1. 1 COZAAR™ (losartan) in Type 2 Diabetes and Nephropathy Michael C. Elia, PhD Director, Regulatory Affairs Merck Research Laboratories

2. 2 Reduction of Endpoints in NIDDM with the AII Antagonist Losartan RENAAL A multicenter, international, double-blind, randomized, placebo- controlled study designed to evaluate the long-term renal protective effects of losartan in patients with type 2 diabetes and nephropathy Prior to initiating RENAAL: –No conclusive, long-term renal outcomes data in patients with type 2 diabetes and nephropathy

3. 3 RENAAL Primary endpoint - time to event analysis of the composite of: –Doubling of serum creatinine, –End-stage renal disease (defined as the need for chronic dialysis or transplantation), or –Death Key results –Losartan delays progression of renal disease ESRD and death status known for all patients –Safety and tolerability consistent with current labeling –Renal protective benefit of losartan exceeds that attributable to reduction in blood pressure alone

4. 4 COZAAR™ (losartan): Proposed New Indication Renal Protection in Type 2 Diabetic Patients with Proteinuria COZAAR is indicated to delay the progression of renal disease as measured by a reduction in the combined incidence of doubling of serum creatinine, end-stage renal disease (need for dialysis or renal transplantation) or death.

5. 5 Evidentiary Standard for Approvals Based Primarily on a Single Study In Jan-02, FDA Cardio-Renal Advisory Committee discussed the evidence needed to support a new claim for renal protection in patients with type 2 diabetes and proteinuria Useful to review the evidentiary standard needed to support a new claim

6. 6 Use of a Single Study to Support a New Claim Points to Consider for COZAAR Large multicenter study Treatment benefit on multiple endpoints involving different events Consistency among pre-defined subgroups Supportive data from separate (smaller) clinical and preclinical studies FDA Guidance - Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998)

7. 7 COZAAR™ (losartan): Proposed New Indication Renal Protection in Type 2 Diabetic Patients with Proteinuria COZAAR is indicated to delay the progression of renal disease as measured by a reduction in the combined incidence of doubling of serum creatinine, end-stage renal disease (need for dialysis or renal transplantation) or death.

8. 8 COZAAR™ (losartan) in Type 2 Diabetes and Nephropathy Agenda for Merck Presentation Dr. S. Shahinfar, Senior Director CV Clinical Research Background and Rationale RENAAL Demographics and Efficacy Results RENAAL Safety Results Review of the Evidence and Conclusions Dr. W. Keane, Vice President Clinical Development

9. 9 Merck Consultants Clinical Consultants –Barry Brenner, MD - Chair, Steering Committee (P.I.) Professor of Medicine, Harvard Medical School Director Emeritus, Renal Division, Brigham and Women’s Hospital, Boston –Steven Haffner, MD - Chair, Adjudication Committee Professor of Medicine, University of Texas Health Science Center, San Antonio –Carl Erik Mogensen, MD - Chair, DSMC Professor of Medicine, Aarhus Kommunehospital, Aarhus, Denmark

10. 10 Merck Consultants Clinical Consultants (cont’d) –Peter Kowey, MD - Member, DSMC Professor of Medicine, Jefferson Medical College Chief, Division of Cardiovascular Diseases Main Line Hospitals, Philadelphia –Marvin Konstam, MD Professor of Medicine & Radiology, Chief of Cardiology Tufts-New England Medical Center, Boston Statistical Consultant –Scott Zeger, PhD Professor and Chair, Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University

11. 11 Losartan in Type 2 Diabetes and Nephropathy Shahnaz Shahinfar, MD Senior Director, Cardiovascular Clinical Research Merck Research Laboratories

12. 12 Losartan in Type 2 Diabetes and Nephropathy Agenda Background and Rationale RENAAL Demographics and Efficacy Results RENAAL Safety Results Review of Evidence and Conclusions

13. 13 End-Stage Renal Disease: An Unmet Medical Need Type 2 diabetes is the most common type of diabetes Up to 40% of Type 2 diabetic patients develop nephropathy Incidence of end-stage renal disease (ESRD) is increasing worldwide Diabetic nephropathy is the leading cause of ESRD in the US –ESRD is an irreversible condition requiring dialysis as life support –Up to 40% of patients die within 2 years after initiating dialysis

14. 14 Diabetic Nephropathy Diabetic nephropathy is primarily a glomerular disease Progression of renal disease is multifactorial –Hemodynamic –Non-hemodynamic Angiotensin II is hypothesized to play an important role in the progression of nephropathy

15. 15 Efferent Arteriole Constriction Glomerulus Increased Albuminuria Afferent Arteriolar Dilatation Increased Glomerular Pressure Angiotensin II Theoretical Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury Blood Flow

16. 16 Theoretical Non-Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury Glomerulosclerosis Angiotensin II Increased filtering membrane permeability Inflammation and fibrosis

17. 17 Preclinical Renal Data: Blockade of Angiotensin II System In experimental diabetic models, blockade of angiotensin II reduced glomerulosclerosis and proteinuria In experimental models of non-diabetic renal disease, blockade of angiotensin II, but not other antihypertensive therapy, reduced glomerulosclerosis and proteinuria

18. 18 Clinical Renal Outcomes Data: Renin-Angiotensin System Blockade in Diabetic Nephropathy Type 1 Diabetes - Captopril Collaborative Study (1993), N=409 –ESRD/death reduced (RR: 50%; 95% CI:18,70) Type 2 Diabetes - No conclusive evidence of a benefit on ESRD

19. 19 Factors that Differentiate Type 2 from Type 1 Diabetic Patients Age Obesity Insulin resistance Advanced atherosclerosis Long standing hypertension

20. 20 Current Clinical Approaches to Delay Progression to ESRD in Type 2 Diabetes Metabolic control Blood pressure control

21. 21 In patients with type 2 diabetes and nephropathy, does angiotensin II blockade with losartan offer renal protection? Primary Study Question in RENAAL

22. 22 Reduction of Endpoints in NIDDM with the AII Antagonist Losartan RENAAL A multicenter, multinational, double-blind, randomized, placebo-controlled study to evaluate the renal protective effects of losartan in patients with type 2 diabetes and nephropathy

23. 23 250 centers from 28 countries worldwide Merck Coordinating and Data Management Center Data and Safety Monitoring Committee (Unblinded) Chairman: Carl Erik Mogensen, MD Professor of Medicine, Aarhus Kommunehospital, Denmark Steering Committee (Blinded) Chairman: Barry M. Brenner, MD Professor of Medicine, Harvard Medical School Director Emeritus, Renal Division Brigham & Women’s Hospital, Boston Endpoint Adjudication Committee (Blinded) Chairman: Steven M. Haffner, MD Professor of Medicine University of Texas Health Science Center RENAAL: Study Organization

24. 24 RENAAL: Primary Hypothesis In type 2 diabetic patients with nephropathy, losartan compared to placebo will increase the time to the first event of the composite endpoint of: –Doubling of serum creatinine (sCr) –ESRD (need for chronic dialysis or transplantation) –Death (all cause mortality)

25. 25 Time Death from any cause may occur at any time ESRD or Death 100% Loss of Renal Function Doubling of sCr ~50% Loss of Renal Function Normal Renal Function Progression of Renal Disease in Type 2 Diabetes

26. 26 RENAAL: Secondary Hypotheses In type 2 diabetic patients with nephropathy, losartan compared to placebo will: –Renal Reduce the rate of progression of renal disease, as measured by the slope of 1/sCr Reduce proteinuria during the course of the study –Cardiovascular Increase the time to the first event of the composite endpoint of cardiovascular morbidity/mortality (cardiovascular death, MI, stroke, first hospitalization for heart failure, first hospitalization for unstable angina, peripheral and coronary revascularization)

27. 27 Type 2 diabetes Age 31-70 years Proteinuria defined as: urine albumin/creatinine (UA/Cr) >300 mg/g or >500 mg protein/24hours Serum creatinine:1.3-3.0 1 mg/dL Known non-diabetic renal disease, e.g., renal artery stenosis HbA 1C >12% History of: MI or CABG (within 1 month) Stroke or PTCA (within 6 months) TIA (within 1 year) Heart failure 2 1 Lower limit 1.5 mg/dL in male patients >60 kg. 2 Protocol amendment. RENAAL: Key Inclusion/Exclusion Criteria Inclusion Criteria Exclusion Criteria

28. 28 RENAAL: Study Design (I) Double-blind Randomized Placebo-controlled Multicenter (250 sites in 28 countries) Stratified for baseline proteinuria (UA/Cr <2000,  2000 mg/g) Clinic visits every 3 months Planned one year enrollment, 5 year maximum follow-up

29. 29 RENAAL: Study Design (II) 4 Wks Losartan 100 mg Losartan 100 mg + Titrate other antihypertensives Goal: Titrate to achieve trough BP <140/90 mmHg Losartan 50 mg Placebo 4 Wks6 Week Run-in Planned 5 year maximum follow-up Maintain other antihypertensives; Discontinue ACEI or AIIA Placebo Baseline Stratification and Randomization Urine Protein Dipstick Placebo + Titrate other antihypertensives

30. 30 Patient Follow-up RENAAL: Study Design (III) Patients were to remain on study therapy, with clinic visits every three months, regardless of a non-fatal event, until study completion For patients who discontinued study therapy: –Clinic visits for renal and CV endpoints were to be conducted every three months –Telephone contact for ESRD and death information was conducted if clinic visits were not feasible, therefore doubling of serum creatinine and CV morbidity were not collected ESRD and death information was collected on all patients

31. 31 1 Heart Outcomes Prevention Evaluation Study, NEJM 2000;342:145-53. 2 Mann et al, Annals of Int Med, 2001;134:629-36. RENAAL: Early Study Termination On February 10, 2001, the Steering Committee, while blinded to the study results, voted unanimously to end RENAAL prior to its planned termination date of March 2002 because of concerns of continuing the placebo group without blockade of the renin- angiotensin system This decision was based on increasing evidence that ACE inhibitors may be effective in reducing cardiovascular events in patients with cardiovascular risk factors 1,2

32. 32 Agenda Background and Rationale RENAAL Demographics and Efficacy Results –Renal (Primary and Secondary) –Cardiovascular (Secondary) RENAAL Safety Results Review of Evidence and Conclusions

33. 33 1513 Randomized 2380 Ineligible 3893 Screened 751 Losartan 762 Placebo RENAAL: Patient Disposition 407 Completed on study drug 142 D/C study drug after a primary event 202 D/C study drug prior to a primary event 359 Completed on study drug 162 D/C study drug after a primary event 241 D/C study drug prior to a primary event

34. 34 N Age (yrs) Male (%) SBP/DBP (mmHg) BMI (kg/m 2 ) 751 60 62 152/82 30 762 60 65 153/82 29 Losartan Placebo RENAAL: Baseline Demographics (I)

35. 35 Race Asian Black Caucasian Hispanic Region Asia Europe Latin America North America 16 17 48 19 17 20 18 45 Losartan (n=751) % 18 14 50 18 17 19 18 46 Placebo (n=762) % RENAAL: Baseline Demographics (II)

36. 36 Treatment for hypertension Angina pectoris Myocardial infarction Stroke Anemia Amputation Neuropathy Retinopathy Laser therapy/photocoagulation Smoking (current) RENAAL: Medical History at Baseline Losartan (n=751) % 92 9 12 0 21 9 50 66 7 20 Placebo (n=762) % 95 10 14 0.1 22 9 49 62 7 17

37. 37 Urine albumin/creatinine (mg/g) 1 Serum creatinine (mg/dL) Serum potassium (mEq/L) Hemoglobin (g/dL) Hemoglobin A 1c (%) Losartan (n=751) Placebo (n=762) 1 UA/Cr1873 mg/g = approximately 3.4 grams per 24 hours (calculated). 1743 mg/g = approximately 3.2 grams per 24 hours (calculated). 1873 1.9 4.6 12.5 8.5 1743 1.9 4.6 12.5 8.4 RENAAL: Selected Mean Baseline Laboratory Values

38. 38 RENAAL: Primary Hypothesis Losartan compared to placebo will increase the time to the first event of the composite endpoint of: –Doubling of serum creatinine (DsCr) –ESRD (need for chronic dialysis or transplantation) –Death (all cause mortality)

39. 39 RENAAL: Analysis of Primary Composite Endpoint ABCDEABCDE Patient Endpoint Captured – – DsCrESRD – Death –

40. 40 RENAAL: Analysis of Primary Composite Endpoint ABCDEABCDE Patient Endpoint Captured – – DsCrESRD – Death –

41. 41 Doubling of Serum Creatinine/ESRD/Death RENAAL: Primary Composite Endpoint 012243648 Months 0 20 40 60 % Patients with an Event p=0.022 Risk Reduction: 16.1% (2.3, 27.9) Pbo Los 75169258333051 76268955429637 Placebo Losartan n at Risk

42. 42 RENAAL: Analysis of Irreversible Clinical Endpoints (Pre-specified) Irreversible clinical endpoints –ESRD, death, composite of ESRD or death Key principles: –Patient counted as having endpoint in all relevant analyses –Patient counted only once in any analysis

43. 43 RENAAL: Analysis of Irreversible Clinical Endpoints (Pre-specified) ESRD: Time to ESRD, regardless of whether doubling of serum creatinine occurred first Death: Time to death regardless of whether doubling of serum creatinine or ESRD occurred first ESRD or death: Time to first event of ESRD or death, regardless of whether doubling of serum creatinine occurred first

44. 44 RENAAL: Analysis of Irreversible Clinical Endpoints (Pre-specified) ABCDEABCDE Patient Endpoint Captured – – DsCrESRD – Death –

45. 45 RENAAL: Analysis of Irreversible Clinical Endpoints (Pre-specified) ABCDEABCDE Patient Endpoint Captured – – DsCrESRD – Death – Clinical Endpoint Analysis ESRD XX–––XX––– Death XXXX–XXXX– ESRD/ Death XXXX–XXXX–

46. 46 ESRD RENAAL: Irreversible Clinical Endpoints (I) 012243648 Months 0 20 40 60 % Patients with an Event 76271561034843 75171462537568 Pbo Los p=0.002 Risk Reduction: 28.6% (11.5, 42.4) n at Risk Placebo Losartan

47. 47 RENAAL: Irreversible Clinical Endpoints (II) 012243648 Months 0 20 40 60 % Patients with an Event p=0.884 Risk Reduction: -1.7% (-26.9, 18.6) 75173068043084 76273269043965 Pbo Los n at Risk Placebo Losartan All Cause Mortality

48. 48 Placebo Losartan ESRD or Death RENAAL: Irreversible Clinical Endpoints (III) Pbo Los 012243648 Months 0 20 40 60 % Patients with an Event p=0.009 Risk Reduction: 19.9% (5.3, 32.3) 75171462537568 76271561034843 n at Risk

49. 49 DsCr/ESRD/Death ESRD Death ESRD or death +500 -50 Percent Risk Reduction (95% CI) Favors Losartan Favors Placebo RENAAL: Summary of Primary Composite and Clinical Endpoints

50. 50 RENAAL: Imbalance in Baseline Risk Patients were stratified for baseline level of proteinuria, <2000 and  2000 mg/g UA/Cr –Equal numbers of patients were randomized to losartan and placebo within the low and high strata However, within the high stratum of  2000 mg/g, an imbalance in the distribution of patients was observed –There were more losartan patients in the highest level of proteinuria that led to the imbalance in risk

51. 51 0 10 20 30 40 50 60 70 % of Patients Losartan Placebo 501 511 250 251 <2000 mg/g  2000 mg/g Baseline Proteinuria (UA/Cr, mg/g) RENAAL: Distribution of Baseline Proteinuria by Stratum

52. 52 RENAAL: Distribution of Baseline Proteinuria within Strata <10001000- 1999 2000- 2999 3000- 3999  4000 Baseline Proteinuria (UA/Cr, mg/g) 0 10 20 30 40 50 % of Patients 326 175 97 61 92 330 181 115 65 71 Losartan Placebo <2000 mg/g Stratum  2000 mg/g Stratum p = 0.012

53. 53 0 5 10 15 Hazard Ratio 300200040006000 1 Baseline Proteinuria (UA/Cr, mg/g) Pooled Analysis RENAAL: Risk for Primary Composite Endpoint Rises with Increasing Baseline Proteinuria

54. 54 Baseline Proteinuria (UA/Cr, mg/g) Hazard Ratio 300200040006000 0 5 10 15 1 RENAAL: Risk for Primary Composite Endpoint Rises with Increasing Baseline Proteinuria Pooled Analysis

55. 55 Placebo Losartan 012243648 Month 0 20 40 60 % Patients with an Event 75169258333051 76268955429637 n at Risk Pbo Los Risk Reduction: 22.2% (9.4, 33.2) p=0.001 RENAAL: Primary Composite Endpoint Adjusted by Baseline Proteinuria (post hoc)

56. 56 +500-50 Percent Risk Reduction (95% CI) Favors Losartan Favors Placebo RENAAL: Endpoints Adjusted for Baseline Proteinuria as a Continuous Covariate (post hoc) ESRD or death Death ESRD DsCr/ESRD/Death Pre-specified Adjusted

57. 57 RENAAL: Pre-defined Sensitivity Analyses HbA 1c Mean arterial pressure (MAP) Baseline subgroups

58. 58 RENAAL: Blood Pressure Control Study therapy –Titrate losartan or placebo from 50 to 100 mg at Month 1 if BP >140/90 mmHg –Increase other open-label antihypertensives if BP >140/90 mmHg at Month 2 or at any subsequent clinic visit (ACEI and AIIA excluded) Clinic visits –Additional visits performed to adjust study therapy and open- label antihypertensives if BP >140/90 mmHg Goal: Trough <140/90 mmHg

59. 59 RENAAL: Concurrent Antihypertensive Medications Losartan Placebo 0 20 40 60 80 100 % of Patients DiureticCCBAlpha Blocker Beta Blocker 85% 81% 42% 36% 85% 83% 47% 38%

60. 60 RENAAL: Comparable Blood Pressure (Trough) Control Between Treatment Groups 012243648 Months 80 100 120 140 160 Blood Pressure (mmHg) 75166252929544 76264149124730 Systolic Diastolic Pbo (n) Los (n) Placebo Losartan

61. 61 Baseline122436>36 Months 70 80 90 100 110 120 130 MAP (mmHg) Losartan Placebo Distribution at 5, 25, 50, 75, and 95 percentiles at each timepoint Pbo762758621469189 Los751749632510228 RENAAL: Mean Arterial Pressure n

62. 62 +500-50 Favors Losartan Percent Risk Reduction (95% CI) RENAAL: Endpoints Adjusted for Mean Arterial Blood Pressure Favors Placebo DsCr/ESRD/Death ESRD Unadjusted Adjusted Death ESRD/Death

63. 63 Percent Risk Reduction (95% CI) Age Gender Race BMI Region SiSBP <65 years  65 years Female Male Asian Black White Hispanic <30 kg/m 2  30 kg/m 2 Asia Latin America Europe North America <140 mmHg  140 mmHg Overall Primary Composite +500-50 Insulin Dihydropyridine CCB Prev. ACEI/AIIA Smoking Duration of Hypertension Yes No Yes No Yes No Yes No <10 yr  10 yr Overall Primary Composite +500-50 Proteinuria Ser. Creatinine Ser. Albumin Ser. Cholesterol Ser. Uric Acid Hemoglobin HbA 1c <2000 mg/g  2000 mg/g <2 mg/dL  2 mg/dL <3.6 g/dL  3.6 g/dL <240 mg/dL  240 mg/dL <7 mg/dL  7 mg/dL <12 g/dL  12 g/dL <10%  10% Overall Primary Composite +500-50 Favors Los Pbo Favors Los Pbo Favors Favors Los Pbo RENAAL: Baseline Subgroups

64. 64 Age Gender Race BMI Region SiSBP <65 years  65 years Female Male Asian Black White Hispanic <30 kg/m 2  30 kg/m 2 Asia Latin America Europe North America <140 mmHg  140 mmHg Overall Primary Composite +500-50 Yes No Yes No Yes No Yes No <10 yr  10 yr Overall Primary Composite +500-50 Proteinuria Ser. Creatinine Ser. Albumin Ser. Cholesterol Ser. Uric Acid Hemoglobin HbA 1c <2000 mg/g  2000 mg/g <2 mg/dL  2 mg/dL <3.6 g/dL  3.6 g/dL <240 mg/dL  240 mg/dL <7 mg/dL  7 mg/dL <12 g/dL  12 g/dL <10%  10% Overall Primary Composite +500-50 Favors Los Pbo Favors Los Pbo Favors Favors Los Pbo RENAAL: Baseline Subgroups Percent Risk Reduction (95% CI) Insulin Dihydropyridine CCB Prev. ACEI/AIIA Smoking Duration of Hypertension

65. 65 RENAAL: Secondary Hypotheses (Renal) In type 2 diabetic patients with nephropathy, losartan compared to placebo will: –Reduce the rate of progression of renal disease, as measured by the slope of 1/sCr –Reduce proteinuria during the course of the study

66. 66 Median 1/sCr Slope -.08 -.06 -.04 -.02 0 Median Change in 1/sCr (dL/mg/yr) LosartanPlacebo 18% Reduction p=0.01 RENAAL: Reduction in the Rate of Loss of Renal Function (On-treatment Approach)

67. 67 03122436>36 Months Change in Mean UA/Cr (%) 1 -60 -40 -20 0 20 1 Based on geometric mean (95% CI). 34% Overall Reduction p<0.001 Losartan 751661558432163 762632529389120 Pbo (n) Los (n) Placebo RENAAL: Losartan Reduces Proteinuria (On-treatment Approach)

68. 68 RENAAL: Efficacy Summary (Renal) In type 2 diabetic patients with proteinuria, losartan: –Is renal protective by delaying the onset of the primary composite endpoint of doubling of serum creatinine, ESRD (need for chronic dialysis or transplantation), or death Reduces the risk of ESRD by 28.6% –Reduces the rate of decline in renal function as measured by the slope of 1/sCr –Reduces proteinuria –Has a beneficial effect on the primary composite endpoint and proteinuria beyond its beneficial effect on blood pressure

69. 69 Agenda Background and Rationale RENAAL Demographics and Efficacy Results –Renal (Primary and Secondary) –Cardiovascular (Secondary) RENAAL Safety Results Review of Evidence and Conclusions

70. 70 RENAAL: Secondary Hypotheses (Cardiovascular) In type 2 diabetic patients with nephropathy, losartan compared to placebo will increase the time to the first event of the composite of cardiovascular morbidity/mortality: –Cardiovascular death –Myocardial infarction –Stroke –First hospitalization for heart failure –First hospitalization for angina –Revascularization (coronary and peripheral)

71. 71 RENAAL: Secondary Cardiovascular Composite Endpoint 012243648 Months 0 20 40 60 % Patients with an Event p=0.253 Risk Reduction: 9.6% (-7.5, 24.0) 75165856932961 76264655132848 n at Risk Pbo Los Placebo Losartan

72. 72 Favors Losartan Favors Placebo +500-50 Percent Risk Reduction (95% CI) RENAAL: Secondary Cardiovascular Composite Endpoint and Components CV composite CV death Myocardial infarction Stroke Hosp. for heart failure Hosp. for angina Revascularization

73. 73 Placebo Losartan 012243648 Months 0 20 40 60 % Patients with an Event p=0.003 Risk Reduction: 21.2% (7.8, 32.6) 75168458535062 76268556531439 Pbo Los n at Risk RENAAL: Composite of ESRD/MI/Stroke/Death (post hoc)

74. 74 RENAAL: Summary of Cardiovascular Data There was no statistically significant difference in cardiovascular morbidity and mortality between losartan and placebo The renal protective effects of losartan are not at the expense of increased risk of cardiovascular outcomes and support the overall benefits of therapy in this population –Post hoc analysis of ESRD/MI/Stroke/Death demonstrated the beneficial effect of losartan in diabetic patients with proteinuria

75. 75 Agenda Background and Rationale RENAAL Demographics and Efficacy Results RENAAL Safety Results Review of Evidence and Conclusions

76. 76 RENAAL: Clinical Adverse Experience Summary Losartan Placebo With One or More AEs With Serious AEs With Drug- Related AEs With Serious Drug-Related AEs Death Due to AE Discon. Due to AE 95.3 17.2 64.0 3.2 19.0 9.1 95.7 13.9 63.9 2.6 24.0 9.2 0 20 40 60 80 100 % of Patients

77. 77 RENAAL: Laboratory Adverse Experience Summary 0 20 40 60 80 100 49.5 0.8 0 2.7 42.4 1.1 0 2.1 % of Patients 14.8 7.5 0.4 2.6 Losartan Placebo With One or More AEs With Serious AEs With Drug- Related AEs With Serious Drug-Related AEs Death Due to AE Discon. Due to AE

78. 78 RENAAL: Pre-specified Analysis of Adverse Experiences Adverse Experience Acute renal failure Hyperkalemia Hypokalemia Anemia Hyperglycemia Hypoglycemia Losartan (n=751) % 1.7 24.2 2.5 14.1 13.0 14.9 Placebo (n=762) % 1.6 12.3 4.7 10.8 15.0 11.8 Losartan vs. Placebo Hazard Ratio (95% CI) 1.01(0.46, 2.21) 2.00(1.56, 2.57) 0.50(0.28, 0.86) 1.25(0.94, 1.67) 0.82(0.63, 1.08) 1.21(0.92, 1.60) p-Value 0.981 <0.001 0.013 0.126 0.156 0.174

79. 79 Baseline122436>36 Months 3 4 5 6 Serum Potassium (mEq/L) Losartan Placebo Distribution at 5, 25, 50, 75 and 95 percentile at each time point RENAAL: Distribution of Serum Potassium Values at Each Time Point

80. 80 Potassium  3.5 mEq/L Potassium  6.0 mEq/L RENAAL: Serum Potassium at Any Time During the Study 32/751 (4.2) 73/751 (10.0) Losartan n/N (%) 43/762 (5.6) 40/762 (5.0) Placebo n/N (%) Patients Who Had at Least One Measurement of  3.5 and/or  6.0 mEq/L

81. 81 RENAAL: Hyperkalemia 0 5 10 15 20 % of Patients With Serious AEs Discon. Due to AE Death Due to AE 2.6 1.3 0 0.7 0 Adverse Experiences Losartan Placebo

82. 82 RENAAL: Summary of Safety In type 2 diabetic patients with proteinuria: –There were no unusual or unexpected adverse experiences beyond those already noted in the US prescribing information for losartan –Losartan had a higher incidence of hyperkalemia and lower incidence of hypokalemia compared to placebo –Losartan was generally well tolerated

83. 83 RENAAL: Review of Evidence and Conclusions William F. Keane, MD Vice President, Clinical Development Merck US Human Health

84. 84 RENAAL: Strength of the Evidence Robust design features Results are clinically important and statistically significant Internal consistency across multiple endpoints and multiple subgroups

85. 85 RENAAL: Robust Study Design Large multinational study conducted in 28 countries at 250 clinical sites Diverse study population consistent with disease demographics No patients lost to follow-up for ESRD and death Renal and cardiovascular endpoints adjudicated For the primary composite endpoint, no patients missing from ITT analysis

86. 86 RENAAL: Clinically Important and Statistically Significant Results Primary composite endpoint: –Doubling sCr/ESRD/death Clinical endpoints: –ESRD –Death –ESRD or death RR (%) 16.1 28.6 -1.7 19.9 p-Value 0.022 0.002 0.884 0.009 Unadjusted

87. 87 RENAAL: Imbalance in Baseline Risk Patients were stratified for baseline level of proteinuria, <2000 and  2000 mg/g UA/Cr However, within the high stratum of  2000 mg/g, an imbalance in the distribution of patients was observed

88. 88 RENAAL: Clinically Important and Statistically Significant Results Primary composite endpoint: –Doubling sCr/ESRD/death Clinical endpoints: –ESRD –Death –ESRD or death RR (%) 16.1 28.6 -1.7 19.9 p-Value 0.022 0.002 0.884 0.009 Unadjusted RR (%) 22.2 36.7 1.3 25.7 p-Value 0.001 <0.001 0.907 <0.001 Adjusted for Baseline Proteinuria

89. 89 RENAAL: Renal Protective Effects and Blood Pressure Control Effective blood pressure control is critically important in treatment of type 2 diabetic patients with proteinuria In RENAAL: –Blood pressure was aggressively treated and comparable BP control was achieved in both treatment groups –Small differences in MAP were not sufficient to account for the renal protective effects of losartan

90. 90 RENAAL: Clinically Important and Statistically Significant Results Secondary renal endpoints –Rate of progression of renal disease (1/sCr) –Reduction in proteinuria 0.01 <0.001 p-Value 18% 34% Reduction

91. 91 RENAAL: Secondary Cardiovascular Composite Endpoint and Components +500-50 Percent Risk Favors Losartan Favors Placebo 0.003 Reduction (95% CI)p-Value Composite of ESRD/MI/ stroke/death (post hoc) 0.253CV composite 0.453CV death 0.079Myocardial infarction 0.783Stroke 0.006Hosp. for heart failure 0.888Hosp. for angina 0.337Revascularization

92. 92 Conclusions As demonstrated in RENAAL, in patients with type 2 diabetes and proteinuria: –The beneficial treatment effects of losartan across multiple renal endpoints provide robust, reliable and clinically relevant evidence for renal protection –The safety profile of losartan in this population is consistent with the current US prescribing information for losartan