Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials

Ann Intern Med. 2009 Jul 7;151(1):11-20, W3-4. doi: 10.7326/0003-4819-151-1-200907070-00120. Epub 2009 May 18.

Abstract

Background: Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preventive therapies are therefore a clinical priority.

Objective: To determine whether the angiotensin-receptor blocker candesartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes.

Design: 3 randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program.

Setting: 309 secondary care centers.

Patients: 3326 and 1905 patients with type 1 and type 2 diabetes, respectively. Most were normotensive, and all had normoalbuminuria (median urinary albumin excretion rate, 5.0 microg/min).

Intervention: Candesartan, 16 mg/d increasing to 32 mg/d, versus placebo. Assignment was done centrally using an interactive voice-response system. Patients, caregivers, and researchers were blinded to treatment assignment. During a median follow-up of 4.7 years, 793 patients discontinued therapy and 63 were lost to follow-up.

Measurements: Urinary albumin excretion rate, assessed annually by 2 overnight collections; if it was 20 microg/min or greater, then 2 further collections were done. The primary end point was new microalbuminuria (3 or 4 collections of urinary albumin excretion rate >or=20 microg/min). The secondary end point was rate of change in albuminuria.

Results: Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; P = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; P = 0.024) with candesartan than with placebo.

Limitations: Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria. Studies were powered for retinal and not renal end points.

Conclusion: Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00252694 NCT00252720 NCT00252733.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Albuminuria / drug therapy*
  • Angiotensin II Type 1 Receptor Blockers / adverse effects
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use*
  • Benzimidazoles / adverse effects
  • Benzimidazoles / therapeutic use*
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 2 / complications
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / urine
  • Double-Blind Method
  • Female
  • Humans
  • Hyperkalemia / chemically induced
  • Male
  • Middle Aged
  • Tetrazoles / adverse effects
  • Tetrazoles / therapeutic use*
  • Young Adult

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Tetrazoles
  • candesartan

Associated data

  • ClinicalTrials.gov/NCT00252694
  • ClinicalTrials.gov/NCT00252720
  • ClinicalTrials.gov/NCT00252733