Rapid weight loss with GLP1 receptor agonists can come at a cost, potentially undermining metabolic and functional outcomes. Emerging evidence suggests that these therapies may lead to significant skeletal muscle loss. To mitigate this risk, clinical strategies prioritizing muscle preservation are advocated.
Recent studies have highlighted the importance of muscle mass in weight management. Research has shown that glucagon-like peptide-1 receptor agonists (GLP1RAs) can lead to substantial changes in lean body mass, with potential long-term consequences on metabolic and functional outcomes (Xie et al., 2025; Neeland et al., 2024). The mechanisms behind this effect are not fully understood but may involve adaptive or maladaptive responses to weight loss (Linge et al., 2024).
To address this concern, several strategies have been proposed. Antibody blockade of activin type II receptors has been shown to preserve skeletal muscle mass and enhance fat loss during GLP1RA therapy (Nunn et al., 2024). Additionally, the SIRT1 pathway has been identified as a potential target for promoting muscle preservation in obesity-induced muscle atrophy (Xiang et al., 2023).
The importance of balancing weight loss with muscle preservation is underscored by studies on exercise and GLP1RA therapy. A randomized placebo-controlled trial found that healthy weight loss maintenance with exercise or GLP1RA therapy, or both combined, was more effective than either treatment alone (Lundgren et al., 2021; Jensen et al., 2024).
As the field continues to evolve, it is essential to prioritize muscle preservation strategies in GLP1RA therapy. By doing so, we can promote long-term success and safety in pharmacological weight management.
References:
Xie, Y., Choi, T., & Al-Aly, Z. (2025). Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat. Med., 31(10), 951–962.
Neeland, I. J., Linge, J., & Birkenfeld, A. L. (2024). Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes Obes. Metab., 26(Suppl. 4), 16–27.
Linge, J., Birkenfeld, A. L., & Neeland, I. J. (2024). Muscle mass and glucagon-like peptide-1 receptor agonists: adaptive or maladaptive response to weight loss? Circulation, 150(10), 1288–1298.
Xiang, J., Qin, L., Zhong, J., Xia, N., & Liang, Y. (2023). GLP-1RA liraglutide and semaglutide improves obesity-induced muscle atrophy via SIRT1 pathway. Diabetes Metab. Syndr. Obes., 16(12), 2433–2446.
Nunn, E., et al. (2024). Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol. Metab., 80(2), 101880.
Kambic, T., Lavie, C. J., & Eijsvogels, T. M. H. (2024). Seeking synergy for novel weight- and glucose-lowering pharmacotherapy and exercise training in heart failure patients with preserved ejection fraction. Eur. Heart J., 45(2), 861–863.
Lundgren, J. R., et al. (2021). Healthy weight loss maintenance with exercise, liraglutide, or both combined. N. Engl. J. Med., 384(14), 1719–1730.
Jensen, S. B. K., et al. (2024). Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial. eClinicalMedicine, 69(2), 102475.
Source: https://www.nature.com/articles/s41574-025-01160-6