Pharmacological intervention: Challenges and promising outcomes for fat loss and preservation of lean body mass in the treatment of overweight and type 2 diabetes

Abstract Treatment with GLP‐1 receptor agonists (GLP‐1 RAs) is effective in reducing body weight in individuals with overweight and type 2 diabetes (T2D). However, measurements indicate that a considerable portion of the weight loss derives from fat‐free mass (FFM), including skeletal muscle, which may compromise metabolic health and physical function. We aimed to evaluate the evidence for the ability of pharmacological interventions to preserve or increase lean body mass (LBM) during weight loss with GLP‐1 RAs, assess their clinical potential and limitations, and identify knowledge gaps requiring further research. A literature review was conducted using PubMed, JAMA, Wiley, ResearchGate, The Royal Danish Library, and ClinicalTrials.gov. Included were preclinical and clinical studies on compounds with documented anabolic effects and established safety profiles. The primary outcomes assessed were changes in LBM, fat mass (FM), physical function, and adverse events. Activin II receptor inhibition with bimagrumab demonstrated significant preservation and increases in LBM, along with FM reduction, in both preclinical and phase 2 studies in individuals with overweight and T2D. Similar effects were observed for myostatin and activin A inhibitors (trevogrumab, garetosmab), latent myostatin inhibitors (apitegromab, SRK‐439), and Selective Androgen Receptor Modulators (enobosarm). Notably, enobosarm also improved physical function. Adverse events were generally mild and reversible; however, long‐term data remain limited. Pharmacological adjunct therapies show potential for improving body composition and physical function during GLP‐1 RA‐induced weight loss. Preliminary findings are promising, but larger, controlled trials are necessary to confirm efficacy and safety before clinical implementation can be considered.