Saving muscle while losing weight: A vital strategy for sustainable results while on glucagon-like peptide-1 related drugs

Abstract

Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications, with cardiovascular disease being a leading cause of mortality. Losing 5%-10% of body weight is considered clinically significant for improving health. This weight loss can be achieved through pharmacotherapy, including glucagon-like peptide 1 (GLP-1) receptor agonists, GLP-1/glucose-dependent insulinotropic peptide dual receptor agonists, and GLP-1/glucose-dependent insulinotropic peptide/glucagon triple receptor agonists (such as semaglutide, tirzepatide, and retatrutide, respectively). While much of the weight loss comes from fat mass, these treatments also result in the loss of lean mass, including muscle. This loss of muscle may contribute to difficulties in maintaining weight over the long term and can lead to sarcopenia. Therefore, the focus of new anti-obesity treatments should be primarily on reducing fat mass while minimizing the loss of muscle mass, ideally promoting muscle gain. Research focusing on human myocytes has identified more than 600 myokines associated with muscle contraction, which may play a crucial role in preserving both muscle mass and function. We explored the potential of new anti-obesity agents and their combinations with incretin-based therapies to achieve these outcomes. Further studies are needed to better understand the functional implications of lean mass expansion during weight loss and weight maintenance programs.

Key Words: Weight maintenance; Myokines; Muscle preservation; Muscle loss; Glucagon-like peptide 1/glucose-dependent insulinotropic peptide/glucagon triple receptor agonists; Glucagon-like peptide 1/glucose-dependent insulinotropic peptide dual receptor agonists; Glucagon-like peptide 1 receptor agonists; Incretin-based therapy; Weight loss

Core Tip: Weight loss medications can lead to a reduction in both fat and muscle mass. Losing muscle can make it more difficult to maintain weight in the long term, and can increase the risk of sarcopenia, as well as the likelihood of regaining weight due to unfavorable changes in body composition. Therefore, it is essential for new medications to focus on preserving muscle mass or even promoting the growth of lean mass as part of weight maintenance programs. Additionally, research is being conducted on the release of myokines during muscle contraction and their roles in autocrine, paracrine, and endocrine functions related to muscle preservation.

INTRODUCTION

Obesity is a chronic disease affecting over 1 billion people worldwide and significantly increasing the risk of more than 230 other health complications. Among these, cardiovascular diseases are the leading cause of death[1]. A weight loss of 5%-10% of body weight is considered clinically significant for improving health, and this amount of weight loss can typically be achieved through pharmacotherapy[2]. In contrast, lifestyle interventions, including restrictive diets and physical exercise, typically do not lead to exceeding 5%, which is considered target threshold for effective weight management. Consequently, these interventions are frequently unjustly categorized as ineffective[3]. Modern anti-obesity treatments, including glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs), dual receptor agonists targeting GLP-1 and glucose-dependent insulinotropic peptide, and triple receptor agonists that include GLP-1, glucose-dependent insulinotropic peptid, and glucagon (such as semaglutide, tirzepatide, and retatrutide, respectively), have been shown to effectively reduce food intake and lead to significant weight loss in overweight and obese individuals. In some instances, the weight loss achieved with these treatments is comparable to that obtained through bariatric surgery[4-6]. Although most of the weight lost is fat mass, some muscle mass is also lost, which can complicate long-term weight maintenance[7]. Data from clinical trials show that stopping treatments like semaglutide and tirzepatide often results in weight regain in about two-thirds of patients[8,9]. This is not exclusive to GLP-1RAs but occurs after the most significant weight loss efforts[10]. Weight loss, whether through dieting, GLP-1 receptor agonism, or surgery, results in reductions of both fat and lean mass[11]. In the STEP-1 clinical trial on semaglutide, it was found that nearly 40% of the weight loss came from lean mass. Similar findings were observed with tirzepatide and retatrutide. However, newer focused studies examining changes in muscle composition during GLP-1-based treatment suggest reassuring results. Additionally, after metabolic surgery performed for morbid obesity, the loss of fat-free mass ranged from 23% to 32.4%[4-6,12-15]. Results of fat and lean (muscle) mass loss reported in different anti-obesity drug clinical trials are presented in Table 1. However, when tirzepatide was combined with low-energy ketogenic therapy, it was found to preserve fat-free mass, muscle strength, and resting metabolic rate for at least 12 weeks[16]. Although this protocol is demanding and might not be feasible for longer periods, it suggests a promising direction for future research. A meta-analysis involving 491 participants who actively engage in exercise and 425 sedentary controls shows that aerobic exercise, without any dietary restrictions, can lead to an average weight loss of 2.6 kg, with no change in fat-free mass. In contrast, resistance training can increase fat-free mass by approximately 2 kg in overweight men and about 1 kg in overweight women, however, this does not result in an overall change in weight[17]. When considering weight loss from diet alone, an expected loss of 10 kg is associated with a reduction of 2.9 kg of fat-free mass in men and 2.2 kg in women. However, if a similar weight loss is achieved through a combination of exercise and dietary restriction, the loss of fat-free mass is reduced to 1.7 kg for both men and women[17].

Table 1 Results of fat and lean (muscle) mass loss for anti-obesity agents.

Drug and dosage	Treatment duration (weeks)	Mechanism of action	Indication	Body weight change from baseline (%)	Lean body mass (%) of total body mass lost
Semaglutide 24 mg[4]	68	GLP-1R agonism	Obesity (without T2DM)	-14.9	39
Tirzepatide 15 mg[5]	72	GLP-1R/GIP dual agonism	Obesity (without T2DM)	-20.9	24
Retatrutide 12 mg[14]	36	GLP-1R/GIP/glucagon triple agonism	T2DM with a BMI of 25-50 kg/m2	-16.9	33
Retatrutide 12 mg[6]	48	GLP-1R/GIP/glucagon triple agonism	Obesity (without T2DM)	-22.8	-

BMI: Body mass index; GLP-1R: Glucagon-like peptide 1 receptor; GIP: Glucose-dependent insulinotropic peptide; T2DM: Type 2 diabetes mellitus.

Skeletal muscle is essential for insulin function, glucose metabolism, and energy expenditure. It also produces myokines that are crucial for various physiological functions[18,19]. Myokines are cytokines or peptides produced and released by myocytes in response to muscular contractions. More than 600 myokines have been identified to date. However, their potential to regulate metabolism in muscles and their influence on other tissues and organs, such as adipose tissue, the liver, and the brain, remain largely unclear. Currently, some myokines are being studied in clinical trials aimed at muscle preservation[20].

Sarcopenic obesity is a commonly overlooked condition in individuals with obesity. It is characterized by an increase in body fat mass accompanied by sarcopenia, which is defined as a decrease in muscle strength and mass. Sarcopenia is an independent risk factor for both all-cause mortality and cardiovascular mortality[21,22]. Moreover, sarcopenic obesity is associated with decreased energy expenditure, which further declines during weight loss. This reduction, along with the loss of skeletal muscle mass, contributes to an increased likelihood of weight regain after a one to five-year period[23,24]. This phenomenon can be attributed to a decrease in energy expenditure that occurs with weight loss, mainly due to the loss of muscle mass. For every kilogram of muscle mass lost, resting energy expenditure decreases by about 13 kcal per day. In contrast, losing fat mass only contributes to a reduction of about 4 kcal per day[11].

Additionally, sarcopenic obesity is frequently linked to a sedentary lifestyle and poor cardiorespiratory fitness, which per se is a risk factor for cardiovascular disease and increases morbidity and mortality[25-27]. Furthermore, there is increasing evidence of the harmful effects of low-grade chronic inflammation on muscle mass, strength, and functionality, as it negatively impacts muscle protein synthesis and breakdown[28].

The incidence of sarcopenic obesity increases with age, particularly in individuals over 65 years old. In this age group, there is a heightened risk of complications from both sarcopenia and obesity, which can be challenging to manage. Currently, there is limited clinical trial evidence regarding the pharmacotherapy options for obesity in older individuals. Traditional treatments, such as orlistat, facilitate weight loss by reducing fat and visceral adipose tissue, while having a minimal effect on lean body mass, making it, together with agents with an anti-inflammatory potential such as incretins, important therapeutic options for managing obesity in older individuals[29,30].

When evaluating weight-loss strategies, it is essential to focus on maintaining weight loss as it is a key indicator of long-term success. A randomized controlled trial involving obese individuals treated with 3.0 mg of liraglutide daily revealed that pairing this medication with physical exercise improved metabolic parameters and cardiorespiratory fitness[31]. Furthermore, this combination led to more sustained weight-loss results over time[31]. Conversely, research shows that sarcopenic obesity has a detrimental impact on weight management outcomes[32]. Thus, a weight loss strategy that aims to preserve lean muscle mass may offer long-term weight maintenance along with metabolic and functional advantages[11].

This review aims to provide the latest evidence on changes in lean body mass and muscle mass associated with GLP-1-based therapies, along with potential strategies to mitigate these effects. It highlights the complex relationship between muscle function and its role in metabolism, as well as how current weight loss treatments influence these aspects. Additionally, the review will explore opportunities to promote muscle health and address sarcopenia during weight loss management.

PHYSICAL EXERCISE AS A PART OF A WEIGHT MANAGEMENT STRATEGY

Regular physical exercise is associated with reduced body weight and improved body composition, especially the decrease of abdominal fat[33]. It is recommended that adults engage in a minimum of 150 minutes of moderate-intensity aerobic exercise each week to attain health benefits[34]. However, for individuals looking to achieve more substantial improvements in body mass and overall health, it may be necessary to exceed the recommended amount of exercise. Different types of exercise and varying intensities can have unique effects on muscle mass. Strength and resistance training, in particular, are the most effective for preserving muscle mass. A recent long-term study showed that participating in higher-load resistance training for one year during retirement age leads to sustained strength maintenance[35]. Additionally, resistance exercise can reduce fat-free mass loss by 50%-95% during calorie-restricted dieting[36]. A small randomized trial involving young male participants found that a combination of high-volume resistance training and anaerobic training, along with a diet containing 2.4 g of protein per kilogram of body weight per day, yielded better results than a diet with only 1.2 g of protein per kilogram of body weight per day. This approach led to a greater fat loss and increased lean body mass. These findings support proposed dietary recommendation for preserving fat-free mass, which include a fluid intake of more than 2-3 Liters per day, a protein intake of 1.5 g/kg body weight/day, and a total energy intake ranging from 1200-1500 kcal/day for women and 1500-1800 kcal/day for men[37,38].

Moreover, data from the Look AHEAD study, which examined the 4-point MACE (a composite measure of cardiovascular death, non-fatal acute myocardial infarction, non-fatal stroke, or hospitalization for angina), involved patients with diabetes and obesity undergoing an intensive lifestyle intervention. This intervention was defined by a weight loss of at least 7%, an increase in physical activity to a minimum of 175 minutes per week of moderate-intensity exercise, and personalized caloric intake reductions based on each participant’s baseline weight: 1200 calories to 1500 calories per day for those weighing over 113.4 kg, and 1500 calories to 1800 calories per day for those weighing less than 113.4 kg. The study suggested that substantial long-term health improvements can only be achieved with significant weight loss, specifically at least 10% of initial body weight. This level of weight loss was accomplished through approximately 287 minutes of exercise per week[39-41]. In practice, even modest physical activity goals can be challenging to achieve and maintain. This often results in periods of weight regain, indicating that some individuals may need alternative strategies to improve muscle mass and function.

SUPPLEMENTATION OF MYOKINES

Recent studies indicate a connection between the muscle-derived hormone irisin and various metabolic functions, including its positive effect on thermogenesis and the browning of fat tissue, which play crucial roles in effective weight management[42]. Irisin’s production is influenced by muscle contraction[43], and its circulating levels correlate with muscle mass[44]. Once released, irisin performs several important functions. It improves insulin resistance (IR) by enhancing the sensitivity of insulin receptors in both skeletal muscles and the heart. Additionally, irisin aids in the metabolism of glucose and lipids in the liver, enhances the function of pancreatic β cells, and promotes the browning of white adipose tissue. Irisin levels can vary significantly. For example, young male athletes tend to have levels that are several times higher than those of middle-aged obese women. Furthermore, circulating levels of irisin increase in response to acute exercise but tend to decrease following weight loss from bariatric surgery, which correlates with an overall reduction in body mass. This decrease has been attributed to a reduction in fat-free mass and lower levels of precursor mRNA for irisin in skeletal muscle. Notably, these changes can be reversed with weight regain[44]. A study conducted by Crujeiras et al[45] found that irisin levels can predict an increased risk of IR and weight gain in obese individuals who regain weight after successfully losing it through restrictive dieting. The association between irisin levels and IR suggests that there may either be an increased secretion of irisin from adipose or muscle tissue, or a compensatory rise in irisin levels to counteract the resistance. It appears that individuals with elevated circulating irisin levels are more likely to develop IR soon after regaining weight following a weight-loss diet[45]. In the clinical context, it is interesting to consider irisin within the “exercise is medicine” framework[46]. Research into the secretome and organokines is enhancing our understanding of how the body functions and the impact of exercise on preventing obesity and managing weight. The modulation of myokines shows promise as a strategy for weight management. However, much of the research is still in its early stages, primarily involving animal studies, with limited human trials. More investigation is necessary to understand the long-term effects and safety of interventions targeting myokines. Currently, the most effective way to boost myokine activity is through regular physical exercise combined with a balanced diet. Some evidence suggests that dietary supplements such as curcumin, resveratrol, astaxanthin, and fortetropin may help maintain muscle mass and stimulate the production of beneficial myokines during weight management[47]. In addition, new agents could be used in adjunct to incretin therapy for accentuated and more prolonged weight-management effects[48].

MUSCLE AS A NEW TARGET FOR PHARMACOTHERAPY?

Muscle mass increases through strength and resistance training due to complex mechanisms involving signaling pathways triggered by myokines[49]. Myokines, such as myostatin and activin A, are transforming growth factor beta-like ligands that inhibit muscle growth by acting on the activin type II receptors (ActRII). Myostatin inhibitors first captured attention in sports as potential doping agents, particularly in strength sports, as it was perceived that they might promote muscle growth. As a result, the World Anti-Doping Agency banned substances that inhibit myostatin in 2008, even though none were legally available at that time[50]. In preclinical and animal studies, the use of autoantibodies to block activin A and myostatin has shown a significant increase in muscle mass and a reduction in fat mass. This discovery opens up new opportunities for developing innovative drugs aimed at treating obesity and metabolic disorders. Recently published data from a phase 2 randomized clinical trial involving 75 patients with type 2 diabetes (body mass index between 28 kg/m² and 40 kg/m²) indicated that those receiving the ActRII antibody bimagrumab once monthly for 48 weeks, in combination with lifestyle counseling, experienced a 20.5% reduction in total body fat mass. Additionally, participants had a 3.6% increase in lean mass and a 0.76% decrease in hemoglobin A1c levels[51]. Relative to placebo, weight loss with bimagrumab was greater than the 1-year Food and Drug Administration agency-set threshold of 5%. Moreover, the distribution of body fat loss was highly favorable, with a reduction of abdominal visceral adipose tissue and waist circumference nearly twice that observed in the SCALE study[52]. Moreover, data reports from animal studies of simultaneous blockade of ActRII signaling and GLP-1R agonism suggest improvements in body composition and metabolic parameters during calorie deficit driven by GLP-1RA alone[49]. Similar agents, including the myostatin-targeted antibody trevogrumab and the activin A-targeted antibody garetosmab, are currently being tested in the COURAGE trial. These agents are being evaluated alone or in combination with semaglutide for treating obesity in adults. Preliminary findings suggest a possible muscle gain of 6%-8% through the co-blockade of activin and myostatin[53].

Another agent currently in phase 2 trials is enobosarm, an oral selective androgen receptor modulator. It has already been studied in 968 older men and postmenopausal women experiencing muscle wasting due to advanced cancer. An ad hoc subset analysis involving 29 obese patients with a body mass index of 30 kg/m² or higher showed that after 21 weeks of treatment with enobosarm at a dosage of 3 mg, there was a 14.4% reduction in total fat mass and a 4.51% decrease in total body weight measured by dual-energy X-ray absorptiometry compared to the placebo group, while maintaining total lean mass. Additionally, patients receiving the 3 mg dose of enobosarm demonstrated statistically significant improvements in physical function compared to those taking a placebo, with a P value of 0.049[54]. The phase 2b QUALITY clinical trial aimed to determine whether enobosarm, when combined with the GLP-1 receptor agonist Wegovy, could enhance fat reduction and weight loss while minimizing muscle loss. The results showed a statistically significant reduction in lean mass loss among subjects taking enobosarm (P = 0.002). On average, patients receiving enobosarm lost 71% less lean mass and gained 27% more fat mass compared to those on Wegovy alone. Additionally, 54.5% fewer patients experienced a ≥ 10% decline in stair climb power while using enobosarm, indicating an improvement in functional ability[55].

CONCLUSION

The primary goal of anti-obesity treatment should be to reduce fat mass while minimizing the loss of lean tissue and its associated functions. Preserving muscle mass is crucial for effective weight management. As sarcopenia is increasingly recognized as a comorbidity in obesity, the relationship between muscle loss and fat reduction becomes particularly significant. Some anti-obesity medications may unintentionally exacerbate muscle wasting, while others may offer protective benefits to muscle tissue. Furthermore, myokines - signaling molecules released by muscle - play a vital role in promoting the metabolic benefits of muscle, underscoring the importance of maintaining muscle health during weight loss. More research is needed to better understand the functional implications of increasing lean mass throughout weight loss and maintenance programs, especially in relation to pharmacological interventions and their impact on the muscle-fat relationship.