Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes

Introduction:  Type 1 diabetes can lead to several complications, including nephropathy and retinopathy.  In this study, researchers aimed to investigate if the progression of nephropathy and retinopathy could be slowed by early administration of medications that block the renin-angiotensin system.

Methods:  This was a multicenter, controlled trial; there were 285 normotensive type 1 diabetes patients.  The patients also had normal albuminuria.

They were randomly assigned to the following groups and followed for 5 years:

The primary endpoint for the study was:  change in the fraction of glomerular volume taken up by mesangium in kidney-biopsy specimens.

A progression of 2 steps or more on a retinopathy severity scale was the retinopathy end point.

Researchers used linear regression and logistic-regression models to analyze intention-to-treat.

Results:  Complete renal-biopsy data was available in 90% of the patients; complete retinopathy data was available for 82%.

The primary endpoint (change in mesangial fractional volume per glomerulus) over the 5-year study did not different significantly between the placebo group and the enalapril groups (0.016 units and 0.005 units, respectively; p = 0.38).  The change also didn’t vary significantly between the placebo group and the losartan group (0.026; p = 0.26).

There were no significant treatment benefits for other biopsy-assessed renal structural variables.

Looking at the 5-year cumulative incidence of microalbuminuria, researchers saw that it was 6% in the placebo group.  It was higher in the losartan group (17%; p = 0.01 by the log-rank test), but it was lower in the enalapril group (4%; p = 0.96 by the log-rank test).

Compared to placebo, the odds of retinopathy progressing by at least 2 steps was 65% lower in the enalapril group (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85).  The odds were reduced 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73).  This was all independent of blood pressure changes.

In the study, there were 3 biopsy-related serious adverse events, but these completely resolved.  In 12 patients on enalapril, chronic cough developed; it also developed in 5 on losartan and 4 in the placebo group.

Conclusions:  Blocking the renin-angiotensin system with medications early can slow the progression of diabetic retinopathy.  This study does not indicate, however, that these agents slow nephropathy progression.

Commentary by Colleen Flynn MD

This study is one of the few that investigates the effect of an RAS blocker in patients with type 1 diabetes, whereas most published studies only look at these agents in type 2 diabetics. Despite the lack of benefit to nephropathy progression with an ACEI or ARB versus placebo, this study does show significant benefit with these agents in preventing retinopathy.