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Background Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin–angiotensin system.
Methods We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models.
Results A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo.
Conclusions Early blockade of the renin–angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949
[ClinicalTrials.gov]
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Source Information
From the Departments of Pediatrics (M.M., A.S., T.S.) and Medicine (M.M.), University of Minnesota, Minneapolis; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto (B.Z., S.D.); the Departments of Medicine (R.G.), Epidemiology and Biostatistics (S.S.), and Pediatrics (K.D., P.G.), McGill University, Montreal; Hôpital Necker–Enfants Malades, Paris (M.C.G.); and the Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison (R.K.).
Address reprint requests to Dr. Mauer at the Department of Pediatrics, University of Minnesota, 420 Delaware St. SE, MMC 491, Minneapolis, MN 55455, or at mauer002{at}umn.edu.
Related Letters:
Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes
Tamsma J. T., Katavetin P., Katavetin P., Mauer M., Zinman B., Klein R.
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N Engl J Med 2009;
361:1410-1411, Oct 1, 2009.
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