Enhancement of blood glucose lowering effect of a sulfonylurea when coadministered with an ACE inhibitor: results of a glucose‐clamp study

Background To investigate if coadministration of enalapril alters the metabolic effect of glibenclamide by employing an euglycemic glucose‐clamp technique in healthy volunteers. Methods A double‐blind crossover study with nine healthy normotensive volunteers (age 27 ± 3 y, BMI 23.3 ± 2.0 kg m −2 ; mean ± SD)—randomly assigned to a 3‐day treatment of either 5 mg enalapril or placebo. In the morning of the fourth day, volunteers orally received 3.5 mg glibenclamide together with either 10 mg enalapril or placebo. Blood glucose levels of volunteers were allowed to fall by 10% from fasting levels and were kept constant thereafter by employing a Biostator‐based euglycemic glucose clamp. Results Coadministration of enalapril—compared with placebo—resulted in a temporarily higher metabolic effect of glibenclamide (AUC GIR 0–120 229 ± 173 vs 137 ± 44 mg kg −1 , p < 0.01; mean ± SD), which lasted from 120 min to 240 min after enalapril administration. In parallel, the maximal metabolic effect of glibenclamide tended to be higher with enalapril (GIR max 5.2 ± 1.9 vs 4.1 ± 1.3 mg kg −1 min −1 ; p = 0.19). However, the total metabolic effect of glibenclamide was almost identical between volunteers taking enalapril or placebo (AUC GIR 0–600 1267 ± 334 vs 1286 ± 249 mg kg −1 , ns). In contrast, serum insulin levels, C‐peptide levels, and serum glibenclamide profiles were not significantly different between enalapril and placebo. Conclusions The results of this study may explain the higher incidence of hypoglycemic episodes observed in patients with type 2 diabetes when taking ACE inhibitors together with sulfonylureas or insulin. ACE inhibitors may cause a temporary increase of the insulin sensitivity, which leads to an increased risk of hypoglycemia under these conditions. Copyright © 2005 John Wiley & Sons, Ltd.