GLP-1 Receptor Agonists and Their Impact on Muscle Size, Strength, and Quality in MASLD

The bidirectional relationship between metabolic dysfunction‐associated steatotic liver disease (MASLD) and muscle health, encompassing muscle mass, strength, and quality, is increasingly recognised as the “liver‐muscle axis” [1]. Hepatic dysfunction has been demonstrated to exacerbate muscle catabolism, while impaired muscular conditioning can compromise metabolic health and potentially worsen liver disease [2, 3]. Accordingly, individuals with MASLD frequently exhibit markers of muscle impairment, including a higher prevalence of sarcopenia [4] and a reduced grip strength‐to‐BMI ratio [5]. This interplay is particularly relevant, as compromised muscle health in MASLD has been linked to adverse clinical outcomes [3, 6].

Central to the shared pathophysiology of MASLD and muscular decline are diabetes and obesity‐related drivers, such as insulin resistance, chronic low‐grade inflammation, and adipose tissue dysfunction [1]. These factors not only promote hepatic steatosis but also impair muscle protein synthesis and quality, often culminating in sarcopenic obesity [7, 8, 9]. Lifestyle factors, including physical inactivity, may further compromise both liver and muscle integrity [2, 10, 11]. Nevertheless, MASLD itself appears to play a direct role in muscle impairment, independently of obesity and insulin resistance [12]. From a clinical perspective, preservation of skeletal muscle remains crucial, as it represents the main insulin‐dependent site for glucose disposal [13], playing a central role in maintaining metabolic homeostasis and attenuating long‐term metabolic risk in this population.

One of the most clinically relevant manifestations of this muscle impairment is sarcopenia. This condition is characterised as a skeletal muscle disorder primarily defined by impaired muscle strength, which is considered the most reliable indicator of muscle function and the strongest predictor of adverse outcomes. The diagnostic algorithm proposed by the European Working Group on Sarcopenia in Older People (EWGSOP2) includes confirmation of low muscle quantity or quality as a second step after identifying reduced muscle strength [14]. However, assessing these parameters remains challenging, particularly muscle quality, which lacks a universally accepted definition and standardised measurement methods. Muscle quality encompasses structural and compositional features that influence muscle function—such as intramuscular lipid infiltration—as well as functional aspects, which can be conceptualised as muscle performance relative to muscle mass [14].

Recent advancements in the therapeutic management of obesity, particularly glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), have shown significant potential in mitigating MASLD by targeting its metabolic drivers [15, 16]. While GLP‐1RAs primarily act through glucose‐dependent insulin secretion, appetite regulation, and improvements in systemic insulin sensitivity, their direct effects on skeletal muscle remain an area of investigation. Preclinical evidence suggests that GLP‐1RAs may favourably impact muscle integrity by modulating myogenic factors, attenuating protein catabolism, and reducing local inflammation [17]. At the same time, concerns persist regarding the loss of muscle mass commonly observed during substantial weight reduction [18, 19]. Given the potential vulnerability of individuals with MASLD to muscle wasting and the widespread use of GLP‐1RAs in this population, clarifying how these agents influence muscle‐related outcomes is clinically relevant. This systematic review aims to evaluate how GLP‐1RA therapy affects muscle mass, strength, and quality in adults with MASLD.

This systematic review provides a comprehensive synthesis of current evidence on how GLP‐1RAs influence muscle outcomes in adults with MASLD. A substantial degree of heterogeneity was observed across studies, particularly in the methods used to quantify muscle mass. While most cohorts showed a downward trend in lean mass, these changes were generally small and statistically non‐significant, likely reflecting modest absolute losses rather than clinically relevant wasting. Importantly, muscle strength remained largely preserved across all functional assessments, and muscle quality showed a directionally consistent numerical improvement through reduced intramuscular fat infiltration, as well as preserved strength‐to‐mass ratio. Taken together, the available data suggest that GLP‐1RA therapy does not lead to clinically meaningful deterioration of muscle mass or function in adults with MASLD, although confirmation from higher‐quality studies using standardised assessment methods is warranted.

The observed relative preservation of muscle outcomes is particularly relevant given the susceptibility of individuals with MASLD to muscle impairment. Findings from the broader literature on incretin‐based therapies in obesity and type 2 diabetes show that quantitative reductions in lean mass typically account for 15% to 45% of total weight loss [35]. Landmark trials such as STEP‐1 (semaglutide) [36], SUSTAIN‐8 (semaglutide) [37], and SURMOUNT‐1 (tirzepatide) [38] offer contextual support for this estimate. Consequently, body composition can be preserved or improved even if there is some absolute loss of lean mass. Nevertheless, most comparative evidence is drawn from broader metabolic cohorts, potentially encompassing individuals with MASLD, yet lacking disease‐specific analyses. Importantly, no direct catabolic effect of GLP‐1RAs on skeletal muscle has been demonstrated; conversely, animal models suggest potential protective effects on muscle tissue within metabolic disease contexts [17, 39]. Furthermore, decreases in lean tissue observed during GLP‐1RA therapy are not unique to this drug class, as they are a well‐recognised component of weight loss achieved through dietary or surgical interventions [40].

According to the data from this systematic review, although numerical reductions in muscle mass were common, evidence for a clinically relevant loss remains limited. Based on MRI data, Ditzenberger et al. [33] observed a reduction in psoas volume; however, this finding derives from a population of individuals with HIV and MASLD undergoing antiretroviral therapy, which likely reflects a distinct clinical and metabolic‐inflammatory profile rather than a generalised effect of GLP‐1RA therapy. Conversely, among studies evaluating body composition by DXA or BIA, even in those reporting larger reductions, lean mass loss represented a smaller proportion of total weight loss. Volpe et al. [32] reported that a reduction in skeletal muscle index exceeding 40% of total weight loss occurred in only 18% of participants. Similarly, based on group mean estimates, lean mass accounted for 27% of total weight loss in Moolla et al. [28], which is within the range typically observed in other weight‐loss interventions [40]. These observations should be interpreted cautiously, given the small sample sizes, heterogeneous assessment methods, and limited follow‐up durations, but they indicate that lean mass reductions, when present, do not necessarily imply disproportionate or clinically relevant muscle wasting.

Beyond quantitative changes in muscle mass, functional and qualitative muscle outcomes may be more clinically meaningful in patients with MASLD. Muscle strength, in particular, is a stronger predictor of disability and adverse outcomes than muscle mass alone [6, 14, 41]. Although limited, the available evidence in this review does not indicate that GLP‐1RA therapy leads to impairment in muscle strength, as assessed by handgrip strength or sit‐to‐stand performance. These findings align with the broader GLP‐1RA literature, in which this drug class has generally been considered neutral or even beneficial with respect to muscle strength [17, 42]. Nevertheless, data from high‐risk populations—such as older adults with diabetes and a high prevalence of sarcopenia—have raised concerns about potential strength decline in specific contexts [43]. Given the scarcity of MASLD‐specific data, conclusions regarding muscle strength should therefore be interpreted cautiously.

Another consideration is whether the apparent preservation of muscle strength reflects a pre‐existing low functional reserve in patients with MASLD, potentially creating a floor effect. However, available data suggest this is unlikely. Baseline strength values in the included studies—such as mean HGS ranging from 30.8 to 33.6 kg [31, 32] and a mean 5‐times STS time of 12.5 s [33]—generally exceed established clinical cutoffs for sarcopenia (e.g., HGS < 27 kg for men and < 16 kg for women, or STS > 15 s) [14]. Although the prevalence of sarcopenia was not reported in the primary studies, these values indicate that participants retained adequate functional reserve. Thus, the stability of muscle strength during GLP‐1RA therapy is unlikely to be explained by depleted baseline muscle capacity.

Finally, muscle quality—most commonly reflected by myosteatosis—represents another clinically relevant dimension in MASLD [44], even in the absence of obesity [45]. Persistent adipose inflammation promotes lipid redistribution toward visceral and skeletal muscle depots, increasing free fatty acid flux and contributing to both MASLD progression and intramuscular fat accumulation [46]. Although MASLD‐specific data on myosteatosis remain limited, findings from populations with obesity and/or type 2 diabetes have shown that incretin‐based therapies tend to reduce intramuscular fat [47, 48]. These observations provide contextual support, even though they do not replace the MASLD‐specific evidence synthesised in this review.

Among the included studies, there was a tendency toward improved muscle quality via reduced myosteatosis. Although these findings require confirmation in larger and more rigorously designed studies, a reduction in muscle fat infiltration would be consistent with the broader pattern observed in this review: Weight loss induced by GLP‐1RAs is associated with modest reductions in lean mass, but appears to spare muscle function and could potentially enhance muscle quality through improvements in intramuscular lipid content, as suggested by Kakegawa et al. [24]. A complementary perspective comes from functional assessments of muscle quality, which also showed reassuring results. This is further supported by data from bariatric surgery, which often shows preservation of grip strength despite significant reductions in lean mass [49], reinforcing that decreases in lean mass do not necessarily translate into functional impairment. Ultimately, reductions in lean mass, particularly when estimated by DXA or BIA, should not be interpreted as loss of contractile tissue alone; these methods cannot distinguish muscle from non‐contractile components [50], so shifts in hydration status or reductions in intramuscular fat may be misclassified as lean‐mass loss. In this context, part of the observed decline could reflect improvements in muscle composition rather than true loss of muscle tissue.

The scope and generalisability of our findings are constrained by several limitations. First, the number of available studies was limited, and most included small sample sizes, non‐randomised designs, and a high risk of bias, substantially limiting statistical power and the ability to detect small‐to‐moderate effects on muscle‐related outcomes. Second, GLP‐1RA interventions varied substantially in drug type, dosing, and treatment duration. Crucially, nearly all studies used glycemic‐control doses and short treatment periods, rather than the higher, obesity‐approved regimens now standard in clinical practice, which are typically used for much longer durations in real‐world settings. This mismatch substantially limits the generalisability of the findings and may partly explain the absence of significant weight reduction in some studies, thereby potentially influencing muscle‐related outcomes. Third, many studies also lacked control for important confounders of the outcome, such as diet and physical activity. In addition, population characteristics differed markedly across the included cohorts, with substantial variation in age, sex distribution, BMI, and diabetes status. These factors are known to influence muscle phenotype and likely contributed to the observed heterogeneity in outcomes. Finally, the assessment of muscle outcomes lacked methodological standardisation across studies, with substantial variability in imaging modalities, surrogate measures, and reporting units. In particular, several studies relying on DXA or BIA used total lean mass or fat‐free mass as proxies for skeletal muscle, which may overestimate true muscle tissue by including non‐muscle, non‐fat components.

Despite these limitations, this systematic review has notable strengths. To our knowledge, it represents the first comprehensive synthesis specifically addressing the effects of GLP‐1RA therapy on skeletal muscle mass, strength, and quality in adults with MASLD. The inclusion of multiple muscle‐related domains and the stratification of results according to assessment modality provide a nuanced interpretation of the existing literature.

From a clinical standpoint, while definitive conclusions cannot yet be drawn, current evidence does not suggest clinically relevant muscle wasting in adults with MASLD receiving GLP‐1RAs. Nonetheless, given the intrinsic vulnerability of this population to muscle impairment, clinicians should consider individualised patient monitoring, particularly for high‐risk groups such as those with advanced liver disease, older age, or pre‐existing sarcopenia. Furthermore, lifestyle strategies such as resistance exercise combined with adequate protein intake are essential for preserving lean mass and functional capacity during pharmacologically induced weight loss [35]. Additionally, evidence suggests that combining supervised exercise with pharmacotherapy may promote healthier long‐term weight maintenance, with benefits persisting even after treatment discontinuation, as observed in populations with obesity [51].

Beyond synthesising current evidence, this review highlights significant gaps in the available literature. Notably, very few studies have performed longitudinal assessments of muscle strength, and none have evaluated muscle mass, quality, and function in a paired, site‐specific manner within the same muscle groups. This methodological limitation precludes a definitive assessment of the relationship between structural, compositional, and functional muscle changes. Integrated approaches that combine imaging‐based assessments of muscle mass and quality with functional measurements of the corresponding muscle groups (e.g., isokinetic dynamometry for knee extension alongside quadriceps cross‐sectional area and composition) would help generate more comparable and clinically meaningful evidence.

In conclusion, the available evidence does not indicate a consistent or disproportionate negative effect of GLP‐1RA therapy on muscle mass, strength, or quality in adults with MASLD. Although modest reductions in lean mass may occur during weight loss, these changes are generally proportional to overall weight reduction and are not accompanied by functional decline. Furthermore, early data suggest potential improvements in muscle quality through reductions in intramuscular fat. Despite these reassuring findings, the evidence base remains limited, and high‐quality trials in patients with MASLD, using standardised muscle assessments, are needed to clarify the long‐term effects of GLP‐1RAs on skeletal muscle health.

F.I. and P.M. were responsible for the study conception and design. F.I. and T.J. contributed to data curation, screening, and extraction. F.I. drafted the original manuscript. All authors contributed to data interpretation. M.Y., M.R.T., B.D.S., and P.M. critically evaluated the manuscript for important intellectual content. All authors revised and approved the final version of the manuscript.

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Finance Code 001.

The authors declare no conflicts of interest.