To assess whether
angiotensin-converting enzyme inhibitors and third-generation
dihydropyridine calcium channel blockers ameliorate
diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with
albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [
Delapril and
Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with
manidipine/
delapril combination (10/30 mg/d; n=126),
delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by
iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined
therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on
delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined
therapy or
delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses.
Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined
therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined
therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for
peripheral neuropathy at 3 years between combined
therapy or
delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively.
Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or
delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined
manidipine and
delapril therapy failed to slow GFR decline but safely ameliorated
cardiovascular disease, retinopathy, and neuropathy and stabilized
insulin sensitivity.