Linagliptin increases incretin levels, lowers glucagon, and improves glycemic control in type 2 diabetes mellitus

Abstract

Introduction: Linagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed with linagliptin. The effects of linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM. Methods: Patients in this phase 2a, multicenter, randomized, double-blind, placebo-controlled study received placebo (n = 40) or linagliptin 5mg (n = 40). Sitagliptin 100 mg (n = 41) once daily for 4 weeks was included for exploratory purposes. Primary endpoints for linagliptinversus placebo: change from baseline to day 28 in 24-h weighted mean glucose (WMG) and intact glucagon-like peptide (GLP)-1 area under the time-effect curve between 0 and 2 h (AUEC0-2h) following meal tolerance test on day 28. Results: Linagliptin increased intact GLP-1 AUEC0-2h (+18.1 pmol/h/L) and lowered 24-h WMG (-1.1 mmol/L) versus placebo (both P\0.0001) after 28 days. Intact glucosedependent insulinotropic polypeptide increased in line with GLP-1 (+91.4 pmol/h/L increase vs. placebo; P\0.0001). Glycated hemoglobin (-0.22%; P = 0.0021), fasting plasma glucose (-0.6 mmol/L; P = 0.0283), and glucose (AUEC0-3h) (-5.9 mmol/h/L; P\0.0001) improved significantly with linagliptin versus placebo. Most adverse events were mild; hypoglycemia or serious adverse events were not reported. Sustained DPP-4 inhibition (C80%) throughout the treatment period was accompanied by significant reductions in glucagon starting at day 1 of linagliptin administration. Conclusion: Linagliptin was well tolerated and effectively inhibited plasma DPP-4 activity in patients with T2DM, producing immediate improvements in incretin levels, glucagon suppression, and glycemic control that were maintained throughout the study period. © The Author(s) 2012.