Exenatide in obesity with accelerated gastric emptying: a randomized, pharmacodynamics study

Abstract

Obesity is associated with differences in satiety, gastric emptying (GE), gastric volume, and psychological traits. Exenatide, a short-acting glucagon-like peptide 1 (GLP-1) receptor agonist, is associated with variable weight loss. We compared the effects of exenatide, 5 μg, and placebo SQ, twice daily for 30 days on GE of solids and liquids (scintigraphy), satiety (ad libitum buffet meal), satiation (nutrient drink test, maximum tolerated volume [MTV]), and weight loss in 20 participants with documented accelerated GE of solids (T1/2 < 90 min). Exenatide delayed GE of solids (T1/2 [Δ] 86 min relative to placebo, P < 0.001) and reduced calorie intake at buffet meal ([Δ] 129 kcal compared to placebo). Median weight loss was −0.95 kg (IQR −0.7 to −2.1) for exenatide and −0.55 kg (0.3 to −2.1) for placebo (P = 0.23); 80% of exenatide group had documented reduction in weight. In the exenatide treatment group, there was an inverse correlation between gastric emptying T1/2 and MTV (R = −0.548, P = 0.089). The univariate association of weight change with posttreatment MTV was borderline (Rs = 0.43, P = 0.06); in the multiple regression model, posttreatment MTV was associated with weight change (P = 0.047). The effect of the short-acting GLP-1 receptor agonist, exenatide, on GE is associated with the change in food intake, and the latter impacts weight loss in response to exenatide treatment.

Allelic variant in the glucagon‐like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: A pilot pharmacogenetics study

“…In the exenatide group, we had preselected participants with accelerated GE (GE T 1/2 82.4 ± 5.1 minutes). The effects of these GLP‐1 agents are published elsewhere . There was a significant correlation between the change in weight and GE at 30 days or 5 weeks ( r s = −.382, P = .004; Figure ).…”

“…We evaluated the genetic variations of GLP1R and TCF7L2 from two different published studies involving single‐center, double‐blinded, placebo‐controlled, randomized clinical trials: the first (ClinicalTrials.gov #NCT02160990) utilized exenatide, 5 μg BID administered for 30 days, in 20 obese individuals with rapid GE of solids (GE T 1/2 <90 minutes), and the second (ClinicalTrials.gov #NCT02647944) studied liraglutide, 3 mg/day, administered over 16 weeks in 40 obese individuals with normal or accelerated GE of solids . Further details of these trials are provided in the relevant publications and in Figures A and B.…”

“…Both studies utilized the same 296 kcal test meal and scintigraphic method to measure GE. Details are available elsewhere …”

“…In a randomized, placebo‐controlled trial of liraglutide, 3.0 mg daily, in obese individuals, we recently reported that liraglutide delayed GE, and this was associated with weight loss with liraglutide over a 16‐week treatment period . Similarly, in a prior randomized, placebo‐controlled trial of exenatide, 5 μg BID for 30 days, obese participants developed significant delay in GE, with non‐significant higher weight loss with exenatide than placebo ( P = .23) . Studies with liraglutide have shown that ~15% of patients lose >15% of body weight, and this is maintained over 1 or 3 years .…”

A working paradigm for the treatment of obesity in gastrointestinal practice

“…Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue (34). Weight loss is mediated by reduced energy intake by reducing appetite, increasing satiety and delaying gastric emptying (40,41). Liraglutide is administered as a subcutaneous injection once daily.…”