Abstract:
Background: Sarcopenia, characterized by progressive loss of skeletal muscle mass, strength, and physical performance, is increasingly recognized as a major contributor to frailty, disability, falls, hospitalization, and mortality in aging and cardiometabolic populations. Beyond chronological aging, diabetes mellitus, obesity, chronic inflammation, sedentary lifestyle, and insulin resistance significantly accelerate muscle deterioration, particularly in Asian Indians who inherently possess lower lean mass and higher adiposity. With the expanding use of newer oral and injectable antidiabetic therapies such as sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and dual GIP/GLP-1 receptor agonists, concerns and interest regarding their influence on muscle biology have intensified.
Objective: To review current mechanistic, preclinical, and clinical evidence regarding the effects of SGLT2i, GLP-1RA, and GIP-GLP-1RA therapies on skeletal muscle mass, muscle quality, and sarcopenic risk in patients with diabetes and obesity.
Discussion: SGLT2 inhibitors induce a fasting-like metabolic state through glycosuria-driven caloric loss, activating SIRT1 and AMPK pathways while improving mitochondrial biogenesis, insulin sensitivity, autophagy, and fatty acid oxidation. Experimental studies demonstrate reduced intramuscular lipotoxicity, suppression of muscle atrophy-related genes, improved grip strength, and preservation of muscle quality. Clinical evidence suggests that although small reductions in skeletal muscle mass may occur, these are often outweighed by substantial reductions in visceral and ectopic fat, resulting in improved muscle-to-fat ratio and metabolic function. GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists exert pleiotropic effects through enhanced insulin signaling, anti-inflammatory actions, improved mitochondrial function, and modulation of protein turnover pathways including PI3K/Akt/mTOR and AMPK/PGC-1α. While these agents produce remarkable weight reduction and cardiometabolic benefits, a proportion of total weight loss consists of lean body mass. Data from STEP and SURPASS trials indicate that approximately 15–25% of weight loss may involve lean tissue reduction. However, emerging evidence also suggests improvements in muscle quality, reduction in myosteatosis, enhanced oxidative muscle fiber composition, and preservation of functional outcomes such as handgrip strength and exercise capacity when accompanied by adequate protein intake and resistance exercise. Dual GIP/GLP-1 receptor agonists such as tirzepatide may further optimize metabolic outcomes, though long-term sarcopenia-specific data remain limited. Novel approaches including myostatin blockade combined with incretin therapy are showing promise in preserving lean mass while enhancing fat loss.
Conclusion: The relationship between newer antidiabetic therapies and skeletal muscle is complex and evolving. SGLT2i appear largely muscle-friendly through improvements in mitochondrial health, inflammation, and muscle quality, whereas GLP-1RA and GIP/GLP-1RA therapies provide profound metabolic and cardiovascular benefits but warrant attention regarding lean mass reduction. Current evidence suggests that these agents are more “friends than foes” when prescribed judiciously with individualized nutritional optimization, resistance training, and monitoring of muscle health. Further long-term randomized studies specifically evaluating sarcopenia-related outcomes are urgently needed.
