Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects

Abstract

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥ 30 kg m(-2) and binge eating scale scores ≥ 19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day(-1) GSK1521498, 5 mg day(-1) GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day(-1) caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day(-1) on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation.

Figure 1

Schematic representation of the study schedule.

Figure 2

Primary and secondary endpoints: the top panel shows the measures on the primary end points of weight, fat mass and binge-eating scale scores. The change in overall hedonic response to sweetened dairy products and the buffet intake are depicted in the middle panel. The bottom panel shows hedonic responses to high-fat and high-sugar concentrations and intake of the high-fat desserts.

Figure 3

Pharmacogenetic analyses: three subjects in the GSK1521498 5 mg day⁻¹ group with one or more copies of the 118 G allele (AG) were compared with A118 homozygotes (AA, N=12). The left panel depicts the mean weight change over the treatment period and the right panel displays the individual weight plots for all 15 Caucasian subjects. It can be seen that greatest weight change is seen in two of the G-carriers (AG). ***P<0.001.

Figure 4

Changes in Visual Analogue Scale measures of alertness, calmness and contentedness in the placebo and GSK1521498 groups over the study duration. *P<0.05.