Trajectory of weight regain after cessation of GLP-1 receptor agonists: a systematic review and nonlinear meta-regression

BackgroundGlucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as breakthrough weight loss agents. 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. MethodsThis 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 December 26, 2024 for randomised controlled trials 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 outcomes included HbA1c and systolic blood pressure. The study protocol is registered with PROSPERO (CRD420250631751). FindingsWe identified 44 relevant studies. Weight, HbA1c and systolic blood pressure consistently rebounded after cessation of GLP-1RAs. Six trials with 3,236 participants were included in the exponential recovery model. Weight regain was estimated to plateau at 75.6% (95% CI 68.5-82.7) of the weight lost on treatment. The rate constant was 0.0302 per week (95% CI 0.0204-0.0399), corresponding to a half-life of 23.0 weeks. At 1 year after cessation, an estimated 40.2% of the on-treatment weight loss remained. Most studies were assessed to have moderate risk of bias. InterpretationGLP-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. FundingNone.