Obesity is a chronic disease associated with increased cardiometabolic risk. In clinical trials, glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide produce substantial weight loss and improvements in blood pressure, glucose metabolism, inflammatory markers and lipids. However, abrupt discontinuation of semaglutide is commonly followed by substantial weight regain and reversal of cardiometabolic benefits, with published reports showing approximately two-thirds of lost weight regained within one year. Compensatory physiologic responses to weight loss — including increased appetite and reduced energy expenditure — are likely contributors to this rebound. There is limited clinical evidence to guide strategies for preserving weight and cardiometabolic improvements after stopping GLP-1 receptor agonist therapy. The REST trial was developed to test whether a gradual dose reduction of semaglutide before complete discontinuation attenuates weight regain and cardiometabolic deterioration compared with immediate cessation.
The primary objective is to evaluate whether a gradual dose reduction of semaglutide prior to complete discontinuation results in a different change in body weight (percent change) compared with immediate treatment cessation. Secondary objectives include assessing changes in 24-hour ambulatory blood pressure and fasting levels of the orexigenic hormone ghrelin, among other cardiometabolic and behavioral measures. The investigators hypothesize that gradual tapering will be associated with less weight regain and less cardiometabolic deterioration than abrupt stopping.
REST is an open-label, parallel-arm, randomized controlled trial. The total protocol duration for each participant is 32 weeks, which incorporates a 16-week discontinuation phase followed by a post-discontinuation follow-up period. Participants attend in-person study visits at baseline, week 16 and week 32, with interim telephone assessments planned. Figures in the protocol illustrate the participant timeline and schematic study design.
Inclusion criteria include men and women aged 18–75 years who have obesity (or are overweight with adiposity-related complications), are receiving weekly subcutaneous semaglutide at a minimum dose of 1 mg, and have achieved at least a 10% reduction in body weight from pre-treatment levels with stable weight over the preceding 12 weeks. Key exclusion criteria are preexisting cardiovascular disease, type 2 diabetes, pregnancy, prior bariatric surgery, active eating disorders, and significant renal, hepatic or malignant disease. The full inclusion and exclusion criteria are provided in the protocol’s table of eligibility.
Participants are randomized 1:1 using a random number generator to one of two semaglutide discontinuation strategies:
All participants receive standardized lifestyle counseling including recommendations for physical activity, portion control and self-monitoring of weight.
Study visits occur at baseline, 16 weeks (end of discontinuation phase) and 32 weeks (post-discontinuation follow-up). Between visits, participants receive interim phone assessments. At each in-person visit, investigators perform anthropometry, collect fasting blood for laboratory analyses, administer questionnaires assessing eating behavior and appetite control, and conduct 24-hour ambulatory blood pressure monitoring (ABPM).
The primary outcome is the between-group difference in percent change in body weight. Secondary and exploratory outcomes include:
The ABPM uses oscillometric devices with daytime readings every 30 minutes and nighttime readings every 60 minutes on an ordinary workday while participants maintain usual activities.
A standardized post-prandial meal test is performed after an overnight fast. Participants consume a commercially available shake (~500–600 kcal; ~51% carbohydrate, 33% fat, 16% protein) and blood is sampled at fasting and at 30, 60, 90, 120 and 150 minutes to characterize post-prandial hormone responses relevant to appetite regulation. Frozen, de-identified samples will be stored at −80°C in the Principal Investigator’s laboratory for future measurement of satiety hormones and for emerging biomarker, proteomic and metabolomic analyses relevant to the research questions. The protocol states that in the event of participant consent withdrawal, stored samples will be disposed according to standards.
The study protocol reports funding from the Heart and Stroke Foundation of Canada; the funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. The article indicates no datasets were generated or analyzed for the protocol paper and that data will be made available upon study completion. Trial registration is listed as NCT07294950. The protocol lists procedural safeguards for sample de-identification and storage; details on statistical power calculations, specific sample size, and the statistical analysis plan were not reported in the protocol paper.