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DIABETES DYSLIPIDEMIA DR.A.P.NAVEEN KUMAR

Type 2 Diabetes Prevalence : Projected to Reach 300 M by 2025 : 

USA 2000: 15M 2025: 21.9M JAPAN 2000: 6.9M 2025: 8.5M EUROPE 2000: 30.8M 2025: 38.5M AMERICAS (Ex-US) 2000: 20M 2025: 42M AFRICA 2000: 9.2M 2025: 21.5M ASIA 2000: 71.8M 2025: 165.7M OCEANIA 2000: 0.8M 2025: 1.5M Adapted from King H et al Diabetes Care 1998;21:1414-1431. Type 2 Diabetes Prevalence : Projected to Reach 300 M by 2025 155 million adults worldwide diagnosed with diabetes in 2000 –(83 million women and 72 million men) Between 1995 and 2025, the prevalence of diabetes in adults will increase by 35% and the number of people with diabetes will increase by 122%

Atherosclerosis Is Common in Newly Diagnosed Diabetes Mellitus : 

Atherosclerosis Is Common in Newly Diagnosed Diabetes Mellitus >50% of patients with newly diagnosed type 2 diabetes show evidence of CVD Atherosclerosis is a major cause of death among patients with diabetes mellitus 75% from coronary atherosclerosis 25% from cerebral or peripheral vascular disease >75% of hospitalizations for individuals with diabetes are for atherosclerotic disease CVD = cardiovascular disease Adapted from Amos AF et al Diabet Med 1997;14:S7-S85; Hill Golden S Adv Stud Med 2002;2:364-370; Haffner SM et al N Engl J Med 1998;339:229-234; Sprafka JM et al Diabetes Care 1991;14:537-543.

Diabetes is a risk equivalent of coronary artery disease : 

Diabetes is a risk equivalent of coronary artery disease Haffner et al. N Engl J Med. 1998 7-year incidence ofmyocardial infarction (%) Non-diabetic (n=1373) Diabetic (n=1059) 3.5% 18.8% 20.2% 45.0% DM=diabetes mellitus MI=myocardial infarction

Greater Risk of Death with Diabetes +1 Risk Factor than with No Diabetes +3 Risk Factors* : 

Greater Risk of Death with Diabetes +1 Risk Factor than with No Diabetes +3 Risk Factors* Diabetes No diabetes Age-adjusted CVD death rate per 10,000 person-years *Serum cholesterol >200 mg/dl, smoking, systolic blood pressure >120 mmHg Adapted from Stamler J et al Diabetes Care 1993;16:434-444. None One only Two only All three Risk factors 0 20 40 60 80 100 120 140

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Non-obese Non - diabetic Normoglycaemia Healthy lipid profile No inflammation Normal coagulation Abdominal obesity Metabolic syndrome Activity Energy intake Triglycerides HDL Small dense LDL Normoglycaemia CRP Endothelial dysfunction -cell failure Abdominal obesity Type 2 diabetes Hyperglycaemia Triglycerides HDL Small dense LDL CRP Endothelial dysfunction PAI-1,Fibrinogen PAI-1,Fibrinogen Cytokines Cytokines Atheromatous disease Micro vascular disease CLUSTER OF ATHEROGENIC METABOLIC ABNORMALITIES

Lipoproteins and atherosclerosis : 

Lipoproteins and atherosclerosis Cholesterol LDL HDL Triglycerides Lp a

Lipid Profile of Diabetes Compared with Nondiabetic, Healthy People : 

Lipid Profile of Diabetes Compared with Nondiabetic, Healthy People Lipid Component Status LDL HDL Triglycerides Normal, with greater number of small, dense particles Low Elevated

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Lipid Profile of Diabetics and Non- Diabetics (Allahabad, 2008) Turkish Journal of Biochemistry 2008; 33 (4) ; 138–141

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PREVALENCE OF DYSLIPIDAEMIA Mohan et al., CUPS,NMJI, 2003

Insulin resistance is associated with atherogenic LDL phenotype : 

Insulin resistance is associated with atherogenic LDL phenotype Reaven GM, et al. J Clin Invest. 1993;92:141-146. LDL-size phenotype Steady-state plasma glucose (mmol/L) A Intermediate pattern B n=52 n=29 n=19

Cumulative distribution of adjusted HDL levels showing prevalence of LDL Phenotype A and Phenotype B : 

Cumulative distribution of adjusted HDL levels showing prevalence of LDL Phenotype A and Phenotype B Cumulative Percent Frequency Circulation 82 – 495-506,1990

LDL mass may underestimate atherogenic risk : 

LDL mass may underestimate atherogenic risk Cholesterol balance 100 mg/dL 100 mg/dL Up to 70% more particles Adapted from Otvos JD, et al. Am J Cardiol 2002; 90 (suppl):22i-29i

“Normal” LDL-C Levels in People with Diabetes Can Be Misleading... : 

“Normal” LDL-C Levels in People with Diabetes Can Be Misleading... Diabetes LDL particles “Normal” LDL-C level, however: “Normal” LDL-C level No diabetes LDL particles Number of LDL particles Concentration of apoB Lower CHD risk Higher Small, dense LDL with more apoB Adapted from Austin MA, Edwards KL Curr Opin Lipidol 1996;7:167-171; Austin MA et al JAMA 1988;260:1917-1921; Sniderman AD et al Diabetes Care 2002;25:579-582. apoB LDL-C Small, Dense LDL-C Particles Are More Atherogenic

High Triglyceride Levels Contribute to Relative Risk of CAD : 

High Triglyceride Levels Contribute to Relative Risk of CAD Framingham Heart Study. Reproduced by Miller M. Am J Cardiol 2000;86(suppl):23L–27L. 0.0 3.0 2.5 2.0 1.5 1.0 0.5 50 100 150 200 250 300 350 400 Relative Risk of CHD Triglyceride (mg/dL) Men Women

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NON-HDL CHOLESTEROL It is calculated routinely as total cholesterol minus HDL cholesterol The sum of VLDL, LDL cholesterol, IDL & Lp(a) is called non-HDL cholesterol Non - HDL cholesterol includes all lipoproteins that contain apo B Single index of all atherogenic apo-B containing lipoprotein

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Global standardization of apo-B assays Not routinely available to the clinician Its cost relative to its potential advantages for clinical decision - making not adequately explored Apo - B

ADA GOALS : 

ADA GOALS Lower LDL Elevate HDL Triglyceride lowering

ADA & ACC CONSENSUS STATEMENT-2008 : 

ADA & ACC CONSENSUS STATEMENT-2008 Greater focus on non – HDL – c and apo –B in patients who are likely to have small-LDL particles such as diabetic subjects. For statin treated patients : LDL – c : < 70 mg/d l Non – HDL-c : < 100 mg/d l apo – B : < 80 mg/ d l Diabetes care 31:811-822.2008

LDL-C Goals for High-Risk Patients : 

AHA/ACC guidelines for patients with CHD*,2 <100 mg/dL: Goal for all patients with CHD†,2 <70 mg/dL: A reasonable goal for all patients with CHD†,2 ATP III Update 20041 <100 mg/dL: Patients with CHD or CHD risk equivalents (10-year risk >20%)1 <70 mg/dL: Therapeutic option for very high-risk patients1 LDL-C Goals for High-Risk Patients <100 mg/dL <70 mg/dL * And other forms of atherosclerotic disease.2 † Factors that place a patient at very high risk: established cardiovascular disesase (CVD) plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic syndrome (triglycerides [TG] ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and acute coronary syndromes.1 1. Grundy SM et al. Circulation. 2004;110:227–239. 2. Smith SC Jr et al. Circulation, 2006; 113:2363–2372. 2006Update Recommended LDL-C treatment goals If it is not possible to attain LDL-C <70 mg/dL because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C─lowering therapy, including drug combinations.

HDL : 

HDL > 40 mgs/dl in males > 50 mgs/dl in females

TG : 

TG No widely accepted targets Glycemic control first > 400 mgs/dl - treat with drugs >1000 mgs/dl - severe diet restriction < 10 % calories from fat Reduce risk of pancreatitis

Treating Non-HDL Cholesterol in Patients with Diabetes: Recent Findings : 

Treating Non-HDL Cholesterol in Patients with Diabetes: Recent Findings Intensification of statin therapy Use of a statin with greater LDL-lowering efficacy Addition of a fibrate or niacin specifically to enhance VLDL reduction. Statins slow the secretion of VLDL from the liver and attenuate the subsequent formation of IDL & LDL from plasma. Generally, statins lower non-HDL and LDLc by similar percentages.

DIET : 

DIET

EXERCISE : 

EXERCISE

GLYCEMIC CONTROL : 

GLYCEMIC CONTROL

Impact of Simvastatin on First Major Vascular Events ALL PATIENTS AND PATIENTS WITH DIABETES : 

Impact of Simvastatin on First Major Vascular Events ALL PATIENTS AND PATIENTS WITH DIABETES Risk of First Major Vascular Event Reduced by 24% in All Patients and by 22% in Diabetics (p<0.0001)

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Relatively Few Randomized Trials of Cholesterol Lowering have Studied their Effects on Macrovascular Complications in Diabetes Only 1500 Patients with Pre-existing CHD in Diabetes Included in Various Trials Suggesting that Proportional Effects of Statins on Coronary Events Similar to Other Groups of Patient Therefore, Lowering LDL-C May be Beneficial in Diabetes Without Symptomatic CHD BACKGROUNDMacrovascular Complications in Diabetes

MEDICAL CONCLUSIONS : 

In more than 20,000 patients at high risk for CHD Simvastatin significantly reduced the risk of major vascular events in high-risk patients With or without prior CHD Regardless of baseline cholesterol levels Simvastatin significantly reduced the risk of major vascular events in patients with diabetes with or without prior CHD Simvastatin 40 mg had a long-term tolerability profile comparable to placebo Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22. MEDICAL CONCLUSIONS

TNT: Hazard Ratios in Patients With andWithout Diabetes: Secondary Efficacy Outcomes : 

TNT: Hazard Ratios in Patients With andWithout Diabetes: Secondary Efficacy Outcomes Shepherd J et al. Diabetes Care. 2006;29:1220-1226.

Primary Prevention Trials of Lipid-Altering Therapy Including Patients with Diabetes : 

Primary Prevention Trials of Lipid-Altering Therapy Including Patients with Diabetes Bays H et al. Future Cardiology 2005;1:39-59. | Colhoun HM et al. Lancet 2004;364:685-696. | Downs JR et al. JAMA 1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Sever PS et al. Lancet 2003;361:1149-1158. | Shepherd J et al. Lancet 2002;360:1623-1630. | Koskinen P et al. Diabetes Care 1992;15:820-825. * By history † Prospective trial in diabetic subjects; others are subgroup analyses ‡ Mean 30 mg/d § Type 1 or 2 diabetes

Secondary Prevention Trials of Lipid-Altering Therapy - Patients with Diabetes : 

Secondary Prevention Trials of Lipid-Altering Therapy - Patients with Diabetes Bays H et al. Future Cardiology 2005;1:39-59. | Pyörälä K et al. Diabetes Care 1997;20:614-620. | Haffner SM et al. Arch Intern Med 1999;159:2661-2667. | Goldberg RB et al. Circulation 1998;98:2513-2519. | Keech A et al. Diabetes Care 2003;26:2713-2721. | Serruys PWJC et al. JAMA 2002;287:3215-3222. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Wanner C. Presented at ASN annual meeting, 2004. | Rubins HB et al. Arch Intern Med 2002;162:2597-2604. | DAIS Investigators. Lancet 2001;357:905-910. *Includes stroke in 4D and VA-HIT †By history ‡By history or glucose 126 mg/dL § Type 1 or 2 diabetes ¶ Prospective trial in diabetic subjects; others are subgroup analyses || Angiographic study

Statin therapy in patients with diabetes: Evidence : 

Statin therapy in patients with diabetes: Evidence 202 4242 5963 785 2829 n = 586

Conclusions : 

34 Conclusions This evidence confirms the benefit of cholesterol lowering with statins in an expanded cohort of patients with diabetes and overt CHD There is no justification for having a threshold level of LDL-C as the sole arbiter Patients with type 2 diabetes should receive statin treatment. The overall cardiovascular risk should be the principle determinant The debate about whether all patients with type 2 diabetes warrant statin therapy should now focus on whether there are any patients at sufficiently low risk for this safe and efficacious treatment to be withheld

Simvastatin reduces plaque volumemeasured by IVUS : 

Simvastatin reduces plaque volumemeasured by IVUS Coronary plaque volume (mm3) Jensen l. et al Abstract AHA 2003 Simvastatin 40 mg 12 months Baseline Diet 3 months 50 40 30 * * p<0.01 vs. baseline

REVERSAL: Atheroma Regression : 

REVERSAL: Atheroma Regression

TNT Trial : 

TNT Trial p<0.001 Presented at ACC 2005 Persistent elevations in liver aminotransferase levels, treatment-related adverse events, and study drug discontinuation due to adverse events were all higher in the high-dose group compared to the low-dose group. p<0.001 p<0.001

EFFICACY- EVIDENCE - EXPERIENCE : 

EFFICACY- EVIDENCE - EXPERIENCE

The Pyramid of TrialsRelative Size of the Various Segments of the Population : 

The Pyramid of TrialsRelative Size of the Various Segments of the Population High cholesterol with CHD/MI Moderately high cholesterol in high risk CHD or MI Normal cholesterol with CHD or MI High cholesterol without CHD or MI No history of CHD or MI History of CHD but low LDL Low LDL without CHD but with High CRP TNT JUPITER Spediel K.M et all E.O.P 2006 Jul;7(10):1291-304

HDL AND TGs IN DIABETES:THE EFFECT OF FIBRATES : 

HDL AND TGs IN DIABETES:THE EFFECT OF FIBRATES The Helsinki Heart Study Gemfibrozil reduced the incidence of major CHD events by 60% compared with placebo Statistically insignificant because of the small patient number Recently published 18 year follow-up data : 33% reduction in all cause mortality 71% reduction in CHD mortality ( P < 0.001 ) Arch Intern Med 166 : 743-748,2006

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acknowledgement of the source as - “Speakers consensus forum on statins in diabetic dyslipidemia, July 2009”