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

ABSTRACT 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 µg, 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=1.9×10 -9 ) and accelerated the rate of glucose disappearance 2.4-fold (p=2×10 -10 ). Minimal model analysis demonstrated that exenatide increased glucose effectiveness (S g ) by 32% (p=0.0008) but did not significantly affect insulin sensitivity (S i ). 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 S g 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 agonists’ 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)