Do Weight-Loss Drugs Eat Muscle? Landmark Review Weighs In on SGLT2 Inhibitors and Incretin Therapies

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies have rewritten the rulebook for treating obesity, type 2 diabetes, heart failure, and chronic kidney disease, delivering substantial metabolic, cardiovascular, and renal benefits. But as their use expands, a quieter question has been building among clinicians and patients alike: what are these drugs doing to our muscles? A new narrative review published in Advances in Therapy by Theocharis Koufakis and colleagues takes on that question head-on, synthesizing randomized controlled trials, observational studies, systematic reviews, and mechanistic investigations into how these blockbuster therapies affect skeletal muscle in the people most at risk of losing it.

The stakes are high because skeletal muscle is far more than a mechanical engine for movement. It is the largest insulin-sensitive organ in the human body, a central regulator of glucose homeostasis and energy metabolism, and an active endocrine tissue that communicates with adipose tissue, the liver, pancreas, heart, kidneys, and the central nervous system through secreted myokines and other bioactive mediators. Deterioration of skeletal muscle contributes not only to impaired mobility and disability but also to insulin resistance, chronic inflammation, cardiovascular disease, and increased mortality. Aging, obesity, type 2 diabetes, heart failure, and chronic kidney disease all profoundly alter muscle biology through overlapping mechanisms, including anabolic resistance, mitochondrial dysfunction, chronic low-grade inflammation, hormonal changes, and inadequate nutritional intake, ultimately culminating in sarcopenia, frailty, or protein-energy wasting in the most vulnerable patients.

SGLT2 inhibitors reduce body weight through urinary glucose excretion, creating a sustained negative energy balance of roughly 200 to 300 kilocalories per day accompanied by lower circulating insulin concentrations and increased reliance on lipid oxidation. Because this mild catabolic state could theoretically promote proteolysis, concerns emerged about muscle loss. Yet a recent meta-analysis restricted to randomized controlled trials with at least 12 months of follow-up, comprising five trials and 695 participants, found that SGLT2 inhibitors reduced body weight by 3.24 kilograms and fat mass by 1.26 kilograms, whereas the reduction in fat-free mass was smaller and not statistically significant at 0.53 kilograms. A broader meta-analysis of randomized trials did report small but significant reductions in estimated skeletal muscle mass of 1.01 kilograms and a borderline reduction in lean mass of 0.76 kilograms, and observational studies show variable changes in appendicular lean mass during treatment.

The biology is likely a tug-of-war between opposing forces. On the catabolic side sits the glycosuria-driven energy deficit. On the anabolic side, accumulating experimental evidence suggests SGLT2 inhibitors reduce glucotoxicity, improve insulin sensitivity, attenuate chronic inflammation and oxidative stress, enhance mitochondrial function, and improve endothelial function and skeletal muscle perfusion. Preclinical models of diabetes and muscle wasting indicate that SGLT2 inhibition may attenuate muscle atrophy and proteolytic signaling while favorably influencing mitochondrial morphology and oxidative metabolism. The review also flags a critical measurement caveat: many studies relied on bioelectrical impedance analysis, a technique particularly susceptible to changes in hydration status, and because SGLT2 inhibitors induce osmotic diuresis, part of the observed reduction in lean tissue may reflect shifts in body water rather than true loss of skeletal muscle.

Incretin-based therapies, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists, produce far greater weight loss and therefore larger absolute reductions in lean tissue. The DXA substudy of SURMOUNT-1, involving 160 participants with overweight or obesity, showed that tirzepatide reduced body weight by 21.3 percent, fat mass by 33.9 percent, and lean mass by 10.9 percent at 72 weeks, compared with reductions of 5.3, 8.2, and 2.6 percent with placebo. Approximately 75 percent of the weight lost with tirzepatide was attributable to fat mass and 25 percent to lean mass, with broadly similar proportions across subgroups defined by age, sex, and magnitude of weight loss. These proportions are comparable to those observed after intensive lifestyle intervention and bariatric surgery, and the relative contribution of lean tissue to total body composition often remains stable or even improves because adiposity is preferentially reduced.

More detailed imaging and functional data add crucial nuance. In the SURPASS-3 MRI substudy, a post hoc analysis of 246 participants with type 2 diabetes showed that tirzepatide reduced thigh muscle volume by 0.64 liters over 52 weeks, but the reduction did not differ significantly from that predicted for the observed weight loss using population-based UK Biobank data. Crucially, muscle fat infiltration decreased by 0.36 percentage points, a reduction significantly greater than predicted from population data, suggesting improved muscle composition despite reduced muscle volume. In the prospective SEMALEAN study of semaglutide 2.4 milligrams in 106 individuals with obesity, body weight fell by approximately 10 percent at 7 months and 13 percent at 12 months, lean mass declined by roughly 3 kilograms during the first 7 months but subsequently stabilized, handgrip strength increased by 4.5 kilograms at 12 months, and the prevalence of sarcopenic obesity fell from 49 to 33 percent. The review also notes that the expression and functional relevance of GLP-1 receptors within human skeletal muscle remain debated, and many beneficial effects are likely mediated indirectly through improvements in whole-body metabolic homeostasis.

For vulnerable populations, the picture is more complicated. A meta-analysis of eight randomized trials including 541 individuals with type 2 diabetes found that SGLT2 inhibitor therapy reduced body weight and fat mass while the reduction in muscle mass was considerably smaller. A meta-analysis of five studies including 1229 older adults aged 65 and over found that GLP-1 receptor agonists provided comparable weight and metabolic benefits in older and younger adults with obesity, without an increased risk of serious adverse events. However, a 24-month retrospective cohort study of adults aged 65 and over with type 2 diabetes reported that semaglutide treatment was associated with greater reductions in appendicular skeletal muscle mass than matched controls, accompanied by deterioration in gait speed and, in men, an initial improvement followed by a decline in grip strength. Higher semaglutide doses, lower baseline muscle mass index, and slower gait speed independently predicted accelerated muscle loss, with the greatest effects seen in individuals with pre-existing sarcopenia. In a Medicare analysis, initiation of either GLP-1 receptor agonists or SGLT2 inhibitors was associated with slower progression of a claims-based frailty index over one year compared with dipeptidyl-peptidase 4 inhibitors, although claims-based studies cannot directly measure muscle strength, physical performance, or nutritional status.

Heart failure and chronic kidney disease data are broadly reassuring but incomplete. In a large retrospective cohort study, 4697 patients with heart failure and malnutrition, frailty, sarcopenia, or cachexia receiving SGLT2 inhibitors were propensity score matched to an equal number of patients not receiving these agents; at one year, SGLT2 inhibitor use was associated with a lower risk of the composite of death or frailty-related events (hazard ratio 0.62), lower mortality (hazard ratio 0.41), and lower frailty-related events (hazard ratio 0.71). In a prospective observational study of 55 patients with chronic kidney disease treated with dapagliflozin for 24 weeks, bioimpedance-estimated skeletal muscle index decreased modestly, whereas handgrip strength and the prevalence of sarcopenia remained unchanged. The review also raises an unproven but intriguing hypothesis: because creatinine generation is partly determined by muscle mass, treatment-associated reductions in skeletal muscle could theoretically lower serum creatinine and influence creatinine-based estimates of kidney function, potentially contributing to the apparent magnitude of renoprotection, although this requires confirmation using kidney function markers independent of muscle mass.

A recent network meta-analysis of 41 randomized controlled trials including 2906 participants sharpened the comparison between the two classes: SGLT2 inhibitors were associated with only minor reductions in lean body mass, whereas significant reductions were observed with liraglutide (1.54 kilograms) and particularly tirzepatide (4.40 kilograms), which also produced the greatest reduction in fat mass (10.70 kilograms). Notably, trials in obesity-related heart failure with preserved ejection fraction showed that substantial incretin-induced weight loss can coexist with improved physical function: in STEP-HFpEF, semaglutide 2.4 milligrams reduced body weight by 13.3 percent versus 2.6 percent with placebo, improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 7.8 points, and increased 6-minute walk distance by 21.5 meters versus 1.2 meters with placebo. In SUMMIT, tirzepatide improved the same score by 6.9 points and reduced the composite risk of cardiovascular death or worsening heart failure (hazard ratio 0.62). Yet observational evidence raises a potential safety signal: in a longitudinal study of 471 individuals with type 2 diabetes, SGLT2 inhibitor use was independently associated with falls (odds ratio 1.80), and combined use of the two classes was associated with a higher risk of falls (odds ratio 2.89), reinforcing the need for a stepwise approach to treatment initiation in vulnerable individuals.

The review concludes that reductions in lean tissue should not be equated with treatment-induced sarcopenia, as current evidence does not consistently demonstrate clinically meaningful impairment in muscle strength or physical performance, and no validated threshold of lean mass loss currently exists at which either class should automatically be discontinued. Instead, the authors advocate a phenotype-based precision medicine approach anchored in multimodal care: resistance exercise involving major muscle groups on at least two days per week, with multicomponent activity emphasizing balance and strength training on at least three days per week in older adults; protein intake of approximately 1.0 to 1.5 grams per kilogram of adjusted body weight per day during active weight loss, with a minimum of 60 grams per day, distributed across meals at roughly 25 to 30 grams per main meal; and routine monitoring extending beyond body weight to handgrip dynamometry, gait speed, chair-rise testing, and dietary intake. Future research should prioritize standardized functional outcomes such as the Short Physical Performance Battery and 6-minute walk distance, dedicated studies in underrepresented vulnerable populations, and prospective evaluation of dual and triple incretin agonists such as retatrutide, whose increasingly profound weight loss demands closer scrutiny of long-term skeletal muscle trajectories. For now, the message is clear: skeletal muscle should be considered neither a casualty of pharmacologically induced weight loss nor a reason to withhold therapies with established benefits, but an integral part of a comprehensive benefit-risk assessment.

Subject of Research: Effects of SGLT2 inhibitors and incretin-based therapies on skeletal muscle in vulnerable populations

Article Title: Skeletal Muscle in Vulnerable Populations Receiving Cardiorenal-Metabolic Therapies: SGLT2 Inhibitors, Incretin-Based Therapies, and the Challenge of Precision Medicine

Article References: Koufakis, T., Tentolouris, A., Manthou, E., Teperikidis, L., Mylonas, A., Kotsa, K., & Doumas, M. (2026). Skeletal Muscle in Vulnerable Populations Receiving Cardiorenal-Metabolic Therapies: SGLT2 Inhibitors, Incretin-Based Therapies, and the Challenge of Precision Medicine. Advances in Therapy. https://doi.org/10.1007/s12325-026-03829-4

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03829-4

Keywords: SGLT2 inhibitors, incretin-based therapies, skeletal muscle, sarcopenia, obesity, type 2 diabetes, heart failure, chronic kidney disease, lean mass, frailty, precision medicine, resistance exercise