Cozaar

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; 345:861-69

* BACKGROUND Interruption of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors is renoprotective both in patients with type 1 diabetes and in patients without diabetes who have overt nephropathy. This study evaluates the effectiveness of losartan, an angiotensin-receptor blocker (ARB), in slowing the progression of nephropathy in type 2 diabetes.

* POPULATION STUDIED The Reduction of Endpoints in Non-insulin--dependent diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study included 1513 people with type 2 diabetes and nephropathy, ranging in age from 31 to 70 years. Nephropathy was defined as urinary protein excretion of at least 500 mg daily and a serum creatinine of 1.3 to 3.0 mg per dL. Patients were excluded if they had a diagnosis of nondiabetic nephropathy; had experienced a recent myocardial infarction, transient ischemic attack, or stroke; had recently undergone coronary artery bypass grafting or percutaneous coronary angioplasty; or had ever had heart failure.

* STUDY DESIGN AND VALIDITY The RENAAL study was a double-blind randomized placebo-controlled trial in which patients were assigned to receive either losartan 50 to 100 mg or placebo. All patients received other antihypertensive therapy (excluding ACE inhibitors and ARBs) as necessary to maintain a blood pressure level of less than 140/90 mm Hg. The groups were similar at baseline, with a mean serum creatinine was 1.9 mg per dL (standard deviation = 0.5). The patients were followed up for a mean of 3.4 years, and an intention-to-treat analysis was reported. The study methods appeared valid, although concealment of allocation was not described.

* OUTCOMES MEASURED The primary outcome was the combined outcomes of a doubling of the baseline serum creatinine concentration, end-stage renal disease, and death.

* RESULTS Treatment with losartan resulted in a 16% reduction in the primary composite end point (95% confidence interval [CI], 2%-28%; P=.02; number needed to treat [NNT]=28). The risk for doubling of serum creatinine concentration was reduced by 25% (95% CI, 8-39; P =.006; NNT=23). The likelihood of reaching end-stage renal disease was reduced by 28% (95% CI, 11-42; P =.002; NNT=17). Losartan also decreased the level of proteinuria by 35% (P < .001) and the rate of decline of renal function by 18% (P =.01). A 32% reduction in a patient's first hospitalization for heart failure was observed (P =.005). There was no difference in the composite end point of morbidity and mortality due to cardiovascular causes, adverse events, or overall mortality.

RECOMMENDATIONS FOR CLINICAL PRACTICE

Losartan showed significant renal benefits in patients with type 2 diabetes and nephropathy. Two other recent papers support this finding. In one, irbesartan (Avapro) protected against the progression of nephropathy in patients with type 2 diabetes compared with either amlodipine (Norvasc) or placebo. (1) Treatment with irbesartan also reduced the rate of progression to overt nephropathy in hypertensive patients with type 2 diabetes and microalbuminuria. (1)

It is unknown whether ACE inhibitors induce the same degree of renoprotection as ARBs in patients with type 2 diabetes. However, ACE inhibitors slow progression of nephropathy due to type 1 diabetes and have significant cardiovascular benefits for patients with type 2 diabetes and hypertension. Interestingly, the RENAAL study was stopped early because of a recently published analysis of the Heart Outcome Prevention Evaluation study, (2) which focused on the effects of an ACE inhibitor on patients with diabetes and mild renal insufficiency (serum creatinine = 1.4-2.3 mg/dL). That analysis showed that ramipril reduced a combined end point of cardiovascular death, myocardial infarction, or stroke by a hazard ratio of 0.48 (95% CI, 0.26-0.86). Although ARBs are clearly renoprotective in patients with type 2 diabetes, the data do not yet provide a rationale for sacrificing the cardiovascular protection of an ACE inhibitor in this high-risk population. For now, ACE inhibitors should be the first agent for patients with diabetes who have hypertension and renal disease, reserving ARBs for those who cannot tolerate the ACE inhibitors.

REFERENCES

(1.) Lewis EJ, Hunsicker LG, Clarke WR, et al. N Engl J Med 2001; 345:851-60.

(2.) Parving HH, Lehnert H, Brochnr-Mortensen J, et al. N Engl J Med 2001; 345:870-78.

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