# Presentation: 768410

## COZAARTM (losartan) inType 2 Diabetes and Nephropathy

- Michael C. Elia, PhD
*Director, Regulatory Affairs**Merck Research Laboratories*

## RENAAL

- 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

## RENAAL

- 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

## COZAARTM (losartan): Proposed New Indication

- COZAARTM (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.

## Evidentiary Standard for ApprovalsBased Primarily on a Single Study

- Evidentiary Standard for ApprovalsBased 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

## 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)

## COZAARTM (losartan): Proposed New Indication

- COZAARTM (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.

## COZAARTM (losartan) inType 2 Diabetes and Nephropathy

**Agenda for Merck Presentation**

*Dr. S. Shahinfar,**Senior Director**CV Clinical Research*

- Background and Rationale
- RENAAL Demographicsand Efficacy Results
- RENAAL Safety Results
- Review of the Evidenceand Conclusions

*Dr. W. Keane, **Vice President**Clinical Development*

## 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*

## 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*

## Losartan in Type 2 Diabetes and Nephropathy

- Shahnaz Shahinfar, MD
*Senior Director, Cardiovascular Clinical Research**Merck Research Laboratories*

## Losartan in Type 2 Diabetes and NephropathyAgenda

- Background and Rationale
- RENAAL Demographics and Efficacy Results
- RENAAL Safety Results
- Review of Evidence and Conclusions

## 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

## 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

## Theoretical Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury

**Efferent Arteriole****Constriction**

**Glomerulus**

**Increased Albuminuria**

**Afferent Arteriolar Dilatation**

**Increased****Glomerular****Pressure**

**Angiotensin II**

- Blood Flow

- Blood Flow

## Theoretical Non-Hemodynamic Role of Angiotensin II in Diabetic Glomerular Injury

## 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

## 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

## Factors that Differentiate Type 2 from Type 1 Diabetic Patients

- Age
- Obesity
- Insulin resistance
- Advanced atherosclerosis
- Long standing hypertension

## Current Clinical Approaches to Delay Progression to ESRD in Type 2 Diabetes 

- Metabolic control
- Blood pressure control

## In patients with type 2 diabetes and nephropathy, does angiotensin II blockade with losartan offer renal protection?

- Primary Study Question in RENAAL

## 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

## RENAAL: Study Organization

**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 AdjudicationCommittee            (Blinded)
- Chairman: Steven M. Haffner, MD
*Professor of Medicine**University of Texas Health Science Center*

## 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)

## Progression of Renal Diseasein Type 2 Diabetes

- Time

- Death from any cause may occur at any time

**ESRD or Death **

*100% Loss of**Renal Function*

*Normal**Renal Function*

- Progression of Renal Diseasein Type 2 Diabetes

## 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)

##  RENAAL: Key Inclusion/Exclusion Criteria 

- Age 31-70 years
- Proteinuria defined as:urine albumin/creatinine (UA/Cr) >300 mg/g or >500 mg protein/24hours
- Serum creatinine:1.3-3.01 mg/dL

- Known non-diabetic renal disease, e.g., renal artery stenosis
- HbA1C  >12%
- History of:
- MI or CABG (within 1 month)
- Stroke or PTCA (within 6 months)
- TIA (within 1 year)
- Heart failure2

- 1 Lower limit 1.5 mg/dL in male patients >60 kg.
- 2 Protocol amendment.

-  RENAAL: Key Inclusion/Exclusion Criteria

- Inclusion Criteria

- Exclusion Criteria

## 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

## 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 Wks

- 6 Week Run-in

- Planned 5 year maximum follow-up

- Maintain other
- antihypertensives;
-  Discontinue   ACEI or AIIA

- Placebo

- Baseline Stratificationand Randomization

- Urine Protein Dipstick

- Placebo + Titrate other antihypertensives

## 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

## RENAAL: Early Study Termination

- 2Mann et al, *Annals of Int Med*, 2001;134:629-36.

- 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 factors1,2

## Agenda

- Background and Rationale
- RENAAL Demographics and Efficacy Results
- Renal (Primary and Secondary)
- Cardiovascular (Secondary)
- RENAAL Safety Results
- Review of Evidence and Conclusions

## RENAAL: Patient Disposition

- 1513 Randomized

- 2380 Ineligible

- 3893 Screened

- 751 Losartan

- 762 Placebo

-  407 Completed onstudy drug
- 142  D/C study drug after aprimary event
- 202  D/C study drug prior toa primary event

-    359 Completed onstudy drug
- 162  D/C study drug after aprimary event
- 241 D/C study drug prior toa primary event

## RENAAL: Baseline Demographics (I)

- Age (yrs)
- Male (%)
- SBP/DBP (mmHg)
- BMI (kg/m2)

-   751
-     60
-     62
- 152/82
-     30

-   762
-     60
-     65
- 153/82
-     29

- Losartan

- Placebo

- RENAAL: Baseline Demographics (I)

## RENAAL: Baseline Demographics (II)

- Region Asia     Europe Latin America North America

## RENAAL: Medical History at Baseline

- Angina pectoris
- Myocardial infarction
- Stroke
- Anemia
- Amputation
- Neuropathy
- Retinopathy
- Laser therapy/photocoagulation
- Smoking (current)

## RENAAL: Selected Mean Baseline Laboratory Values

- Serum creatinine (mg/dL)
- Serum potassium (mEq/L)
- Hemoglobin (g/dL)
- Hemoglobin A1c (%)

- Losartan(n=751)

- Placebo(n=762)

- 1UA/Cr	1873 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: 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)

## RENAAL: Analysis of Primary Composite Endpoint

- A
- B
- C
- D
- E

- Patient

- Endpoint Captured

- 
- –
- 
- –
- 

- DsCr

- ESRD

- 
- 
- –
- –
- –

- Death

- 
- 
- 
- 
- –

## RENAAL: Analysis of Primary Composite Endpoint

- A
- B
- C
- D
- E

- Patient

- Endpoint Captured

- 
- –
- 
- –
- 

- DsCr

- ESRD

- 
- 
- –
- –
- –

- Death

- 
- 
- 
- 
- –

##  RENAAL: Primary Composite Endpoint

- Doubling of Serum Creatinine/ESRD/Death

-  RENAAL: Primary Composite Endpoint

- 0

- 12

- 24

- 36

- 48

- Months

- % Patients with an Event

- p=0.022

- Risk Reduction: 16.1% (2.3, 27.9)

- Pbo

- Los

- 751

- 692

- 583

- 330

- 51

- 762

- 689

- 554

- 296

- 37

- _n at Risk_

## 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

## 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

## RENAAL: Analysis of IrreversibleClinical Endpoints (Pre-specified)

- A
- B
- C
- D
- E

- Patient

- Endpoint Captured

- 
- –
- 
- –
- 

- DsCr

- ESRD

- 
- 
- –
- –
- –

- Death

- 
- 
- 
- 
- –

## RENAAL: Analysis of IrreversibleClinical Endpoints (Pre-specified)

- A
- B
- C
- D
- E

- Patient

- Endpoint Captured

- 
- –
- 
- –
- 

- DsCr

- ESRD

- 
- 
- –
- –
- –

- Death

- 
- 
- 
- 
- –

## RENAAL: Irreversible Clinical Endpoints (I)

- ESRD

- 0

- 12

- 24

- 36

- 48

- Months

- 0

- 20

- 40

- 60

- % Patients with an Event

- 762

- 715

- 610

- 348

- 43

- 43

- 43

- 43

- 43

- 43

- 751

- 714

- 625

- 375

- 68

- 68

- 68

- 68

- 68

- 68

- Pbo

- Los

- p=0.002

- Risk Reduction: 28.6% (11.5, 42.4)

- _n at Risk_

##  RENAAL: Irreversible Clinical Endpoints (II)

-  RENAAL: Irreversible Clinical Endpoints (II)

- Months

- 0

- 20

- 40

- 60

- % Patients with an Event

- p=0.884

- Risk Reduction: -1.7% (-26.9, 18.6)

- 751

- 730

- 680

- 430

- 84

- 762

- 732

- 690

- 439

- 65

- Pbo

- Los

- _n at Risk_

- All Cause Mortality

##  RENAAL: Irreversible Clinical Endpoints (III)

- ESRD or Death

-  RENAAL: Irreversible Clinical Endpoints (III)

- Pbo

- Los

- 0

- 12

- 24

- 36

- 48

- Months

- 0

- 20

- 40

- 60

- % Patients with an Event

- p=0.009

- Risk Reduction: 19.9% (5.3, 32.3)

- 751

- 714

- 625

- 375

- 68

- 68

- 68

- 68

- 68

- 68

- 762

- 715

- 610

- 348

- 43

- 43

- 43

- 43

- 43

- 43

- _n at Risk_

## RENAAL: Summary of Primary Compositeand Clinical Endpoints

- ESRD

- Death

- ESRD or death

- +50

- 0

- -50

- Percent Risk Reduction (95% CI)

- Favors Losartan         Favors Placebo

- RENAAL: Summary of Primary Compositeand Clinical Endpoints

##  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

## RENAAL: Distribution of Baseline Proteinuria by Stratum

- 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 within Strata 

- RENAAL: Distribution of Baseline Proteinuria within Strata

- <1000

- 1000-1999

- 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

## RENAAL: Risk for Primary Composite Endpoint Rises with Increasing Baseline Proteinuria

- Hazard Ratio

- 300

- 2000

- 4000

- 6000

- 1

- Baseline Proteinuria (UA/Cr, mg/g)

- Pooled Analysis

## RENAAL: Risk for Primary Composite Endpoint Rises with Increasing Baseline Proteinuria

- Hazard Ratio

- 300

- 2000

- 4000

- 6000

- 1

- Pooled Analysis

## RENAAL: Primary Composite Endpoint Adjusted by Baseline Proteinuria (post hoc)

- 0

- 12

- 24

- 36

- 48

- Month

- 0

- 20

- 40

- 60

- % Patients with an Event

- 751

- 692

- 583

- 330

- 51

- 762

- 689

- 554

- 296

- 37

- _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)

## RENAAL: Endpoints Adjusted for Baseline Proteinuria as a Continuous Covariate (post hoc)

- +50

- 0

- -50

- Percent Risk Reduction (95% CI)

- Favors Losartan          Favors Placebo

## RENAAL: Pre-defined Sensitivity Analyses

- HbA1c
- Mean arterial pressure (MAP)
- Baseline subgroups

## 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

## RENAAL: Concurrent Antihypertensive Medications

- Losartan

- Placebo

- 0

- 20

- 40

- 60

- 80

- 100

- % of Patients

- Diuretic

- CCB

- AlphaBlocker

- BetaBlocker

- 85%

- 81%

- 42%

- 36%

- 85%

- 83%

- 47%

- 38%

## RENAAL: Comparable Blood Pressure (Trough) Control Between Treatment Groups

- Blood Pressure (mmHg)

- 751

- 662

- 529

- 295

- 44

- 762

- 641

- 491

- 247

- 30

- Systolic

- Diastolic

- Pbo (n)

- Los (n)

## RENAAL: Mean Arterial Pressure

- Months

- MAP (mmHg)

- Losartan

- Placebo

- Distribution at 5, 25, 50, 75, and 95 percentiles at each timepoint

- Pbo

- 762

- 758

- 621

- 469

- 189

- Los

- 751

- 749

- 632

- 510

- 228

- n

## RENAAL: Endpoints Adjusted for Mean Arterial Blood Pressure

- +50

- 0

- -50

- FavorsLosartan

- Percent Risk Reduction (95% CI)

- FavorsPlacebo

## RENAAL: Baseline Subgroups

**Age**

**Gender**

**Race**

**BMI**

**Region**

**SiSBP**

- <65 years

****65 years

- Female

- Male

- Asian

- Black

- White

- Hispanic

- <30 kg/m2

****30 kg/m2

- Asia

- Latin America

- Europe

- North America

- <140 mmHg

****140 mmHg

**Overall Primary Composite**

- +50

- 0

- -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**

- +50

- 0

- -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**

- +50

- 0

- -50

-   Favors     Favors
- Los          Pbo

## RENAAL: Baseline Subgroups

**Gender**

**Race**

**BMI**

**Region**

**SiSBP**

- <65 years

****65 years

- Female

- Male

- Asian

- Black

- White

- Hispanic

- <30 kg/m2

****30 kg/m2

- Asia

- Latin America

- Europe

- North America

- <140 mmHg

****140 mmHg

**Overall Primary Composite**

- +50

- 0

- -50

- Yes

- No

- Yes

- No

- Yes

- No

- Yes

- No

- <10 yr

****10 yr

**Overall Primary Composite**

- +50

- 0

- -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**

- +50

- 0

- -50

-   Favors     Favors
- Los          Pbo

- Percent Risk Reduction (95% CI)

**Insulin**

**Dihydropyridine**
**CCB**

**Prev. ACEI/AIIA**

**Smoking**

**Duration of **

**Hypertension**

## 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

## RENAAL: Reduction in the Rate of Loss of Renal Function (On-treatment Approach)

- Median 1/sCr Slope

- -.08

- -.06

- -.04

- -.02

- 0

- Median Changein 1/sCr(dL/mg/yr)

- Losartan

- Placebo

- 18% Reductionp=0.01

## RENAAL: Losartan Reduces Proteinuria(On-treatment Approach)

- 0

- 3

- 12

- 24

- 36

- >36

- Months

- Change in Mean UA/Cr (%)1

-  1Based on geometric mean (95% CI).

- 34% OverallReductionp<0.001

- Losartan

- 751

- 661

- 558

- 432

- 163

- 762

- 632

- 529

- 389

- 120

- Pbo (n)

- Los (n)

- Placebo

- RENAAL: Losartan Reduces Proteinuria(On-treatment Approach)

## 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

## Agenda

- Background and Rationale
- RENAAL Demographics and Efficacy Results
- Renal (Primary and Secondary)
- Cardiovascular (Secondary)
- RENAAL Safety Results
- Review of Evidence and Conclusions

## 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)

## RENAAL: Secondary Cardiovascular Composite Endpoint

- 0

- 12

- 24

- 36

- 48

- Months

- 0

- 20

- 40

- 60

- % Patients with an Event

- p=0.253

- Risk Reduction: 9.6% (-7.5, 24.0)

- 751

- 658

- 569

- 329

- 61

- 762

- 646

- 551

- 328

- 48

- _n at Risk_

- Pbo

- Los

## RENAAL: Secondary Cardiovascular Composite Endpoint and Components

- +50

- 0

- -50

- Percent Risk Reduction (95% CI)

## RENAAL: Composite of ESRD/MI/Stroke/Death (post hoc)

- 0

- 12

- 24

- 36

- 48

- Months

- 0

- 20

- 40

- 60

- % Patients with an Event

- p=0.003

- Risk Reduction: 21.2% (7.8, 32.6)

- 751

- 684

- 585

- 350

- 62

- 762

- 685

- 565

- 314

- 39

- Pbo

- Los

- _n at Risk_

## 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

## Agenda

- Background and Rationale
- RENAAL Demographics and Efficacy Results
- RENAAL Safety Results
- Review of Evidence and Conclusions

## RENAAL: Clinical Adverse Experience Summary

- Losartan

- Placebo

- With Oneor MoreAEs

- WithSeriousAEs

- With
- Drug-RelatedAEs

- With SeriousDrug-RelatedAEs

- DeathDue 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

## 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 Oneor MoreAEs

- WithSeriousAEs

- With
- Drug-RelatedAEs

- With SeriousDrug-RelatedAEs

- DeathDue to
- AE

- Discon.Due to
- AE

## RENAAL: Pre-specified Analysis of Adverse Experiences

## RENAAL: Distribution of Serum Potassium Values at Each Time Point

- 12

- 24

- 36

- >36

- Months

- Serum Potassium (mEq/L)

- Losartan

- Placebo

- Distribution at 5, 25, 50, 75 and 95 percentile at each time point

## RENAAL: Serum Potassium at Any Time During the Study

-      Potassium **** 6.0 mEq/L

- 32/751   (4.2)
- 73/751 (10.0)

- Losartann/N (%)

- 43/762 (5.6)
- 40/762 (5.0)

- Placebon/N (%)

- Patients Who Had at Least One Measurement
- of 3.5 and/or 6.0 mEq/L

## RENAAL: Hyperkalemia

- 0

- 5

- 10

- 15

- 20

- % of Patients

- WithSerious AEs

- Discon.Due to AE

- DeathDue to AE

- 2.6

- 1.3

- 0

- 1.3

- 0.7

- 0

-  Adverse Experiences

- Losartan

- Placebo

## 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

## RENAAL:Review of Evidence and Conclusions

- William F. Keane, MD
*Vice President, Clinical Development**Merck US Human Health*

## RENAAL: Strength of the Evidence

- Robust design features
- Results are clinically important and statistically significant
- Internal consistency across multiple endpoints and multiple subgroups

## 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

## RENAAL: Clinically Important and Statistically Significant Results

- Primary composite endpoint:
- Doubling sCr/ESRD/death
- Clinical endpoints:
- ESRD
- Death
- ESRD or death

## 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

## RENAAL: Clinically Important and Statistically Significant Results

- Primary composite endpoint:
- Doubling sCr/ESRD/death
- Clinical endpoints:
- ESRD
- Death
- ESRD or death

- RR (%)

- 22.2
- 36.7
- 1.3
- 25.7

- p-Value

- 0.001
- <0.001
- 0.907
- <0.001

- Adjusted forBaselineProteinuria

## 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

## 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

## RENAAL: Secondary Cardiovascular Composite Endpoint and Components

- +50

- 0

- -50

- Percent Risk

- Favors Losartan      Favors Placebo

- 0.003

- Reduction (95% CI)

- p-Value

**Composite of ESRD/MI/****stroke/death (post hoc)**

- 0.253

**CV composite**

## 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