Post-cessation Weight Regain After Weight Management Medications: A Systematic Review and Meta-Analysis.

Approved weight management medications achieve clinically meaningful weight loss, yet post-cessation weight regain is the central barrier to sustained benefit. No prior synthesis has pooled regain estimates exclusively from longitudinal studies published since January 2020, the period in which incretin-based pharmacotherapy became the standard of care. PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from January 2020 to May 2026. Eligible designs included randomised controlled trials (RCTs) with a withdrawal phase, prospective cohort studies, and retrospective database analyses. Risk of bias was assessed with Cochrane RoB 2 for RCTs and the Newcastle-Ottawa Scale (NOS) for observational studies. A DerSimonian-Laird random-effects model was applied in R 4.3.3 (metafor 4.4.0). The primary outcome was mean percentage body weight regain from end-of-treatment to follow-up. Seventeen studies met all eligibility criteria: three RCTs, three prospective cohort studies, and 11 retrospective database analyses (N = 3,793 participants in cessation arms). Fifteen of 17 studies (88.2%) were rated high quality. Pooled mean weight regain was 7.20% (95% CI: 5.93-8.48; I² = 97.6%; Q[df = 16] = 676.74; p < 0.001). Subgroup analysis by drug class yielded: semaglutide 2.4 mg, 7.19% (k = 6; 95% CI: 6.42-7.96); liraglutide 3.0 mg, 4.83% (k = 4; 95% CI: 3.87-5.79); and tirzepatide, 13.04% (k = 3; 95% CI: 11.87-14.21). In three comparative RCTs, cessation arms gained a mean 14.26 percentage points more than continuation arms (95% CI: 8.86-19.65). Egger's test was not statistically significant (z = 1.91, p = 0.056), consistent with no systematic reporting bias. Stopping approved weight management medications consistently produces clinically significant weight regain across drug classes, study designs, and geographic regions. The magnitude of regain tracks initial efficacy and supports a long-term pharmacotherapy model analogous to chronic disease management. Future trials should pre-specify post-cessation follow-up as a mandatory outcome.