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© 2002 by the American Diabetes Association, Inc.
Emerging Treatments and Technologies |
Inhibition of Dipeptidyl Peptidase IV Improves Metabolic Control Over a 4-Week Study Period in Type 2 Diabetes
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
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, 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.
Abbreviations: 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
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|
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|
|
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|
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|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
 C M. B Edwards GLP-1: target for a new class of antidiabetic agents? J R Soc Med, June 1, 2004; 97(6): 270 - 274. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
L. Zhu, C. Tamvakopoulos, D. Xie, J. Dragovic, X. Shen, J. E. Fenyk-Melody, K. Schmidt, A. Bagchi, P. R. Griffin, N. A. Thornberry, et al. The Role of Dipeptidyl Peptidase IV in the Cleavage of Glucagon Family Peptides: IN VIVO METABOLISM OF PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE-(1-38) J. Biol. Chem., June 13, 2003; 278(25): 22418 - 22423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 S. L. Conarello, Z. Li, J. Ronan, R. S. Roy, L. Zhu, G. Jiang, F. Liu, J. Woods, E. Zycband, D. E. Moller, et al. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance PNAS, May 27, 2003; 100(11): 6825 - 6830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
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|
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|
|
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