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

Nov 3, 2025Diabetes, obesity & metabolism

Drug treatments for losing fat and keeping muscle in people with overweight and type 2 diabetes: challenges and hopeful results

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Abstract

Activin II receptor inhibition with bimagrumab is associated with significant preservation and increases in lean body mass during weight loss with GLP-1 receptor agonists.

Weight loss from GLP-1 receptor agonists may include considerable losses in fat-free mass, which could impact metabolic health.
Bimagrumab has shown the ability to preserve and increase lean body mass while reducing fat mass in individuals with overweight and type 2 diabetes.
Similar benefits were observed with other compounds such as myostatin and activin A inhibitors and Selective Androgen Receptor Modulators.
Enobosarm also improved physical function alongside its effects on body composition.
Adverse events from these pharmacological interventions were generally mild and reversible, but long-term data are limited.
Further research with larger, controlled trials is necessary to confirm the efficacy and safety of these adjunct therapies.

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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.

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

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