1513 Patients; 250 Centers; 28 Countries RENAAL Reduction of Endpoints in NIDDM with the AII 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 RENAAL Reduction of Endpoints in NIDDM with the AII Antagonist Losartan The RENAAL study was an investigator-initiated, randomized, double-blind, placebo-controlled trial to evaluate the renal protective effects of losartan in hypertensive patients with Type 2 diabetes (formerly referred to as non–insulin-dependent diabetes mellitus—NIDDM) and nephropathy. The study involved 1513 patients in 250 clinical sites in 28 countries. The RENAAL study is a landmark endpoint trial because it was the first trial to show that specific blockade of AII with losartan provided significant (risk reduction 16%, p=0.02) renal protection and a cardioprotective benefit in hypertensive patients with Type 2 diabetes and nephropathy. The chairperson of the Steering Committee of RENAAL was Professor Barry M. Brenner, Brigham and Women's Hospital, Boston, Massachusetts, USA. The chairperson of the Data and Safety Monitoring Committee was Professor Carl Erik Mogensen, Aarhus Kommunehospital, Denmark. The chairperson of the Clinical Endpoint Adjudication Committee was Professor Steven Haffner, University of Texas Health Science Center, San Antonio, Texas, USA. Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334; Brenner BM et al N Engl J Med 2001; 345(12):861-869. Steering Committee Chair B. M. Brenner, MD Data and Safety Monitoring Committee Chair C. E. Mogensen, MD Clinical Endpoint Adjudication Committee Chair S. Haffner, MD Coordinating Center: Merck Research Labs Study Director S. Shahinfar, MD Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334; Brenner BM et al N Engl J Med 2001; 345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

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 RENAAL: Primary Hypothesis The primary hypothesis of RENAAL was that long-term treatment with losartan vs. placebo, alone or in combination with CT (excluding ACE inhibitors and AII antagonists in each group), in Type 2 diabetic patients with nephropathy, would increase the time to first event and decrease the incidence of doubling of serum creatinine, ESRD (defined as the need for dialysis and renal transplantation), or death. The primary efficacy endpoint was a composite of the time to first event of doubling of serum creatinine, ESRD, or death. Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334; *Excluding ACE inhibitors and other AII antagonists sCr=serum creatinine Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Secondary Hypothesis 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 RENAAL: Secondary Hypothesis The secondary hypothesis of RENAAL was that long-term treatment with losartan versus placebo alone or in combination with CT (excluding ACE inhibitors and other AII antagonists) in Type 2 diabetic patients with nephropathy would: 1) Increase the time to first event and decrease the incidence of cardiovascular morbidity/mortality 2) Reduce proteinuria 3) Decrease the rate of progression of renal disease (slope of the reciprocal of serum creatinine) Tertiary efficacy endpoints included health-related quality of life (US patients only), healthcare resource utilization, and incidence of amputation. These endpoints will be the subject of future publications. Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334 *Excluding ACE inhibitors and other AII antagonists Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Study Design Mean follow-up 3.4 years Losartan 100 mg qd (+CT) Maintain conventional antihypertensive therapy (CT)* (excluding ACE inhibitors, AII antagonists) Goal trough BP: <140/<90 mmHg RENAAL: Study Design The RENAAL study began with an initial screening–treatment phase lasting six weeks. During this phase no placebo was administered. The majority (93.5%) of patients entered the study on prior antihypertensive therapy. Those hypertensive patients being treated with either an ACE inhibitor or an AII antagonist within six weeks of trial enrollment discontinued these medications and received an alternative conventional antihypertensive (open-label CT including CCBs, diuretics, beta or alpha blockers, or centrally acting agents) as appropriate, to control hypertension to a goal of <140/90 mmHg. Hypertensive patients not being treated with an ACE inhibitor or an AII antagonist continued to receive their prior conventional antihypertensive therapy. The screening–treatment phase was followed by a double-blind treatment phase designed to have a 3.5-year follow-up after the last patient had been randomized. However, the study was discontinued early by the steering committee, while blinded to all treatment assignments for external reasons. The mean follow-up time was 3.4 years. The double-blind phase began with the randomization of eligible patients into two treatment groups. The first group received losartan 50 mg once daily, alone or in combination with CT, excluding ACE inhibitors and other AII antagonists (losartan + CT). The second treatment group received placebo once daily, alone or in combination with CT, excluding ACE inhibitors and other AII antagonists (placebo + CT). The randomization was stratified based on the level of baseline proteinuria (urine albumin:creatinine ratio above or below 2000 mg/g). Four weeks after randomization, or at any phase during the study, if the target trough sitting systolic/diastolic blood pressure of <140/90 mmHg was not achieved, the daily dose of losartan (or placebo) was increased to losartan 100 mg once daily or two placebo tablets once daily. However, if losartan 100 mg or the two placebo tablets were not sufficient to reduce trough blood pressures below the target values, additional open-label antihypertensives were added. The open-label antihypertensives were as described above. Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334 n=1513 Placebo (+CT) Placebo (+CT) Placebo (+CT) 6 wk 4 wk 8 wk Mean follow-up 3.4 years qd=once daily *CT=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents. Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334. CARD-1071592-0000-CZR-SS-02/2015

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 HbA1c >12% RENAAL: Inclusion/Exclusion Criteria The inclusion criteria for RENAAL included hypertensive patients with Type 2 diabetes and nephropathy. Patients with Type 2 diabetes were defined as those who were diagnosed after the age of 30, who did not require insulin within six months of diagnosis, and who had no history of diabetic ketoacidosis. Proteinuria was defined by two qualifying urinary albumin:creatinine ratios on first morning specimen of at least 300 mg/g (or 24-hour urine protein >500 mg) and two qualifying serum creatinine measurements between 1.3 and 3.0 mg/dl. In addition, patients were required to be 31 to 70 years of age. The exclusion criteria for RENAAL included uncontrolled diabetes (HbA1c >12%), Type 1 diabetes, non-diabetic renal disease or known renal artery stenosis; recent MI; or coronary artery bypass graft (CABG) within one month; or cerebral vascular accident (CVA); or percutaneous transluminal coronary angioplasty (PTCA) within six months, or transient ischemic attacks (TIA) within one year prior to enrollment; and any history of heart failure. Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334 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 Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Enrollment by Region N=1513 Asia 17% North America 46% Europe 19% RENAAL: Enrollment by Region RENAAL was a truly international study with patient representation from North America (46%), Europe (19%), Latin America (18%), and Asia (17%). Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334 Latin America 18% Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Baseline Characteristics Losartan (+CT) Placebo (+CT) (n=751) (n=762) Age, years 60 60 Male, % 62 65 Female, % 38 35 Race, % Asian 16 18 Black 17 14 Caucasian 48 50 Hispanic 19 18 Other 2 1 Systolic BP, mmHg 152 153 Diastolic BP, mmHg 82 82 BMI, kg/m2 30 29 RENAAL: Baseline Characteristics I A total of 1513 patients were enrolled in the RENAAL study. Of the total cohort, 63.2% were male and 36.8% were female, with a mean (SD) age of 59.6 (±7.4) years. There was no significant difference between the losartan + CT and the placebo + CT treatment groups with respect to the baseline characteristics of age, gender, race, duration of hypertension or diabetes, systolic or diastolic blood pressure, or body mass index. Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334 Data from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):328-334. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Primary Composite Endpoint and Components Losartan (+CT) Placebo (+CT) Composite (n=751) (n=762) % Risk and components n (%) n (%) p Value reduction 95% CI DsCr, ESRD, Death 327 (43.5) 359 (47.1) 0.02 16 (2, 28) DsCr 162 (21.6) 198 (26.0) 0.006 25 (8, 39) ESRD 147 (19.6) 194 (25.5) 0.002 28 (11, 42) Death 158 (21.0) 155 (20.3) 0.88 –2 (–27, 19) ESRD or death 255 (34.0) 300 (39.4) 0.01 20 (5, 32) RENAAL: Primary Composite Endpoint and Components The primary composite endpoint of RENAAL was the time to the first event of doubling of serum creatinine (DsCr), ESRD, or death. In an intention-to-treat (ITT) analysis (which was the primary analysis approach of the study), the primary composite endpoint was reached in 327 (43.5%) patients receiving losartan + CT and 359 (47.1%) patients receiving placebo + CT. Losartan + CT treatment resulted in a significant decrease in risk of 16% (p=0.02) in the primary composite endpoint. For those patients who remained on treatment throughout the protocol (per-protocol analysis), losartan + CT treatment conferred a 22% risk reduction (p=0.008) in the primary composite endpoint. Brenner BM et al N Engl J Med 2001; 345(12):861-869. DsCr=doubling of serum creatinine; CI=confidence interval Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Primary Components ESRD 12 24 36 48 10 20 30 % with event RR: 28% p=0.002 12 24 36 48 10 20 30 Doubling of sCr Months % with event Placebo (+CT) 762 715 610 347 42 Losartan (+CT) 751 714 625 375 69 RR: 25% p=0.006 12 24 36 48 10 20 30 40 50 ESRD or Death RENAAL: Primary Components This slide shows the individual Kaplan-Meier plots for the components of the composite primary endpoint. Doubling of serum creatinine and ESRD are both important renal endpoints. Once-daily losartan + CT significantly reduced the risk of the development of doubling serum creatinine (25%; p=0.006) and ESRD (28%; p=0.002). The composite endpoint of ESRD or death also showed a significant risk reduction (20%; p=0.010). There was no significant risk reduction of death alone with losartan + CT. Brenner BM et al N Engl J Med 2001; 345(12):861-869. Months % with event Placebo (+CT) 762 689 554 295 36 Losartan (+CT) 751 692 583 329 52 RR: 20% p=0.010 sCr=serum creatinine; RR=risk reduction Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. Months Placebo (+CT) 762 715 610 347 42 Losartan (+CT) 751 714 625 375 69 Slide 9 CARD-1071592-0000-CZR-SS-02/2015

RENAAL Primary Composite Endpoint Doubling of sCr / ESRD / Death ITT analysis Per-protocol analysis 50 50 40 40 30 30 % with event 20 20 RENAAL: Primary Composite Endpoint: Doubling of sCr/ESRD/Death The primary endpoint of RENAAL was a composite endpoint of doubling of serum creatinine, ESRD, or death. In the primary ITT data analysis, losartan + CT produced a significant risk reduction of 16% (p=0.02). The secondary per-protocol analysis included only those patients who followed protocol and remained on treatment throughout the study. According to the per-protocol analysis, losartan + CT conferred a significant risk reduction of 22% (p=0.008) in the primary composite endpoint. Brenner BM et al N Engl J Med 2001; 345(12):861-869. 10 RR: 16% p=0.02 10 RR: 22% p=0.008 12 24 36 48 12 24 36 48 Months Months Placebo (+CT) 762 689 554 295 36 760 584 431 214 24 Losartan (+CT) 751 692 583 329 52 746 612 479 263 36 Data from Brenner BM et al N Engl J Med 2001;345(12):861-869 CARD-1071592-0000-CZR-SS-02/2015

RENAAL BP (mmHg) Baseline Year 1 Year 2 Study End Systolic/diastolic Losartan (+CT) 152/82 146/78 143/77 140/74 Placebo (+CT) 153/82 150/80 144/77 142/74 Mean arterial pressure Losartan (+CT) 105.5 100.9 99.1 95.9 Placebo (+CT) 106.0 103.1 99.7 96.8 Pulse pressure Losartan (+CT) 69.4 67.8 66.2 66.7 Placebo (+CT) 70.8 69.8 67.1 67.4 RENAAL: BP (mmHg) The majority (93.5%) of patients in the RENAAL trial were hypertensive (systolic/diastolic 140/90 mmHg) at baseline and were taking at least one antihypertensive drug. Normotensive patients (i.e., those with sitting systolic/diastolic blood pressures <140/90 mmHg) could be included in the trial. An additional 3% of the patients had hypertension but were not receiving antihypertensive therapy. CT consisted of CCBs, diuretics, beta and alpha blockers, and centrally acting agents, excluding ACE inhibitors and other AII antagonists. Trough blood pressures (systolic, diastolic, and mean) fell progressively during the study. Trough systolic/diastolic blood pressure at baseline averaged 153/82 mmHg in the placebo group and 152/82 in the losartan group (mean arterial pressure was 106.0 for placebo vs. 105.5 for losartan, p=0.38). At one year, values averaged 150/80 (placebo) and 146/78 (losartan) (103.1 for placebo vs. 100.9 for losartan, p<0.001). At year 2, values averaged 144/77 for placebo and 143/77 for losartan (99.7 for placebo vs. 99.1 for losartan, p=0.38). At study end, final values were 142/74 for placebo and 140/74 for losartan (96.8 for placebo vs. 95.9 for losartan, p=0.59). The small differences in blood pressures observed during the first year of the study were not sustained, and after the second year, the trough blood pressures were not statistically different in the two treatment groups. Brenner BM et al N Engl J Med 2001; 345(12):861-869. Data from Brenner BM et al N Engl J Med 2001;345(12):861-869 CARD-1071592-0000-CZR-SS-02/2015

RENAAL Risk Reduction for Primary Composite Endpoint and Components After Adjusting for Mean Arterial Pressure DsCr/ESRD/Death ESRD ESRD/Death RR p Value RR p Value RR p Value Unadjusted 16% 0.02 28% 0.002 20% 0.01 Adjusted 15% 0.03 26% 0.007 19% 0.016 RENAAL: Risk Reduction for Primary Composite Endpoint and Components After Adjusting for Mean Arterial Pressure The risk reduction of the primary composite endpoint (doubling of serum creatinine, ESRD, or death) with losartan + CT was 16% (p=0.02) with no adjustment for the small differences in mean blood pressure. After statistically adjusting for this small difference in mean blood pressure, the risk reduction with losartan + CT was 15% (p=0.03). Likewise, the risk reductions for ESRD and ESRD/death were little changed after adjusting for the small changes in blood pressure (28% before and 26% after for ESRD and 20% before and 19% after for ESRD/death). Statistical analysis that corrected for these small differences confirmed that the renal protection conferred by losartan exceeded that attributable to any small difference in blood pressure. Brenner BM et al N Engl J Med 2001; 345(12):861-869 Data from Brenner BM et al N Engl J Med 2001;345(12):861-869 CARD-1071592-0000-CZR-SS-02/2015

RENAAL Dose of Losartan The daily dose of losartan ranged from 50–100 mg Losartan* n=751 % 71 RENAAL: Dose of Losartan Seven hundred fifty-one of the 1513 enrollees in RENAAL received losartan; 71% of these 751 patients received losartan 100 mg once daily. Brenner BM et al N Engl J Med 2001; 345(12):861-869 100 mg qd *Patients who took the dose more than 50% of the time. Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Concurrent Antihypertensive Medications Losartan Placebo Therapeutic Class (n=751) (n=762) Calcium-channel blocker, % 77.9 81.1 Dihydropyridine, % 60.7 63.9 Diuretic, % 83.8 84.0 Alpha blocker, % 40.2 45.7 Beta blocker, % 34.1 36.7 Centrally acting agents ,% 18.0 21.7 RENAAL: Concurrent Antihypertensive Medications After randomization, or at any phase during the study, if the target trough sitting systolic/diastolic blood pressure of <140/90 mmHg was not achieved, the daily dose was increased to 100 mg losartan once daily or two placebo tablets once daily plus CT. However, if losartan 100 mg or the two placebo tablets were not sufficient to reduce trough blood pressures below the target values, additional open-label antihypertensives were added. The open-label antihypertensives included CCBs, diuretics, beta blockers, alpha blockers, or centrally acting agents (ACE inhibitors or other AII antagonists were excluded throughout the trial). The type (therapeutic class) of concurrent antihypertensive medication used was similar between the losartan + CT and placebo + CT treatment groups. CCBs as a class were the most widely used open-label antihypertensives in RENAAL, followed by diuretics, alpha blockers, and beta blockers. Brenner BM et al N Engl J Med 2001; 345(12):861-869. Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Secondary Composite Endpoint and Components Losartan (+CT) Placebo (+CT) Composite (n=751) (n=762) % Risk and components n (%) n (%) p Value reduction 95% CI CV morbidity/mortality 247 (32.9) 268 (35.2) 0.255 10 (–8, 24) CV death 90 (12.0) 79 (10.4) 0.455 –12 (–52, 17) HF 89 (11.9) 127 (16.7) 0.005 32 (11, 48) MI 50 (6.7) 68 (8.9) 0.079 28 (–4, 50) Unstable angina 42 (5.6) 41 (5.4) 0.881 –3 (–59, 33) Stroke 47 (6.3) 50 (6.6) 0.787 5 (–41, 36) Revascularization 69 (9.2) 60 (7.9) 0.331 –19 (–68, 16) RENAAL: Secondary Composite Endpoint and Component A secondary endpoint for the RENAAL study was cardiovascular (CV) morbidity and mortality. This secondary endpoint was a composite of CV death, heart failure hospitalizations, unstable angina, MI, stroke, and coronary or peripheral revascularization. It should be noted that patients were excluded from the RENAAL trial if they had a history of heart failure or MI, CABG, CVA, PTCA, or TIA within one to 12 months of enrollment. This means that many patients with high CV risk were excluded from the RENAAL trial. In contrast, the HOPE trial included patients with high CV risk (history of CV disease or diabetes plus one other CV risk factor) and excluded patients with nephropathy (serum creatinine >200 µmol/L or dipstick-positive proteinuria >1+). There was no significant difference between the losartan group and the placebo group in the composite endpoint of morbidity and mortality from CV causes. This might be because the study was not large enough (relatively small sample size) to detect a difference in CV morbidity/mortality. It might also result from the patient selection (strict enrollment criteria that excluded patients at high risk for CV events). Although diabetic patients with severe renal disease are at higher risk for CV morbidity/mortality, many, especially high-risk patients, were excluded as described. There was a statistically and potentially clinically important benefit of losartan + CT versus placebo + CT with respect to the risk reduction of heart failure hospitalization. There was a highly significant (p=0.005) 32% risk reduction in heart failure hospitalization (11,48; 95% CI). Brenner BM et al N Engl J Med 2001; 345(12):861-869. CV=cardiovascular Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL First Hospitalization for Heart Failure 20 15 % with event 10 5 RENAAL: First Hospitalization for Heart Failure Rate of a first hospitalization for heart failure was a component of the secondary composite CV morbidity/mortality endpoint. In this Kaplan-Meier curve, the benefit of once-daily losartan + CT versus placebo + CT is shown. The benefit of losartan + CT is apparent very early (within the first six months) and is maintained throughout the trial. The overall risk reduction was 32% (p=0.005). Brenner BM et al N Engl J Med 2001; 345(12):861-869. Risk reduction: 32% p=0.005 12 24 36 48 Months Placebo (+CT) 762 685 616 375 53 Losartan (+CT) 751 701 637 388 74 Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Change from Baseline in Proteinuria 40 20 Median % change –20 RENAAL: Change from Baseline in Proteinuria A key inclusion criterion of the RENAAL trial was proteinuria. In this study, proteinuria was defined by the urinary albumin: creatinine ratio determined from first morning specimens of urine. This slide shows the dramatic effects of losartan + CT in reducing proteinuria in patients with Type 2 diabetes. In the placebo + CT treatment group, proteinuria was not reduced. By contrast, once-daily losartan significantly reduced proteinuria throughout the study period. The magnitude of this reduction was approximately 40% by 36 months. Losartan + CT led to an average reduction in proteinuria of 35% (p<0.001 vs. placebo + CT). Brenner BM et al N Engl J Med 2001; 345(12):861-869. –40 35% Overall reduction p<0.001 –60 12 24 36 48 Months Placebo (+CT) 762 632 529 390 130 Losartan (+CT) 751 661 558 438 167 Proteinuria measured as the urine albumin:creatinine ratio from a first morning void. Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Rate of Progression of Renal Disease (median 1/sCr slope) 18% reduction –0.08 –0.069 –0.06 –0.056 dl/mg/yr RENAAL: Rate of Progression of Renal Disease (median 1/sCr slope) Losartan reduced the rate of decline in renal function, as assessed by the reciprocal of the serum creatinine concentration (median slope –0.056 dl/mg/year with losartan + CT versus –0.069 dl/mg/year with placebo + CT, p=0.01). Thus, losartan slowed the rate of loss of renal function by 18% relative to placebo. Brenner BM et al N Engl J Med 2001; 345(12):861-869. –0.04 –0.02 Losartan (+CT) Placebo (+CT) Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

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 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 Herman WH et al Diabetes Care 2003;26(3):683-687 Costs are reported in 2001 US dollars. Data from Herman WH et al Diabetes Care 2003;26(3):683-687. CARD-1071592-0000-CZR-SS-02/2015

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 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 Gerth WC et al Kidney Int 2002;62(suppl 82) S68-S72 Costs based on ESRD costs in Germany in 1999. Data from Gerth WC et al Kidney Int 2002;62(suppl 82) S68-S72. CARD-1071592-0000-CZR-SS-02/2015

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 hospitalization for heart failure These benefits were largely independent of BP 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 hospitalization for heart failure These benefits were largely independent of BP Brenner BM et al N Engl J Med 2001; 345(12):861-869. Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Summary (II) In patients with Type 2 diabetes and nephropathy Losartan and placebo, added to CT, 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 RENAAL: Summary II In patients with Type 2 diabetes and nephropathy Losartan and placebo, added to CT, 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 Brenner BM et al N Engl J Med 2001; 345(12):861-869. Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Conclusions Losartan confers significant benefits on renal outcomes in Type 2 diabetic patients with nephropathy Losartan therapy results in a significant reduction in hospitalizations for heart failure These benefits of losartan are largely independent of achieved BP Losartan is generally well tolerated RENAAL: Conclusions Losartan confers significant benefits on renal outcomes in Type 2 diabetic patients with nephropathy Losartan therapy results in a significant reduction in hospitalizations for heart failure These benefits of losartan are largely independent of achieved BP Losartan is generally well tolerated Brenner BM et al N Engl J Med 2001; 345(12):861-869. Data from Brenner BM et al N Engl J Med 2001;345(12):861-869. CARD-1071592-0000-CZR-SS-02/2015

RENAAL Losartan Renal Protection Study RENAAL results show that losartan + CT 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 shows potential of losartan for substantial healthcare savings RENAAL: Losartan Renal Protection Study This slide summarizes the key findings of the RENAAL study. RENAAL results demonstrate that losartan added to conventional antihypertensive therapy did not increase the incidence of adverse events. The number of clinical adverse events with losartan added to conventional therapy showed no significant difference from placebo added to conventional therapy. This means that the beneficial effects of losartan were tested in the presence of concurrent antihypertensive therapy, such as amlodipine and other CCBs, diuretics, and beta blockers. RENAAL data show that losartan, in addition to lowering blood pressure, can protect the kidneys by decreasing the risk of ESRD and by reducing proteinuria. The mechanism of this renal-protective effect may involve blockade of many pathological actions of AII in the kidneys. RENAAL data have also been used to calculate the potential healthcare savings that would be possible if patients with RENAAL-like entry criteria would be given losartan with conventional antihypertensive therapy. RENAAL data show that, in addition to lowering blood pressure and protecting the kidney, losartan provided a cardioprotective benefit in hypertensive patients with Type 2 diabetes and nephropathy. Brenner BM et al N Engl J Med 2001; 345(12):861-869; Herman WH et al Diabetes Care 2003;26(3):683-687; Gerth WC et al Kidney Int 2002;62(suppl 82):S68-S72. Data from Brenner BM et al N Engl J Med 2001;345(12):861-869; Herman WH et al Diabetes Care 2003;26(3):683-687; Gerth WC et al Kidney Int 2002;62(suppl 82):S68-S72. CARD-1071592-0000-CZR-SS-02/2015

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 AII 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 Why Is RENAAL Relevant to the Treatment of Hypertension? It is well established that hypertension can cause an increased risk in cardiac, renal, and cerebrovascular events. It is also well established that lowering blood pressure improves outcomes in patients with hypertension. The RENAAL data provide strong evidence that losartan has a significant benefit when added to conventional antihypertensive therapy and that these effects are largely independent of reduction in blood pressure. Thus, AII is a pathologic factor separate from blood pressure. RENAAL is a study of hypertensive patients with Type 2 diabetes and nephropathy. The RENAAL data show that, even in these patients with advanced disease, blood pressure control is not the only important goal of therapy. The implication of the RENAAL data is that blood pressure lowering is necessary, but added renal protection is achieved by blocking AII. Brenner BM et al N Engl J Med 2001; 345(12):861-869 Whelton PK et al J Hypertens 1992;10(suppl 7):S77-S84; MacMahon S et al Lancet 1990;335:765-774; Kannel WB JAMA 1996;274(24):1571-1576; Klag MJ et al N Engl J Med 1996;334:13-18; Brenner BM et al N Engl J Med 2001;345(12):861-869. . Data from Whelton PK et al J Hypertens 1992;10(suppl 7):S77-S84; MacMahon S et al Lancet 1990;335:765-774; Kannel WB JAMA 1996;274(24):1571-1576; Klag MJ et al N Engl J Med 1996;334:13-18; Brenner BM et al N Engl J Med 2001;345(12): 861-869. CARD-1071592-0000-CZR-SS-02/2015

References Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4): 328-334 Brenner BM et al N Engl J Med 2001;345(12):861-869 Herman WH et al Diabetes Care 2003;26(3):683-687 Gerth WC et al Kidney Int 2002;62(suppl 82):S68-S72 Whelton PK et al J Hypertens 1992;10(suppl 7):S77-S84 MacMahon S et al Lancet 1990;335:765-774 Kannel WB JAMA 1996;274(24):1571-1576 Klag MJ et al N Engl J Med 1996;334:13-18 CARD-1071592-0000-CZR-SS-02/2015

Data dep AIFA 23/12/2009 Copyright 2003, 2009 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehaouse Station, NJ, U.S.A. All rights reserved CARD-1071592-0000-CZR-SS-02/2015 Prima della prescrizione, consultare il Riassunto delle caratteristiche del prodotto. CARD-1071592-0000-CZR-SS-02/2015