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.)
Mauer
Michael
M
Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA. mauer002@umn.edu
Zinman
Bernard
B
Gardiner
Robert
R
Suissa
Samy
S
Sinaiko
Alan
A
Strand
Trudy
T
Drummond
Keith
K
Donnelly
Sandra
S
Goodyer
Paul
P
Gubler
Marie Claire
MC
Klein
Ronald
R
D000328:Adult; D000419:Albuminuria; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000517:prevention & control; D003930:Diabetic Retinopathy / Q000517:prevention & control; D018450:Disease Progression; D004311:Double-Blind Method; D004656:Enalapril / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology; D016015:Logistic Models; D019808:Losartan / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012160:Retina / Q000187:drug effects* / Q000473:pathology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D019808:Losartan