Short- and long-term effects of semaglutide 2.4 mg on energy intake, appetite, and food reward: a 60-week, double-blind randomized controlled trial.

BACKGROUND: Studies of ≤20 wk have demonstrated reductions in energy intake, appetite, and food reward with semaglutide that may drive initial weight loss. These brief studies could not assess whether semaglutide has long-term effects on eating that support the maintenance of lost weight. OBJECTIVES: The goal of the present study was to compare short- and long-term energy intake, appetite, and food reward with semaglutide 2.4 mg to placebo. METHODS: This 60-wk, double-blind trial randomly assigned 120 adults with overweight/obesity in a 3:2 ratio to semaglutide 2.4 mg or placebo. In laboratory assessments at weeks 0, 20, 40, and 60, participants rated their appetite when fasting and for 4 h after a standardized breakfast. Energy intake was measured during an ad libitum lunch. Measures of food reward included the Power of Food Scale. Missing data were estimated using jump-to-reference multiple imputation, and analyses of covariance compared the groups in change at each assessment, controlling for baseline. RESULTS: The semaglutide group had significantly larger reductions from baseline in ad libitum energy intake relative to placebo at weeks 20, 40, and 60, consuming a mean ± standard error of 291.9 ± 64.4, 240.2 ± 87.8, and 269.5 ± 83.6 kcal less, respectively. At week 20, semaglutide-treated participants had significantly greater increases from baseline in appetite suppression after the standardized breakfast [mean difference (MD) = 2197 ± 823] and greater reductions in past-week hunger (MD = -17.4 ± 4.8) and food preoccupation (MD = -14.9 ± 4.5). However, the groups did not differ significantly in appetite outcomes at weeks 40 or 60. The semaglutide group had greater reductions in responsiveness to the rewarding value of food at weeks 20 and 40 (MD = -0.4 ± 0.2 and -0.6 ± 0.2, respectively). CONCLUSIONS: Semaglutide 2.4 mg continues to help participants consume fewer calories at 20, 40, and 60 wk of treatment, even though some subjective benefits decline. These findings suggest that reduced energy intake is a central mechanism by which semaglutide both induces and maintains weight loss. This study is registered at clinicaltrials.gov as NCT05548647.