SUN-880 - Hormonal Characterization of the MAFI Axis Under Short-term Liraglutide: A Randomized Crossover Trial

While GLP-1 receptor agonist-induced lean body mass loss has been demonstrated before, the mechanisms by which this occurs remain incompletely understood. Our lab has previously demonstrated via proteomic analyses that liraglutide significantly modulates the myostatin-activin-follistatin (MAFI) axis, a key pathway involved in regulating muscle homeostasis. Here we performed targeted hormone level analyses to provide comprehensive characterization of the MAFI axis in response to liraglutide in the same cohort of patients. In a randomized, placebo-controlled, cross-over, double-blind clinical trial participants (n=20) with obesity received liraglutide (3.0 mg) or placebo for 5 weeks in random order, followed by a 3-week washout period. Blood samples were collected at the end of 6 patient visits. Circulating levels of myostatin, activin A, activin B, activin AB, follistatin, and follistatin-like 3 were quantified by ELISA. Longitudinal changes were assessed using mixed-effects models testing Time, Treatment, and Time x Treatment interactions (ITT-LOCF). ELISA quantification revealed significant downregulation of myostatin (MSTN) with liraglutide as compared to placebo (Time x Treatment p=0.0497). Activin A (Time x Treatment p=0.0027) and Follistatin (Time x Treatment p=0.0208) were similarly significantly reduced under liraglutide. Activin B, Activin AB, and follistatin-like 3 (FSTL-3), however, showed no significant changes with liraglutide treatment as compared to placebo. Additionally, Liraglutide reduced body weight, BMI, and total and regional mass (trunk, hip, and extremities). Absolute fat-free mass was slightly but significantly lower. Absolute lean mass in the trunk and extremities decreased, whereas relative lean mass and fat-free mass percentages remained stable at treatment completion. These findings provide the first comprehensive characterization of the MAFI axis under short-term liraglutide treatment, demonstrating selective suppression of myostatin, Activin A, and follistatin, but no significant impact on Activin B, Activin AB, and FSTL-3. Downregulation of Myostatin and Activin A, both well characterized inhibitors of muscle growth, suggests a potential adaptive mechanism to preserve muscle mass. As Follistatin is an inhibitor of Myostatin and Activin A, its downregulation could potentially be a compensatory response to their suppression. While further analysis is required to make more definitive conclusions, these data highlight the potential of the MAFI axis, especially myostatin, as a clinical target for muscle mass preservation during pharmacologic weight loss. These hormonal and body composition findings will be discussed in the context of recently published proteomic data from the same cohort, providing a comprehensive multi-modal characterization of liraglutide's early effects on muscle-regulatory pathways.

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