Slide 1 RENAAL Altering the Course of Renal Disease in Hypertensive Patients with Type 2 Diabetes and Nephropathy with the A II Antagonist Losartan

Slide 2 Angiotensin II Drives Pathology in Hypertension Hypertension Vascular Dysfunction Endothelial dysfunction Remodeling/hypertrophy Fibrosis Atherosclerosis Tissue Dysfunction Cell loss Fibrosis Remodeling Ischemia Heart MI, HF Kidney ESRD Brain Stroke Genetics, risk factors (diabetes, hypercholesterolemia) Environment (diet, smoking, stress) MI=myocardial infarction; HF=heart failure; ESRD=end-stage renal disease Adapted from Weir MR, Dzau VJ Am J Hypertens 1999;12:205S-235S; Timmermans PB et al Pharmacol Rev 1993;45(2): ; and Jessup M, Brozena S N Engl J Med 2003;348:

Slide 3 Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are Lacking Endpoints Studied ACE Inhibitor Trials in Type 2 DiabeticsTotalReduction ofReduction ofReduction in Risk with >1 Year Follow-UpSampleProteinuriaGFR Decline of ESRD * Ravid et al Ann Intern Med YesYesNo Lebovitz et al Kidney Int YesYesNo Bakris et al Kidney Int YesYesNo Ahmad et al Diabetes Care YesYesNo Nielsen et al Diabetes Care YesYesNo UKPDS et al Br Med J YesNoNo Fogari et al J Hum Hypertens YesNoNo ABCD Diabetes Care YesYesNo Ruggenenti et al (REIN) 352 (27)**YesYesYes** Am J Kidney Dis 2000 MICRO-HOPE** Lancet YesNoYes*** GFR=glomerular filtration rate *Reduction in the risk of end-stage renal disease (renal transplant or dialysis) **Only 27 (8%) of the 352 patients in this study were Type 2 diabetics ***In this study there was no reduction of risk for renal dialysis for ramipril compared to placebo (p=0.70)

Slide 4 Controlling the Course of Renal Disease with Losartan Rationale for RENAAL (Losartan Renal Protection Study): Losartan significantly lowered BP comparable to other classes of antihypertensive drugs Losartan demonstrated superior tolerability compared to other classes of antihypertensive drugs (placebo-like side-effect profile) Losartan was a specific antagonist of angiotensin II (significant driver of pathology in renal disease) Losartan had significant renoprotective effects in animal models of renal disease Losartan was well tolerated and lowered BP in hypertensive patients with renal insufficiency BP=blood pressure Adapted from Goa KL, Wagstaff AG Drugs 1996;51(5): ; Goldberg AI et al J Hypertens 1995;13(suppl 1):S77-S80; Lafayette RA et al J Clin Invest 1992;90: ; Remuzzi A et al J Am Soc Nephrol 1993;4(1):40-49; Toto R et al Hypertension 1998;31:

Slide 5 Effect of Losartan on Microalbuminuria Urinary albumin (mg/24 hr) Type 2 diabetes Type 1 diabetes Renal transplant Hypertension n= n= n= n= n= n= n= n= n= n=29

Slide 6 RENAAL Reduction of Endpoints in NIDDM with the A II Antagonist Losartan An investigator-initiated, multicenter, double-blind, randomized, placebo-controlled study to evaluate the renal protective effects of losartan in patients with Type 2 diabetes and nephropathy 1513 Patients; 250 Centers; 28 Countries 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 Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4): ; Brenner BM et al N Engl J Med 2001; 345(12):

Slide 7 RENAAL Primary Hypothesis Long-term treatment with losartan versus placebo (alone or in combination with conventional antihypertensive therapy*) in Type 2 diabetic patients with nephropathy will increase the time to first event and decrease the incidence of doubling of sCr, ESRD, or death *Excluding ACE inhibitors and other A II antagonists sCr=serum creatinine Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):

Slide 8 Losartan compared to placebo (alone or in combination with conventional antihypertensive therapy*) in 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 *Excluding ACE inhibitors and other A II antagonists Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4): RENAAL Secondary Hypothesis

Slide 9 RENAAL Study Design qd=once daily *CTx=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents. Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4): wk Losartan 100 mg qd (+CTx) Maintain conventional antihypertensive therapy (CTx)* (excluding ACE inhibitors, A II antagonists) Losartan 100 mg qd (+CTx) Placebo (+CTx) Goal trough BP: <140/<90 mmHg n=1513 Placebo (+CTx) Losartan 50 mg qd (+CTx) Placebo (+CTx) 8 wk 6 wk Mean follow-up 3.4 years

Slide 10 RENAAL Inclusion/Exclusion Criteria Inclusion criteria Type 2 diabetes Age 31–70 years Proteinuria: urine albumin:cr >300 mg/g or 24-hr protein >500 mg sCr: 1.3–3.0 mg/dl, 115–265 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 HF HbA 1c >12% CABG=coronary artery bypass graft; PTCA=percutaneous transluminal coronary angioplasty; CVA=cerebral vascular accident; TIA=transient ischemic attacks *Lower limit 1.5 mg/dl (133 µmol/L) in male patients >60 kg Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):

Slide 11 Europe 19% Latin America 18% North America 46% Asia 17% Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4): RENAAL Enrollment by Region N=1513

Slide 12 Losartan (+CTx)Placebo (+CTx) (n=751)(n=762) Age, years 6060 Male, %6265 Female, % 3835 Race, % Asian1618 Black1714 Caucasian4850 Hispanic1918 Other21 Systolic BP, mmHg Diastolic BP, mmHg8282 BMI, kg/m Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4): RENAAL Baseline Characteristics

Slide 13 RENAAL Primary Composite Endpoint and Components Losartan (+CTx) Placebo (+CTx) Composite (n=751) (n=762) % Risk and componentsn (%) n (%) p Value reduction 95% CI DsCr, ESRD, Death 327 (43.5) 359 (47.1) (2, 28) DsCr 162 (21.6) 198 (26.0) (8, 39) ESRD 147 (19.6) 194 (25.5) (11, 42) Death 158 (21.0) 155 (20.3)0.88–2 (–27, 19) ESRD or death 255 (34.0) 300 (39.4) (5, 32) DsCr=doubling of serum creatinine; CI=confidence interval Adapted from Brenner BM et al N Engl J Med 2001;345(12):

ESRD Months % with event RR: 28% p=0.002 ESRD or Death Months % with event sCr=serum creatinine; RR=risk reduction Adapted from Brenner BM et al N Engl J Med 2001;345(12): RENAAL Primary Components Doubling of sCr Months % with event RR: 25% p=0.006 Placebo (+CTx) Losartan (+CTx) RR: 20% p=0.010 Placebo (+CTx) Losartan (+CTx) Placebo (+CTx) Losartan (+CTx) Slide 14

Slide 15 RENAAL Primary Composite Endpoint Doubling of sCr / ESRD / Death Months % with event RR: 16% p=0.02 Months RR: 22% p=0.008 Placebo (+CTx) Losartan (+CTx) ITT analysis Per-protocol analysis Adapted from Brenner BM et al N Engl J Med 2001;345(12): ; Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19,

Slide 16 RENAAL Time to ESRD from Doubling of sCr Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, Months % with event RR: 30% p=0.013 Placebo (+CTx) Losartan (+CTx)

Slide 17 BaselineYear 1Year 2Study End Systolic/diastolic Losartan (+CTx)152/82146/78143/77140/74 Placebo (+CTx)153/82150/80144/77142/74 Mean arterial pressure Losartan (+CTx) Placebo (+CTx) Pulse pressure Losartan (+CTx) Placebo (+CTx) Adapted from Brenner BM et al N Engl J Med 2001;345(12): ; Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, RENAAL BP (mmHg)

Slide 18 RRp Value RRp Value RRp Value Unadjusted16%0.0228% %0.01 Adjusted15%0.0326% %0.016 DsCr/ESRD/DeathESRD ESRD/Death RENAAL Risk Reduction for Primary Composite Endpoint and Components After Adjusting for Mean Arterial Pressure Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

Slide 19 RENAAL Dose of Losartan The daily dose of losartan ranged from 50–100 mg 100 mg qd Losartan* n=751 % 71 * Patients who took the dose more than 50% of the time. Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

Slide 20 RENAAL Concurrent Antihypertensive Medications LosartanPlacebo Therapeutic Class(n=751)(n=762) Calcium-channel blocker, % Dihydropyridine, % Diuretic, % Alpha blocker, % Beta blocker, % Centrally acting agents,% Adapted from Brenner BM et al N Engl J Med 2001;345(12):

Slide 21 RENAAL Secondary Composite Endpoint and Components RENAAL Secondary Composite Endpoint and Components Losartan (+CTx) Placebo (+CTx) Composite (n=751) (n=762) % Risk and componentsn (%) n (%) p Value reduction 95% CI CV morbidity/mortality 247 (32.9) 268 (35.2) (–8, 24) CV death 90 (12.0) 79 (10.4)0.455–12 (–52, 17) HF 89 (11.9) 127 (16.7) (11, 48) MI 50 (6.7) 68 (8.9) (–4, 50) Unstable angina 42 (5.6) 41 (5.4)0.881 –3(–59, 33) Stroke47 (6.3) 50 (6.6) (–41, 36) Revascularization 69 (9.2) 60 (7.9)0.331–19 (–68, 16) CV=cardiovascular Adapted from Brenner BM et al N Engl J Med 2001;345(12):

Slide 22 RENAAL First Hospitalization for Heart Failure Months % with event Risk reduction: 32% p=0.005 Placebo (+CTx) Losartan (+CTx) Adapted from Brenner BM et al N Engl J Med 2001;345(12):

Slide Months Median % change –60 –40 – % Overall reduction p<0.001 RENAAL Change from Baseline in Proteinuria Proteinuria measured as the urine albumin:creatinine ratio from a first morning void. Adapted from Brenner BM et al N Engl J Med 2001;345(12): Placebo (+CTx) Losartan (+CTx)

Slide 24 RENAAL Rate of Progression of Renal Disease (median 1/sCr slope) Losartan (+CTx)Placebo (+CTx) 0 –0.02 –0.04 –0.06 –0.08 dl/mg/yr –0.056 –0.069 p= % reduction Adapted from Brenner BM et al N Engl J Med 2001;345(12):

Slide 25 RENAAL Most Common Clinical and Laboratory Adverse Experiences Leading to Discontinuation of Study Therapy Heart failure ESRDMIStrokeWorsening renal insufficiency sCrHyper- kalemia Percentage Clin and Lab AEs bars Apr24 Apr. 25, 2001 Losartan (+CTx) Placebo (+CTx) LaboratoryClinical Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

Slide 26 Public Health and Economic Implications of RENAAL (US) For diabetic patients at risk over a 3.5-year period, it is estimated that –Addition of losartan to the treatment regimens of 100 patients with Type 2 diabetes and nephropathy would be expected to lead to a reduction of 6.3 cases of ESRD –In RENAAL, losartan reduced ESRD days by 31% Reduction in days with ESRD saves $5144 (p=0.003) per treated patient at 3.5 years and $7058 (p=0.002) per patient over 4 years After accounting for costs of losartan, reduction in ESRD resulted in net savings of $3522 per patient over 3.5 years (95% CI: $143–$6900) and $5298 (95% CI: $954–$9643) per patient over 4 years Costs are reported in 2001 US dollars. Adapted from Herman WH et al Diabetes Care 2003;26(3):

Slide 27 Public Health and Economic Implications of RENAAL (EU) Extrapolating the addition of losartan to the treatment regimen of patients with Type 2 diabetes and proteinuria in the EU –44,092 cases of ESRD averted (95% CI: 11,898–76,286) after 3.5 years –64,383 years with ESRD averted (95% CI: 20,886–107,879) after 3.5 years –Reduction in ESRD-related costs of €2.6 billion after 3.5 years, increasing to €3.6 billion after 4 years Costs based on ESRD costs in Germany in Adapted from Gerth WC et al Kidney Int 2002;62(suppl 82) S68-S72.

Slide 28 RENAAL Summary ( I ) In patients with Type 2 diabetes and nephropathy –Losartan delayed onset of the primary composite endpoint (DsCr/ESRD/Death) and delayed progression to ESRD –Losartan reduced proteinuria and the rate of decline in renal function (assessed by the reciprocal of sCr concentration) –Losartan reduced the incidence of first hospitalization for heart failure –These benefits were largely independent of BP Adapted from Brenner BM et al N Engl J Med 2001;345(12):

Slide 29 RENAAL Summary ( II ) In patients with Type 2 diabetes and nephropathy –Losartan and placebo, added to CTx, showed no significant difference in 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 Adapted from Brenner BM et al N Engl J Med 2001;345(12):

Slide 30 RENAAL Conclusions Losartan conferred significant benefits on renal outcomes in Type 2 diabetic patients with nephropathy Losartan therapy resulted in a significant reduction in first hospitalizations for heart failure These benefits of losartan were independent of achieved BP control Losartan was generally well tolerated Adapted from Brenner BM et al N Engl J Med 2001;345(12):

Slide 31 RENAAL results show that losartan + CTx –Provided excellent tolerability –Provided proven renal protection and cardioprotective benefit 28% risk reduction in ESRD 32% risk reduction in incidence of first hospitalization for heart failure 35% reduction in proteinuria Analysis of the public health implications of RENAAL suggested potential of losartan for substantial healthcare savings RENAAL Losartan Renal Protection Study Adapted from Brenner BM et al N Engl J Med 2001;345(12): ; Herman WH et al Diabetes Care 2003;26(3): ; Gerth WC et al Kidney Int 2002;62(suppl 82):S68-S72.

Slide 32 Why Is RENAAL Relevant to the Treatment of Hypertension? High BP causes increased risk for cardiac, renal and cerebrovascular events (MI, HF, ESRD, stroke) RENAAL provided strong evidence of a need to block the pathological effects of angiotensin II beyond BP RENAAL demonstrated that specific A II blockade with losartan in hypertensive patients with Type 2 diabetes and nephropathy helps control the course of disease and delays ESRD RENAAL demonstrated that losartan provides renal protection and a cardioprotective benefit Adapted from Whelton PK et al J Hypertens 1992;10(suppl 7):S77-S84; MacMahon S et al Lancet 1990;335: ; Kannel WB JAMA 1996;274(24): ; Klag MJ et al N Engl J Med 1996;334:13-18; Brenner BM et al N Engl J Med 2001;345(12):

Slide 33 Losartan Endpoint Trials ELITE II —The losartan heart failure survival study No significant difference was observed between treatment with losartan or captopril on all-cause mortality in HF patients, but losartan was significantly better tolerated RENAAL—The losartan renal protection study Losartan provided renal protection and a cardioprotective benefit with excellent tolerability LIFE—The losartan hypertension survival study Losartan provided protection against stroke and new-onset diabetes OPTIMAAL—The losartan post-MI survival study Losartan provided cardiovascular benefits comparable to captopril ELITE=Evaluation of Losartan in the Elderly; LIFE=Losartan Intervention For Endpoint reduction; OPTIMAAL=Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan Adapted from Pitt B et al Lancet 2000;355: ; Brenner BM et al N Engl J Med 2001;345(12): ; Dahlöf B et al Lancet 2002;359: ; Dickstein K et al Lancet 09/01/02; available at

Slide 34 References Please refer to notes page.

Slide 35 References (cont’d) Please refer to notes page.

Slide 36 References (cont’d) Please refer to notes page.

Slide 37 Before prescribing, please consult the manufacturers’ prescribing information. Merck does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved CZR 2001-W-6747-SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT