1. RENAAL
Altering the Course of Renal Disease in Hypertensive Patients with Type 2 Diabetes and Nephropathy with the AII Antagonist Losartan
Slide 1: RENAAL: Altering the Course of Renal Disease in Hypertensive Patients with Type 2 Diabetes and Nephropathy with the AII Antagonist Losartan
The scientific and medical rationale, protocol, and baseline data for the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial have been previously described.1
The results of the RENAAL trial have also been published.2

2. Angiotensin II Drives Pathology in Hypertension
Vascular Dysfunction Endothelial dysfunction Remodeling/hypertrophy Fibrosis Atherosclerosis
Heart MI, HF
Kidney ESRD
Brain Stroke
Tissue Dysfunction
Cell loss
Fibrosis
Remodeling
Ischemia
Hypertension
Slide 2: Angiotensin II Drives Pathology in Hypertension
Angiotensin II (AII) acting at the AT1 receptor is an important driver of pathology in hypertension and cardiovascular disease and can act at many sites in the progression from uncomplicated hypertension to the end-stage morbid events (see slide).3
Hypertension, if left untreated, sets up a series of vascular and tissue changes which may lead to a progressive loss of heart, kidney, or brain function, and ultimately to the potentially morbid events such as myocardial infarction (MI), end-stage renal disease (ESRD), and stroke. Working in concert with genetic factors, other risk factors, and environmental factors, AII can exacerbate the progressive development of cardiovascular disease by acting both directly to raise blood pressure (vasoconstriction) or indirectly by releasing aldosterone, enhancing the release of norepinephrine, or by releasing other factors such as endothelin or transforming growth factor (TGF)-1.3-6
Inhibitors of AII, which include angiotensin-converting enzyme (ACE) inhibitors and AII receptor antagonists (AII antagonists) such as losartan, have been shown to chronically lower blood pressure and to beneficially effect changes in the blood vessels, heart, and kidney.5
The results of the RENAAL trial (see notes, Slide 14) showed that blocking AII with losartan significantly improved the course of ESRD (p=0.002).2
Genetics, risk factors (diabetes, hypercholesterolemia) Environment (diet, smoking, stress)
MI=myocardial infarction; HF=heart failure; ESRD=end-stage renal disease
Adapted from Weir MR, Dzau VJ Am J Hypertens 1999;12:205S-235S; Timmermans PB et al Pharmacol Rev 1993;45(2): ; and Jessup M, Brozena S N Engl J Med 2003;348:

3. Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are Lacking
Endpoints Studied
ACE Inhibitor Trials
in Type 2 Diabetics Total Reduction of Reduction of Reduction in Risk with >1 Year Follow-Up Sample Proteinuria GFR Decline of ESRD*
Ravid et al Ann Intern Med Yes Yes No
Lebovitz et al Kidney Int Yes Yes No
Bakris et al Kidney Int Yes Yes No
Ahmad et al Diabetes Care Yes Yes No
Nielsen et al Diabetes Care Yes Yes No
UKPDS et al Br Med J Yes No No
Fogari et al J Hum Hypertens Yes No No
ABCD Diabetes Care Yes Yes No
Ruggenenti et al (REIN) 352 (27)** Yes Yes Yes**
Am J Kidney Dis MICRO-HOPE** Lancet Yes No Yes***
Slide 3: Clinical Endpoint Data for ESRD in Type 2 Diabetes with ACE Inhibitors Are Lacking
ACE inhibitors have been shown to beneficially alter surrogate markers of progressive renal disease (reduce proteinuria) in patients with diabetic and non-diabetic renal disease.7 ACE inhibitors have also been shown to beneficially alter endpoints (ESRD data) in diabetic (Type 1) and non-diabetic patients.8 However, much less is known about the effects of ACE inhibitors and other therapies on ESRD in patients with Type 2 diabetes.9-18
At the time when the RENAAL trial was initiated, there were no renal endpoint data with ACE inhibitors in patients with Type 2 diabetes.1 Since that time, endpoint studies have been reported with ACE inhibitors in Type 2 diabetic patients.19,20 The first was a small study (The Ramipril Efficacy in Nephropathy study) of 352 patients which included only 27 (8%) Type 2 diabetic patients. In this study, ramipril was shown to substantially reduce the risk of ESRD by almost 50% but, as the majority of these patients were not diabetic, the results should not be extrapolated to Type 2 patients.19 Another endpoint study involving an ACE inhibitor and Type 2 diabetic patients was the Heart Outcomes Prevention Evaluation (HOPE) study. In this trial of 9541 participants, 3654 patients were diabetic (97% Type 2) at randomization, 3577 of whom were included in a pre-specified analysis reported as the MIcroalbuminuria, Cardiovascular, and Renal Outcomes (MICRO)-HOPE substudy.20 Patients in the HOPE trial were excluded if they had overt nephropathy at baseline. Only 32% (n=1140) of the diabetic subpopulation had microalbuminuria; therefore, the majority of the HOPE/MICRO-HOPE patients had little nephropathy.20 Overt nephropathy as an outcome measure in HOPE/MICRO-HOPE was a secondary endpoint.20
It is important to note that in MICRO-HOPE ramipril did not reduce the risk of dialysis (p=0.70) or heart failure (p=0.93) compared to placebo.20 However, there was a 24% risk reduction for overt nephropathy (p=0.027) and a 16% risk reduction on the combined microvascular outcome of overt nephropathy, laser therapy, or dialysis (p=0.036).20 The MICRO-HOPE data are consistent with a renoprotective effect of ACE inhibition in Type 2 diabetic patients with little or no nephropathy.20 These limited beneficial effects of ramipril are in contrast to the greater significant renal (reduction in ESRD) and cardiac protective (reduction in hospitalization for heart failure) effects of losartan observed in the RENAAL trial in patients with Type 2 diabetes and overt nephropathy.2
GFR=glomerular filtration rate
*Reduction in the risk of end-stage renal disease (renal transplant or dialysis)
**Only 27 (8%) of the 352 patients in this study were Type 2 diabetics
***In this study there was no reduction of risk for renal dialysis for ramipril compared to placebo (p=0.70)

4. Controlling the Course of Renal Disease with Losartan
Rationale for RENAAL (Losartan Renal Protection Study):
Losartan significantly lowered BP comparable to other classes of antihypertensive drugs
Losartan demonstrated superior tolerability compared to other classes of antihypertensive drugs (placebo-like side-effect profile)
Losartan was a specific antagonist of angiotensin II (significant driver of pathology in renal disease)
Losartan had significant renoprotective effects in animal models of renal disease
Losartan was well tolerated and lowered BP in hypertensive patients with renal insufficiency
Slide 4: Controlling the Course of Renal Disease with Losartan
The idea of a “RENAAL” trial started with the question of whether losartan could alter the course of renal disease. There was ample evidence that losartan was a potent AII antagonist, demonstrated renal protective effects in animal models, lowered blood pressure in humans and animals, and was well tolerated In addition, losartan had been shown to be well tolerated and efficacious in hypertensive patients with renal insufficiency.25 Losartan was also shown to reduce proteinuria in diabetic and non-diabetic patients in acute and short-term studies.26,27 Thus, before RENAAL was initiated, there was growing evidence that losartan could beneficially alter surrogate markers of renal disease.
It was known at that time that ACE inhibitors could beneficially alter surrogate markers of renal disease in Type 1 diabetic patients8 and in patients with non-diabetic renal disease.19 However, there were no renal endpoint data with ACE inhibitors in Type 2 diabetic patients with nephropathy.
Importantly, before RENAAL it was not known whether the beneficial effects of ACE inhibitors were due to potentiation of bradykinin or to blocking AII synthesis. The RENAAL trial showed that blocking AII with losartan could alter the course of renal disease in the presence of other concurrent conventional antihypertensive therapy, including calcium-channel blockers (CCBs).
The rationale for the RENAAL trial was based on the growing wealth of clinical and experimental data suggesting that AII was driving pathology in renal disease, and on the beneficial blood pressure–lowering and renal properties of losartan. In addition, RENAAL, by utilizing Type 2 diabetic patients with nephropathy, would provide important new data not available with ACE inhibitors.
BP=blood pressure
Adapted from Goa KL, Wagstaff AG Drugs 1996;51(5): ; Goldberg AI et al J Hypertens 1995;13(suppl 1):S77-S80; Lafayette RA et al J Clin Invest 1992;90: ; Remuzzi A et al J Am Soc Nephrol 1993;4(1):40-49; Toto R et al Hypertension 1998;31:

5. Effect of Losartan on Microalbuminuria
250
Type 2 diabetes
Type 1 diabetes
Renal transplant
Hypertension
211
200
188
173
153
150
Urinary albumin (mg/24 hr)
Slide 5: Renal Protection of Losartan: Microalbuminuria
RENAAL was a study of Type 2 diabetic patients with hypertension and nephropathy that demonstrated that losartan added to conventional therapy (CTx) for hypertension significantly (p<0.001 vs. placebo + CTx) lowered proteinuria compared to CTx alone.2
Losartan had been previously studied in diabetic and non-diabetic patients with less severe nephropathy as well. This slide shows the renal protective effects of losartan to lower microalbuminuria (6–98 mg of protein excreted/day) in different patient populations. The results of each of these studies show that antagonism of AII with losartan lowered microalbuminuria in patients with Type 2 and Type 1 diabetes, renal transplant, and hypertensive renal disease.26-35
115
100 92 83 94 57 66 50 60 37 55 30 21 40 39 22 15 15
n=29
n=12
n=9
n=10
n=194
n=103
n=424
n=14
n=8
n=40
Calculations for Protein Excretion
µg/min  60 = µg/hr
µg/hr  24 = µg/24 hr
µg/24 hr  1000 = mg/24 hr (1000 µg=1 mg)
So (µg/min  60  24)  1000 = µg/min  1.44 = mg/24 hr
Chan Baseline: 21 mg/24 hr Final: 15 mg/ 24 hr
Bauer Baseline: 21 µg/min Final: 15 µg/min
211.44=30.24 mg/24 hr 151.44=21.6 mg/24 hr
Erley Baseline: 37 mg/24 hr Final: 15 mg/24 hr
Fauvel Baseline: 57 mg/24 hr Final: 40 mg/24 hr
Hortal Baseline: µg/min Final: µg/min
57.481.44=82.77 mg/24 hr 1.44=39.36 mg/24 hr
Lacourcière Baseline: 64.1 µg/min Final: µg/min
64.11.44=92.3 mg/24 hr 41.51.44=59.8 mg/24 hr
Lozano Baseline: 115 mg/24 hr Final: 66 mg/24 hr
Esmatjes Baseline: 106 µg/min Final: 38 µg/min
1061.44=152.6 mg/24 hr 381.44=54.72 mg/24 hr
Buter Baseline: 188 mg/24 hr Final: 94 mg/24 hr
de Pablos Velasco Baseline: µg/min Final: µg/min
146.81.44= mg/24 hr 1.44=173.2 mg/24 hr

6. 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
Slide 6: 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.1,2
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 related to first hospitalization due to heart failure 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, San Antonio, Texas, USA.
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
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4): ; Brenner BM et al N Engl J Med 2001; 345(12):

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

8. 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
Slide 8: RENAAL: Secondary Hypothesis
The secondary hypothesis of RENAAL was that long-term treatment with losartan versus placebo alone or in combination with CTx (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)1
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.1
*Excluding ACE inhibitors and other AII antagonists
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):

9. RENAAL Study Design Mean follow-up 3.4 years Losartan 100 mg qd (+CTx)
Maintain conventional
antihypertensive therapy (CTx)*
(excluding ACE inhibitors, AII antagonists)
Goal trough BP:
<140/<90 mmHg
Slide 9: 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 CTx including CCBs, diuretics, beta or alpha blockers, or centrally acting agents) as appropriate, to control hypertension to a goal of <140/90 mmHg.1,2 Hypertensive patients not being treated with an ACE inhibitor or an AII antagonist continued to receive their prior conventional antihypertensive therapy.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 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 CTx, excluding ACE inhibitors and other AII antagonists (losartan + CTx). The second treatment group received placebo once daily, alone or in combination with CTx, excluding ACE inhibitors and other AII antagonists (placebo + CTx). The randomization was stratified based on the level of baseline proteinuria (urine albumin:creatinine ratio above or below 2000 mg/g).1,2
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
n=1513
Placebo
(+CTx)
Placebo
(+CTx)
Placebo (+CTx)
6 wk
4 wk
8 wk
Mean follow-up 3.4 years
qd=once daily
*CTx=conventional therapy: Open-label calcium-channel blocker, diuretic, beta blocker, alpha blocker, or centrally acting agents.
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):

10. RENAAL Inclusion/Exclusion Criteria
Inclusion criteria
Type 2 diabetes
Age 31–70 years
Proteinuria: urine albumin:cr >300 mg/g or 24-hr protein >500 mg
sCr: 1.3–3.0 mg/dl, 115–265 µmol/L*
Exclusion criteria
Type 1 diabetes
Known non-diabetic renal disease or renal artery stenosis
Recent history of MI, CABG, PTCA, CVA, TIA
History of HF
HbA1c >12%
Slide 10: 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 24-hour urine protein >500 mg) and two qualifying serum creatinine measurements between 1.3 and 3.0 mg/dl.1 In addition, patients were required to be 31 to 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 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.1
CABG=coronary artery bypass graft; PTCA=percutaneous transluminal coronary angioplasty; CVA=cerebral vascular accident; TIA=transient ischemic attacks
*Lower limit 1.5 mg/dl (133 µmol/L) in male patients >60 kg
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):

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

12. RENAAL Baseline Characteristics
Losartan (+CTx) Placebo (+CTx) (n=751) (n=762)
Age, years
Male, % 62 65
Female, %
Race, %
Asian 16 18
Black 17 14
Caucasian 48 50
Hispanic 19 18
Other 2 1
Systolic BP, mmHg
Diastolic BP, mmHg 82 82
BMI, kg/m
Slide 12: 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. 1
There was no significant difference between the losartan + CTx and the placebo + CTx 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.1,2
Adapted from Brenner BM et al J Renin-Angiotens-Aldoster Syst 2000;1(4):

13. RENAAL Primary Composite Endpoint and Components
Losartan (+CTx) Placebo (+CTx)
Composite (n=751) (n=762) % Risk and components n (%) n (%) p Value reduction 95% CI
DsCr, ESRD, Death 327 (43.5) 359 (47.1) (2, 28)
DsCr 162 (21.6) 198 (26.0) (8, 39)
ESRD 147 (19.6) 194 (25.5) (11, 42)
Death 158 (21.0) 155 (20.3) 0.88 –2 (–27, 19)
ESRD or death 255 (34.0) 300 (39.4) (5, 32)
Slide 13: 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 + CTx and 359 (47.1%) patients receiving placebo + CTx. Losartan + CTx 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 + CTx treatment conferred a 22% risk reduction (p=0.008) in the primary composite endpoint. 2
DsCr=doubling of serum creatinine; CI=confidence interval
Adapted from Brenner BM et al N Engl J Med 2001;345(12):

14. 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 (+CTx)
Losartan (+CTx)
RR: 25%
p=0.006 12 24 36 48 10 20 30 40 50
ESRD or Death
Slide 14: 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 + CTx 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=0.010). There was no significant risk reduction of death alone with losartan + CTx.2
Months
% with event
Placebo (+CTx) Losartan (+CTx)
RR: 20%
p=0.010
sCr=serum creatinine; RR=risk reduction
Adapted from Brenner BM et al N Engl J Med 2001;345(12):
Months
Placebo (+CTx)
Losartan (+CTx)
Slide 14

15. RENAAL Primary Composite Endpoint Doubling of sCr / ESRD / Death
ITT analysis
Per-protocol analysis 50 50 40 40 30 30
% with event 20 20
Slide 15: 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 + CTx produced a significant risk reduction of 16% (p=0.02).2 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 + CTx conferred a significant risk reduction of 22% (p=0.008) in the primary composite endpoint.2,36 10
RR: 16%
p=0.02 10
RR: 22%
p=0.008 12 24 36 48 12 24 36 48
Months
Months
Placebo (+CTx) Losartan (+CTx)
Adapted from Brenner BM et al N Engl J Med 2001;345(12): ; Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

16. RENAAL Time to ESRD from Doubling of sCr80 60
% with event 40 20
RR: 30%
p=0.013
Slide 16: RENAAL: Time to ESRD from Doubling of sCr
This slide shows a Kaplan-Meier plot of the percentage of patients with ESRD against the time from the doubling of serum creatinine. Zero time is the time at which a patient experienced a doubling of serum creatinine. Losartan + CTx significantly reduced the risk of reaching ESRD by 30% (p=0.013).36 This means that it is still important to continue losartan + CTx treatment even after the doubling of serum creatinine is observed. 6 12 18 24
Months
Placebo (+CTx)
Losartan (+CTx)
Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

17. RENAAL BP (mmHg) Baseline Year 1 Year 2 Study End Systolic/diastolic
Losartan (+CTx) 152/82 146/78 143/77 140/74
Placebo (+CTx) 153/82 150/80 144/77 142/74
Mean arterial pressure
Losartan (+CTx)
Placebo (+CTx)
Pulse pressure
Losartan (+CTx)
Placebo (+CTx)
Slide 17: 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. CTx consisted of CCBs, diuretics, beta and alpha blockers, and centrally acting agents, excluding ACE inhibitors and other AII antagonists.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 for placebo vs for losartan, p=0.38). At one year, values averaged 150/80 (placebo) and 146/78 (losartan) (103.1 for placebo vs for losartan, p<0.001). At year 2, values averaged 144/77 for placebo and 143/77 for losartan (99.7 for placebo vs 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 for losartan, p=0.59).2,36 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
Adapted from Brenner BM et al N Engl J Med 2001;345(12): ; Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

18. 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% % % 0.01
Adjusted 15% % % 0.016
Slide 18: 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 + CTx 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 + CTx 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).36 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.2
Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

19. RENAAL Dose of Losartan
The daily dose of losartan ranged from 50–100 mg
Losartan*
n=751 % 71
Slide 19: 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. 2,36
100 mg qd
*Patients who took the dose more than 50% of the time.
Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

20. RENAAL Concurrent Antihypertensive Medications
Losartan Placebo Therapeutic Class (n=751) (n=762)
Calcium-channel blocker, %
Dihydropyridine, %
Diuretic, %
Alpha blocker, %
Beta blocker, %
Centrally acting agents ,%
Slide 20: 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 CTx. 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).2
The type (therapeutic class) of concurrent antihypertensive medication used was similar between the losartan + CTx and placebo + CTx treatment groups. CCBs as a class were the most widely used open-label antihypertensives in RENAAL, followed by diuretics, alpha blockers, and beta blockers.2
Adapted from Brenner BM et al N Engl J Med 2001;345(12):

21. RENAAL Secondary Composite Endpoint and Components
Losartan (+CTx) Placebo (+CTx)
Composite (n=751) (n=762) % Risk and components n (%) n (%) p Value reduction 95% CI
CV morbidity/mortality 247 (32.9) 268 (35.2) (–8, 24)
CV death 90 (12.0) 79 (10.4) –12 (–52, 17)
HF 89 (11.9) 127 (16.7) (11, 48)
MI (6.7) (8.9) (–4, 50)
Unstable angina (5.6) (5.4) –3 (–59, 33)
Stroke 47 (6.3) (6.6) (–41, 36)
Revascularization (9.2) (7.9) –19 (–68, 16)
Slide 21: 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.2
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+).2,20
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.2
There was a statistically and potentially clinically important benefit of losartan + CTx versus placebo + CTx 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).2
CV=cardiovascular
Adapted from Brenner BM et al N Engl J Med 2001;345(12):

22. RENAAL First Hospitalization for Heart Failure20 15
% with event 10 5
Slide 22: 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 + CTx versus placebo + CTx is shown. The benefit of losartan + CTx was apparent very early (within the first six months) and was maintained throughout the trial. The overall risk reduction was 32% (p=0.005).2
Risk reduction: 32%
p=0.005 12 24 36 48
Months
Placebo (+CTx)
Losartan (+CTx)
Adapted from Brenner BM et al N Engl J Med 2001;345(12):

23. RENAAL Change from Baseline in Proteinuria40 20
Median % change
–20
Slide 23: 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 + CTx in reducing proteinuria in patients with Type 2 diabetes. In the placebo + CTx 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 + CTx led to an average reduction in proteinuria of 35% (p<0.001 vs. placebo + CTx).2
–40
35% Overall reduction p<0.001
–60 12 24 36 48
Months
Placebo (+CTx)
Losartan (+CTx)
Proteinuria measured as the urine albumin:creatinine ratio from a first morning void.
Adapted from Brenner BM et al N Engl J Med 2001;345(12):

24. RENAAL Rate of Progression of Renal Disease (median 1/sCr slope)
18% reduction
–0.08
–0.069
–0.06
–0.056
dl/mg/yr
Slide 24: 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 + CTx versus –0.069 dl/mg/year with placebo + CTx, p=0.01). Thus, losartan slowed the rate of loss of renal function by 18% relative to placebo.2
–0.04
–0.02
Losartan (+CTx)
Placebo (+CTx)
Adapted from Brenner BM et al N Engl J Med 2001;345(12):

25. RENAAL Most Common Clinical and Laboratory Adverse Experiences Leading to Discontinuation of Study Therapy 6 6
Losartan (+CTx)
Placebo (+CTx) 4 3 3
Percentage 2 2 2 2 1 1 1 1 1 1 1
Slide 25: RENAAL: Most Common Clinical and Laboratory Adverse Experiences Leading to Discontinuation of Study Therapy
The most common clinical adverse experiences causing discontinuation of study therapy in the RENAAL trial were heart failure, ESRD, MI, stroke, and worsening renal insufficiency. The heart failure, ESRD, and MI adverse experiences causing discontinuation of study therapy were fewer in the losartan versus the placebo treatment group (3% vs. 6%; 2% vs. 3%, and 1% vs. 2%, respectively).36
The most common laboratory adverse experiences were increases in serum creatinine and hyperkalemia. The incidence of serum creatinine elevations was low and not significantly different between groups. The incidence of hyperkalemia was also low, but a few more patients were hyperkalemic with losartan than with placebo.36
0.4
Heart failure
ESRD MI
Stroke
Worsening renal insufficiency
sCr
Hyper- kalemia
Clinical
Laboratory
Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
Clin and Lab AEs bars Apr24 Apr. 25, 2001

26. Public Health and Economic Implications of RENAAL (US)
For diabetic patients at risk over a 3.5-year period, it is estimated that
Addition of losartan to the treatment regimens of 100 patients with Type 2 diabetes and nephropathy would be expected to lead to a reduction of 6.3 cases of ESRD
In RENAAL, losartan reduced ESRD days by 31%
Reduction in days with ESRD saves $5144 (p=0.003) per treated patient at 3.5 years and $7058 (p=0.002) per patient over 4 years
After accounting for costs of losartan, reduction in ESRD resulted in net savings of $3522 per patient over 3.5 years (95% CI: $143–$6900) and $5298 (95% CI: $954–$9643) per patient over 4 years
Slide 26: Public Health and Economic Implications
of RENAAL (US)
For diabetic patients at risk over a 3.5-year period, it is estimated that
Addition of losartan to the treatment regimens of 100 patients with Type 2 diabetes and nephropathy is projected to lead to a reduction of 6.3 cases of ESRD
In RENAAL, losartan reduced ESRD days by 31%37
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 years37
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 years37
Costs are reported in 2001 US dollars.
Adapted from Herman WH et al Diabetes Care 2003;26(3):

27. Public Health and Economic Implications of RENAAL (EU)
Extrapolating the addition of losartan to the treatment regimen of patients with Type 2 diabetes and proteinuria in the EU
44,092 cases of ESRD averted (95% CI: 11,898–76,286) after 3.5 years
64,383 years with ESRD averted (95% CI: 20,886–107,879) after 3.5 years
Reduction in ESRD-related costs of €2.6 billion after 3.5 years, increasing to €3.6 billion after 4 years
Slide 27: Public Health and Economic Implications
of RENAAL (EU)
Extrapolating the addition of losartan to the treatment regimen of patients with Type 2 diabetes and proteinuria in the EU
44,092 cases of ESRD averted (95% CI: 11,898–76,286) after 3.5 years38
64,383 years with ESRD averted (95% CI: 20,886–107,879) after 3.5 years38
Reduction in ESRD-related costs of €2.6 billion after 3.5 years, increasing to €3.6 billion after 4 years38
Costs based on ESRD costs in Germany in 1999.
Adapted from Gerth WC et al Kidney Int 2002;62(suppl 82) S68-S72.

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

29. RENAAL Summary (II) In patients with Type 2 diabetes and nephropathy
Losartan and placebo, added to CTx, showed no significant difference in all-cause mortality, MI, stroke, revascularization, hospitalizations for unstable angina, and death due to CV disease
Losartan was generally well tolerated in this patient population
Slide 29: RENAAL: Summary II
In patients with Type 2 diabetes and nephropathy
Losartan and placebo, added to CTx, showed no significant difference in all-cause mortality, MI, stroke, revascularization, hospitalizations for unstable angina, and death due to CV disease
Losartan was generally well tolerated in this patient population
Adapted from Brenner BM et al N Engl J Med 2001;345(12):

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

31. RENAAL Losartan Renal Protection Study
RENAAL results show that losartan + CTx
Provided excellent tolerability
Provided proven renal protection and cardioprotective benefit
28% risk reduction in ESRD
32% risk reduction in incidence of first hospitalization for heart failure
35% reduction in proteinuria
Analysis of the public health implications of RENAAL suggested potential of losartan for substantial healthcare savings
Slide 31: RENAAL: Losartan Renal Protection Study
This slide summarizes the key findings of the RENAAL study.
RENAAL results demonstrated that losartan added to conventional antihypertensive therapy did not increase the incidence of adverse events.2 The number of clinical adverse events with losartan added to conventional therapy showed no significant difference from placebo added to conventional therapy (see notes, slide 25).2 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 (see slides 13, 23).2 The mechanism of this renal-protective effect may involve blockade of many pathological actions of AII in the kidneys.2
RENAAL data show that, in addition to lowering blood pressure and protecting the kidney, losartan provided a cardioprotective benefit of significant risk reduction (in first hospitalizations for heart failure) in hypertensive patients with Type 2 diabetes and nephropathy.2
Adapted from Brenner BM et al N Engl J Med 2001;345(12): ; Herman WH et al Diabetes Care 2003;26(3): ; Gerth WC et al Kidney Int 2002;62(suppl 82):S68-S72.

32. Why Is RENAAL Relevant to the Treatment of Hypertension?
High BP causes increased risk for cardiac, renal and cerebrovascular events (MI, HF, ESRD, stroke)
RENAAL provided strong evidence of a need to block the pathological effects of angiotensin II beyond BP
RENAAL demonstrated that specific 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
Slide 32: 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.39,40 It is also well established that lowering blood pressure improves outcomes in patients with hypertension.41,42
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.2
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 can be achieved by blocking AII.2
Adapted from Whelton PK et al J Hypertens 1992;10(suppl 7):S77-S84; MacMahon S et al Lancet 1990;335: ; Kannel WB JAMA 1996;274(24): ; Klag MJ et al N Engl J Med 1996;334:13-18; Brenner BM et al N Engl J Med 2001;345(12):

33. Losartan Endpoint Trials
ELITE II—The losartan heart failure survival study No significant difference was observed between treatment with losartan or captopril on all-cause mortality in HF patients, but losartan was significantly better tolerated
RENAAL—The losartan renal protection study Losartan provided renal protection and a cardioprotective benefit with excellent tolerability
LIFE—The losartan hypertension survival study Losartan provided protection against stroke and new-onset diabetes
OPTIMAAL—The losartan post-MI survival study Losartan provided cardiovascular benefits comparable to captopril
Slide 33: Losartan Endpoint Trials
The ability of losartan to alter the course of cardiac and renal disease has now been explored in two large endpoint trials, ELITE II and RENAAL. In these, the beneficial effects (efficacy and/or tolerability) of losartan have been demonstrated (see slide for description of losartan endpoint trials).2,43
Data from the LIFE (in hypertensive patients with left ventricular hypertrophy) and OPTIMAAL (in post-myocardial infarction patients) trials became available after RENAAL.44,45 Results from these trials confirmed the important pathological role of AII in cardiac and renal disease Results of LIFE and OPTIMAAL, as well as those of RENAAL, show that AII antagonists such as losartan can play an important role in the long-term management of hypertensive patients with cardiovascular or renal disease.
ELITE=Evaluation of Losartan in the Elderly; LIFE=Losartan Intervention For Endpoint reduction; OPTIMAAL=Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan
Adapted from Pitt B et al Lancet 2000;355: ; Brenner BM et al N Engl J Med 2001;345(12): ; Dahlöf B et al Lancet 2002;359: ; Dickstein K et al Lancet 09/01/02; available at

34. References Please refer to notes page. References
1. Brenner BM, Cooper ME, de Zeeuw D et al. The losartan renal protection study—rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan). J Renin-Angiotens-Aldoster Syst 2000;1(4):
2. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345(12):
3. Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: A specific target for hypertension management. Am J Hypertens 1999;12:205S-213S.
4. Timmermans PBMWM, Wong PC, Chiu AT et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993;45(2):
5. Weir MR, Henrich WL. Theoretical basis and clinical evidence for differential effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 blockers. Curr Opin Nephrol Hypertens 2000;9:
6. Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348(20):
7. Jafar TH, Schmid CH, Landa M et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. Ann Intern Med 2001;135(2):73-87.
8. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329(20):
9.   Parving H-H, Hovind P, Rossing K et al. Evolving strategies for renoprotection: Diabetic nephropathy. Curr Opin Nephrol Hypertens 2001;10:
10. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: From ACE I to angiotensin II antagonists. Kidney Int 2000;57:
11. Ravid M, Savin H, Jutrin I et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993;118(8):
12. Lebovitz HE, Wiegmann TB, Cnaan A et al. Renal protective effects of enalapril in hypertensive NIDDM: Role of baseline albuminuria. Kidney Int 1994;45(suppl 45):S150-S155.
13. Bakris GL, Copley JB, Vicknair N et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996;50:
14. Ahmad J, Siddiqui MA, Ahmad H. Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care 1997;20(10):
15. Nielsen FS, Rossing P, Gall M-A et al. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes 1997;46:
16. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J 1998;317:
17. Fogari R, Zoppi A, Corradi L et al. Long-term effects of ramipril and nitrendipine on albuminuria in hypertensive patients with type II diabetes and impaired renal function. J Hum Hypertens 1999;13:47-53.
18. Estacio RO, Gifford N, Jeffers BW et al. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000;23(suppl 2):B54-B64.
Please refer to notes page.

35. References (cont’d) Please refer to notes page. References: (cont’d)
19. Ruggenenti P, Perna A, Gherardi G et al. Chronic proteinuric nephropathies: Outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis 2000;35(6):
20. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:
21. Goa KL, Wagstaff AJ. Losartan potassium: A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996;51(5):
22. Goldberg AI, Dunlay MC, Sweet CS. Safety and tolerability of losartan compared with atenolol, felodipine and angiotensin converting enzyme inhibitors. J Hypertens 1995;13(suppl 1): S77-S80.
23. Lafayette RA, Mayer G, Park SK et al. Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 1992;90:
24. Remuzzi A, Perico N, Amuchastegui CS et al. Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol 1993;4(1):40-49.
25. Toto R, Shultz P, Raij L et al. Efficacy and tolerability of losartan in hypertensive patients with renal impairment. Hypertension 1998;31:
26. Chan JCN, Critchley JAJH, Tomlinson B et al. Antihypertensive and anti-albuminuric effects of losartan potassium and felodipine in Chinese elderly hypertensive patients with or without non-insulin dependent diabetes mellitus. Am J Nephrol 1997;17:72-80.
27. Bauer JH, Reams GP, Wu Z et al. Effects of losartan on the renin-angiotensin-aldosterone axis in essential hypertension. J Hum Hypertens 1995;9:
28. Erley CM, Bader B, Scheu M et al. Renal hemodynamics in essential hypertensives treated with losartan. Clin Nephrol 1995;43(suppl 1):S8-S11.
29. Fauvel JP, Velon S, Berra N et al. Effects of losartan on renal function in patients with essential hypertension. J Cardiovasc Pharmacol 1996;28(2):
30. Hortal L, Fernández A, Vega N et al. Losartan versus ramipril in the treatment of postrenal transplant erythrocytosis. Transplant Proc 1998;30(5):
31.  Lacourcière Y, Bèlanger A, Godin C et al. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Kidney Int 2000;58:
32. Lozano JV, Llisterri JL, Aznar J et al on behalf of a Spanish Working Group. Losartan reduces microalbuminuria in hypertensive microalbuminuric type 2 diabetics. Nephrol Dial Transplant 2001;16(suppl 6):1-5.
33. Esmatjes E, Flores L, Iñigo P et al. Effect of losartan on TGF-1 and urinary albumin excretion in patients with type 2 diabetes mellitus and microalbuminuria. Nephrol Dial Transplant 2001;16(suppl 6):1-4.
34. Buter H, van Tol A, Navis GJ et al. Angiotensin II receptor antagonist treatment lowers plasma total and very low + low density lipoprotein cholesterol in type 1 diabetic patients with albuminuria without affecting plasma cholesterol esterification and cholesteryl ester transfer. Diabet Med 2000;17: (Letter).
35. de Pablos Velasco PL, Martínez Martín FJ. Effects of losartan and diltiazem on blood pressure, insulin sensitivity, lipid profile and microalbuminuria in hypertensive type 2 diabetics. Clin Drug Invest 1998;16(5):
Please refer to notes page.

36. References (cont’d) Please refer to notes page. References: (cont’d)
36. Brenner B. Reduction of endpoints in non-insulin-dependent diabetes mellitus with the angiotensin II antagonist losartan. Presented at the 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
37. Herman WH, Shahinfar S, Carides GW et al. Losartan reduces the costs associated with diabetic end-stage renal disease. Diabetes Care 2003;26(3):
38. Gerth WC, Remuzzi G, Viberti G et al. Losartan reduces the burden and cost of ESRD: Public health implications from the RENAAL study for the European Union. Kidney Int 2002; 62(suppl 82):S68-S72.
39. Whelton PK, Perneger TV, Brancati FL et al. Epidemiology and prevention of blood pressure-related renal disease. J Hypertens 1992;10(suppl 7):S77-S84.
40. MacMahon S, Peto R, Cutler J et al. Blood pressure, stroke, and coronary heart disease. Lancet 1990;335:
41. Kannel WB. Blood pressure as a cardiovascular risk factor: Prevention and treatment. JAMA 1996;275(24):
42. Klag MJ, Whelton PK, Randall BL et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334(1):13-18.
43. Pitt B, Poole-Wilson PA, Segal R et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:
44. Dahlöf B, Devereux RB, Kjeldsen SE et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 2002;359:
45. Dickstein K, Kjekshus J, the OPTIMAAL Steering Committee. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: The OPTIMAAL randomised trial. Published online September 1, Available at:
46. Dahlöf B. Left ventricular hypertrophy and angiotensin II antagonists. Am J Hypertens 2001;14(2):
47. Spinar J, Vitovec J, Spinarova L et al. A comparison of intervention with losartan or captopril in acute myocardial infarction. Eur J Heart Fail 2000;2:
48. Spinar J, Vitovec J, Pluhacek L et al. First dose hypotension after angiotensin converting enzyme inhibitor and angiotensin II blocker losartan in patients with acute myocardial infarction. Int J Cardiol 2000;75:
Please refer to notes page.

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