Incretin Receptor Agonism, Fat-free Mass, and Cardiorespiratory Fitness: A Narrative Review

Individuals with obesity often exhibit low muscle quality and are at risk of reduced muscle mass and diminished cardiorespiratory fitness (CRF). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) and dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (GLP-1/GIPRA) promote significant loss in adipose tissue but are also associated with notable reductions in fat-free mass (FFM). It is not yet understood how these drugs affect CRF which is an independent predictor of all-cause and cardiovascular mortality. People with obesity frequently have low CRF which is defined by the Fick principle - the product of cardiac output and peripheral oxygen extraction. Cardiovascular dysfunction and reduced muscle quality, due to lipid infiltration, relatively low muscle mass, and dysfunctional microvasculature, work in concert to affect the determinants of the Fick equation and cause low CRF in this population. Weight loss interventions, including GLP-1RAs and dual GLP-1/GIPRA, may improve these measures. However, recent trials show GLP-1RAs and dual GLP-1/GIPRA therapy accelerates FFM loss. Evidence indicates that approximately 25-40% of weight loss attributed to GLP-1RAs and dual GLP-1/GIPRA comes from FFM loss, a rate far exceeding the annual age-related decline of FFM in adults. While these therapies have revolutionized obesity and glycemic management by inducing significant weight loss, reducing blood glucose levels, and demonstrating cardiovascular benefits in individuals with or without type 2 diabetes, clinical studies have failed to show improvements in CRF, a critical determinant of long-term cardiovascular health, and the long-term implications of FFM loss in these individuals remain unknown. GLP-1RAs and dual GLP-1/GIPRA significantly reduce body weight and adiposity, along with a substantial FFM loss but with no clear evidence of CRF enhancement. Further research is needed to elucidate the complex interplay among GLP-1 and dual GLP-1/GIP receptor agonism, FFM, direct cardiovascular measures, and determinants of CRF to optimize clinical outcomes in obesity and type 2 diabetes.