Over the previous decade, incretin-based pharmacotherapy — particularly, the category of glucagon-like peptide 1 receptor (GLP-1R) agonists and successor multi-agonists — have created a lot pleasure within the weight problems discipline(1).
These brokers are largely based mostly on the confirmed motion of GLP-1R to
suppress urge for food and cut back meals consumption. Potent incretin-based multi-agonist drug candidates at the moment are being developed at tempo in a number of drug-development pipelines.
By regulating a number of vitality stability pathways, these brokers can cut back complete physique weight by 10–25% 1, which matches what will be achieved with surgical interventions. Nevertheless, skeletal muscle upkeep throughout weight-loss remedy is rising as an important consideration for the event of those medication.
Why Skeletal Muscle Issues
Skeletal muscle contains roughly 40% of complete physique weight and performs numerous features, together with motion, posture and stability upkeep, respiratory, and essential metabolic duties like nutrient storage, vitality metabolism, and warmth manufacturing. Its function in vitality expenditure is
important for supporting sustainable weight reduction.
Determine: Chosen key roles of skeletal muscle as a structural versus metabolic organ. Muscle serves a twin function as each a structural/useful and metabolic organ. Functionally, muscle mass are essential for motion, stability, posture, and energy, all of that are important for bodily efficiency. Metabolically, muscle acts as a reservoir for amino acids important for stress response, restoration from trauma, and managing infections. Muscle additionally performs a major function in regulating glucose stability and synthesizing glutamine, an necessary amino acid for nitrogen transport and immune operate. The determine highlights the function of muscle-derived myokines—signaling molecules that act as endocrine elements—facilitating communication between muscle mass and numerous organs. This inter-organ interplay underscores muscle’s central function in total metabolic well being. Myokines improve endothelial operate, regulate urge for food by means of interactions with BDNF, and assist bone well being by selling bone mineralization. Moreover, myokines support in lipolysis and the browning of white adipose tissue, which boosts metabolic exercise and vitality expenditure. Tailored from Severinsen et al.(2)
Muscle additionally performs a major function in regulating glucose stability and synthesizing glutamine, an necessary amino acid for nitrogen transport and immune operate.
The determine highlights the function of muscle-derived myokines—signaling molecules that act as endocrine elements—facilitating communication between muscle mass and numerous organs.
This inter-organ interplay underscores muscle’s central function in total metabolic well being.
Myokines improve endothelial operate, regulate urge for food by means of interactions with BDNF, and assist bone well being by selling bone mineralization. Moreover, myokines support in lipolysis and the browning of white adipose tissue, which boosts metabolic exercise and vitality expenditure. Tailored from Severinsen et al.(2)
Nevertheless, any type of weight reduction tends to end in a discount of lean tissue and skeletal muscle mass.
Sarcopenia, which is characterised by low muscle energy mixed with decreased muscle amount or high quality, is acknowledged as a major danger issue for incapacity, sickness, and mortality(3).
Including to the complexity is sarcopenic weight problems, a situation the place intricate metabolic interactions between fats tissue and skeletal muscle end in muscle irritation, lipotoxicity, and weak spot in people with weight problems.
Muscle Loss in Weight-Loss Drug Trials
Part III trials have supplied an preliminary perception into the impact of latest weight-loss pharmacotherapies on lean physique mass and skeletal muscle mass. Within the STEP-1 trial, a subanalysis of 140 folks with weight problems with out diabetes given semaglutide at a dose of as much as 2.4 mg as soon as weekly over 68 weeks indicated that ~40% (6.92 kg or 15.2 lbs) of the full body-weight loss got here from lean mass (as measured by dual-energy X-ray absorptiometry (DXA)(4).
This proportion of lean physique mass to complete body-weight loss noticed is in line with semaglutide 1.0 mg as soon as weekly within the SUSTAIN 8 trial(5). Regardless of these findings, the proportion of lean physique mass relative to complete physique weight elevated in each research. Intriguingly, in human, GLP-1 infusions recruit skeletal muscle microvasculature and result in improved tissue oxygenation and metabolism(6).
Therefore, it’s believable that the impact of GLP-1R agonism on
skeletal muscle would possibly afford a protecting impact within the face of vitality restriction.
Thus, the discount in fats mass following GLP-1R (with or with out GIPR)-induced weight reduction might mitigate the antagonistic results of weight problems on muscle operate and contribute to enhanced mobility. Scientific trials persistently present a lack of lean physique mass with GLP-1R- and GLP-1R–GIPR-targeted therapies; nonetheless, the proof linking this to decreased muscle energy or sarcopenia is proscribed. Quite the opposite, there may be proof supporting improved muscle composition and total bodily efficiency and exercise(7).
Issues Measuring Muscle Loss
A serious problem in advancing analysis on this discipline is the dearth of standardized metrics for assessing skeletal muscle. Scientific research usually report totally different measurements of skeletal muscle mass, together with oblique assessments resembling fat-free mass or lean physique mass. Notably, lean physique mass represents a mixed measurement of muscle, ligaments, tendons, organ tissues, and water, whereas fat-free mass sometimes additionally contains bone mass.
Because of this, these metrics don’t present a exact measurement of skeletal muscle mass.
Moreover, the imaging strategies used differ extensively, starting from DXA and bioelectrical impedance evaluation to extra muscle-specific strategies like MRI or CT.
Whereas skeletal muscle mass and its proxies are incessantly reported, energy assessments are hardly ever included in weight-loss pharmacotherapy trials, as beforehand talked about. Muscle mass alone will not be a dependable indicator of energy, which is a stronger predictor of the antagonistic outcomes related to sarcopenia.
Consequently, worldwide consensus definitions of sarcopenia prioritize decreased muscle energy, supported by adjustments in muscle mass, high quality, or bodily efficiency.
Transferring ahead, standardizing skeletal muscle evaluation in giant medical trials is important for bettering comparability. Entire-body DXA, MRI, and CT imaging are validated strategies for evaluating skeletal muscle mass, as outlined in worldwide sarcopenia pointers.
Muscle high quality will be assessed by means of cross-sectional imaging strategies that present detailed insights into muscle structure and composition. For evaluating muscle energy and bodily efficiency, a mixture of assessments resembling chair-stand, grip energy, gait velocity, and the quick bodily efficiency battery will be utilized(3).
Do weight reduction medication improve likelihood of sarcopenia in these in danger?
An necessary problem for multi-agonist weight-loss medication is knowing their impression on skeletal muscle in people at excessive danger for sarcopenia or these already identified with the situation. Past getting old and weight problems, danger elements for sarcopenia embrace power diseases, bodily inactivity, and poor dietary standing. Due to this fact, learning weight-loss pharmacotherapy in populations with diminished skeletal muscle mass and energy is essential(7).
If weight-loss pharmacotherapy results in a lack of skeletal muscle mass and doubtlessly exacerbates sarcopenia, can this be prevented? Whereas rising dietary protein consumption alongside train seems to be a logical suggestion, there isn’t any clear consensus on the optimum quantity or kind of protein.
Equally,
the best frequency, kind, and depth of train interventions stay unsure and require additional research. That is significantly necessary since many sufferers might have already got sarcopenia or different disabilities that restrict their means to interact in vigorous bodily exercise.
Abstract
The emphasis of weight-loss pharmacotherapy ought to transfer from simply decreasing weight to selling wholesome weight reduction whereas preserving skeletal muscle mass, energy, and high quality.
Nevertheless, there are numerous unanswered questions that stay:
- Is there a discount in each muscle mass and performance (that’s, sarcopenia) with weight-loss medication?
- Which muscle consequence measures are finest utilized in medical trials?
- Does the danger of sarcopenia improve with advancing age, weight problems, MAFLD or MLTC?
- Is the danger of muscle loss elevated with GCGR-targeted multi-agonists?
- How finest can we deploy train and dietary protein supplementation methods?
- Are muscle anabolic brokers an answer to guard skeletal muscle?
Extra analysis is required to grasp the results of multi-agonists on skeletal muscle, particularly in
sufferers with sarcopenia. This strategy will in the end result in simpler and personalised weight-loss therapies sooner or later.
To attenuate the lack of lean mass, methods resembling rising protein consumption and including resistance train to remedy plans have been steered. These approaches can assist preserve muscle mass whereas nonetheless reaping the advantages of fats loss achieved by means of GLP-1-based therapies.
It is necessary to grasp that resistance train—loading the muscle mass—will all the time be the first think about retaining muscle throughout any weight reduction course of. Whereas protein is helpful, it performs a secondary function as compared, like its significance in
gaining lean mass by means of weightlifting.
You may be taught extra about methods to mitigate muscle loss whereas utilizing weight reduction medication like Ozempic
References:
1. Ansari S, Khoo B, Tan T: Focusing on the incretin system in weight problems and kind 2 diabetes mellitus. Nat Rev Endocrinol 20:447-459, 2024
2. Severinsen MCK, Pedersen BK: Muscle–Organ Crosstalk: The Rising Roles of Myokines. Endocrine Critiques 41:594-609, 2020
3. Cruz-Jentoft AJ, Bahat G, Bauer J, et al: Sarcopenia: revised European consensus on definition and analysis. 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 Impression of Semaglutide on Physique Composition in Adults With Chubby or Weight problems: Exploratory Evaluation of the STEP 1 Research. J Endocr Soc 3:A16–A17, 2021
5. McCrimmon RJ, Catarig AM, Frias JP, et al: Results of once-weekly semaglutide vs once-daily canagliflozin on physique composition in kind 2 diabetes: a substudy of the SUSTAIN 8 randomised managed medical 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 wholesome people. Scientific Science 127:163-170, 2014
7. Hope DCD, Tan TM: Skeletal muscle loss and sarcopenia in weight problems pharmacotherapy. Nat Rev Endocrinol 20:695-696, 2024
