Background: Incretin-based therapies (IBTs), including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (GIP/GLP-1 RAs), have transformed the management of obesity and type 2 diabetes mellitus (T2DM). Although these agents provide substantial metabolic and cardiometabolic benefits, their effects on skeletal muscle, particularly in older adults at increased risk of sarcopenia and functional decline, remain incompletely understood. Methods: This narrative review synthesizes evidence from randomized controlled trials (RCTs) and observational studies evaluating the effects of semaglutide and tirzepatide on skeletal muscle mass (SMM), muscle quality, strength, and physical performance. Current evidence on nutritional and exercise strategies aimed at preserving skeletal muscle during IBT was also reviewed. Results: Both semaglutide and tirzepatide induce substantial weight loss accompanied by reductions in lean body mass (LBM). However, current evidence indicates that LBM loss is generally proportional to the magnitude of weight loss and should not be interpreted as a direct surrogate for skeletal muscle loss or drug-induced myotoxicity. Tirzepatide appears to improve skeletal muscle composition by reducing muscle fat infiltration (MFI), whereas semaglutide shows more heterogeneous effects on muscle strength and physical performance, particularly in older or frail individuals. Emerging evidence highlights the importance of muscle quality, nutritional adequacy, and resistance exercise as key determinants of muscle preservation, although functional outcomes and data in older adults remain limited. Conclusions: The effects of incretin-based therapies (IBTs) on skeletal muscle are multifactorial and influenced by age, baseline muscle reserve, nutritional status, and physical activity. Preserving skeletal muscle health should be considered an integral component of obesity management through individualized nutritional care, adequate protein intake, resistance exercise, and regular functional assessment. Future research should prioritize the standardized evaluation of muscle quality and function and determine whether targeted nutritional interventions can improve the quality of weight loss and support healthy aging during IBT.
