Renal and retinal effects of enalapril and losartan in type 1 diabetes

Michael Mauer, Bernard Zinman, Robert Gardiner, Samy Suissa, Alan Sinaiko, Trudy Strand, Keith Drummond, Sandra Donnelly, Paul Goodyer, Marie Claire Gubler, Ronald Klein

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539 Scopus citations

Abstract

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.)

Original languageEnglish (US)
Pages (from-to)40-51
Number of pages12
JournalNew England Journal of Medicine
Volume361
Issue number1
DOIs
StatePublished - Jul 2 2009

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    Mauer, M., Zinman, B., Gardiner, R., Suissa, S., Sinaiko, A., Strand, T., Drummond, K., Donnelly, S., Goodyer, P., Gubler, M. C., & Klein, R. (2009). Renal and retinal effects of enalapril and losartan in type 1 diabetes. New England Journal of Medicine, 361(1), 40-51. https://doi.org/10.1056/NEJMoa0808400