Linagliptin Increases Incretin Levels, Lowers Glucagon, and Improves Glycemic Control in Type 2 Diabetes Mellitus

• Published in: Diabetes therapy Vol. 3; no. 1; p. 10
• Main Authors: Rauch, Thomas, Graefe-Mody, Ulrike, Deacon, Carolyn F., Ring, Arne, Holst, Jens J., Woerle, Hans-Juergen, Dugi, Klaus A., Heise, Tim
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Healthcare Communications 01.12.2012
• Subjects: Cardiology; Diabetes; Endocrinology; Internal Medicine; Medicine; Medicine & Public Health; Original Research; Glycemic control; Dipeptidyl peptidase-4 inhibitors; Glucagon-like peptide-1; Linagliptin; Type 2 diabetes mellitus; Glucagon
• ISSN: 1869-6953; 1869-6961
• DOI: 10.1007/s13300-012-0010-y

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 5 mg ( n  = 40). Sitagliptin 100 mg ( n  = 41) once daily for 4 weeks was included for exploratory purposes. Primary endpoints for linagliptin versus 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 (AUEC 0–2h ) following meal tolerance test on day 28. Results Linagliptin increased intact GLP-1 AUEC 0–2h (+18.1 pmol/h/L) and lowered 24-h WMG (−1.1 mmol/L) versus placebo (both P  < 0.0001) after 28 days. Intact glucose-dependent 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 (AUEC 0–3h ) (−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 (≥80%) 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.