Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes

Abstract

OBJECTIVE - Glucagon-like peptide-1 (GLP-1) has been proposed as a new treatment modality for type 2 diabetes. To circumvent the drawback of the short half-life of GLP-1, inhibitors of the GLP-1-degrading enzyme dipeptidyl peptidase IV (DPP IV) have been examined. Such inhibitors improve glucose tolerance in insulin-resistant rats and mice. In this study, we examined the 4-week effect of 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano- (S)-pyrrolidine (NVP DPP728), a selective, orally active inhibitor of DPP IV, in subjects with diet-controlled type 2 diabetes in a placebo-controlled double-blind multicenter study. RESEARCH DESIGN AND METHODS - A total of 93 patients (61 men and 32 women), aged 64 ± 9 years (means ± SD) and with BMI 27.3 ± 2.7 kg/m2, entered the study. Fasting blood glucose was 8.5 ± 1.5 mmol/l, and HbA1c was 7.4 ± 0.7%. Before and after treatment with NVP DPP728 at 100 mg X 3 (n = 31) or 150 mg X 5 (n = 32) or placebo (n = 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal). RESULTS - Compared with placebo, NVP DPP728 at 100 mg t.i.d. reduced fasting glucose by 1.0 mmol/l (mean), prandial glucose excursions by 1.2 mmol/l, and mean 24-h glucose levels by 1.0 mmol/l (all P < 0.001). Similar reductions were seen in the 150-mg b.i.d. treatment group. Mean 24-h insulin was reduced by 26 pmol/l in both groups (P = 0.017 and P = 0.023). Although not an efficacy parameter foreseen in the study protocol, HbA 1c was reduced to 6.9 ± 0.7% in the combined active treatment groups (P < 0.001). Laboratory safety and tolerability was good in all groups. CONCLUSIONS - We conclude that inhibition of DPP IV is a feasible approach to the treatment of type 2 diabetes in the early stage of the disease.