Muscle Mass and Glucagon-Like Peptide-1 Receptor Agonists: Adaptive or Maladaptive Response to Weight Loss?

Recent studies have shown that pharmacologic weight loss with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and combination therapies is approaching magnitudes achieved with surgery. However, as more weight loss is achieved, there is concern for potential adverse effects on muscle quantity, composition, and function. This primer aims to address whether muscle-related changes associated with weight loss treatments such as GLP-1 RAs may be maladaptive (ie, adversely affecting muscle health or function), adaptive (ie, a physiologic response to weight loss maintaining or minimally affecting muscle health or function), or perhaps an enhanced response to weight loss (ie, improved muscle health or function after treatment). Based on contemporary evidence with the addition of studies using magnetic resonance imaging, skeletal muscle changes with GLP-1 RA treatments appear to be adaptive: changes in muscle volume z-score indicate a change in muscle volume that is commensurate with what is expected given aging, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and prefrailty may influence the selection of appropriate candidates for these therapies because of risk for sarcopenia. Several pharmacologic treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. For future development of GLP-1-based therapies (and other therapies) designed for weight loss, as well as for patient-centered treatment optimization, the introduction of more objective and comprehensive ways of assessing muscle health (including accurate and meaningful assessments of muscle quantity, composition, function, mobility, and strength) is important for the substantial numbers of patients who will likely be taking these medications well into the future.
Competing Interests: Dr Neeland has received honoraria, consulting, and speaker’s bureau fees and travel support from Boehringer-Ingelheim/Lilly Alliance, consulting and speaker’s bureau fees from Bayer Pharmaceuticals, and consulting fees from Novo Nordisk, and has participated in scientific advisory boards for Lilly, Boehringer Ingelheim, Novo Nordisk, and AMRA Medical. Dr Birkenfeld has received consulting fees from Novo Nordisk and Bayer, as well as research support from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lilly, and Daiichi Sankyo, all given to Tübingen University. Dr Linge is an employee and shareholder of AMRA Medical AB, has received consulting and travel support from Eli Lilly, and has received speaker’s bureau fees and travel support from BioMarin.