Rebound or Retention: A Meta-Analysis of Weight Regain After the Discontinuation of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists and Other Anti-obesity Drugs

Anti-obesity pharmacotherapies, such as glucagon-like peptide-1 (GLP-1) receptor agonists and orlistat, are effective for weight loss; however, weight regain following treatment discontinuation remains a major concern. This meta-analysis aimed to quantify the magnitude of weight regain after reaching peak weight loss, and to compare rebound effects across four commonly used agents: semaglutide, liraglutide, exenatide, and orlistat. A systematic search was conducted in PubMed (n = 498), Cochrane Library (n = 41), Scopus (n = 258), ScienceDirect (n = 248), and Web of Science (n = 158) from January 2010 to October 2024. After removing 153 duplicates, 950 records were screened. Following full-text assessment, 36 studies were included in the final analysis. Data extraction was performed using Excel (Microsoft® Corp., Redmond, WA, USA), and graphical data were digitized using WebPlotDigitizer. Risk of bias was assessed using RoB 2.0, and meta-analyses were conducted with Comprehensive Meta-Analysis (v3.7), using mean difference (MD) and 95% confidence intervals (CI). I² statistics were used to assess heterogeneity, and Egger's and Begg's tests were used to evaluate publication bias. Semaglutide showed the highest weight regain after discontinuation (MD = -5.15 kg; 95% CI: -5.27 to -5.03), followed by exenatide (MD = -3.06 kg; 95% CI: -3.91 to -2.22), liraglutide (MD = -1.50 kg; 95% CI: -2.41 to -0.26), and orlistat (MD = -1.66 kg; 95% CI: -2.75 to -0.58). Heterogeneity was moderate to high (I² ranging from 41.7% to 99.7%). Egger's test showed significant bias for liraglutide (p = 0.013), while no major bias was found for the other agents. This meta-analysis demonstrates that weight regain is common and drug-dependent following the discontinuation of anti-obesity pharmacotherapies. The findings emphasize the need for sustained, long-term treatment strategies to maintain weight loss and to manage obesity as a chronic disease.