Vildagliptin - Mode of Action

Abstract

Incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are important for normal pancreatic islet function and glucose homeostasis. There is a surge in GLP-1 and GIP secretion at the beginning of each meal followed within minutes by their rapid inactivation by the enzyme dipeptidyl peptidase 4 (DPP-4). Both GLP-1 and GIP increase the sensitivity to glucose of the β-cells and thus enhances glucose-dependent insulin secretion, GLP-1 also improves the sensitivity to glucose of the α-cells under hyperglycemic conditions and thus reduces inappropriate glucagon secretion thereby decreasing insulin resistance [1], and GIP improves the sensitivity of the α-cell to glucose under hypoglycemic conditions and thus enhances glucagon counter-regulation [2]. Independent of GLP-1 and GIP action, the sensitivities to glucose of the α and β-cells of the pancreas are diminished in type 2 diabetes (T2DM) leading to impaired insulin secretion, insulin resistance due to elevated glucagon levels in hyperglycemia and impaired glucagon counter regulation in hypoglycemia[1]. In addition, T2DM is associated with increased lipo-toxicity induced insulin resistance due inappropriate fasting lipolysis leading increased stored triglyceride in liver, muscle and β-cells [3-4]. Vildagliptin (LAF237), a member of the DPP-4 inhibitor class of oral antidiabetic drugs for the treatment of T2DM, prolongs the meal induced increases of GLP-1 and GIP by blocking the enzyme DPP-4, leading to improved glucose control1. In general DPP-4 inhibitors prolong the physiological meal induced increase in GLP-1 and GIP. How long these levels are prolonged depends on how complete the DPP-4 inhibition is. A 50% inhibition would extend the half-life 2-fold, a 90% inhibition 10-fold, a 95% inhibition 20-fold and with 100% inhibition the half-life would be determined by the renal clearance of GLP-1 and GIP. Competitive DPP-4 inhibitors, such as sitagliptin, which achieve 90-95% inhibition of DPP-4 can maintain GLP-1 and GIP levels above the threshold required for their actions in the pancreas over the course of each meal, falling below this threshold between meals and overnight. Vildagliptin is a slow substrate for DPP-4 which blocks GLP-1 and GIP inactivation over 24 hours resulting in maintenance of GLP-1 and GIP levels above the threshold for their actions in the pancreas over the entire 24 hours of each day.