1. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study was a double-blind, randomized, placebo-controlled study.
The objective of this study was to assess the role of the angiotensin II receptor antagonist losartan in patients with type 2 diabetes and nephropathy.
A total of 1,513 patients who had received diagnoses of type 2 diabetes and nephropathy took part in the study.
Patients were randomized to losartan ( mg/d) (n=751) or placebo (n=762), both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally-acting agents).
The mean age was 60 years; 63% were male; and 49% were Caucasian.
The mean follow-up was 3.4 years.
Brenner BM et al. N Engl J Med. 2001;345:

2. In the RENAAL study, the composite of morbidity and mortality from cardiovascular causes was similar in the losartan and placebo groups, but the rate of first hospitalization for HF was significantly lower with losartan than with placebo (11.9% vs 16.7%; risk reduction, 32%; P=0.005).
Brenner BM et al. N Engl J Med. 2001;345:

3. In the LIFE trial, the primary composite endpoint (cardiovascular mortality, stroke, and MI) occurred in 508 patients in the losartan-based group (23.8 per 1,000 patient-years) and 588 patients in the atenolol-based group (27.9 per 1,000 patient-years; relative risk 0.87; 95% CI, ; P=0.021).
For the primary endpoint, the overall 13.0% relative risk reduction with losartan therapy is based on progressive separation of the survival curves over time. If not adjusted for Framingham Risk Score and ECG-LVH at baseline, the relative risk reduction is slightly greater, at 14.6% (P=0.009).
Based on the results of this study, losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in BP and is better tolerated.
Dahlöf B et al. Lancet. 2002;359:

4. For the individual endpoint of fatal and nonfatal stroke in the LIFE study, 232 losartan-treated and 309 atenolol-treated patients suffered strokes (adjusted relative risk 0.75, 95% CI , P=0.001).
The curves for stroke separated early, with the outcome showing a 24.9% adjusted risk reduction in favor of losartan compared with atenolol (P=0.001).
Dahlöf B et al. Lancet. 2002;359:

5. Chobanian AV et al. JAMA. 2003;289:2560-2572.
Initial recommended therapy for hypertension in patients with diabetes consists of diuretics, BBs, ACEIs, and CCBs.
Initial therapy for hypertension in patients with chronic kidney disease includes ARBs and ACEIs.
For hypertensive patients at risk for recurrent strokes, a diuretic plus an ACEI is recommended.
Chobanian AV et al. JAMA. 2003;289:
NKF-ADA=National Kidney Foundation/American Diabetes Association. UKPDS=United Kingdom Prospective Diabetes Study; RENAAL=Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT=Irbesartan in Diabetic Nephropathy Trial; REIN=Ramipril Efficacy in Nephropathy; AASK=African-American Study of Kidney Disease and Hypertension; PROGRESS=Perindopril Protection Against Recurrent Stroke Study

6. Chobanian AV et al. JAMA. 2003;289:2560-2572.
Hypertension may exist in association with other conditions in which there are compelling indications for use of specific treatments. Such compelling indications include HF, ischemic heart disease, high CAD risk, diabetes, chronic kidney disease, and recurrent stroke. Therapeutic decisions in such patients should be directed at both the compelling indication and lowering blood pressure. Evidence for the use of treatments for compelling indications is derived from several clinical trials.
Initial therapy for hypertension in the setting of HF consists of diuretics, BBs, ACEIs, ARBs, and aldosterone antagonists. Initial therapy for hypertension post-MI patients includes BBs, ACEIs, and aldo ants. When high-risk CAD is present with hypertension, diuretics, BBs, ACEIs, and CCBs are recommended.
Chobanian AV et al. JAMA. 2003;289:
ACC/AHA=American College of Cardiology/American Heart Association; MERIT-HF= Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; COPERNICUS=Carvedilol Prospective Randomized Cumulative Survival; CIBIS=Cardiac Insufficiency Bisoprolol Study; SOLVD=Studies of Left Ventricular Dysfunction; AIRE=Acute Infarction Ramipril Efficacy; TRACE=Trandolapril Cardiac Evaluation Study; Val-HeFT=Valsartan Heart Failure Trial; RALES=Randomized Spironolactone Evaluation Study; BHAT=Beta-Blocker in Heart Attack Trial; SAVE=Survival and Ventricular Enlargement Study; Capricorn=Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction; EPHESUS=Eplerenone Post-AMI Heart Failure Efficacy and Survival Study; ALLHAT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; HOPE=Heart Outcomes Prevention Evaluation; ANBP2=Australian National Blood Pressure Study; LIFE=Losartan Intervention For Endpoint Reduction; CONVINCE=Controlled Onset Verapamil Investigation of Cardiovascular Endpoints

7. Chobanian AV et al. JAMA. 2003;289:2560-2572.
Initial recommended therapy for hypertension in patients with diabetes consists of diuretics, BBs, ACEIs, and CCBs.
Initial therapy for hypertension in patients with chronic kidney disease includes ARBs and ACEIs.
For hypertensive patients at risk for recurrent strokes, a diuretic plus an ACEI is recommended.
Chobanian AV et al. JAMA. 2003;289:
NKF-ADA=National Kidney Foundation/American Diabetes Association. UKPDS=United Kingdom Prospective Diabetes Study; RENAAL=Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT=Irbesartan in Diabetic Nephropathy Trial; REIN=Ramipril Efficacy in Nephropathy; AASK=African-American Study of Kidney Disease and Hypertension; PROGRESS=Perindopril Protection Against Recurrent Stroke Study

8. The impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 Caucasian patients type 2 diabetes followed for 5 years.
At the end of the study 8% of patients with normoalbuminuria, 20% of patients with microalbuminuria, and 35% of patients with macroalbuminuria had died (predominantly from cardiovascular disease) (P<0.01 [normoalbuminuria versus micro- and macroalbuminuria] and P<0.05 [microalbuminuria versus macroalbuminuria]).
Gall MA et al. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes. 1995;44:

10. RENAAL began with an initial, 6-week screening-treatment phase without placebo. Ninety-four percent of patients who entered the study were undergoing antihypertensive treatment. Those treated with either an ACE inhibitor (ACEI) or an angiotensin II blocker (ARB) within 6 weeks of enrollment discontinued these medications and received open-label diuretics, calcium channel blockers, alpha- or beta-blockers, or centrally acting agents as needed to control high blood pressure (BP). The goal trough BP was <140/<90 mm Hg.
Four weeks after randomization, or at any other phase during this study, if the target trough sitting systolic/diastolic BP of <140/<90 mm Hg was not achieved, the daily dose of losartan or placebo was increased to losartan 100 mg once daily or corresponding placebo once daily.
Brenner BM et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
N Engl J Med. 2001;345:

11. The Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE) was a 4-year, double-masked, randomized, parallel-group trial.
The objective of this study was to establish whether selective blocking of angiotensin II improves left ventricular hypertrophy (LVH) beyond reducing blood pressure and, consequently, reduces cardiovascular morbidity and death.
Participants included 9,193 patients with essential hypertension (sitting BP, / mm Hg) and LVH ascertained by electrocardiography.
Patients were randomized to losartan-based (n=4,605) or atenolol-based (n=4,588) therapy.
Mean age was 66.9 years; 54% of the participants were women; and most participants were Caucasian (92.5%).
Dahlöf B et al. Lancet. 2002;359:

12. Completion of the RENAAL study was planned for 3
Completion of the RENAAL study was planned for 3.5 years after the last patient was randomized, which would have provided a 4.5-year mean follow-up time. However, the study was discontinued early by the Steering Committee. While blinded to all treatment assignments, the Steering Committee acted for external reasons, ie, accumulating evidence suggesting that ACEIs, which were excluded by design from RENAAL, may be effective in reducing cardiovascular events in type 2 diabetic patients, including those with renal impairment.
Brenner BM et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:

13. In the RENAAL study, the composite of morbidity and mortality from cardiovascular causes was similar in the losartan and placebo groups, but the rate of first hospitalization for HF was significantly lower with losartan than with placebo (11.9% vs 16.7%; risk reduction, 32%; P=0.005).
Brenner BM et al. N Engl J Med. 2001;345:

14. The LIFE study (Losartan Intervention for Endpoint Reduction in Hypertension) was designed to compare losartan with the b-blocker atenolol. Eligible patients had hypertension and signs of left ventricular hypertrophy (LVH) on an electrocardiogram.
The primary hypothesis tested in the study was that selective angiotensin II type 1 receptor antagonism with losartan would be more effective than b-blockade with atenolol in reducing cardiovascular morbidity and mortality.
One additional predefined study endpoint was new-onset diabetes mellitus. The adjusted risk reduction for new-onset diabetes with losartan compared to atenolol was 25% (P=0.001).
The stepped survival curve is the result of new-onset diabetes being diagnosed at scheduled annual visits.
Lindholm LH et al. Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens. 2002;20:

15. In the RENAAL study, patients were randomized to losartan or placebo
In the RENAAL study, patients were randomized to losartan or placebo. Both groups continued to take other antihypertensive medications (calcium channel antagonists, diuretics, a-blockers, b-blockers, and centrally acting agents) as required.
Progression of renal disease, defined here as a composite of doubling of serum creatinine, end-stage renal disease, or death, was statistically significantly reduced with the use of losartan.
Brenner BM et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345: