Abstract
Weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic polypeptide receptor agonists is coming closer to the magnitudes achieved with surgery. However, with greater weight loss there is concern about potential side effects on muscle quantity (mass), health and function. There is heterogeneity in the reported effects of GLP-1-based therapies on lean mass changes in clinical trials: in some studies, reductions in lean mass range between 40% and 60% as a proportion of total weight lost, while other studies show lean mass reductions of approximately 15% or less of total weight lost. There are several potential reasons underlying this heterogeneity, including population, drug-specific/molecular, and comorbidity effects. Furthermore, changes in lean mass may not always reflect changes in muscle mass as the former measure includes not only muscle but also organs, bone, fluids, and water in fat tissue. Based on contemporary evidence with the addition of magnetic resonance imaging-based studies, skeletal muscle changes with GLP-1RA treatments appear to be adaptive: reductions in muscle volume seem to be commensurate with what is expected given ageing, 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 severity of disease may influence the selection of appropriate candidates for these therapies due to risk of sarcopenia. To further improve muscle health during weight loss, several pharmacological treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. Future research on GLP-1-based and other therapies designed for weight loss should focus on more accurate and meaningful assessments of muscle mass, composition, as well as function, mobility or strength, to better define their impact on muscle health for the substantial number of patients who will likely be taking these medications well into the future.
Keywords: GLP‐1 receptor agonist; cardiovascular disease; insulin resistance; muscle; obesity; sarcopenia; type 2 diabetes.
INTRODUCTION
Recent studies have shown that pharmacologically assisted weight loss with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/ glucose-dependent insulinotropic polypeptide receptor agonists (GIP-RAs) is approaching magnitudes close to that achieved with bariatric surgery.1,39,92 However, with greater weight loss there is concern about potential adverse effects on muscle quantity (mass), health and function, especially in more vulnerable patients. Lean body mass, although contentious, is widely used as a surrogate measurement for muscle mass.3 Lean body mass is calculated as the difference between total body weight and body fat weight, or more simply, the weight of all body tissues and fluids except the fat. The range of lean body mass considered to be healthy is approximately 70%–90%, with women being towards the lower end of the range and men in the higher end of the range. Maintenance of lean mass is important during weight loss because muscles and internal organs have a higher metabolic rate than the equivalent weight of fat. Consequently, maintenance of lean body mass facilitates a higher metabolic rate and makes it easier to lose and maintain body weight during a weight loss intervention. Describing the impact and clinical significance of reductions in lean mass, and especially muscle mass, with GLP-1-based weight loss is important to understand the quality of the weight loss achieved. One important question is whether the loss of muscle mass associated with weight loss treatments is adaptive (i.e., a physiological response to weight loss maintaining or minimally affecting muscle health/function), or maladaptive (i.e., adversely impacting muscle health/function). The aim of this review was to provide the most contemporary evidence addressing changes in lean body mass and muscle composition with GLP-1-based therapies and potential mitigation strategies in current use and in development. Focus was placed on the complex interplay between muscle quantity, composition and function, and metabolic physiology and the impact of GLP-1-based treatments, as well as on the challenges and opportunities associated with methods of assessing and addressing muscle health and sarcopenia during weight loss.
CONCLUSIONS
In conclusion, it is challenging to make statements, or define endpoints, for what is an expected (or excessive) reduction of muscle quantity during weight loss, especially in the light of the highly variable results reported on lean mass effects from GLP-1RA-based treatments. However, based on contemporary evidence with the addition of MRI-based studies, skeletal muscle changes with GLP-1RA 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 ageing, 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. Several pharmacological treatments to maintain or improve muscle mass are under development and future directions may lead to a combination of these molecules with GLP-1-based therapies. Future research of GLP-1-based therapies should focus on more accurate and meaningful assessments (including more precise imaging) of muscle mass, composition, as well as function, mobility or strength to better define their impact on muscle health for the substantial numbers of patients who will likely be taking these medications well into the future.
ACKNOWLEDGEMENTS
This manuscript was commissioned by the Editor as part of a Special Issue made possible by funding from Nestle. Sponsor identity was not disclosed to the authors prior to publication.
CONFLICT OF INTEREST STATEMENT
Ian J. 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 on scientific advisory boards for Lilly, Boheringer Ingelheim and AMRA Medical. Jennifer Linge is an employee and shareholder of AMRA Medical AB, has received consulting and travel support from Eli Lilly, and speaker's bureau fees and travel support from BioMarin. Andreas L. 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.