Obesity is a chronic condition associated with substantial cardiometabolic morbidity and mortality. Incretin-based anti-obesity therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, have transformed obesity management by producing clinically meaningful weight loss and improvements in glycemic and cardiometabolic risk profiles. However, weight loss achieved with these agents includes reductions in lean tissue in many studies, and the clinical significance of these body-composition changes remains incompletely defined. Importantly, reductions in DXA-derived lean mass should not be assumed to represent impaired muscle quality, strength, or function, as no published clinical trial has demonstrated that incretin-based therapy impairs muscle function. Metabolic rehabilitation encompasses structured exercise training, nutrition optimization, and behavioral support that have independently demonstrated benefits in preserving lean mass, improving insulin sensitivity, and enhancing cardiopulmonary fitness. Emerging evidence suggests that combining incretin-based therapy with metabolic rehabilitation may provide additive and complementary benefits, promote sustainable fat loss, while mitigating adverse metabolic adaptations. Metabolic rehabilitation also addresses skeletal muscle quality, bone health, and functional capacity, domains not directly targeted by pharmacologic appetite suppression. This narrative review synthesizes current evidence on the physiological effects of incretin-based obesity pharmacotherapy and metabolic rehabilitation, explores the mechanistic rationale for their combined use, reviews available clinical data, and proposes a practical framework for integrated obesity care. Key knowledge gaps and future research priorities are highlighted.
