Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness

Background: GLP1R agonists provide multiple benefits to patients with type 2 diabetes, including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Methods: Exenatide (5 mcg, sc) or saline (0.2 mL, sc) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was designed as a crossover study in which participants received exenatide and saline in random order. Results: Exenatide increased first phase insulin secretion 1.9-fold (p=1.9x10-9) and accelerated the rate of glucose disappearance 2.4-fold (p=2x10-10). Minimal model analysis demonstrated that exenatide increased glucose effectiveness (Sg) by 32% (p=0.0008) but did not significantly affect insulin sensitivity (Si). The exenatide-induced increase in insulin secretion made the largest contribution to inter-individual variation in exenatide-induced acceleration of glucose disappearance while inter-individual variation in the drug effect on Sg contributed to a lesser extent (β=0.58 or 0.27, respectively). Conclusions: This pilot study provides validation for the value of an FSIGT (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide (NCT05071898). Three endpoints provide quantitative assessments of GLP1R agonist effects on glucose metabolism: first phase insulin secretion, glucose disappearance rates, and glucose effectiveness. Registration:NCT02462421(clinicaltrials.gov) Funding: American Diabetes Association (1-16-ICTS-112); National Institute of Diabetes and Digestive and Kidney Disease (R01DK130238, T32DK098107, P30DK072488)