Over the past decade, incretin-based pharmacotherapy — specifically, the class of glucagon-like peptide 1 receptor (GLP-1R) agonists and successor multi-agonists — have created much excitement in the obesity field(1).
These agents are largely based on the proven action of GLP-1R to
suppress appetite and reduce food intake. Potent incretin-based multi-agonist drug candidates are now being developed at pace in several drug-development pipelines.
By regulating multiple energy balance pathways, these agents can reduce total body weight by 10–25% 1, which matches what can be achieved with surgical interventions. However, skeletal muscle maintenance during weight-loss treatment is rising as a crucial consideration for the development of these drugs.
Why Skeletal Muscle Matters
Skeletal muscle comprises approximately 40% of total body weight and performs various functions, including movement, posture and balance maintenance, breathing, and crucial metabolic tasks like nutrient storage, energy metabolism, and heat production. Its role in energy expenditure is
vital for supporting sustainable weight loss.
Figure: Selected key roles of skeletal muscle as a structural versus metabolic organ. Muscle serves a dual role as both a structural/functional and metabolic organ. Functionally, muscles are crucial for movement, balance, posture, and strength, all of which are essential for physical performance. Metabolically, muscle acts as a reservoir for amino acids vital for stress response, recovery from trauma, and managing infections. Muscle also plays a significant role in regulating glucose balance and synthesizing glutamine, an important amino acid for nitrogen transport and immune function. The figure highlights the role of muscle-derived myokines—signaling molecules that act as endocrine factors—facilitating communication between muscles and various organs. This inter-organ interaction underscores muscle’s central role in overall metabolic health. Myokines enhance endothelial function, regulate appetite through interactions with BDNF, and support bone health by promoting bone mineralization. Additionally, myokines aid in lipolysis and the browning of white adipose tissue, which boosts metabolic activity and energy expenditure. Adapted from Severinsen et al.(2)
Muscle also plays a significant role in regulating glucose balance and synthesizing glutamine, an important amino acid for nitrogen transport and immune function.
The figure highlights the role of muscle-derived myokines—signaling molecules that act as endocrine factors—facilitating communication between muscles and various organs.
This inter-organ interaction underscores muscle’s central role in overall metabolic health.
Myokines enhance endothelial function, regulate appetite through interactions with BDNF, and support bone health by promoting bone mineralization. Additionally, myokines aid in lipolysis and the browning of white adipose tissue, which boosts metabolic activity and energy expenditure. Adapted from Severinsen et al.(2)
However, any form of weight loss tends to result in a reduction of lean tissue and skeletal muscle mass.
Sarcopenia, which is characterized by low muscle strength combined with reduced muscle quantity or quality, is recognized as a significant risk factor for disability, illness, and mortality(3).
Adding to the complexity is sarcopenic obesity, a condition where intricate metabolic interactions between fat tissue and skeletal muscle result in muscle inflammation, lipotoxicity, and weakness in individuals with obesity.
Muscle Loss in Weight-Loss Drug Trials
Phase III trials have provided an initial insight into the effect of new weight-loss pharmacotherapies on lean body mass and skeletal muscle mass. In the STEP-1 trial, a subanalysis of 140 people with obesity without diabetes given semaglutide at a dose of up to 2.4 mg once weekly over 68 weeks indicated that ~40% (6.92 kg or 15.2 lbs) of the total body-weight loss came from lean mass (as measured by dual-energy X-ray absorptiometry (DXA)(4).
This proportion of lean body mass to total body-weight loss observed is consistent with semaglutide 1.0 mg once weekly in the SUSTAIN 8 trial(5). Despite these findings, the proportion of lean body mass relative to total body weight increased in both studies. Intriguingly, in human, GLP-1 infusions recruit skeletal muscle microvasculature and lead to improved tissue oxygenation and metabolism(6).
Hence, it is plausible that the effect of GLP-1R agonism on
skeletal muscle might afford a protective effect in the face of energy restriction.
Thus, the reduction in fat mass following GLP-1R (with or without GIPR)-induced weight loss may mitigate the adverse effects of obesity on muscle function and contribute to enhanced mobility. Clinical trials consistently show a loss of lean body mass with GLP-1R- and GLP-1R–GIPR-targeted treatments; however, the evidence linking this to decreased muscle strength or sarcopenia is limited. On the contrary, there is evidence supporting improved muscle composition and overall physical performance and activity(7).
Problems Measuring Muscle Loss
A major challenge in advancing research in this field is the lack of standardized metrics for assessing skeletal muscle. Clinical studies often report different measurements of skeletal muscle mass, including indirect assessments such as fat-free mass or lean body mass. Notably, lean body mass represents a combined measurement of muscle, ligaments, tendons, organ tissues, and water, while fat-free mass typically also includes bone mass.
As a result, these metrics do not provide a precise measurement of skeletal muscle mass.
Additionally, the imaging techniques used vary widely, ranging from DXA and bioelectrical impedance analysis to more muscle-specific methods like MRI or CT.
While skeletal muscle mass and its proxies are frequently reported, strength assessments are rarely included in weight-loss pharmacotherapy trials, as previously mentioned. Muscle mass alone is not a reliable indicator of strength, which is a stronger predictor of the adverse outcomes associated with sarcopenia.
Consequently, international consensus definitions of sarcopenia prioritize reduced muscle strength, supported by changes in muscle mass, quality, or physical performance.
Moving forward, standardizing skeletal muscle assessment in large clinical trials is essential for improving comparability. Whole-body DXA, MRI, and CT imaging are validated methods for evaluating skeletal muscle mass, as outlined in international sarcopenia guidelines.
Muscle quality can be assessed through cross-sectional imaging techniques that provide detailed insights into muscle architecture and composition. For evaluating muscle strength and physical performance, a combination of tests such as chair-stand, grip strength, gait speed, and the short physical performance battery can be utilized(3).
Do weight loss drugs enhance chance of sarcopenia in those at risk?
An important challenge for multi-agonist weight-loss drugs is understanding their impact on skeletal muscle in individuals at high risk for sarcopenia or those already diagnosed with the condition. Beyond aging and obesity, risk factors for sarcopenia include chronic illnesses, physical inactivity, and poor nutritional status. Therefore, studying weight-loss pharmacotherapy in populations with diminished skeletal muscle mass and strength is crucial(7).
If weight-loss pharmacotherapy leads to a loss of skeletal muscle mass and potentially exacerbates sarcopenia, can this be prevented? While increasing dietary protein intake alongside exercise appears to be a logical recommendation, there is no clear consensus on the optimal amount or type of protein.
Similarly,
the ideal frequency, type, and intensity of exercise interventions remain uncertain and require further study. This is particularly important since many patients may already have sarcopenia or other disabilities that limit their ability to engage in vigorous physical activity.
Summary
The emphasis of weight-loss pharmacotherapy should move from just reducing weight to promoting healthy weight loss while preserving skeletal muscle mass, strength, and quality.
However, there are many unanswered questions that remain:
- Is there a reduction in both muscle mass and function (that is, sarcopenia) with weight-loss drugs?
- Which muscle outcome measures are best used in clinical trials?
- Does the risk of sarcopenia increase with advancing age, obesity, MAFLD or MLTC?
- Is the risk of muscle loss increased with GCGR-targeted multi-agonists?
- How best do we deploy exercise and dietary protein supplementation strategies?
- Are muscle anabolic agents a solution to protect skeletal muscle?
More research is needed to understand the effects of multi-agonists on skeletal muscle, especially in
patients with sarcopenia. This approach will ultimately lead to more effective and personalized weight-loss treatments in the future.
To minimize the loss of lean mass, strategies such as increasing protein intake and adding resistance exercise to treatment plans have been suggested. These approaches can help maintain muscle mass while still reaping the benefits of fat loss achieved through GLP-1-based therapies.
It’s important to understand that resistance exercise—loading the muscles—will always be the primary factor in retaining muscle during any weight loss process. While protein is beneficial, it plays a secondary role in comparison, like its importance in
gaining lean mass through weightlifting.
You can learn more about strategies to mitigate muscle loss while using weight loss drugs like Ozempic
here.
References:
1. Ansari S, Khoo B, Tan T: Targeting the incretin system in obesity and type 2 diabetes mellitus. Nat Rev Endocrinol 20:447-459, 2024
2. Severinsen MCK, Pedersen BK: Muscle–Organ Crosstalk: The Emerging Roles of Myokines. Endocrine Reviews 41:594-609, 2020
3. Cruz-Jentoft AJ, Bahat G, Bauer J, et al: Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48:601, 2019
4. John P H Wilding RLB, Salvatore Calanna, Luc F Van Gaal, Barbara M McGowan, Julio Rosenstock, Marie T D Tran, Sean Wharton, Koutaro Yokote, Niels Zeuthen, Robert F Kushner Impact of Semaglutide on Body Composition in Adults With Overweight or Obesity: Exploratory Analysis of the STEP 1 Study. J Endocr Soc 3:A16–A17, 2021
5. McCrimmon RJ, Catarig AM, Frias JP, et al: Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial. Diabetologia 63:473-485, 2020
6. Subaran SC, Sauder MA, Chai W, et al: GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans. Clinical Science 127:163-170, 2014
7. Hope DCD, Tan TM: Skeletal muscle loss and sarcopenia in obesity pharmacotherapy. Nat Rev Endocrinol 20:695-696, 2024
