SEP 30, 2011
The authors conducted this multicenter, controlled study published in The New England Journal of Medicine in 2009 to assess the effect of renin-angiotensin system blockade on renal and retinal morphologic features in normotensive patients with type 1 diabetes and normoalbuminuria. They randomized patients to treatment with losartan, an angiotensin-receptor blocker (ARB); enalapril, an angiotensin-converting-enzyme (ACE) inhibitor; or placebo. After five years, early blockade of the renin-angiotensin system did not slow nephropathy but did slow progression of retinopathy by at least 65 percent.
The study included 285 patients randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily) or placebo. Stereoscopic fundus photographs were taken at 30 degrees for seven standard Early Treatment Diabetic Retinopathy Study (ETDRS) fields at baseline and five years. They were graded by observers unaware of drug assignments using the modified Airlie House Classification and the ETDRS severity scale.
The authors found that the change in mesangial fractional volume per glomerulus did not differ significantly between the three groups nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The five-year cumulative microalbuminuria incidence was significantly higher than placebo (6 percent) with losartan (17 percent; P = 0.01) but not with enalapril (4 percent; P = 0.96). However, the odds compared with placebo of retinopathy progression by two steps or more, the study's retinopathy end point, were reduced by 65 percent with enalapril and by 70 percent with losartan, independent of changes in blood pressure.
A progression in retinopathy of two steps or more occurred in 38 percent of patients receiving placebo but only 25 percent receiving enalapril (P = 0.02) and 21 percent receiving losartan (P = 0.008), with similar results for the progression of three steps or more. These effects remained even after adjustment for the mean of all blood-pressure measurements obtained during the five-year study, time to first retinal photograph and time to doubled drug dose (which occurred after new data became available indicating greater reduction in proteinuria with higher doses), and also after multiple imputation analyses accounting for patients lacking second photographs.
The authors conclude that the reduction in the progression of diabetic retinopathy, which is unrelated to glycemia, seen among the patients treated with enalapril or losartan might be from blood-pressure lowering or the direct effects of blockage of the retinal renin-angiotensin system.