Based on Ceasovschih et al., 2025, Pharmacological Research
Glucagon-like peptide-1 receptor agonists have become a cornerstone of modern obesity and metabolic disease management. In their 2025 review published in Pharmacological Research, Ceasovschih and colleagues provide a comprehensive synthesis of clinical and preclinical data exploring not only the well-known metabolic benefits of GLP-1 RAs but also their effects on lean body mass, including skeletal muscle.
Metabolic benefits and mechanisms of action
According to Ceasovschih et al. (2025), GLP-1 receptor activation “supports insulin synthesis and release, suppresses glucagon, slows gastric emptying, reduces energy intake through central mechanisms, decreases visceral and subcutaneous adiposity, and may improve endothelial function and capillary perfusion.”
These diverse effects arise from receptor expression across multiple tissues including the pancreas, central nervous system, and vasculature. Clinically, GLP-1 RAs have been shown to produce “substantial weight loss and improvements in glycaemia, lipids, and blood pressure,” with cardiovascular benefits observed in some high-risk type 2 diabetes populations.
Lean mass changes during treatment
While the benefits of GLP-1 RAs are well established, Ceasovschih et al. (2025) report that treatment is often accompanied by a reduction in lean body mass, particularly during periods of rapid weight loss. Across clinical contexts, “lean mass losses of roughly 20 to 50 percent of total weight lost have been reported in studies using GLP-1 RAs,” with the most pronounced changes occurring “during the initial 3 to 6 months when weight loss is most rapid.”
The authors emphasize that many datasets describe fat-free mass rather than skeletal muscle specifically. Since fat-free mass includes other tissues such as organs and bone, interpretation must be cautious. The potential concern is greatest among “older or frail individuals with limited reserves, in whom accelerated lean loss may intersect with sarcopenic risk.”
Evidence from preclinical models
Experimental work reviewed by Ceasovschih et al. (2025) suggests that GLP-1 RAs may exert protective or adaptive effects in muscle tissue. In animal and cell studies, agents including liraglutide, dulaglutide, exendin-4, and semaglutide have been shown to:
- Suppress atrophy-related genes (atrogin-1, MuRF-1)
- Reduce inflammatory signalling
- Enhance myogenic factor expression
- Improve mitochondrial function and protein synthesis
- Decrease intramuscular lipid accumulation
These effects were linked to improved muscle function in several models, although dose dependency was noted — “excessive liraglutide exposure induced atrophic changes in vitro.”
Human body composition and imaging data
Clinical imaging studies provide a mixed but informative picture. MRI and CT analyses in patients treated with liraglutide, semaglutide, and tirzepatide have documented proportional reductions in muscle volume, yet these often coincided with “improvements or stability in muscle fat infiltration and attenuation,” suggesting better muscle quality despite reduced size.
In BIA- and DXA-based human studies, fat loss generally exceeded lean loss, and measures of handgrip strength or functional performance were often preserved in the short term. However, the review notes that “small samples, heterogeneous methods, and limited strength or performance assessments constrain firm conclusions about longer-term functional outcomes.” The authors call for standardized measurement of muscle quantity, quality, and performance in future GLP-1 RA trials.
Mitigation strategies: exercise and nutrition
Ceasovschih et al. (2025) outline two key non-pharmacological strategies to reduce the risk of excessive lean loss during GLP-1 RA-induced weight reduction:
- Structured exercise, particularly moderate- to high-intensity resistance training, is recommended to promote a more favorable fat-to-lean mass loss ratio. Evidence from older adult populations indicates that such programs “improve function and attenuate muscle loss,” and prospective trials are underway to evaluate this specifically in GLP-1 RA users.
- Increased protein intake above standard dietary guidelines is advised, drawing parallels with post-bariatric settings. The authors note that “practical considerations for appetite reduction and gastric emptying during therapy” must be managed carefully to ensure adequate intake.
Additionally, investigational adjunct therapies, including ACVR2B-pathway antibodies such as bimagrumab, are being studied for their potential to preserve or even increase lean mass when combined with GLP-1 RAs.
Conclusions
The review concludes that GLP-1 receptor agonists are highly effective agents for weight and cardiometabolic risk reduction, with strong evidence of benefit across metabolic and vascular endpoints. However, “an associated reduction in lean tissue that may include skeletal muscle” has been observed, particularly during early treatment phases.
For most individuals, these changes appear proportional to overall weight loss and may occur alongside improvements in muscle quality. Yet the authors caution that vulnerable populations, such as older adults or those with limited muscle reserves, may require closer monitoring and targeted interventions.
They recommend that GLP-1 RA therapy be accompanied by longitudinal monitoring of body composition, muscle strength, and performance, supported by structured exercise and nutritional strategies to safeguard muscular integrity.
Adaptog Recommendation
At Adaptog, we interpret these findings as evidence that successful weight management involves more than weight loss alone. As Ceasovschih et al. (2025) note, structured exercise, particularly resistance training, and adequate protein intake are “reasonable strategies for attenuating clinically relevant lean loss” during GLP-1 RA therapy.
A balanced, nutrient-rich diet and regular physical activity remain essential for maintaining metabolic health, functional strength, and overall wellbeing. Individuals using GLP-1 therapies should work with qualified clinicians and nutrition professionals to integrate sustainable exercise and dietary practices into their treatment plan, ensuring that improvements in weight and cardiometabolic health are matched by the preservation of muscle quality and function.
Reference
Ceasovschih, A., Asaftei, A., Lupo, M. G., Kotlyarov, S., Bartušková, H., Balta, A., Sorodoc, V., Sorodoc, L., & Banach, M. (2025). Glucagon-like peptide-1 receptor agonists and muscle mass effects. Pharmacological Research, 107927. [Open Access]
