Impact of semaglutide withdrawal on cardiometabolic profile and physiology of energy balance: Recovery effects after semaglutide termination – The REST trial study protocol

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide have been shown to induce substantial weight loss and improve cardiometabolic risk factors in patients living with obesity. However, most individuals regain weight after abrupt withdrawal of semaglutide, with reversal of its beneficial cardiometabolic effects. METHODS: We propose a randomized controlled trial to determine whether a gradual dose reduction of semaglutide prior to complete discontinuation is associated with differential changes in weight and cardiometabolic profile as compared to immediate treatment cessation. Individuals living with obesity without preexisting cardiovascular disease who are receiving semaglutide for weight management and have achieved prior weight reduction of at least 10% with no further weight loss over past 12 weeks will be randomized to either gradual dose reduction over 16 weeks or abrupt treatment discontinuation. The primary outcome will be the difference in body weight change (%) between the study groups. Secondary outcomes will include 24-hour ambulatory blood pressure and fasting ghrelin levels. DISCUSSION: We hypothesize that gradual reduction of semaglutide will be associated with less weight regain and cardiometabolic deterioration compared with immediate cessation. This study addresses an important real-world problem regarding treatment discontinuation strategies and may inform future approaches for long-term obesity management. TRIAL REGISTRATION: NCT07294950 (ClinicalTrials.gov).