GLP-1 receptor agonists (GLP-1RAs), dual GLP-1/GIP agonists, and the more recent triple GLP-1/GIP/glucagon agonists have transformed the treatment of type 2 diabetes mellitus (T2DM) and obesity, resulting in significant weight reduction. However, a substantial proportion (20-40%) of this weight loss is attributable to a decrease in lean mass, thereby raising concerns regarding potential sarcopenia-related risk. However, decreased lean mass is not sufficient to determine sarcopenia, which is now defined by the combined presence of decreased muscle mass, diminished strength, and impaired physical function, particularly in older or frail individuals. Thus, a further clarification of the potential mechanisms through which these molecules affect skeletal muscle is needed to optimize their use. The objective of this study is to synthesize preclinical, metabolomic, and clinical evidence on the effects of GLP-1RAs and dual/triple agonists on skeletal muscle, with a specific comparison between semaglutide and tirzepatide. This narrative review was based on a comprehensive literature search of PubMed/MEDLINE, Scopus, and Google Scholar, encompassing articles published through June 2026. This search was supplemented by manual citation tracking, which identified additional studies including preclinical and metabolomic investigations, randomized controlled trials, observational studies, and meta-analyses. Preclinical data suggest that GLP-1R/GIPR activation can positively modulate anabolic pathways, mitochondrial biogenesis, and muscle inflammation. Metabolomic evidence reveals lipid and amino acid remodeling compatible with improved mitochondrial function. Clinically, lean mass loss proportional to weight reduction is consistently observed, generally without meaningful declines in strength or performance; data for tirzepatide are more limited. Lean mass, however, is not synonymous with skeletal muscle. A paradox emerges between the presence of protective molecular signals and the clinical evidence of lean-mass loss. This phenomenon may be explained by a systemic energy/protein deficit rather than a direct catabolic effect of the drugs, although current evidence does not fully distinguish these mechanisms. The effectiveness of weight reduction should be considered a pivotal metric in clinical practice, particularly in populations susceptible to sarcopenia.
