Abstract / Summary
Background: Weight regain and loss of cardiometabolic benefit commonly follow the withdrawal of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists, yet maintenance strategies are incompletely characterized. Methods: We conducted a systematic review reported according to PRISMA 2020 of primary studies in adults with overweight or obesity, with or without type 2 diabetes. PubMed/MEDLINE, Europe PMC and ClinicalTrials.gov were searched from inception to September 2026, supplemented by backward/forward citation searching and cross-checking of recent systematic reviews. Eligible reports quantified weight or cardiometabolic outcomes at least 12 weeks after planned or unplanned treatment cessation, or tested a post-cessation maintenance strategy. Randomized reports were assessed with RoB 2 and non-randomized reports with ROBINS-I. Owing to incompatible estimands, follow-up schedules, cointerventions and overlapping trial families, results were synthesized narratively without a new pooled estimate. Results: Eighteen reports representing 16 study families were included. Randomized withdrawal trials showed renewed weight gain after treatment cessation: +6.9% over 48 weeks after switching from semaglutide to placebo in STEP 4, and +14.0% over 52 weeks after switching from tirzepatide to placebo in SURMOUNT-4. In the STEP 1 extension, participants regained 11.6 percentage points over one year, approximately two-thirds of their prior loss, while several cardiometabolic measures moved toward baseline. Real-world estimates were smaller and more variable because discontinuation was often inferred from prescriptions, follow-up weights were missing, and many patients restarted or switched therapy. Cardiometabolic rebound was associated with the degree of weight regain, but clinical cardiovascular events were not evaluated. Evidence for maintenance strategies was sparse: one randomized post-treatment study supported supervised exercise, with the exercise-plus-liraglutide group retaining an additional 5.1 kg of weight loss one year after both interventions ended compared with liraglutide alone; a small pilot supported sitagliptin plus metformin after liraglutide in polycystic ovary syndrome. No eligible controlled trial isolated a specific diet after cessation. Conclusions: Weight regain is frequent after stopping GLP-1-based therapy, although magnitude varies by drug, design, follow-up and subsequent treatment. Structured exercise may help reduce regain and preserve lean mass, but evidence for dietary, behavioral, tapering or pharmacologic transition strategies remains limited. Discontinuation should therefore be planned as part of chronic obesity care, with explicit monitoring and shared decision-making, rather than presented as a predictable short course.