Exenatide has a Pronounced Effect on Energy Intake but not Energy Expenditure in Non-Diabetic Subjects with Obesity: A Randomized, Double-blind, Placebo-Controlled Trial

Aims Exenatide is a glucagon-like peptide 1 (GLP-1) mimetic which induces weight loss predominantly, it is presumed, via decreased food intake. However, circulating GLP-1 is also a determinant of energy expenditure. We sought to quantify the effect of exenatide on energy expenditure (EE) and energy intake. Materials and Methods In this single-center, randomized double-blind placebo controlled trial, we randomized 80 healthy, non-diabetic volunteers with obesity (46 women, age: 34.4 ± 8.7 y, body fat by DXA: 44.2 ± 7.8%) to subcutaneous exenatide 10 μg twice daily or placebo. Subjects were admitted to our clinical research unit for measurement of 24 h-EE in a whole-room indirect calorimeter and ad libitum food intake using an automated vending machine paradigm before and after randomization. Furthermore, energy expenditure and ad libitum food intake measures were repeated at 24-week after readmission for 7-day inpatient stay. Body weight was obtained weekly for up to 5 weeks and was recorded at each monthly follow up visit up to 24 weeks. Results Prior to randomization, participants over ate during the 3-day vending machine period in the whole study group (114.6 ± 35.2%), expressed as percentage of weight maintaining energy needs (WMEN) with those who were eventually randomized to exenatide overeating more (121.6 ± 37.7%) compared to placebo group (107.6 ± 31.5%). In the exenatide group, ad libitum absolute energy intake decreased by 1016.1 ± 724.5 kcal/day (95% CI: −1250.9 to −781.2) versus a 245.1 ± 710.5 kcal/day (95% CI: −475.4 to −14.7) decrease in placebo (Δ = −624.8 Kcal/day, p < 0.0001) whereas the reduction in ad libitum caloric intake relative to WMEN was a more modest 366.8 ± 752.1 kcal/day (95% CI: −614.0 to −119.6) decrease compared to 8.0 ± 860.1 kcal/day (95% CI: −286.8 to 270.8) reduction in placebo (Δ = −382.3 Kcal/day, p = 0.03). The decrease was uniform across all macronutrients groups. No differences in 24hEE or substrate oxidation rates were found. In the exenatide group, body weight decreased more over the 5 weeks (β = −0.039 kg/week, p = 0.02) and was lower compared to placebo at the end of fifth week (−1.48 ± 0.77 kg; 95% CI: −3.02 to 0.05, p = 0.06). At the 24-week follow up, there was no difference in energy intake between exenatide group and placebo group and the treatment group decreased 24-h EE more compared to placebo (β = −160.6 Kcal/day, 95% CI: −307.6 to 13.6, p = 0.03) compared to their pre-randomization measurement. However, this reduction was not present after adjustment for changes in FM and FFM (β = −87 kcal/day, p = 0.14). No difference was observed in body weight (Δ = −1.72 kg, 95% CI: −5.77 to 2.30, p = 0.39) in exenatide versus placebo over 24 weeks. Conclusion Compared with placebo, exenatide decreased early ad libitum energy intake but did not change 24 h-EE. However, the reduction was more modest in relative versus absolute terms (i.e. below that needed for WMEN). Thus, although rate of weight change was greater in the exenatide treated subjects at 5 weeks, the absolute difference in weight was not significant. These findings indicate that although exenatide reduces food intake, it may be more beneficial in blunting overeating and thus may serve to more prevent weight regain following initial weight loss