0902CZR01NL537SS0901 RENAAL Altering the Course of Renal Disease in Hypertensive Patients with Type 2 Diabetes and Nephropathy with the A II Antagonist Losartan

0902CZR01NL537SS0901 An investigator initiated, multicenter, double-blind, randomized, placebo-controlled study to evaluate the renal protective effects of losartan in hypertensive patients with Type 2 diabetes and nephropathy 1513 Patients; 250 Centers; 28 Countries RENAAL Reduction of Endpoints in NIDDM with the A II Antagonist Losartan Steering CommitteeChairB. M. Brenner, MD Data and Safety Monitoring CommitteeChairC.E. Mogensen, MD Clinical Endpoint Adjudication Committee ChairS. Haffner, MD Coordinating Center: Merck Research LabsStudy DirectorS. Shahinfar, MD Brenner BM et al New Engl J Med 2001;345(12):

0902CZR01NL537SS0901 RENAAL Primary Hypothesis Long-term treatment with losartan versus placebo (alone or in combination with conventional anti hypertensive therapy*) in Type 2 diabetic patients with hypertension and nephropathy will increase the time to first event and decrease the incidence of doubling of sCr, ESRD or death. Brenner BM et al New Engl J Med 2001;345(12): * Excluding ACEIs and other AIIAs

0902CZR01NL537SS0901 Losartan compared to placebo (alone or in combination with conventional antihypertensive therapy*) in hypertensive patients with Type 2 diabetes and nephropathy will: increase the time to first event and decrease the incidence of cardiovascular morbidity/mortality reduce proteinuria decrease the rate of progression of renal disease RENAAL Secondary Hypothesis Brenner BM et al New Engl J Med 2001;345(12): * Excluding ACEIs and other AIIAs

0902CZR01NL537SS0901 RENAAL Study Design *CT=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents. 4 Wks Losartan 100 mg qd (+CT) Maintain conventional antihypertensive therapy (CT)* (excluding ACEI, AIIA) Losartan 100 mg qd (+CT) Placebo (+CT) Goal trough BP: < 140/<90 mmHg n=1513 Placebo (+CT) Losartan 50 mg qd (+CT) Placebo (+CT) 8 Wks 6 Wks Mean follow-up 3.4 years Brenner BM et al J Renin-Angio-Aldo System 2000;1(4):

0902CZR01NL537SS0901 RENAAL Inclusion/Exclusion Criteria Inclusion criteria Type 2 diabetes Age years Proteinuria: urine alb:cr >300 mg/g, >25 mg/mmol Serum Creatinine: mg/dl, µmol/L* Exclusion criteria Type 1 diabetes Known non-diabetic renal disease or renal artery stenosis Recent history of MI, CABG, PTCA, CVA, TIA History of heart failure HbA 1c >12% *Lower limit 1.5 mg/dl (133 µmol/L) in male patients >60 kg Brenner BM et al J Renin-Angio-Aldo System 2000;1(4): Brenner BM et al New Engl J Med 2001;345(12):

0902CZR01NL537SS0901 RENAAL Enrollment by Region n=1513 Europe 19% Latin America 18% North America 46% Asia 17% Brenner BM et al New Engl J Med 2001;345(12):

0902CZR01NL537SS0901 RENAAL Baseline Characteristics (I) Age, years Male, % Female, % Race, % Asian Black Caucasian Hispanic Other Systolic (mmHg) Diastolic (mmHg) BMI (kg/m 2 ) % Losartan (+CT) (n=751) Placebo (+CT) (n=762) Brenner BM et al New Engl J Med 2001;345(12):

0902CZR01NL537SS0901 RENAAL Primary Composite Endpoint and Components DsCr, ESRD, Death Doubling of sCr ESRD Death ESRD or Death Losartan (+CT) (n=751) n (%) 327 (43.5) 162 (21.6) 147 (19.6) 158 (21.0) 255 (34.0) 359 (47.1) 198 (26.0) 194 (25.5) 155 (20.3) 300 (39.4) P-Value % Risk Reduction % CI (2, 28) (8, 39) (11, 42) (-27, 19) (5, 32) Composite and Components Placebo (+CT) (n=762) n (%) Brenner BM et al New Engl J Med 2001;345(12):

RENAAL Primary Components ESRD Months % with event p=0.002 Risk Reduction: 28% P L ESRD or Death P (+ CT) L (+ CT) Months % with event P L p=0.01 Risk Reduction: 20% Doubling of Serum Creatinine Months % with event p=0.006 Risk Reduction: 25% P (+ CT) L (+ CT) P L P (+ CT) L (+ CT) Brenner BM et al New Engl J Med 2001;345(12): CZR01NL537SS0901

RENAAL Blood Pressures (mmHg) BaselineYear 1Year 2Study End L (+CT) S/D152/82146/78143/77140/74 P (+CT) S/D153/82150/80144/77142/74 L (+CT) MAP P (+CT) MAP L (+CT) PP P (+CT) PP S/D: Systolic/Diastolic MAP: Mean arterial pressure PP: Pulse pressure Brenner BM et al New Engl J Med 2001;345(12): L = losartan P = placebo CT = conventional therapy

0902CZR01NL537SS0901 RENAAL Dose of Losartan 100 mg QD Losartan* n=751 % 71 * Patients who took the dose more than 50% of the time. Brenner BM et al New Engl J Med 2001;345(12):  The daily dose of losartan ranged from mg

0902CZR01NL537SS0901 RENAAL Concurrent Antihypertensive Medications Therapeutic Class Calcium-Channel Blocker (%) - Dihydropyridine (%) Diuretic (%) Alpha blocker (%) Beta blocker (%) Centrally acting agents (%) Losartan n= Placebo n= Brenner BM et al New Engl J Med 2001;345(12):

0902CZR01NL537SS0901 CV Morbidity/Mortality Heart Failure MI RENAAL Secondary Composite Endpoint and Components Losartan (+CT) (N=751) n (%) 247 (32.9) 89 (11.9) 50 (6.7) Placebo (+CT) (N=762) n (%) 268 (35.2) 127 (16.7) 68 (8.9) P-Value % Risk Reduction Composite and Components Brenner BM et al New Engl J Med 2001;345(12):

0902CZR01NL537SS0901 RENAAL First Hospitalization for Heart Failure Months % with event Risk Reduction: 32% p=0.005 P (+CT) L (+CT) P L Brenner BM et al New Engl J Med 2001;345(12): L = losartan P = placebo CT = conventional therapy

0902CZR01NL537SS0901 RENAAL Change from Baseline in Proteinuria Proteinuria measured as the urine albumin:creatinine ratio from a first morning void Months Median Percent Change p<0.001 P (+CT) L (+CT) P L 35% Overall Reduction Brenner BM et al New Engl J Med 2001;345(12): L = losartan P = placebo CT = conventional therapy

0902CZR01NL537SS0901 RENAAL Rate of Progression of Renal Disease (median 1/sCr Slope) LosartanPlacebo dl/mg/yr p= % reduction (+CT) Brenner BM et al New Engl J Med 2001;345(12): sCr=serum creatinine

0902CZR01NL537SS0901 RENAAL Summary ( I )  In hypertensive patients with Type 2 diabetes and nephropathy: –losartan delayed the onset of the primary composite endpoint (DsCr/ESRD/Death) and delayed the progression to ESRD. –losartan reduced proteinuria and the rate of decline in renal function (1/sCr slope). –losartan reduced the incidence of hospitalization for heart failure. –these benefits were largely independent of achieved blood pressure. Brenner BM et al New Engl J Med 2001;345(12):

0902CZR01NL537SS0901 RENAAL Summary ( II )  In hypertensive patients with Type 2 diabetes and nephropathy: –losartan and placebo, on a background of conventional therapy, showed no significant difference on all-cause mortality, MI, stroke, revascularization, hospitalizations for unstable angina, and death due to CV disease. –losartan was generally well tolerated in this patient population. Brenner BM et al New Engl J Med 2001;345(12):

0902CZR01NL537SS0901 RENAAL Conclusions  Losartan confers significant benefits on renal outcomes in Type 2 diabetic patients with hypertension and nephropathy.  Losartan therapy results in a significant reduction in hospitalizations for heart failure.  Losartan is generally well tolerated.  Benefits of losartan seen in RENAAL complement many previous losartan studies which demonstrate a reduction in microalbuminuria and macroalbuminuria. Brenner BM et al New Engl J Med 2001;345(12):