Inhibition of Dipeptidyl Peptidase IV Improves Metabolic Control Over a 4-Week Study Period in Type 2 Diabetes
- Bo Ahrén, MD, PHD12,
- Erik Simonsson, MD1,
- Hillevi Larsson, MD, PHD1,
- Mona Landin-Olsson, MD, PHD2,
- Hlin Torgeirsson, MD2,
- Per-Anders Jansson, MD, PHD3,
- Madeléne Sandqvist, MD3,
- Peter Båvenholm, MD, PHD4,
- Suad Efendic, MD, PHD4,
- Jan W. Eriksson, MD, PHD5,
- Sheila Dickinson, MSC6 and
- David Holmes, MD6
- 1Department of Medicine, Lund University, Malmö, Sweden
- 2Department of Medicine, Lund University, Lund, Sweden
- 3Department of Medicine, Göteborg University, Göteborg, Sweden
- 4Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden
- 5Department of Medicine, Umeå University, Umeå, Sweden
- 6Novartis, 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/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 × 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, HbA1c 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.
- DDP IV, dipeptidyl peptidase IV
- FPG, fasting plasma glucose
- GIP, gastric inhibitory polypeptide
- GLP-1, glucagon-like peptide-1
- NVP DPP728, 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine
Footnotes
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Address correspondence and reprint requests to Dr. Bo Ahrén, Department of Medicine, Lund University, B11 BMC, S-221 84 Lund, Sweden. E-mail: bo.ahren{at}med.lu.se.
Received for publication 15 August 2001 and accepted in revised form 5 February 2002.
Bo Ahrén, Peter Båvenholm, Suad Efendic, Per-Anders Jansson, Madeléne Sandqvist, and Erik Simonsson have received grant support and Jan W. Eriksson has received consulting fees from Novartis, Basel, Switzerland.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
