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

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.)

Pubmed ID: 19571282

Authors

  • Mauer M
  • Zinman B
  • Gardiner R
  • Suissa S
  • Sinaiko A
  • Strand T
  • Drummond K
  • Donnelly S
  • Goodyer P
  • Gubler MC
  • Klein R

Journal

The New England journal of medicine

Publication Data

July 2, 2009

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK51975
  • Agency: NCRR NIH HHS, Id: M01-RR00400
  • Agency: NIDDK NIH HHS, Id: R01 DK051975
  • Agency: NIDDK NIH HHS, Id: R01 DK051975-05

Mesh Terms

  • Adult
  • Albuminuria
  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Diabetes Mellitus, Type 1
  • Diabetic Nephropathies
  • Diabetic Retinopathy
  • Disease Progression
  • Double-Blind Method
  • Enalapril
  • Female
  • Follow-Up Studies
  • Glomerular Filtration Rate
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Glomerulus
  • Logistic Models
  • Losartan
  • Male
  • Mesangial Cells
  • Renin-Angiotensin System
  • Retina