On Combination Therapy of Diabetes With Metformin and Dipeptidyl Peptidase IV Inhibitors

Recently, data were presented showing that metformin increased plasma active glucagon-like peptide (GLP)-1_[7–36NH2] concentrations in obese nondiabetic male patients (1), and it was suggested that metformin was a direct dipeptidyl peptidase (DP) IV inhibitor. Contradiction of this hypothesis is simply found by examining the modes of action of metformin and of the DP IV inhibitors. Although the specific molecular target of metformin is still unknown, biguanides generally act to sensitize peripheral tissues to insulin action (particularly, skeletal muscle) and inhibit hepatic gluconeogenesis and glycogenolysis (2,3,4). In contrast, DP IV inhibitors act to enhance the insulin response to a meal, via preservation of intact bioactive incretins, GLP-1_[7–36NH2] and GIP_[1–42OH] (5,6,7,8,9,10). Notably, metformin does not improve glucose tolerance via an increase in circulating insulin levels, implicating different antidiabetic mechanisms for metformin and DP IV inhibitors.

Unfortunately, Mannucci et al. (1) did not measure total GLP-1 (GLP-1_[7–36NH2] + GLP-1_[9–36NH2]) levels in their study. An increase NH₂-terminal intact GLP-1 was interpreted as indicating protection from degradation by DP IV, and the possibility of an increase in total GLP-1 levels, yielding a proportional rise in intact GLP-1 concentrations, was not considered. This possibility is consistent with prior studies examining glucagon and GLP-1 levels after metformin treatment (11,12,13). A simplistic interpretation of these findings would be that metformin either enhances the glucose sensitivity of the islet α-cell and enteroendocrine l-cell, the secretory rate of these cells, or increases transcription/translation of the proglucagon gene, resulting in greater hormone release with metformin treatment. Regardless, we initiated a series of in vitro biochemical studies to test the hypothesis of Mannucci et al., but were unable to duplicate their earlier work or support this hypothesis by other means (13).

Traditional treatment of type 2 diabetes begins with diet control and oral monotherapy (metformin, sulfonylureas, acarbose, or certain glitazones), and as the disease progresses, combinatorial treatment follows, until finally insulin injections are required to achieve glycemic control (3). Considering the different modes of action of DP IV inhibitors (enhancing the postprandial insulin response due to active incretin preservation) and metformin or glitazones (sensitizing peripheral tissue to insulin), we predict that type 2 diabetic patients receiving combinatorial treatment of these therapies will produce an even greater (additive) antidiabetic effect. However, because both DP IV inhibitors and sulfonylureas enhance insulin release, the potential of combination therapy with these agents is doubtful. A corollary to our hypothesis was recently published by Zander et al. (14), who found that subcutaneous infusion of GLP-1 had an additive antidiabetic effect when given in combination with metformin; it was also commented that data were inconsistent with the findings of Mannucci et al. Direct testing using laboratory models of type 2 diabetes and clinical trials will ultimately confirm or refute our prediction on combination therapies.