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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00856609.

Keywords: Energy expenditure; Energy intake; GLP-1 receptor agonists; Weight loss.

Conflict of interest statement

The authors declare no conflict of interest.

Published by Elsevier Inc.

Figures

Figure 1. Consort flow diagram

Figure 2. Study diagram of the clinical study

We divided the outline of the study in 2 portions (described in detail below): first inpatient stay (composed by inpatient admission prior to randomization and inpatient admission after randomization) and second (return) inpatient stay at week 24. Inpatient Admission prior to randomization: Day 1: Screening interview including screening labs and informed consent Day 3: DXA (dual energy X-ray absorptiometry) Day 4: OGTT (oral glucose tolerance test) Day 5: Whole room indirect calorimetry for the assessment of the 24h energy expenditure at baseline Day 6-7-8: Assessment of ad libitum food intake with vending machine paradigm at baseline Inpatient Admission after randomization: Day 9-10: Exenatide/Placebo injection education (subcutaneous) Day 11: Whole room indirect calorimetry for the assessment of the 24h energy expenditure during Exenatide/Placebo Day 12-13-14: Assessment of ad libitum food intake with vending machine paradigm during intervention period Day 15: Lifestyle recommendations After the first 2 weeks of inpatient visit, volunteers returned for weekly follow up visit up to 5 weeks, and then, for monthly follow up visits up to week 24 Return Inpatient Admission on week 24: Day 1: Screening interview including screening labs and informed consent Day 3: DXA (dual energy X-ray absorptiometry) Day 4: OGTT (oral glucose tolerance test) Day 5: Whole room indirect calorimetry for the assessment of the 24h energy expenditure at baseline Day 6-7-8: Assessment of ad libitum food intake with vending machine paradigm at baseline

Figure 3. Ad Libitum Food intake changes between pre and post-randomization in exenatide and placebo groups

A. Mean of 3-day food intake absolute change between pre and post-randomization, expressed in Kcal/day; B. Mean of 3-day food intake, expressed as the absolute change in percentage of their weight maintaining energy need (WMEN); C. Mean of 3-day food intake change relative to the weight maintaining energy need between pre and post-randomization, expressed in Kcal/day D. Mean of 3-day food intake, expressed as the change in percentage of their WMEN relative to the weight maintaining calories. The βs indicate the absolute values of the difference between pre and post-randomization changes in food intake between the exenatide and placebo groups. Error bars represent the mean with 95% confidence interval. Thirty-nine individuals in each group had complete vending machine data.

Figure 4. Energy expenditure and RQ changes between pre and post-randomization in exenatide and placebo groups

A Change in 24h-EE expressed as Kcal/day; B. Change in RQ; C. Change in AFT expressed as Kcal/day. D. Change in SMR expressed as Kcal/day. The β indicate the absolute values of the difference between pre and post randomization measurements between the exenatide and placebo groups. Error bars represent the mean with 95% confidence interval. Thirty-eight participants in the exenatide group and 32 in the placebo group had complete EE data.

Figure 5. Post-randomization EE measures as assessed in the whole-room indirect calorimeter over 24 hours in exenatide and placebo groups

The graph shows the average EE trajectories measured every minute. The β coefficient indicates the difference between the EE trajectories of exenatide and placebo groups by mixed model analysis adjusting for age, sex, FFM, FM, physical activity and accounting for repeated measures.

Figure 6

A. Change in body weight (kg) from baseline over 5 weeks. The baseline weight was the weight at the time of the DXA scan. The β is the absolute difference (Kg), between the body weight at the 5-week follow up visit and the baseline weight. B. Weight trajectory in the exenatide versus placebo groups over 5 weeks. Data represents the mean body weight at the time of the DXA scan, at the day of discharge and at each weekly follow up visit. The two fitted regression lines represent the weekly rate of weight change in the 2 groups. The β value represents the difference in the rates of body weight change between the 2 groups. Analyses used mixed models for repeated measures of change from baseline adjusted for baseline weight (as baseline comparator). C. Correlation between body weight change and total energy intake from baseline over 5 weeks. Correlation between the pre and post-randomization change in ad libitum food intake, expressed as mean Kcal/day versus weight change at 5 weeks. D. Correlation between FFM change and 24h EE change from baseline over 24 weeks. This panel shows the association between 24h-EE, expressed in Kcal/day, in the Exenatide-treated individuals (8) compared to placebo (16) over 24 weeks and change in fat free mass, expressed in Kg. The Δ value indicate the difference in reduction in 24h-EE change between the 2 groups.

1. In the panel A, the sample size (Exenatide=31, Placebo= 33) indicate the numbers of volunteers who have the weight measure at 5-week follow up visit. In the panel B, some values were not analyzed due to unavailability of some body weight measurements. In the panel C, the sample size (Exenatide =30, Placebo=33) shows participants having 5-week follow up weight and completed data of food intake. In the panel D, the sample size (Exenatide =8, Placebo=16) shows participants having 24-week follow up body composition measurements and completed data of chambers.

2. Error bars represent the mean with 95% confidence interval.