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. -A total of 93 patients (61 men and 32 women), aged 64 Ϯ 9 years (means Ϯ SD) and with BMI 27.3 Ϯ 2.7 kg/m 2 , entered the study. Fasting blood glucose was 8.5 Ϯ 1.5 mmol/l, and HbA 1c was 7.4 Ϯ 0.7%. Before and after treatment with NVP DPP728 at 100 mg ϫ 3 (n ϭ 31) or 150 mg ϫ 5 (n ϭ 32) or placebo (n ϭ 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal). RESEARCH DESIGN AND METHODSRESULTS -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 Ͻ 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 ϭ 0.017 and P ϭ 0.023).Although not an efficacy parameter foreseen in the study protocol, HbA 1c was reduced to 6.9 Ϯ 0.7% in the combined active treatment groups (P Ͻ 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. Diabetes Care 25:869 -875, 2002T he gut hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are both incretin hormones that are released postprandially and markedly augment glucose-stimulated insulin secretion through sensitizing the ␤-cell action of glucose (1-3). GLP-1 also exhibits other effects of importance for glucose homeostasis, viz., inhibiting glucagon secretion, delaying gastric emptying, and stimulating insulin biosynthesis (2,3). These effects, along with a potential increase in peripheral insulin action (4), will together be antidiabetogenic. GLP-1 has also been shown to reduce postprandial and fasting glycemia in subjects with type 1 and type 2 diabetes (3,4 -9) and may, therefore, be a potentially useful new therapeutic agent in the treatment of diabetes. However, GLP-1 is rapidly degraded in plasma by the enzyme dipeptidyl peptidase IV (DPP IV), resulting in the short circulating half-life of intact GLP-1 being Ͻ1 min (3,10,11). Therefore, GLP-1 is unattractive as chronic therapy because multiple daily injections are required to maintain glycemic control.The short half-life of GLP-1 has prompted development of alternate strategies to harness the potent antidiabetic activity of GLP-1. One approach is to inhibit DPP IV activity, thereb...

Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance

“…Therefore, strategies for GLP-1-based treatment of diabetes have focused on injections of GLP-1 derivatives that are resistant to DP-IV or stabilization of endogenous GLP-1 through the use of DP-IV inhibitors. Such approaches have led to promising agents with glucose-lowering efficacy in diabetic patients (46,47). The data presented in this study provide strong evidence that chronic ablation of DP-IV activity may have added benefits in metabolic control extending beyond glucose homeostasis per se and may serve as a unique intervention for treating both diabetes and obesity.…”

Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

“…However, the rapid degradation of GLP-1 in the bloodstream by the enzyme DPP IV giving rise to the truncated and inactive GLP-1(9-36)amide is a major stumbling block to the efficient use of this hormone therapeutically (Mentlein et al 1993, Kieffer et al 1995. Administration of specific inhibitors of DPP IV have produced improved glucose tolerance in both animals (Sudre et al 2002, Pospisilik et al 2002 and humans (Ahren et al 2002). However, as DPP IV is involved in diverse physiological processes including the inactivation of key regulatory hormones other than GLP-1 (Mentlein 1999), inhibition of DPP IV activity may not be a suitable means of prolonging the action of either endogenous or exogenous GLP-1.…”

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

“…After these promising preclinical studies, the first clinical proof-of-concept was obtained using the short-acting inhibitor, NVP-DPP728 [85]. When given twice or three times daily for 4 weeks in patients with relatively mild type 2 diabetes (mean HbA 1 c 7.4%), both fasting and prandial glucose levels were lowered significantly, resulting in a 0.5% reduction in HbA 1 c; despite the fall in glycaemia, fasting and post-prandial insulin levels were sustained.…”