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

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.)

• Authors: Michael Mauer, Bernard Zinman, Robert Gardiner, Samy Suissa, Alan Sinaiko, Trudy Strand, Keith Drummond, Sandra Donnelly, Paul Goodyer, Marie Claire Gubler, Ronald Klein
• Journal: The New England journal of medicine (N Engl J Med) Vol. 361 Issue 1 Pg. 40-51 (Jul 02 2009) ISSN: 1533-4406 [Electronic] United States
• PMID: 19571282 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Massachusetts Medical Society

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Angiotensin-Converting Enzyme Inhibitors
• Enalapril
• Losartan

Topics

• Adult
• Albuminuria
• Angiotensin II Type 1 Receptor Blockers (adverse effects, pharmacology, therapeutic use)
• Angiotensin-Converting Enzyme Inhibitors (adverse effects, pharmacology, therapeutic use)
• Diabetes Mellitus, Type 1 (drug therapy, pathology, physiopathology)
• Diabetic Nephropathies (prevention & control)
• Diabetic Retinopathy (prevention & control)
• Disease Progression
• Double-Blind Method
• Enalapril (adverse effects, pharmacology, therapeutic use)
• Female
• Follow-Up Studies
• Glomerular Filtration Rate (drug effects)
• Humans
• Kaplan-Meier Estimate
• Kidney Glomerulus (drug effects, pathology)
• Logistic Models
• Losartan (adverse effects, pharmacology, therapeutic use)
• Male
• Mesangial Cells (drug effects, pathology)
• Renin-Angiotensin System (drug effects)
• Retina (drug effects, pathology)