Glucagon-like peptide-1 receptor agonists and newer dual- and triple-incretin receptor agonists have transformed obesity treatment by producing substantial and sustained weight loss. However, reported reductions in lean body mass have raised concerns about potential skeletal muscle loss and sarcopenia, particularly in older adults and individuals with limited muscle reserves. This review examines the cellular and tissue-level mechanisms that may contribute to lean mass changes during GLP-1-based therapy and evaluates strategies for preserving skeletal muscle. Reductions in fat-free or lean body mass should not be interpreted as equivalent to loss of contractile skeletal muscle, as these compartments also include body water, organs, connective tissue, and the fat-free component of adipose tissue. Incretin-based therapies predominantly reduce fat mass, while preclinical studies and limited human evidence suggest possible improvements in skeletal muscle quality through enhanced insulin sensitivity, reduced myosteatosis and inflammation, and favourable mitochondrial adaptations. Nevertheless, the proportion of lean mass reduction attributable to true skeletal muscle loss and its long-term functional significance remain uncertain. Rapid weight loss and inadequate nutrient intake may increase the risk of clinically relevant muscle loss in susceptible populations. Individualized protein intake, progressive resistance exercise, management of gastrointestinal adverse effects, and functional monitoring therefore represent the reasonable strategies for skeletal muscle preservation. Emerging anabolic combination therapies remain investigational and should be evaluated using strength and physical performance outcomes in addition to body composition. Accordingly, this review explores the potential mechanisms underlying skeletal muscle changes during GLP-1-based therapy and discusses strategies to support muscle preservation during therapy-induced weight loss. Ultimately, the success of GLP-1-based therapy should be defined not only by the magnitude of weight loss, but also by the extent of that weight loss and the preservation of skeletal muscle mass and function.
