Mitigating loss of lean muscle in GLP-1 and dual GLP-1/GIP agonists: Pipeline opportunities and limitations

Jan 26, 2026Biochimica et biophysica acta. Molecular basis of disease

Reducing muscle loss with GLP-1 and combined GLP-1/GIP treatments: potential and challenges

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Abstract

15-40% of weight loss in trials like STEP and SURMOUNT may come from lean muscle mass.

Loss of lean muscle mass can impair glucose disposal, muscle strength, and physical function.
Elevated risks of losing force-generating capacity in skeletal muscles could lead to sarcopenia, especially in elderly patients.
Current FDA guidelines prioritize total weight reduction but do not address body composition, indicating a critical unmet need.
Emerging therapeutics to preserve lean muscle include selective androgen receptor modulators and myostatin-targeting therapies.
Limitations in existing studies include reliance on biologics, short trial durations, and insufficient functional outcome data.

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Glucagon-like peptide-1 (GLP-1) receptor and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists drive significant transformation in the landscape for type 2 diabetes and obesity management, yet 15-40% of weight loss in trials like STEP and SURMOUNT stems from lean muscle mass. This catabolic loss impairs glucose disposal, muscle strength, and physical function; elevating risks for the loss of force generating capacity in the skeletal muscles leading to sarcopenia, particularly in elderly patients. Unfortunately, current FDA guidelines emphasize total weight reduction over body composition, featuring an unmet critical need for elucidating strategies to preserve loss of lean muscle. This review will feature the emerging therapeutics to mitigate loss of lean muscle, including selective androgen receptor modulators, myostatin-targeting TGF-β inhibitors, and gene-silencing siRNA therapies. Despite promising preclinical and early clinical data, limitations persist, including reliance on parenteral biologics, limited mechanistic diversity, short trial durations, and sparse functional outcome data. Future research must prioritize precise muscle assessments, body composition, long-term trials, and accessible interventions integrating pharmacotherapy. These advances could redefine weight loss paradigms, ensuring therapeutic efficacy aligns with optimal body composition and patient outcomes.

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Mitigating loss of lean muscle in GLP-1 and dual GLP-1/GIP agonists: Pipeline opportunities and limitations

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