Loss of Muscle Mass During Treatment with GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists: A Systematic Review of Current Evidence

This systematic review demonstrates that treatment with GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists is consistently associated with significant reductions in body weight and adiposity, accompanied by measurable decreases in lean body mass. Across the included studies [18-27], lean tissue accounted for approximately 20–40% of total weight loss, whereas most weight reduction was attributable to decreases in fat mass. These data are consistent with the bodily adaptations usually observed during intentional weight loss and do not support selective or excessive skeletal muscle wasting attributable to incretin-based therapy.

Research has demonstrated that these treatments produce significant changes in body composition, with major reductions in body fat, especially around organs and in muscle [21,23,24]. This type of fat is closely linked to problems like insulin resistance, inflammation, and heart disease [35]. As a result, the positive changes in body composition are likely to have a significant role in the treatments' ability to improve heart health, control blood sugar levels, and reduce obesity-related complications [35], this is especially important for people at risk of heart disease, diabetes, and other conditions linked to obesity, as it can help them manage their conditions more effectively and reduce their risk of long-term complications.

Comparison with Lifestyle-Induced Weight Loss: When you lose weight with medicines like GLP-1 receptor agonists, you also lose lean tissue, which is like what happens when you try to lose weight by changing your diet and exercise routine. Usually, when you cut calories, about 20-30% of the weight you lose is from muscle and other lean tissue, not just fat [36]. Even when you make big changes to your diet to lose weight, you might still lose some muscle mass, even though you're getting healthier and losing fat [36].

This data shows that when people lose lean tissue while on incretin-based therapy, it's mostly due to weight loss and their bodies adjusting to having less energy. It's not necessarily a bad side effect of the drug. So, when we're worried about losing lean mass, we should think about it in terms of how our body works when we lose weight.

Comparison with Bariatric Surgery: For people who are severely obese, having bariatric surgery is still the best way to lose a lot of weight and keep it off [37]. But after the surgery, people often lose muscle mass too [38]. Studies have shown that about a quarter of the weight people lose after bariatric surgery is muscle, not just fat [36,39]. This is like what happens when people take certain medications, like semaglutide and tirzepatide, to lose weight. It's worth noting that these medications may also produce significant muscle loss, which is why it's critical to monitor and maintain muscle health during weight loss. By doing so, people can ensure they lose weight in a healthy, sustainable way.

When you're trying to lose weight, it's common to lose some muscle mass too. This doesn't just happen with certain medications but with many weight-loss methods. So, it's a good idea to include strategies to preserve muscle in all weight-loss plans, no matter what method you're using (table). This way, you can make sure you're losing fat, not muscle.

Critical Appraisal of Evidence on Lean Body Mass Changes with GLP-1-Based Therapies

The current evidence evaluating changes in lean body mass during treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonists is derived predominantly from randomized controlled trials (RCTs originally designed to assess weight reduction and glycaemic efficacy rather than body composition outcomes. Consequently, although these trials provide high-quality evidence regarding treatment success and safety, their ability to determine the impact of incretin-based therapies on skeletal muscle preservation remains limited.

Neeland et al. [18] provided a comprehensive review of the available evidence on changes in lean body mass associated with GLP-1-based therapies. They considered potential mitigation approaches, including strength exercise and adequate protein intake. The review provides important mechanistic insight into the physiological basis of lean mass reduction during pharmacological weight loss and highlights the need to preserve muscle during obesity treatment. However, as a narrative review, it is subject to potential selection bias, lacks quantitative synthesis, and relies on the methodological quality of the underlying studies. Therefore, although valuable for clinical interpretation, it represents a lower level of evidence compared with systematic reviews and meta-analyses.

The STEP clinical trial program provided some of the strongest evidence on semaglutide-associated changes in body composition. In STEP 2, Davies et al. [19] conducted a large, multicentre, randomized, double-blind, placebo-controlled phase 3 trial evaluating semaglutide 2.4 mg weekly in adults with overweight or obesity and type 2 diabetes mellitus. The study demonstrated substantial weight reduction accompanied by improvements in glycaemic and cardiometabolic parameters. However, body composition assessment was performed only in a subgroup, and lean mass was not a primary endpoint. Additionally, the study did not evaluate muscle strength or physical function, limiting interpretation of whether the observed reductions in lean mass represented clinically significant muscle loss. Despite these limitations, the randomized design, large sample size, and prolonged follow-up provide robust evidence regarding treatment efficacy.

Similarly, the STEP 3 trial by Wadden et al. [20] revealed considerable weight loss with semaglutide combined with intensive behavioural therapy. The trial benefited from rigorous randomization, standardized lifestyle intervention, and high-quality outcome assessment. However, interpretation of changes in lean mass is limited because body composition was not comprehensively assessed across the entire cohort. Furthermore, the contribution of intensive behavioural therapy to changes in dietary intake and physical activity may have influenced body composition outcomes independently of pharmacological treatment.

Earlier liraglutide studies, including the SCALE Obesity [21] and SCALE Diabetes trials [22], provided important evidence regarding weight reduction with GLP-1 receptor agonism. Pi-Sunyer et al. [21] demonstrated clinically meaningful weight loss with liraglutide 3.0 mg in adults with obesity, while Davies et al. [19] confirmed similar benefits among individuals with type 2 diabetes. However, these studies primarily focused on weight and metabolic outcomes, and detailed assessments of fat mass and lean mass were not included as major endpoints. Therefore, conclusions regarding muscle preservation are indirect and largely based on assumptions regarding the proportional composition of weight loss.

The emerging evidence from dual GIP/GLP-1 receptor agonists provides additional insight into changes in body composition. The SURMOUNT-1 body composition sub-study by Look et al. [23] is among the most extensive analyses of tirzepatide-associated changes in fat and lean mass. The study used dual-energy X-ray absorptiometry (DXA) to directly assess body composition. It demonstrated substantial reductions in total body weight, predominantly driven by decreases in fat mass, accompanied by decreases in lean mass. A major strength of this study was the prespecified evaluation of body composition. However, DXA cannot differentiate skeletal muscle tissue from other lean compartments, including organs, connective tissue, and changes in extracellular water. In addition, muscle strength and physical performance outcomes were not assessed, limiting conclusions regarding sarcopenia risk.

The SURPASS-2 trial by Frías et al. [24] evaluated tirzepatide versus semaglutide in individuals with type 2 diabetes and displayed superior reductions in glycated haemoglobin and body weight with tirzepatide. However, the open-label design brings potential performance bias, and body composition outcomes were not included. Consequently, although the trial provides important comparative efficacy data, it contributes limited evidence regarding preservation of lean body mass.

Other landmark GLP-1RA cardiovascular and diabetes efficacy trials, including SUSTAIN 2 (semaglutide versus sitagliptin) [25], LEAD-2 (26), and AWARD-3 (dulaglutide versus metformin) [27], demonstrated favourable effects on glycaemic control and modest weight reduction. However, these studies did not incorporate direct measurements of body composition. The absence of DXA, bioelectrical impedance measurement, magnetic resonance imaging, or functional muscle assessments limits the contribution of these assessments to understanding the effects of GLP-1-based therapies on muscle health.

Overall, the available evidence demonstrates that GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists produce considerable weight loss mainly through reductions in adipose tissue, with smaller reductions in lean body mass. Nevertheless, several important methodological restrictions remain. First, most clinical trials were not designed with body composition as a primary outcome. Second, available assessments have relied primarily on DXA, which estimates lean tissue but does not directly quantify skeletal muscle mass or quality. Third, few studies have incorporated clinically meaningful measures of muscle strength, physical performance, frailty, or sarcopenia. Finally, older adults and people at high risk of sarcopenia remain underrepresented.

Potential Mechanisms Underlying Lean Mass Reduction:

Several physiological mechanisms may contribute to the reduction in lean body mass observed during incretin-based therapy (Table 5). The main mechanism is reduced energy intake due to appetite suppression and delayed gastric emptying, which together create a sustained negative energy balance. Although adipose tissue serves as the principal source of mobilized energy, some degree of lean tissue catabolism is an inevitable component of weight loss.

When you don't eat enough, you might not get the protein your body needs. This can hurt your muscles and make it harder for them to grow and repair themselves. For older people or those who already have muscle problems, not getting enough protein can worsen symptoms and bring about muscle loss. Weight loss also reduces mechanical loading of skeletal muscle. Decreased mechanical stress may attenuate anabolic signalling pathways that normally maintain muscle hypertrophy and maintenance, particularly in sedentary individuals.

When you lose weight, your body goes through some big changes. Your hormones, such as insulin, leptin, and growth hormone, start working differently. This can affect how your body builds and breaks down muscle. As a result, you might see changes in your lean body mass, which is the parts of your body that aren't fat, like your muscles. Testosterone, cortisol, and other hormones also have a role in this process. All such hormonal changes can be complex, but they're an important part of what happens when you're trying to lose weight.

Potential Protective Effects of GLP-1 Signalling: When you lose weight, you also tend to lose some muscle mass, but recent research suggests that GLP-1 signalling might help protect your muscles. Studies have shown that GLP-1 can improve how well your muscles use insulin, help them take up more glucose, reduce oxidative stress-related damage, and even make your mitochondria work better. It can also reduce chronic inflammation, which is a major contributor to muscle damage. All these effects combined might help keep your muscles healthy and strong, even if you're losing some overall muscle mass. This is important because it means that even if you're not building new muscle, you can still maintain the quality of the muscle you have, which is important for overall health and mobility.

When you lose weight, you're more likely to be able to move around and exercise, which can help keep your muscles strong. This is important because even if you lose some muscle mass, you might still be able to do everyday tasks and physical activities. So, it's not only about how much muscle you have, but also how well it works.

Clinical Implications: The findings of this review have several important consequences for clinical practice. First, clinicians should anticipate modest reductions in lean body mass during treatment with GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists as part of the expected physical response to weight loss. Second, current evidence indicates that these reductions are generally proportional to total weight loss and should not be interpreted as evidence of pathological skeletal muscle wasting.

It's important to keep your muscles healthy and strong, especially as you get older or if you have certain health problems. When trying to manage your weight, it's not only about losing fat, and about keeping your muscles from wasting away. This is why it's a good idea to combine medicine with other proven methods that help preserve muscle mass.

Progressive resistance exercise remains the most effective intervention for minimizing loss of lean body mass and improving muscle strength during weight reduction. Adequate dietary protein intake, generally in the range of 1.2–1.6 g/kg/day depending on age, renal function, and comorbidities, should be encouraged to maintain muscle protein synthesis. Regular participation in both aerobic and resistance exercise improves muscle quality, physical performance, and long-term maintenance of weight loss. Finally, patients at increased risk of sarcopenia should undergo periodic nutritional assessment and individualized dietary counselling, ideally under the guidance of a registered dietitian, to ensure adequate energy and protein intake throughout treatment.