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

Abstract

Aim: Glucagon-like peptide-1 receptor agonists provide multiple benefits to patients with type 2 diabetes, including improved glycaemic 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, subcutaneously) or saline (0.2 ml, subcutaneously) 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 a crossover design in which participants received exenatide and saline in random order.Results: Exenatide increased first phase insulin secretion 1.9-fold (p = 1.9 Â 10 À9 ) and accelerated the rate of glucose disappearance 2.4-fold (p = 2 Â 10 À10 ). Minimal model analysis showed that exenatide increased glucose effectiveness (S g ) by 32% (p = .0008) but did not significantly affect insulin sensitivity (S i ). The exenatide-induced increase in insulin secretion made the largest contribution to interindividual variation in exenatide-induced acceleration of glucose disappearance while interindividual 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 a frequently sampled intravenous glucose tolerance test (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 the effects of glucagon-like peptide-1 receptor agonists on glucose metabolism: first phase insulin secretion, glucose disappearance rates and glucose effectiveness.

Acute pharmacodynamic responses to sitagliptin: Drug‐induced increase in early insulin secretion in oral glucose tolerance test

“…Data on pharmacodynamic effects of exenatide are based on data from the parent clinical trial with exenatide. 7 Correlation coefficients were calculated using software provided in Microsoft Excel. therapy with metformin may provide acceptable control in the course of the it is often necessary to add one or more drugs to restore acceptable metabolic control.…”

“…gov). 7 All procedures were reviewed and approved by the University of Maryland Baltimore Institutional Review Board.…”

“…This hypothesis is supported by the observation that individual values of the drug effect on insulin levels were correlated with individual values of the drug effect on GLP1 levels (r = 0.29, p = 0.04) (Figure 5). As this clinical trial was a sub-study within our pilot clinical trial of pharmacodynamic responses to exenatide, 7 we inquired whether responses to sitagliptin were correlated with responses to exenatide. Forty-five participants completed both frequently sampled intravenous glucose tolerance tests in our exenatide clinical trial and OGTTs in our sitagliptin clinical trial.…”

Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test

“…To date, ~10,000 Amish adults participated in one or more studies as part of the Amish Complex Disease Research Program (http://www.medschool.umaryland.edu/endocrinology/Amish-Research-Program/). The present study was a sub-study of a pilot study in healthy volunteers in which we investigated pharmacodynamic responses to exenatide 6 . A research nurse, accompanied by a member of the Amish community, made home visits to invite individuals to participate in the study.…”

“…As this clinical trial was a sub-study within our pilot clinical trial of pharmacodynamic responses to exenatide 6 , we inquired whether responses to sitagliptin were correlated with responses to exenatide. Forty-five participants underwent both frequently sampled intravenous glucose tolerance tests in our exenatide clinical trial and oral glucose tolerance tests in our sitagliptin clinical trial.…”