Dipeptidyl Peptidase-4 Inhibitors Administered in Combination With Metformin Result in an Additive Increase in the Plasma Concentration of Active GLP-1

Abstract

The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon-like peptide 1 (GLP-1) (9-36) and glucagon. In healthy subjects, a DPP-4 inhibitor elevated both active GLP-1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP-1 (but not GIP), and the combination resulted in additive increases in active GLP-1 plasma concentrations. Metformin did not inhibit plasma DPP-4 activity either in vitro or in vivo. The study results show that metformin is not a DPP-4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP-1 concentrations. DPP-4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP-1 in plasma.

The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies

“…Interestingly, the increase in plasma GLP-1 levels resulting from metformin administration is similar to that of a DPP-4i (20) and thus could explain much of the glucoselowering effect of metformin. In addition, unlike a DPP-4i that reduces GLP-1 degradation, metformin increases GLP-1 secretion and thus can significantly increase concentrations local to the L cell, which may in turn enhance neural signaling in the gut and portal vein to rapidly regulate glycemic control (28)(29)(30).…”

“…However, metformin also accumulates in the intestine at concentrations 300 times greater than in plasma (12). Thus, the gut is a major reservoir for metformin exposure and is potentially responsible for much of its glucose-lowering effects, including enhanced secretion of GLP-1 and peptide YY, which in turn affects systemic mechanisms including reducing hepatic glucose production through glucagon suppression and enhanced glucose-dependent insulin secretion (15,(20)(21)(22)(23).…”

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

“…Certainly, the addition of a DPP-4 inhibitor to metformin therapy can boost GLP-1 levels much higher than the addition of a sulfonylurea [26]. Clinical studies have also indicated that metformin alone can increase GLP-1 levels, via a mechanism distinct from DPP-4 inhibition, and that combination therapy has a complementary effect on GLP-1 concentrations [27]. These findings suggest that a mechanism similar to that observed in mice [10] is at work in humans and that combining metformin with DPP-4 inhibitors appears to be a rational way of enhancing GLP-1 signalling in pancreatic beta cells.…”

Effects of Sitagliptin on Glycemia, Incretin Hormones, and Antropyloroduodenal Motility in Response to Intraduodenal Glucose Infusion in Healthy Lean and Obese Humans and Patients With Type 2 Diabetes Treated With or Without Metformin

“…Metformin augments GLP-1 concentrations by uncertain means (25,26) and in mice, can increase expression of GLP-1 and GIP receptors in pancreatic islets (25). Although plasma DPP-4 activity is reportedly reduced in type 2 diabetic patients treated with metformin (27), in vitro studies have failed to show any direct effect of metformin on the catalytic activity of DPP-4 (27,28).…”

“…Although plasma DPP-4 activity is reportedly reduced in type 2 diabetic patients treated with metformin (27), in vitro studies have failed to show any direct effect of metformin on the catalytic activity of DPP-4 (27,28). Regardless, coadministration of metformin and sitagliptin results in an additive increase in plasma intact GLP-1 concentrations and improvement in postprandial glycemia in both healthy individuals and type 2 diabetic patients (26,29).…”