Mechanism-based population modelling of the effects of vildagliptin on GLP-1, glucose and insulin in patients with type 2 diabetes

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), leading to increased concentrations of active glucagon-like peptide 1 (GLP-1) and thereby decreased plasma glucose concentrations. Vildagliptin is approved for treatment of type 2 diabetes mellitus in more than 76 countries including the European Union and Japan where 85 to 95 of all diabetes cases are type 2 [1]. Such patients exhibit insufficient insulin activity due to decreased insulin action in glucose-utilizing tissues (peripheral insulin resistance) and impaired insulin secretion from the b-cells in the pancreas (beta-cell failure). After ingestion of a meal, GLP-1, an incretin hormone, is released from the L-cells in the gut wall. Its secretion is stimulated both by endocrine and neural signals and by direct stimulation of the intestinal cells by digested nutrients in the gut. Active GLP-1 stimulates glucosedependent insulin secretion from b-cells, enhances b-cell proliferation and increases b-cell resistance to apoptosis [2]. GLP-1 has also been demonstrated to suppress hepatic glucose production and delay gastric emptying [3], thereby decreasing high blood glucose concentrations after food intake. GLP-1 is rapidly inactivated by the ubiquitous enzyme DPP-4 with a half-life of approximately 2 min in humans. Reduced secretion of GLP-1 in type 2 diabetic patients compared with healthy subjects has been reported [4, 5]. Vildagliptin, a DPP-4 inhibitor, prolongs the action of active GLP-1 by inhibiting its inactivation by the DPP-4 enzyme. While the effects of vildagliptin from this study in type 2 diabetic patients were previously described by noncompartmental analysis (NCA) [6], a mechanism-based compartmental modelling approach has not been applied. Simultaneous modelling of PD endpoints such as DPP-4, GLP-1, insulin and glucose by taking the pathophysiology into account allows the exploration of the dynamic aspects of mechanisms of action