Abstract
BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as breakthrough agents for weight loss. However, discontinuation is common, and clinical trials have demonstrated significant weight regain following cessation. In this systematic review, we aimed to characterise the trajectory of weight regain after GLP-1RA cessation. METHODS: This systematic review and meta-regression analysis followed Cochrane and PRISMA guidelines. We searched MEDLINE, Embase, Cochrane Library, Scopus and Web of Science from inception to August 28, 2025 for randomised controlled trials (RCTs), non-randomised interventional studies and observational studies reporting weight outcomes after cessation of GLP-1RAs in adults with overweight or obesity. Weight regain was the primary outcome and was modelled using nonlinear regression. Secondary, exploratory outcomes included HbA1c and systolic blood pressure. The study protocol is registered with PROSPERO (CRD420250631751). FINDINGS: A total of 48 relevant studies were included. Weight consistently rebounded after cessation of GLP-1RAs. Six RCTs with 3236 participants were included in the nonlinear meta-regression, which utilised a mixed-effect exponential recovery model with random effects applied to the rate constant. At 1 year post-cessation, 60% of the weight lost during treatment was regained. Beyond 52 weeks, weight trajectories were extrapolated, with weight regain estimated to plateau at 75.3% (95% CI 68.9-81.6) of the weight lost on treatment. The rate constant was 0.0302 per week (95% CI 0.0202-0.0401), corresponding to a half-life of 23.0 weeks (95% CI 17.3-34.3). Most studies were assessed to have a moderate risk of bias. INTERPRETATION: GLP-1RA cessation is associated with a predictable and decelerating pattern of weight regain, which appears to plateau below pre-treatment levels, suggesting that partial weight-loss benefit may persist long-term but is substantially attenuated. FUNDING: None.