active antiretroviral therapy HAART 31 86–7 highly sensitive C-reactive protein hsCRP 38 Himsworth Harold Percival 79 HIV infection 31 hormone excess 28–9. See also secondary diabetes human leukocyte antigen HLA 12 hyperglycemia 134–42. See also hypoglycemia adverse effects 134–5 APACHE scores/mortality data 138t development of 6 glycemic treatment goals for 100–101 intervention studies 135–8 pharmacotherapy and 65 prevalence rate 134 risk of cardiovascular disease and 35–6 hyperlipidemia 107 hypertension congestive heart failure and 87 obesity and 1–7 107 117 prediabetes and 4 revascularization and 150 secondary diabetes and 23 sodium restriction 60 hypertriglyceridemia 116–17 alcohol intake and 60 coronary heart disease risk and 120–23 metabolic syndrome and 124 treatment of 123–5 hypoglycemia 60. See also hyperglycemia in critical illness/postoperative period 138–9 glucose control and 99 glucose testing 139–40 risk of 73 immunosuppressants 65–6 impaired fasting glucose IFG 3–4 6 36 impaired glucose tolerance IGT 3–4 36 incretin 91–4 112 128 Indian Diabetes Prevention Programme 6 insulin glargine 24 31 74 92 insulin insensitivity 79 insulin resistance 117f insulin sensitizers 71–6. See also secretagogues beta-cell preservation 75 biguanides 79–83 body weight effect on 73 bone disease risk of 73 cancer risk and 73–4 cardiovascular disease and 74–5 case study 80 cost-effectiveness of 76 durability 75 end-points 72t glucose control 72–3 hypoglycemia risk of 73 insulin therapy and 79–89 lipid effects 73 risks 75–6 vs. secretagogues 71–6 insulin therapy 27 anti-CD3 and 19 caloric restriction and 67 carbohydrate counting and 62 cardiac surgery and 150 in gestational diabetes mellitus 48 for hyperglycemia 135–6 for hypoglycemia 139 incretin and 93 insulin sensitizers and 81–9 self-monitoring of blood glucose and 44–5 insulin-dependent diabetes 22 INTERHEART study 37–8 internal thoracic artery ITA 149 islet cell antibodies ICA 12 JUPITER trial 38 ketoacidosis 66 ketosis-prone type 2 diabetes 30 Kineret 20 Kumamoto study 97 lactic acidosis 83 legacy effect 44 lifestyle changes 64–9 lipodystrophies 87 liraglutide 92 112 liver cirrhosis 23 25 86 Long-term Intervention with Pravastatin in Ischemic Disease LIPID study 118–19 Look AHEAD Action for Health in Diabetes 68 low-density lipoprotein LDL cholesterol 38 73 86–7 116 lymphoid phosphatase LYP 12 M2 muscarinic receptors 65 macronutrients 58–9. See also medical nutrition therapy MNT carbohydrates 58 fats 59 fiber 58t proteins 58–9 macrovascular disease 3–4 maturity onset diabetes of the young syndrome MODY 32 measles 13 medical nutrition therapy MNT 56–63 alcohol 60 calories 57–8 carbohydrate counting 62 carbohydrates 58 for children/adolescents with diabetes 61 fats 59 fiber 58t glycemic index 63 goals 56 hypoglycemia and 60 implementation 61–2 macronutrients 59 micronutrients 59–60

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Index 157 pregnancy and 60–61 proteins 58–9 sweeteners 60 meglitinides. See also insulin sensitizers body weight effect on 73 cardiovascular disease and 74 cost effectiveness of 76 end-points 72t glucose control 72–3 lipid effects 73 metabolic memory 44 metabolic syndrome 36–7 79 117 118b metformin 74–5. See also biguanides insulin sensitizers adverse effects 83 gastrointestinal 83 lactic acidosis 83 beta-cell preservation 75 cancer risk and 74 cardiovascular disease and 74–5 contraindications 83 direct/indirect effects 80t durability 75 efficacy of combination therapy 81–2 end-points 72t fatty acids and 82f glucose control 72–3 hepatic glucose production and 81f indications 82–3 lifestyle intervention and 64–5 lipid effects 73 mechanism of action 79–81 81f pharmacokinetics 81 in prediabetes management 6 risks 75 self-monitoring of blood glucose and 47 side effects 109–10t weight loss and 111–12 micronutrients 59–60. See also medical nutrition therapy MNT microvascular disease 4 milk albumin 13–14 monounsaturated fatty acids MUFAs 58t 59 mumps 13 myocardial infarction 123–4 148–50 nateglinide 72 National Glycohemoglobin Stan- dardization Program NGSP 97 National Screening Committee NSC 23–5 NAVIGATOR trial 7 nephropathy 4–5 new-onset diabetes mellitus after transplantation NODAT 29 nicotinamide 19 nonalcoholic fatty liver disease NAFLD 86 non-autoimmune diabetes 22 nonesterified free fatty acid NEFA 117 non-insulin-dependent diabetes 22 non-insulin-treated type 2 diabetes 45–8 non-ST-segment elevation myocardial infarction NSTEMI 147–8 normoglycemia 6 nutrition support 140–42 obesity 107–14 bariatric surgery for 113 127–32 body mass index and 57t 107 diet changes 108–13 exercise for 112–13 hypertension and 107 weight loss 108 olanzapine 30 65 omega-3 fatty acids 59 oral glucose 3–4 73 128. See also blood glucose oral glucose tolerance test OGTT 5–6 18 24t 26–7 30 orlistat 110t 113 overweight 57t 58 67 74 107–8 111. See also obesity pancreatic cancer 24t pancreatic-cancer-associated diabetes 28 percutaneous coronary intervention PCI 147–50 in acute coronary syndromes 147–8 for asymptomatic patients with diabetes 35 clinical trials 148–50 vs. coronary artery bypass grafting 147 recommendations for 146t peroxisome-proliferator-activated receptors PPARs 83–5 phaeochromocytoma 24t pharmacotherapy 64–9 phenformin 79 pheochromocytoma 28 Pima Indians 4–5 pioglitazone 73 polycystic ovary syndrome 82–3 86 polydipsia 66 polyunsaturated fatty acids PUFAs 58t 59 polyuria 66 postprandial glucose 49–50 postprandial self-monitoring of blood glucose 48–50 post-transplant diabetes mellitus 29–30. See also secondary diabetes clinical features 29–30 incidence of 29 risk factors 29 screening 30 pramlintide 93 pravastatin 118f prediabetes 3–7 atherosclerosis and 5 definition of 3 management of 6–7 microvascular effects of 4 oral glucose tolerance test 5–6 prevalence rate 3 pregnancy diet and 60–61 gestational diabetes mellitus 48 self-monitoring of blood glucose in 48 PREVEFIN study 16 proteins. See also medical nutrition therapy MNT PTPN22 gene 12 Rahbar Samuel 96 Randomized Intervention Treatment of Angina RITA trial 148 Reaven Gerald 79 repaglinide 72 resting energy expenditure 57–8 retinopathy 4–5 retroviruses 13 revascularization 145–51. See also coronary artery bypass grafting CABG in preventing subsequent myocardial infarction 148–50 for prolonging life 148–50 recommendations for 145–6 risk factor modification 150–51 for symptom control 147–8

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158 Index risperidone 65 RNA viruses 13 rosiglitazone 7 73 75 111 Roux-en-Y gastric bypass RYGB 67 130–31 San Antonio Heart Study 5 saturated fatty acids 58t 59 saxagliptin 92 schizophrenia 65 screening cardiovascular disease 34–9 cystic fibrosis-related diabetes CFRD 27–8 hematochromatosis 25 post-transplant diabetes mellitus 30 prediabetes 34–9 secondary diabetes 22–32 antipsychotic drugs and 30–31 cystic fibrosis-related diabetes CFRD 25–8 definition of 22 hematochromatosis 23–5 HIV infection 31 hormone excess 24t 28–9 pancreatic disease 24t pancreatic-cancer-associated diabetes 28 post-transplant diabetes mellitus 29–30 secretagogues 71–6. See also insulin sensitizers beta-cell preservation 75 body weight effect on 73 bone disease risk of 73 cancer risk and 73–4 cardiovascular disease and 74–5 cost-effectiveness of 76 durability 75 end-points 72t glucose control 72–3 hypoglycemia risk of 73 vs. insulin sensitizers 71–6 lipid effects 73 risks 75–6 side effects 109t self-monitoring of blood glucose SMBG 43–50. See also continuous glucose monitoring GCM legacy effect/metabolic memory 44 in non-insulin-treated type 2 diabetes 45–8 postprandial 48–50 in type 1 diabetes 44–5 in type 2 diabetes 44–5 sensitizers insulin 71–6 beta-cell preservation 75 body weight effect on 73 bone disease risk of 73 cancer risk and 73–4 cardiovascular disease and 74–5 cost-effectiveness of 76 durability 75 end-points 72t glucose control 72–3 hypoglycemia risk of 73 lipid effects 73 risks 75–6 sibutramine 110t 112 Sibutramine Cardiovascular Outcome Trial SCOUT 112 simvastatin 118f 119 sitagliptin 92 112 sodium 60 somatostatinoma 28 South Asians 6 ST elevation myocardial infarction STEMI 147–8 statins 118–20 steatosis 86 Stop-NIDDM trial 50 sucrose 58 60 sugar alcohols 60 sulfonylureas 71. See also insulin sensitizers body weight effect on 73 111 cardiovascular disease and 74 durability 75 glucose control 72–3 hypoglycemia and 47 lipid effects 73 risks 76 side effects 109–10t syndrome X 117 tacrolimus 29 66 taspoglutide 92 thiazolidinediones 83–8 91–2. See also insulin sensitizers adverse effects 88 body weight effect on 73 bone disease risk of 73 cancer risk and 74 cardiovascular disease and 75 clinical trials 86 contraindications 87–8 cost effectiveness of 76 durability 75 effects of 85–6 end- points 72t glucose control 72–3 glycemic control and 47 indications 86–7 carotid intima-media thickness 87 lipid lowering 86–7 lipodystrophies 87 nonalcoholic fatty liver disease 86 polycystic ovary syndrome 86 lipid effects 73 mechanism of action 84–5 peroxisome-proliferator-activated receptors 83–4 pharmacokinetics 85 risks 75–6 side effects 109t thyroxine 140 trans-fatty acids 58t Treating to New Targets TNT study 119 TRIGR trial 16 troglitazone 6–7 89 type 1 diabetes mellitus 11–20 beta-cell mass preserving 15f in children/adolescents 11 clinical features 27t cow’s milk and 13–14 defined 22 early diagnosis of 11–20 incidence of 11 pathogenesis of 12–13 prediction of 14 prevalence of 11 prevention of 14–20 15f 15t primary 15–17 secondary 17–18 tertiary 19–20 self-monitoring of blood glucose 44–5 statin therapy for 119 vitamin D deficiency and 14 type 2 diabetes mellitus bariatric surgery for 127–32

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Index 159 clinical features 27t dyslipidemia in 116–18 insulin-requiring 44–5 non-insulin-requiring 45–8 obesity and 107–14 self-monitoring of blood glucose 44–8 United Kingdom Prospective Diabetes Study UKPDS 44 97 100 University Group Diabetes Program UGDP 74 unstable angina 148 US Preventive Services Taskforce 23 vertical sleeve gastrectomy 128 very low density lipoprotein VLDL 116 117f Veterans Administration Diabetes Trial VADT 100 vildagliptin 112 visual impairment 4 vitamin D 19 vitamin D deficiency 14 weight gain antipsychotics and 65 glucose control and 99–100 weight loss bariatric surgery 128 131–2 lifestyle changes and 68t obesity and 108 pharmacotherapy and 66 weight management 61. See also obesity Wolfram syndrome 32

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