Microalbuminuria in Diabetic and hypertensive patients: Therapeutic Ap

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microalbuminuria is early sign of general vasculopathy and hurbinger of ESRD, the significance of microalbuminuria in diabetic and hypertensive patients is risky sign for further cardiovascular diseases, in this discussion I aimed to discuss the therapeutic approach for these patients

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Microalbuminuria in Diabetic and hypertensive patients: Therapeutic approach :

Microalbuminuria in Diabetic and hypertensive patients: Therapeutic approach By Dr.Abdelsalam Sherif Consultant Cardiologist RNH

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Microalbuminuria. Hypertension. Diabetes Mellitus. Interventions.

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Microalbuminuria

JNC 7: CVD Risk Factors:

JNC 7: CVD Risk Factors Hypertension* Cigarette smoking Obesity* (BMI > 30 kg/m2) Physical inactivity Dyslipidemia* Diabetes mellitus* Microalbuminuria estimated GFR <60 ml/min Age (older than 55 for men, 65 for women) Family history of premature CVD (men under age 55 or women under age 65 ) JAMA 2003:289:2560 *Components of the metabolic syndrome.

Definition of Adversal Albumin Excretion:

>300 mg/g creatinine 30-300 mg/g creatinine < 30 mg/g creatinine Albumin-to-creatinine ratio** Male 2.5-30 mg/mmol Female 3.5-30 mg/mmol 30-300 mg/24hours 20-200 μ g/minute Microalbuminuria ≥30 mg/mmol Male <2.5 mg/mmol Female < 3.5mg/mmol >300 mg/24 hours >200 μ g/minute <30 mg/24 hours <20 μ g/minute Albumin excretion rate* Macroalbuminuria Normoalbuminuria Measure Definition of Adversal Albumin Excretion *24-hour collection **spot urine; normalizes for urine volume; low muscle mass: false positive results; high muscle mass: false negative results Tagle R et al. Cleave Clin J Med 2003; 70:225-265

Definitions of Microalbuminuria and Macroalbuminuria:

Definitions of Microalbuminuria and Macroalbuminuria Parameter Normal Micro-albuminuria Macro-albuminuria Urine AER (  g/min) < 20 20 - 200 >200 Urine AER (mg/24h) < 30 30 - 300 >300 Urine albumin/ Cr # ratio (mg/gm) < 30 30 - 300 >300 AER=Albumin excretion rate CR # =creatinine

MAU is Independently Associated with a Variety of CV Risk Factors:

1 Gould et al., BMJ,306:240-242, 1993; 2 Damsgaard et al., BMJ,300:297-300, 1990; 3 Viberti et al., Lancet 1:1430-1432, 1982; 4 Valensi et al., Int J of Obesity,20:574-579, 1996 5 Cirillo et al., Archive of inter Med,158:1933-1939, 1998; 6 Mykkanen et al.,Diabetes,47:793-800, 1998; 7 Watchell et al., AHJ 2002. 143:319-326; 8 Liu et al., J Am Coll Cardiol. 2003;41(11):2022-8. , 9 Barzilay et al., Am J Kidney disease 2004 Jul;44(1):25-34. MAU is Independently Associated with a Variety of CV Risk Factors MAU can be found in 5 to 15% of the general population, and in 3 to 8% of apparently healthy individuals (without diabetes or hypertension). Non modifiable Male gender1 Older age 2 Modifiable Diabetes 3 Obesity 4 Smoking 5 Insulin resistance syndrome 6 LVH (Left-Ventricular Hypertrophy)7 Left ventricular dysfunction 8 CRP (C-Reactive Protein) 9

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Correlation Coefficient between micoalbuminoria and different parameters P r Parameters Blood pressures : <0.01 0.678 Systolic BP NS 0.133 Diastolic BP Blood Glucose : <0.05 0.201 FBS <0.05 0.218 PPBS Lipogram: <0.05 0.443 T.Cholesterol NS 0.179 Triglycerides <0.05 -0.319 HDL – C NS 0.134 LDL – C

Albuminuria and CV Diseases: the LIFE Study:

Wachtell et al. J Hypertens 2002;20:405–12 8,029 subjects with hypertension and LV hypertrophy, mean age 66 years Prevalence (%) 40 30 20 10 0 Diabetes Cerebrovascular Peripheral Coronary disease vascular vascular disease disease Normoalbuminuria Microalbuminuria (Alb/Crea >3.5 mg/mmol) Macroalbuminuria (Alb/Crea >35 mg/mmol ) Albuminuria and CV Diseases: the LIFE Study

Microalbuminuria Compared To Traditional Risk Factors For Ischemic Heart Disease:

Microalbuminuria Compared To Traditional Risk Factors For Ischemic Heart Disease N=2,085; 10 year follow-up Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997. A/C ratio > 0.65mg/mmol > 7.0 mmol/L > 160 mmHg

HOPE TRIAL: Independent Predictive Variables for Combined Endpoints of CV Death, MI, and Stroke:

HOPE TRIAL: Independent Predictive Variables for Combined Endpoints of CV Death, MI, and Stroke Variable Hazard Ratio Microalbuminuria 1.59 Creatinine > 1.4 mg/dL 1.40 CAD 1.51 PVD 1.49 Diabetes Mellitus 1.42 Male 1.20 Age 1.03 Waist-Hip Ratio 1.13 Mann JFE, et al. Ann Intern Med. 2001;134(8):629-636.

Low Levels of MAU are Predictive of CAD and Death:

Klausen et al., Hypertension. 2005; 46:33-37 30 20 10 0 30 20 10 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 CHD incidence CHD mortality Cumulative CHD incidence (%) Cumulative mortality (%) UAE ≥ 4.8 μ g/min UAE < 4.8 μ g/min UAE ≥ 4.8 μ g/min UAE < 4.8 μ g/min Years from entry Years from entry Cox-estimated age-adjusted curves of cumulative mortality for a 60-year-old person based on 1734 hypertensive subjects with microalbuminuria (UAE ≥ 4.8 µg/min; n=522) and normoalbuminuria (UAE < 4.8 µg/min; n=1212; P <0.001). Cox-estimated age-adjusted curves of cumulative coronary heart disease (CHD) for a 60-year-old person based on 1734 hypertensive subjects with microalbuminuria (UAE ≥ 4.8 µg/min; n=522) and normoalbuminuria (UAE < 4.8 µg/min; n=1212; P <0.001). Low Levels of MAU are Predictive of CAD and Death

Cardiovascular Events by Degree of Albuminuria in HOPE:

Cardiovascular Events by Degree of Albuminuria in HOPE Gerstein et al. JAMA 2001;286:421-6. Incidence (%) 30 25 20 15 10 5 0 All participants With diabetes Without diabetes Microalbuminuria threshold Albumin/creatinine Ratio Deciles 1 & 2 3 4 5 6 7 8 9 10

Microalbuminuria Screening is Important!!:

Microalbuminuria Screening is Important!! Marker of small vessel disease in both the kidney and the heart Marker of increased cardiovascular morbidity and mortality for both diabetics and the general population Progresses to overt proteinuria in up to 40% of patients with type 2 diabetes within 5 to 10 years American Diabetes Association. Diabetes Care 2002;25:S85-S89

Modifiable Risk Factors / Markers for Progression of Microalbuminuria to Clinical Proteinuria:

Modifiable Risk Factors / Markers for Progression of Microalbuminuria to Clinical Proteinuria Blood pressure Level of microalbumin excretion rate Hemoglobin A 1c Serum cholesterol Drugs that block the renin-angiotensin-aldosterone system (RAAS)

Detection of Microalbuminuria (American Diabetes Association):

Exclusion of artefacts (exercise, urinary infections, fever etc.) Microalbuminuria ? (> 30 mg/24 h; > 20 m g/min; > 20 mg/l; > 2 mg/mmol creatinine) Repeat 2 x in 3 months 2 of 3 positive tests Repeat at 1 y yes yes no no Diagnosis of microalbuminuria start management ADA. Diabetes Care 1996; 19:S103-S105 Detection of Microalbuminuria (American Diabetes Association)

Hypertension:

Hypertension

Hypertension Has a High Prevalence That Is Expected To Rise Over the Coming Decades :

Hypertension Has a High Prevalence That Is Expected To Rise Over the Coming Decades Kearney PM, et al. Lancet 2005; 365:217–223 Hypertension is an important public health challenge worldwide. Prevention, detection, treatment and control should receive high priority 2000 2025 Established Market Economie s Former Socialist Economies India Latin America and the Caribbean Middle Eastern Crescent China Other Asia And islands Sub-Saharan Africa % Population with Hypertension % Population with Hypertension 37.4 35.3 20.6 40.7 22 22.6 17 26.9 37.2 39.1 20.9 34.8 23.7 19.7 14.5 28.3 0 10 20 30 40 50 Men Women 41.6 39.1 22.9 44.5 24 27.7 18.8 27 42.5 45.9 23.6 40.2 27 27 17.1 28.2 0 10 20 30 40 50

Hypertension Burden on Healthcare:

Hypertension Burden on Healthcare Worldwide, hypertension is responsible for 62% of strokes 1 49% of heart attacks 1 Hypertension is the third leading risk factor for disease Causes 7.1 million premature deaths each year 1 4.5% of global burden of disease 1 Hypertension represents a high burden on healthcare expenditure In 2004, the direct and indirect cost of high blood pressure in the US was $55.5 billion; drug costs accounted for $21 billion 2 Thus, hypertension management is a public health priority WHO, 2002; 2. AHA, 2004 AHA. Heart Disease and Stroke Statistics -- 2004 Update

Elevated Blood Pressure Increases the Risk of Cardiovascular Disease:

0.25 0.50 1.00 2.00 4.00 123 76 136 84 148 91 162 98 175 85 Approximate mean usual BP Approximate mean usual BP Stroke CAD Relative Risk Elevated Blood Pressure Increases the Risk of Cardiovascular Disease Collins R et al. Br Med Bull 1994;50: 272 – 298 123 76 136 84 148 91 162 98 175 85 0.25 0.50 1.00 2.00 4.00 Relative Risk

Hypertension (HTN) and Microalbuminuria (MAU):

Hypertension (HTN) and Microalbuminuria (MAU) HTN is associated with MAU. However, real prevalence of MAU in hypertensive patients is unknown In patients with HTN, MAU is an independent risk marker for cardio-vascular events like ischemic heart disease and stroke, but also all-cause mortality MAU is a marker of generalized endothelial dysfunction which is considered as an early stage of Atherothrombosis Screening for MAU is simple and easy to perform and is recommended by international treatment guidelines RAS-blockade and adequate BP-control are the cornerstone for the treatment of MAU and HTN

MAU is a Predictor of Ischemic Heart Disease in Hypertensive Patients:

Normoalbuminuria Microalbuminuria (UA/Cr ratio > 1.07 mg/mmol) 0 1 2 3 4 5 6 7 8 9 10 100 95 90 85 80 75 70 Proportion without ischemic heart disease (%) Jensen et al., Hypertension.2000;35:898-903 204 hypertensive subjects drawn from 2085 general population subjects. No previous CV events, no diabetes. No renal or urinary disease. Follow up from 1983–1984 till 1993. 18 coronary events. MAU is a Predictor of Ischemic Heart Disease in Hypertensive Patients Years

MAU Reduction in Hypertensive Patients is Accompanied by CV Event Reduction:

Kaplan–Meier plot for the composite end point by UACR categories (fractions of patients experiencing from an end point). Primary composite end points (CEP): the first occurrence of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction. LIFE Study: Double-blind, randomized trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in high-risk patients with hypertension and left ventricular hypertrophy (LVH) Ibsen et al., Hypertension. 2005;45:198-202 Low baseline/low year 1 Analysis from LIFE trial 0.20 0.15 0.10 0.05 0.00 Fraction suffering CEP Time (months) High baseline/high year 1 High baseline/low year 1 Low baseline/high year 1 MAU Reduction in Hypertensive Patients is Accompanied by CV Event Reduction 0 10 20 30 40 50 60 70

Risk of Ischemic Heart Disease Related to SBP and Microalbuminuria:

Risk of Ischemic Heart Disease Related to SBP and Microalbuminuria Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 999;19(8):1992-1997. With permission from Lippincott Williams & Wilkins. N=2,085; 10 year follow-up

MAU Screening Recommended in Patients with Hypertension:

1 ESH/ESC guidelines, Journal of hypertension 2003,21:1011-1053; 2 The JNC 7 Hyperten s.2003;42:1206-1252 MAU Screening Recommended in Patients with Hypertension ESH/ESC Guidelines for the management of arterial hypertension, 2003 1 : “…searching for microalbuminuria is recommended, because of the mounting evidence that it may be a sensitive marker of organ damage, not only in diabetes but also in hypertension.” The JNC-7 Report, The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure, 2003 2 : “Optional tests include measurement of urinary albuminuria excretion or albumin/creatinine ratio.”

Recommendations by ADA, ISHIB, and NKF consistent with JNC 7:

Recommendations by ADA, ISHIB, and NKF consistent with JNC 7 Drug therapy is recommended for all patients with hypertension (SBP/DBP >140/90 mmHg) BP goals <140/90 mmHg <130/80 mmHg for patients with diabetes mellitus or chronic kidney disease Multiple drug therapy with 2 or more agents at adequate doses (thiazide diuretic, ACE inhibitor, ARB, beta-blocker, CCB ) is usually required to achieve BP targets ISHIB guidelines: consider initiating treatment with 2 drugs if BP is 15 /10 mmHg above goal American Diabetes Association (ADA). Diabetes Care 2005; 28:S4–S36. The International Society on Hypertension in Blacks (ISHIB). Arch Intern Med 2003;163:525–541. The National Kidney Foundation (NKF). Am J Kidney Dis 2000; 36:646–661.

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Diabetes

The Diabetes Epidemic:

From Zimmet P et al. Diabet Med . 2003;20:693-702 . 25.0 39.7 59% 10.4 19.7 88% 38.2 44.2 16% 1.1 1.7 59% 13.6 26.9 98% 81.8 156.1 91% 18.2 35.9 97% 189 mill. in 2003 324 mill. Estimated for 2025 72% increase The Diabetes Epidemic

Type 2 diabetes increases the risk of cardiovascular disease:

Rates (per 10,000 person-year) Adjusted for age, race, income, cholesterol, systolic blood pressure, smok ing Total CVD CHD Stroke Other CVD 75 50 25 0 Diabetes No diabetes Relative risk 3.0 3.2 2.8 2.3 Type 2 diabetes increases the risk of cardiovascular disease n = 342,815 n = 5,163

The presence of diabetes was associated with a higher CHD risk in the VA-HIT placebo group:

The presence of diabetes was associated with a higher CHD risk in the VA-HIT placebo group 36.5% 34.3% 23.8% 21%

Association of Systolic Blood Pressure (SBP) and CV Death in Type 2 Diabetes:

0 25 50 75 100 125 150 175 200 225 250 SBP (mm Hg) CV Mortality (deaths/10,000 person-years) No diabetes Diabetes  120 120–139 140–159 160–179 180–199  200 Adapted from Stamler J et al. Diabetes Care. 1993;16:434-444. Association of Systolic Blood Pressure (SBP) and CV Death in Type 2 Diabetes

Proteinuria levels predict stroke and CHD events in type 2 diabetes:

Proteinuria levels predict stroke and CHD events in type 2 diabetes > 300 < 150 150-300 U-Prot = Urinary protein concentration Miettinen H et al. Stroke 1996;27:2033–9 . Survival curves (CV mortality) Incidence (%) 1.0 0.9 0.8 0.7 0.6 0.5 0 40 30 20 10 0 Stroke CHD events Overall: p < 0.001 Time (months) 10 20 30 40 50 60 70 80 90 0 U-Prot < 150 mg/L U-Prot 150-300 mg/L U-Prot > 300 mg/L p < 0.001 7-year follow-up of 1,056 patients with type 2 diabetes with or without hypertension

Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes:

1.0 0.9 0.8 0.7 0.6 0.5 0 1 2 3 4 5 6 Years Survival (all-cause mortality) Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51) P<0.01 normoalbuminuria vs microalbuminuria P<0.001 normoalbuminuria vs macroalbuminuria P<0.05 microalbuminuria vs macroalbuminuria Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes Gall MA, et al. Diabetes. 1995;44:1303-1309. Copyright ©1995, American Diabetes Association. Reprinted with permission.

Relative prognostic value of MAU in type 2 diabetes:

Relative prognostic value of MAU in type 2 diabetes Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32 . MAU Smoking Diastolic BP Mortality from CHD (odds ratio) Cholesterol 10 6.5 2.3 3.2 10 8 6 4 2 0

Therapeutic Approach:

Therapeutic Approach

Effective Blood Pressure Control Reduces Cardiovascular Morbidity and Mortality:

Effective Blood Pressure Control Reduces Cardiovascular Morbidity and Mortality ESH/ESC Guidelines. J Hypertens 2003; 21:1779 – 1786 . 10 -40 -30 -20 -10 0 -50 Isolated-systolic hypertension Stroke CHD All Causes CV Non CV Stroke CHD All Causes CV Non CV Systolic-diastolic hypertension Fatal and non fatal events Mortality Fatal and non fatal events Mortality <0.001 <0.001 <0.001 <0.001 <0.01 <0.01 NS NS 0.02 0.01 Event reduction in patients on active antihypertensive treatment versus placebo or no treatment. CHD: coronary heart disease; CV: cardiovascular

UKPDS Relative Risk Reduction for Intensive vs Less Intensive Glucose Control:

% relative risk reduction P=0.03 P<0.01 P<0.01 P=0.05 P=0.02 UKPDS Group. Lancet. 1998;352:837-853. UKPDS Relative Risk Reduction for Intensive vs Less Intensive Glucose Control Over 10 years, HbA 1c was 7.0% (6.2-8.2) in the intensive group (n=2,729) compared with 7.9% (6.9-8.8) in the conventional group (n=1,138).

HOT-Study: Optimal blood pressure in hypertensive and diabetics (Type II):

Hypertensive diabetics profit most from stringent blood pressure control HOT = Hypertension Optimal Treatment 0 5 10 15 20 25 Serious cardiovascular events/1000 pat.years  90  85  80 30 mm Hg diastolic target blood pressure - 51% risk reduction Hansson L at al. Lancet 1998; 351:1755-1762 HOT-Study: Optimal blood pressure in hypertensive and diabetics (Type II)

Microalbuminuria Resets the Focus on CV Risk Reduction Strategies:

Microalbuminuria Resets the Focus on CV Risk Reduction Strategies BP <130/80 mmHg Evaluate lipids Normalize microalbuminuria Reduction in dietary salt/saturated fat Intensify glycemic control Anti-platelet therapy

JNC-7 Guidelines Diabetic hypertension:

JNC-7 Guidelines Diabetic hypertension Thiazide diuretics, ß-blockers, ACE inhibitors, ARBs and CCBs have been shown to reduce CVD and stroke incidence in diabetic hypertension In diabetic hypertension, combinations of 2 or more medications are usually needed to achieve target BP of < 130/80 mmHg ACE- and ARB-based treatments favourably affect the progression of diabetic nephropathy and reduce albuminuria Chobanian AV et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003;289:2560-72.

JNC 7 - Algorithm for treatment of hypertension:

Hypertension with compelling indications Stage 1 hypertension (SBP 140-159 or DBP 90-99 mmHg) Thiazide-type diuretics for most May consider ACE inhibitor, ARB,  -blocker, CCB, or combination Stage 2 hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACE inhibitor or ARB or  -blocker or CCB) Drug(s) for compelling indications Other antihypertensive drugs (diuretics, ACE inhibitor, ARB,  -blocker, CCB) as needed Not at goal BP Lifestyle modifications JNC 7 VII, Hypertens. 2003;42:1206-1252 . Not at goal BP (<140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease) Initial drug choices Hypertension without compelling indications Optimize dosages or add additional drugs until goal BP is achieved Consider consultation with hypertension specialist JNC 7 - Algorithm for treatment of hypertension

National Kidney Foundation Algorithm for Achieving Target BP Goals in Hypertensive Diabetic Patients:

Reprinted from Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661 with permission from National Kidney Foundation. National Kidney Foundation Algorithm for Achieving Target BP Goals in Hypertensive Diabetic Patients Start ACE inhibitor titrate upwards If BP still not at goal (130/80 mm Hg) BP still not at goal (130/80 mm Hg) Baseline pulse <84 Add low-dose beta blocker or alpha/beta blocker Add other subgroup of CCB (ie, amlodipine-like agent if verapamil or diltiazem already being used and the converse) Refer to a clinical hypertension specialist BP still not at goal (130/80 mm Hg) If BP goal achieved, convert to fixed dose combinations (ACE inhibitor + CCB or ACE inhibitor + diuretic) Baseline pulse 84 Add Thiazide Diuretic or long-acting CCB* Blood pressure >130/80 mm Hg *If proteinuria present (>300 mg per day) non-DHP preferred.

Chronic Renal Disease: Initial Treatment Recommendations:

Chronic Renal Disease: Initial Treatment Recommendations Renal Insufficiency Cl cr <60 mL/min Cr Serum >1.4 mg/dL* Microalbuminuria (only Abnormality) Diabetes Mellitus ACE Inhibitor (or ARB) Start And Titrate To Maximum Tolerable Dose  130/80  130/80 Proteinuria *for women, CR Serum >1.2 mg/dL

Importance of Long-Term BP-Control for MAU-Reduction:

Importance of Long-Term BP-Control for MAU-Reduction SBP reduction leads to MAU-reduction Cumulative hazard risk in developing MAU Time of follow-up Pascual et al.,Hypertension. 2005;45:1132-1137 1.00 0.75 0.50 0.25 0.00 0 5 10 15 <130mmHg 130–139 mmHg >139 mmHg

The RAS showing ACE and non-ACE pathways:

ACE PATHWAY (< 30%) NON-ACE PATHWAY (> 70%) Angiotensin Angiotensinogen Chymase Tonin Cathepsin Kallikrei n Angiotensin I Renin ACE McConnaughey et al. J Clin Phamacol 1999;39: 547–59. The RAS showing ACE and non-ACE pathways

Angiotensin II Formation:

Angiotensin II Formation Angiotensin II Angiotensin I Angiotensinogen Angiotensin II Receptors ACE Renin CAGE Cathepsin G Chymase t-PA Cathepsin G Tonin * The clinical significance of alternate pathways is unknown. Dzau VJ et al. J Hypertens. April 1993;11(suppl):S13-S18. Alternate Pathways*

Mechanism of Action of Angiotensin II Receptor Blockers (ARBs):

Mechanism of Action of Angiotensin II Receptor Blockers (ARBs) Adapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A. AT 1 Receptor Na reabsorption Aldosterone release Sympathetic outflow Vasopressin secretion Vasoconstriction Vascular and cardiac hypertrophy Angiotensinogen Angiotensin I Angiotensin II Non-ACE enzymes (cathepsin, chymase) Renin Bradykinin ACE Inactive Fragments AT 2 Receptor Vasodilation Growth inhibition Apoptosis Blood Pressure ARBs

Angiotensin II effects at the AT1 and AT2 receptors:

Adapted from McConnaughey et al. J Clin Phamacol 1999;39: 547–59. Angiotensin II AT 1 Receptor AT 2 Receptor -sartan Angiotensin II effects at the AT 1 and AT 2 receptors Vasoconstriction Activate sympathetic activity Increase sodium retention Increase vasopressin release Promote myocyte hypertrophy and proliferation Stimulate vascular and cardiac fibrosis Stimulate plasminogen activator inhibitor 1 Stimulate superoxide formation Antiproliferation Apotosis Endothelial cell growth Vasodilation (NO mediated?) Stimulate renal bradykinin and NO

Interventions to Reduce Microalbuminuria:

Interventions to Reduce Microalbuminuria Non Pharmacological measures:- Weight Loss. Exercise. Eating a low fat diet Pharmacological agents:- Statins. ACE inhibitors. ARBs. Cobination of ACEI and ARBs. CCBs

ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Diabetic and Non-Diabetic Nephropathy:

ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Diabetic and Non-Diabetic Nephropathy Study Year Conclusions about ACE inhibitors (ACE-I) Bjork et al 1992 ACE-I reduced both the rate of decline in GFR and the amount of albuminuria. Lewis et al 1993 In Type I diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced. REIN 1997 In non-diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced. MicroHOPE 2000 ACE-I reduced progression of proteinuria from normoalbuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria. AASK 2001 ACE-I was superior to amlodipine in reducing proteinuria among non-diabetic African Americans with hypertension and kidney disease.

Albumin excretion rate in hypertensive diabetic patients treated with lercanidipine or ramipril.:

Albumin excretion rate in hypertensive diabetic patients treated with lercanidipine or ramipril. Dalla Vestra M et al, Diab Nutr Metab, 2004 P<0.05 P<0.05 Lercanidipine Ramipril Change in Albumin Excreation Rate (AER) from baseline to the end point according to treatment groups: ( □ )Lercanidipine group p<0.05; (∆)Ramipril group p<0.05. From th comparison between groups, p<0.05 at baseline and NS at the endpoint

Benefit of Angiotensin Receptor Blockers in Diabetes: Important Findings of 3 Major Clinical Trials:

Benefit of Angiotensin Receptor Blockers in Diabetes: Important Findings of 3 Major Clinical Trials RENAAL (2001) The angiotensin receptor blocker losartan compared to placebo reduced the risk of diabetic nephropathy developing to renal failure IRMA II (2001) Higher doses of the angiotensin receptor blocker irbesartan reduced the risk of progression of renal insufficiency IDNT (2001) The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure

ARB (Losartan) Reduces Urinary Albumin and TGF-1 in Type 2 Diabetes with Microalbuminuria:

ARB (Losartan) Reduces Urinary Albumin and TGF-  1 in Type 2 Diabetes with Microalbuminuria Esmatjes E, et al. Nephrol Dial Transplant. 2001;16(Suppl1):90-93. 160 140 130 120 24-hour Systolic BP P <0.01 vs baseline mmHg 4 Weeks 90 80 70 60 24-hour Diastolic BP P <0.03 vs baseline Baseline 8 Weeks mmHg 50 Urinary Albumin Excretion P<0 .01 vs baseline 100 90 80 70 60 mcg/min 6 5 4 3 2 1 TGF-  P<0 .005 vs baseline Baseline 4 Weeks 8 Weeks ng/mL

Benefit of Angiotensin Receptor Blockers in Diabetes: Important Findings of 3 Major Clinical Trials:

Benefit of Angiotensin Receptor Blockers in Diabetes: Important Findings of 3 Major Clinical Trials RENAAL (2001) The angiotensin receptor blocker losartan compared to placebo reduced the risk of diabetic nephropathy developing to renal failure IRMA II (2001) Higher doses of the angiotensin receptor blocker irbesartan reduced the risk of progression of renal insufficiency IDNT (2001) The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure

The IRbesartan MicroAlbuminuria Type 2 Diabetes In Hypertensive Patients Study:

The IRbesartan MicroAlbuminuria Type 2 Diabetes In Hypertensive Patients Study IRMA II Objectives Randomized multi-site, double-blind, placebo-controlled study to evaluate the renal protective effect of the angiotensin II receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria Population 590 patients (30 to 70 years old) Type 2 diabetes Hypertension (a mean systolic BP >135 mmHg or a mean diastolic BP >85 mmHg, or both, on 2 of 3 consecutive measurements) Persistent microalbuminuria Albumin excretion rate of 20 to 200  g/min in 2 of 3 samples Serum creatinine concentration of no more than 1.5 mg/dL for men and 1.1 mg/dL for women Parving HH, et al. N Engl J Med. 2001;345(12):870-878 .

IRMA II Incidence of Progression to Diabetic Nephropathy:

IRMA II Incidence of Progression to Diabetic Nephropathy Incidence of Diabetic Nephropathy (%) 0 3 6 12 18 22 24 201 201 164 154 139 195 195 167 161 148 194 194 180 172 159 129 142 150 36 45 49 Placebo (n) Irbesartan 150 mg (n) Irbesartan 300 mg Months of Follow-up Placebo 150 mg of irbesartan 300 mg of irbesartan P<0.001 for difference between 300 mg irbesartan group and placebo Parving HH, et al. N Engl J Med. 2001;345(12):870-878. ©2001 Massachusetts Medical Society. All rights reserved.

IRMA II Change in Urinary Albumin Excretion*:

IRMA II Change in Urinary Albumin Excretion * % change in urinary albumin excretion 0 3 6 12 18 22 24 Months of Follow-up 150 mg of irbesartan 300 mg of irbesartan Placebo Parving HH, et al. N Engl J Med. 2001;345(12):870-878. ©2001 Massachusetts Medical Society. All rights reserved. *P<0.001 for difference between both irbesartan groups and placebo

IRMA II Irbesartan vs Placebo Secondary Endpoints:

IRMA II Irbesartan vs Placebo Secondary Endpoints During the first 3 months, the decline in creatinine clearance (mL/min/m 2 body surface area per month) was greater than the decline between 3 and 24 months* 0.9 vs 0.1 for the placebo group 1.0 vs 0.2 for the 150 mg group 1.9 vs 0.2 for the 300 mg group Irbesartan reduced the level of urine albumin excretion… 24% in the 150 mg group (P=NS) † 38% in the 300 mg group (P<0.001) † Parving HH, et al. N Engl J Med. 2001;345(12):870-878. *Neither the initial nor long-term decline differed significantly among the 3 groups † Compared to placebo

IRMA II Adverse outcomes:

IRMA II Adverse outcomes Parving H-H et al. N Engl J Med 2001;345:870–78 . Cardiovascular events Serious adverse events Discontinuations due to adverse events 18 47 19 (8.7) (22.8) (9.2) Control 14 32 18 (6.9) (15.8) (8.9) Irbesartan (150 mg) 9 30 11 (4.5) (15.0) (5.5) Irbesartan (300 mg) No. of adverse outcomes (%)

IRMA II Summary of Important Findings:

IRMA II Summary of Important Findings Irbesartan significantly reduces the rate of progression from microalbuminuria to diabetic nephropathy. Renoprotection from irbesartan in patients with type 2 diabetes and microalbuminuria is independent of its blood pressure lowering effect. Antihypertensive treatment has a renoprotective effect in hypertensive patients with type 2 diabetes and microalbuminuria Parving HH, et al. N Engl J Med. 2001;345(12):870-878.

Benefit of Angiotensin Receptor Blockers in Diabetes: Important Findings of 3 Major Clinical Trials:

Benefit of Angiotensin Receptor Blockers in Diabetes: Important Findings of 3 Major Clinical Trials RENAAL (2001) The angiotensin receptor blocker losartan compared to placebo reduced the risk of diabetic nephropathy developing to renal failure IRMA II (2001) Higher doses of the angiotensin receptor blocker irbesartan reduced the risk of progression of renal insufficiency IDNT (2001) The angiotensin receptor blocker irbesartan compared to the calcium channel blocker amlodipine provided better renal protection in hypertensive type 2 diabetics, reducing the chance of diabetic nephropathy developing to renal failure

IDNT Primary Endpoint:

Subjects (%) 0 6 12 18 24 30 36 42 48 54 Follow-up (mo) 60 0 10 20 30 40 50 60 IDNT Primary Endpoint Irbesartn Amlodipie Control RRR 20% P =0.02 P =NS RRR 23% P =0.006 23% RRR P=0.006 Time to Doubling of Serum Creatinine, ESRD, or Death Lewis EJ et al. N Engl J Med 2001;345:851-860.

RECOMMENDATIONS FOR THERAPY SUMMARY:

Guidelines are consistent in aiming to reduce cardiovascular and renal morbidity. ‘Goal’ or ‘Target’ BP’s consistent: <140/90 mm Hg for all hypertensive patients <130/80 mm Hg in diabetic patients. BP goals are not attained by many patients US and European guidelines recommend use of combination therapy early in the management of specific groups of patients US and European guidelines recommend use of combination therapy following failure to reach goal with monotherapy RECOMMENDATIONS FOR THERAPY SUMMARY JNC 7 Report . JAMA 2003; 289: 2560-2572 ESH/ESC Guidelines. J Hypertens 2003 ; 21: 1011-1053 Guidelines Sub-Committee. 1999 WHO/ISH. J Hypertens 1999; 17:151–18 3

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