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


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


METHODS
309 secondary care centers.


METHODS
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).


METHODS
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.


METHODS
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.


CONCLUSIONS
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.


CONCLUSIONS
Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.
Bilous
Rudy
R
Newcastle University, Newcastle upon Tyne, United Kingdom.
Chaturvedi
Nish
N
Sjølie
Anne Katrin
AK
Fuller
John
J
Klein
Ronald
R
Orchard
Trevor
T
Porta
Massimo
M
Parving
Hans-Henrik
HH
D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000188:drug therapy*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000652:urine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C081643:candesartan