Combining Incretin-Based Therapies With Insulin

Abstract

### What is the rationale for adding incretin-based therapies to insulin? The combination of the incretin-based therapies, i.e., the dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists (GLP-1RAs), with basal insulin has, in theory, logical appeal. While basal insulin primarily improves fasting plasma glucose (FPG) control, the glucose-dependent effect of incretins will additionally benefit postprandial plasma glucose (PPG) control. This should enable improved control of A1C with the expectation of relatively stable blood glucose concentrations, and the combination of incretins with basal insulin might reduce insulin dose requirement and, consequently, weight gain. This also supports the concept that combining the incretin-based therapies with basal insulin should enable tight glycemic control with a low risk of hypoglycemia. Furthermore, a reciprocal benefit of this combination is that the basal insulin will theoretically supplement endogenous insulin production and “rest” the β-cell, enabling greater recovery of the endogenous insulin response when required. The basis of this theory is formed from research showing benefits with incretin therapies for β-cell function (1) and β-cell mass in experimental systems (2–4). In addition to their antihyperglycemic properties, GLP-1RAs also reduce gastrointestinal motility, which, together with increased satiety, produces a weight-sparing effect (2). This quality could mitigate the weight gain associated with insulin therapy and might be further enhanced through any reductions in insulin dose. ### Evidence to date: how do the data from insulin plus incretin clinical studies meet with expectations? #### Glycemic control. Using basal insulin to reduce FPG is an effective way of improving glycemic control; however, the second component of glycemic control, PPG, requires additional consideration. This is one area where incretin-based therapies and basal insulin should have complementary actions. ##### Adding incretin-based therapies to insulin. In an uncontrolled, retrospective investigation involving a cohort of 188 patients receiving insulin, the addition of exenatide produced an A1C reduction of –0.66% ( P < 0.001) from a baseline value of 8.05% after 6 months of combination therapy—an improvement that was maintained at 27 months (5). Moreover, the patients in this …