Inhibition of Dipeptidyl Peptidase IV Improves Metabolic Control Over a 4-Week Study Period in Type 2 Diabetes

Inhibition of Dipeptidyl Peptidase IV Improves Metabolic Control Over a 4-Week Study Period in Type 2 Diabetes Bo Ahrén , MD, PHD 1 2 , Erik Simonsson , MD 1 , Hillevi Larsson , MD, PHD 1 , Mona Landin-Olsson , MD, PHD 2 , Hlin Torgeirsson , MD 2 , Per-Anders Jansson , MD, PHD 3 , Madeléne Sandqvist , MD 3 , Peter Båvenholm , MD, PHD 4 , Suad Efendic , MD, PHD 4 , Jan W. Eriksson , MD, PHD 5 , Sheila Dickinson , MSC 6 and David Holmes , MD 6 1 Department of Medicine, Lund University, Malmö, Sweden 2 Department of Medicine, Lund University, Lund, Sweden 3 Department of Medicine, Göteborg University, Göteborg, Sweden 4 Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden 5 Department of Medicine, Umeå University, Umeå, Sweden 6 Novartis, Basel, Switzerland 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/m 2 , entered the study. Fasting blood glucose was 8.5 ± 1.5 mmol/l, and HbA 1c was 7.4 ± 0.7%. Before and after treatment with NVP DPP728 at 100 mg × 3 ( n = 31) or 150 mg × 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 t