Alirio Angulo Quintero R1 Medicina Interna UMNG RENAAL EFFECTS OF LOSARTAN ON RENAL AND CARDIOVASCULAR OUTCOMES IN PATIENTS WITH TYPE 2 DIABETES AND NEPHROPATHY  Alirio Angulo Quintero R1 Medicina Interna UMNG

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 hypertensive patients with Type 2 diabetes and nephropathy 1513 Patients; 250 Centers; 28 Countries 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 Slide 2: Title Slide The RENAAL study is 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.1 The RENAAL study is a landmark endpoint trial because, it provided for the first time data showing that specific blockade of angiotensin II (A II) 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.2 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, SanAntonio, Texas, USA. Brenner BM et al New Engl J Med 2001;345(12):861-869.

Hipótesis primaria Tratamiento a largo plazo con LOSARTÁN versus placebo (solo o en combinación con los convencionales terapia antihipertensiva *) en pacientes con diabetes tipo 2 con hipertensión y nefropatía aumentará el tiempo hasta el primer evento y disminuirá la incidencia de duplicación de sCr, ESRD o muerte. Slide 3: RENAAL: Primary Hypothesis The primary hypothesis of RENAAL was that long-term treatment with losartan vs. placebo, alone or in combination with conventional therapy (excluding angiotensin converting enzyme (ACE) inhibitors and angiotensin II antagonists (AIIAs) in each group), in Type 2 diabetic patients with nephropathy and hypertension, will increase the time to first event and decrease the incidence of doubling of serum creatinine (sCr), End-Stage Renal Disease (ESRD defined as the need for dialysis and renal transplantation), or death.1 The primary efficacy is a composite of the time to first event of doubling of sCr, ESRD, or death.1 * Excluding ACEIs and other AIIAs Brenner BM et al New Engl J Med 2001;345(12):861-869.

Hipòtesis secundaria Losartan comparado con placebo (solo o en comvinaciòn con terapia antihipertensiva convencional*) en pacientes con Diabetes tipo 2 y Nefropatia podria: Aumentar el tiempo hasta el primer evento y disminuir la incidencia de morbilidad - mortalidad cardiovascular Reducir la proteinuria Disminuir la tasa de progresiòn de la enfermedad Slide 4: RENAAL: Secondary Hypothesis The secondary hypothesis of RENAAL stated that long-term treatment with losartan vs. placebo alone or in combination with conventional therapy (excluding ACE inhibitors and other AIIAs) in Type 2 diabetic patients with nephropathy will: 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) 1 * Excluding ACEIs and other AIIAs Brenner BM et al New Engl J Med 2001;345(12):861-869.

Mean follow-up 3.4 years Losartan 100 mg qd (+CT) Losartan 100 mg qd Maintain conventional antihypertensive therapy (CT)* (excluding ACEI, AIIA) Goal trough BP: < 140/<90 mmHg n=1513 Placebo (+CT) Placebo (+CT) Placebo (+CT) 6 Wks Slide 5: 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 AIIA within six weeks of trial enrollment discontinued these medications and received an alternative conventional antihypertensive (open-label conventional therapy including CCBs, diuretics, beta or alpha blockers, or centrally acting agents) as appropriate, to control hypertension to a goal of <140/<90 mmHg. 1 Hypertensive patients not being treated with an ACE inhibitor or an AIIA continued to receive their prior conventional antihypertensive therapy. 93,5% of the patients were receiving antihypertensive treatment at baseline. 1, 2 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 asignments 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 50 mg once daily losartan, alone or in combination with conventional therapy (CT), excluding ACE inhibitors and other AIIAs (losartan + CT). The second treatment group received once daily placebo, alone or in combination with conventional therapy (CT), excluding ACE inhibitors and other AIIAs (placebo + CT). The randomization was stratified based on the level of baseline proteinuria (urine albumin:creatinine ratio above or below 2000 mg/g).1 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.1 4 Wks 8 Wks Mean follow-up 3.4 years *CT=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents. Brenner BM et al J Renin-Angio-Aldo System 2000;1(4):328-335.

Inclusion/Exclusion Criteria Inclusion criteria Type 2 diabetes Age 31-70 years Proteinuria: urine alb:cr >300 mg/g, >25 mg/mmol Serum Creatinine: 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 heart failure HbA1c >12% Slide 6: 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.1 Proteinuria was defined by two qualifying urinary albumin:creatinine ratios on first morning specimen of at least 300 mg/g (or a 24-hour urine protein of greater than 500 mg) and two qualifying serum creatinine measurements between 1.3 and 3.0 mg/dl.1 In addition, patients were not included over 70 years of age.1 The exclusion criteria for RENAAL included uncontrolled diabetes (HbA1c >12%), Type 1 diabetes, non-diabetic renal disease or known renal artery stenosis; recent myocardial infarction (MI); or coronary artery bypass graft (CABG) within 1 month; or cerebral vascular accident (CVA); or percutaneous transluminal coronary angioplasty (PTCA) within 6 months, or transient ischemic attacks (TIA) within 1 year prior to enrollment; and any history of heart failure.1 *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):328-335. Brenner BM et al New Engl J Med 2001;345(12):861-869.

Regiones inscritas n=1513 Asia North America 46% Europe 19% 17% North America 46% Europe 19% Slide7: RENAAL: Enrollment by Region RENAAL is a truly international study with patient representation from North America (46%), Europe (19%), Latin America (18%) and Asia (17%).1 Latin America 18% Brenner BM et al New Engl J Med 2001;345(12):861-869.

RENAAL Baseline Characteristics (I) Losartan (+CT) (n=751) 60 62 38 16 17 48 19 2 152 82 30 Placebo (+CT) (n=762) 60 65 35 18 14 50 1 153 82 29 Age, years Male, % Female, % Race, % Asian Black Caucasian Hispanic Other Systolic (mmHg) Diastolic (mmHg) BMI (kg/m2) % Slide 8: RENAAL: Baseline Characteristics I A total of 1513 patients were enrolled in the RENAAL study. Of the total cohort, 63.2% were male and 36.4% were female with a mean (SD) age of 59.6 (+/- 7.4) years. 1 There was no significant difference between the losartan + CT (conventional therapy) 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. 1 Brenner BM et al New Engl J Med 2001;345(12):861-869.

Primary Composite Endpoint and Components Losartan (+CT) (n=751) n (%) 327 (43.5) 162 (21.6) 147 (19.6) 158 (21.0) 255 (34.0) Placebo (+CT) (n=762) n (%) Composite and Components % Risk Reduction 16 25 28 -2 20 DsCr, ESRD, Death Doubling of sCr ESRD Death ESRD or Death P-Value 0.02 0.006 0.002 0.88 0.01 95% CI (2, 28) (8, 39) (11, 42) (-27, 19) (5, 32) 359 (47.1) 198 (26.0) 194 (25.5) 155 (20.3) 300 (39.4) Slide 9: 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 (need for long-term dialysis or renal transplantation), or death. By 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 (conventional therapy) and 359 (47.1%) patients receiving placebo + CT. Losartan + CT treatment resulted in a significant decrease in risk reduction 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. 2 Brenner BM et al New Engl J Med 2001;345(12):861-869.

Doubling of Serum Creatinine Primary Components ESRD 12 24 36 48 10 20 30 Risk Reduction: 28% p=0.002 P % with event L Doubling of Serum Creatinine 12 24 36 48 10 20 30 P L Risk Reduction: 25% p=0.006 Months P (+ CT) 762 715 610 347 42 L (+ CT) 751 714 625 375 69 % with event 12 24 36 48 10 20 30 40 50 ESRD or Death Risk Reduction: 20% p=0.01 P % with event L Months P (+ CT) Slide 10: RENAAL: Components of the Primary Composite Endpoint 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). 2 The composite endpoint of ESRD or death also showed a significant risk reduction (20%; p=0.01). There was no significant risk reduction of death alone with losartan + CT. 2 762 689 554 295 36 L (+ CT) 751 692 583 329 52 Months P (+ CT) 762 715 610 347 42 L (+ CT) 751 714 625 375 69 Brenner BM et al New Engl J Med 2001;345(12):861-869. 0902CZR01NL537SS0901

Blood Pressures (mmHg) Baseline Year 1 Year 2 Study End L (+CT) S/D 152/82 146/78 143/77 140/74 P (+CT) S/D 153/82 150/80 144/77 142/74 L (+CT) MAP 105.5 100.9 99.1 95.9 P (+CT) MAP 106.0 103.1 99.7 96.8 L (+CT) PP 69.4 67.8 66.2 66.7 P (+CT) PP 70.8 69.8 67.1 67.4 Slide 11: RENAAL: Trough Arterial Blood Pressure (Systolic, Diastolic, and Mean) 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. Conventional therapy (CT) consisted of CCBs, diuretics, beta and alpha blockers, and centrally acting agents, excluding ACE inhibitors and other AIIAs. 2 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 versus 105.5, respectively; p = 0.38). At one year, values averaged 150/80 and 146/78 (103.1 versus 100.9, p<0.001); at year 2, 144/77 and 143/77 (99.7 versus 99.1, p=0.38); and at the study end, 142/74 and 140/74 (96.8 versus 95.9, 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. 2 S/D: Systolic/Diastolic MAP: Mean arterial pressure PP: Pulse pressure L = losartan P = placebo CT = conventional therapy Brenner BM et al New Engl J Med 2001;345(12):861-869.

*Patients who took the dose more than 50% of the time. Dose of Losartan El rango de la dosis diaria de Losartan 50-100 mg Losartan* n=751 % 71 100 mg QD Slide 12: RENAAL: Dose of Losartan The daily dose of losartan ranged from 50 mg to 100 mg, with 71% of the patients receiving 100 mg. 2 *Patients who took the dose more than 50% of the time. Brenner BM et al New Engl J Med 2001;345(12):861-869.

Concurrent Antihypertensive Medications Losartan n=751 77.9 60.7 83.8 40.2 34.1 18.0 Placebo n=762 81.1 63.9 84.0 45.7 36.7 21.7 Therapeutic Class Calcium-Channel Blocker (%) - Dihydropyridine (%) Diuretic (%) Alpha blocker (%) Beta blocker (%) Centrally acting agents (%) Slide 13: RENAAL: Concurrent Conventional 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 conventional therapy. 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 AIIAs were excluded throughout the trial). 2 The type (therapeutic class) of concurrent antihypertensive medication used was similar between the losartan + CT (conventional therapy) and placebo + CT treatment groups. CCBs as a class were the most widely open-label antihypertensives used in RENAAL, followed by diuretics, alpha blockers, and beta blockers. 2 Brenner BM et al New Engl J Med 2001;345(12):861-869. .

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) Composite and Components % Risk Reduction 10 32 28 P-Value 0.26 0.005 0.08 CV Morbidity/Mortality Heart Failure MI Slide 14: RENAAL: Secondary Composite Endpoint and Component Analysis 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 1-12 months of enrollment. This means that many patients with high CV risk were excluded from the RENAAL trial, which is in contrast to the HOPE trial in which patients with high CV risk (history of CV disease or diabetes plus one other CV risk factor) were included, whereas patients with nephropathy (sCr>200 µmol/L or dipstick-positive proteinuria > 1+) were excluded. 2, 17 There was no significant difference between the losartan group and the placebo group in the composite endpoint of morbidity and mortality from cardiovascular 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 previously.2 There was a statistically and potentially clinically important benefit of losartan + CT (conventional therapy) 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 hospitalization2. Brenner BM et al New Engl J Med 2001;345(12):861-869.

RENAAL First Hospitalization for Heart Failure 5 10 15 20 Risk Reduction: 32% p=0.005 P % with event L 12 24 36 48 Slide 15: RENAAL: Hospitalization for Heart Failure Heart failure hospitalization was a component of the secondary composite CV morbidity/mortality endpoint. In this Kaplan-Meier curve, the benefit of once-daily losartan + CT (conventional therapy) versus placebo + CT is shown. The benefit of losartan + CT is apparent very early (within the first 6 months) and is maintained throughout the trial. The overall risk reduction was 32% (p=0.005). 2 Months P (+CT) 762 685 616 375 53 L (+CT) 751 701 637 388 74 L = losartan P = placebo CT = conventional therapy Brenner BM et al New Engl J Med 2001;345(12):861-869.

RENAAL Change from Baseline in Proteinuria 40 20 P Median Percent Change p<0.001 -20 35% Overall Reduction -40 L -60 12 24 36 48 Months Slide 16: RENAAL: Change from Baseline in Proteinuria A key inclusion criterion of the RENAAL trial was proteinuria. In this study using first morning specimens of urine, proteinuria was defined as the urinary albumin:creatinine ratio. This slide shows the dramatic effects of losartan + CT (conventional therapy) to reduce proteinuria in patients with Type 2 diabetes. In the placebo + CT treatment group the 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).2 P (+CT) 762 632 529 390 130 130 130 130 130 130 L (+CT) 751 661 558 438 167 167 167 167 167 167 Proteinuria measured as the urine albumin:creatinine ratio from a first morning void. L = losartan P = placebo CT = conventional therapy Brenner BM et al New Engl J Med 2001;345(12):861-869.

RENAAL Rate of Progression of Renal Disease (median 1/sCr Slope) 18% reduction -.08 -0.069 -.06 -0.056 dl/mg/yr -.04 -.02 Slide 17: RENAAL: Decline in Renal Function (1/serum creatinine) Losartan reduced the rate of decline in renal function, as assessed by the reciprocal of 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. 2 Losartan Placebo (+CT) (+CT) sCr=serum creatinine Brenner BM et al New Engl J Med 2001;345(12):861-869.

Summary (I) En pacientes hipertensos con Diabetes tipo 2 y nfropatia: Losartan retrazo el inicio de los desenlaces primarios (DsCr/ESRD/Death) y retardo al progresiòn de la ESRD. losartan redujo la proteinuria y la tasa de disminución de la función renal (1/sCr slope). losartan redujo la incidencia de hospitalización por falla cardíaca. Estos beneficios fueron en gran medida independientes de la presión arterial alcanzada . Slide 18: RENAAL: Summary I Brenner BM et al New Engl J Med 2001;345(12):861-869.

Conclución En pacientes hipertensos con Diabetes tipo 2 y nefropatia: Losartán y placebo, en un contexto de terapia convencional, no mostraron diferencias significativas en la mortalidad por todas las causas, infarto de miocardio, accidente cerebrovascular, revascularización, hospitalizaciones por angina inestable y muerte por enfermedad CV Losartan fue generalmente mejor tolerado en esta población. Slide 19: RENAAL: Summary II Read Slide2 Brenner BM et al New Engl J Med 2001;345(12):861-869.

Conclusions Losartan confiere beneficios significativos a nivel renal en pacientes con diabetes tipo 2 con hipertensión y nefropatia. La terapia con Losartan resulto en una reducción significativa en las hospitalizaciones por falla cardiaca.. Losartan es generalmente mejor tolerado. Los beneficios de este estudio complementan, los de estudiós previos con losartan en los cuales se demuestra una reducción en la microalbuminuria y la macroalbuminuria. Slide 20: RENAAL: Conclusions Brenner BM et al New Engl J Med 2001;345(12):861-869.

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