Structured Exercise During and After Incretin-Based Pharmacotherapy Discontinuation: A Narrative Review of Mechanisms, Evidence, and Prescription Guidance

Background/Objectives: Incretin-based pharmacotherapies are the most effective non-surgical treatments for obesity to date, yet 85% of patients discontinue within the second year of real-world use. No established framework exists for managing this post-cessation transition. This narrative review evaluates the evidence for structured exercise to mitigate physiological rebound and support long-term weight management following discontinuation. Methods: A narrative review was conducted per Assessment of Narrative Review Articles (SANRA) guidelines using PubMed, Scopus, and Web of Science from January 2005 through to June 2026. Results: Post-cessation weight regain averages 5.6 kg within one year and is observationally associated with dose-dependent cardiometabolic worsening. Lean mass losses averaging 6–7 kg and reductions in bone mineral density are seen during active treatment, creating a metabolically unfavorable state at cessation compounded by fat-preferential regain. Exercise and pharmacotherapy generate fundamentally different body composition outcomes. Exercise preserves lean mass, bone density, cardiorespiratory fitness, and insulin sensitivity, while pharmacotherapy alone does not, with downstream implications for resting metabolic rate and post-cessation rebound. Controlled trial data show exercise initiated during incretin treatment is associated with significantly less weight regain, greater sustained weight loss, and maintained physical activity levels one year after medication and supervised program end. This evidence derives from a single liraglutide-based trial and may not generalize directly to semaglutide, tirzepatide, or next-generation agents. Real-world data associate exercise counseling with durable weight loss after discontinuation. Conclusions: No randomized controlled trial has directly evaluated exercise at pharmacotherapy cessation; conclusions are based on post-treatment extension, real-world observational, and mechanistic evidence. Combined aerobic and resistance training is a biologically plausible, low-risk adjunct to incretin-based pharmacotherapies. Resistance training, adequate dietary protein, and individualized clinical screening are likely important components pending direct evidence from post-cessation trials.