GLP-1 Agonists & Muscle Mass: Research Concerns

Reviewed by PeptideJournal Science Team | Updated February 2026

Semaglutide and tirzepatide have delivered something obesity medicine has chased for decades: consistent, meaningful weight loss without surgery. But a question shadows every prescription written and every injection administered — how much of that lost weight is muscle?

The numbers depend on whom you ask. In Novo Nordisk's STEP 1 trial, roughly 40% of semaglutide-induced weight loss came from lean body mass. In Eli Lilly's SURMOUNT-1 trial, tirzepatide fared somewhat better at around 26%. And a 24-month retrospective study in older adults linked semaglutide to accelerated sarcopenia, declining grip strength, and slower walking speed.

None of this means GLP-1 receptor agonists are dangerous. It means the conversation about these drugs needs to move beyond pounds lost and start asking what kind of pounds are being lost. This article breaks down the research — what the trials actually measured, where the data gaps sit, and what patients and clinicians can do about it.

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Table of Contents

1. Why Muscle Mass Matters During Weight Loss
2. The Quarter Fat-Free Mass Rule
3. STEP 1 Body Composition Data: Semaglutide Under the DXA Scanner
4. SURMOUNT-1: How Tirzepatide Compares
5. Semaglutide vs. Tirzepatide: A Cross-Trial Body Composition Comparison
6. The Sarcopenia Concern in Older Adults
7. Is This Worse Than Normal Dieting?
8. The Measurement Problem: Why DXA Doesn't Tell the Whole Story
9. Mitigation Strategies: What the Evidence Supports
10. Next-Generation Approaches: CagriSema & Anti-Myostatin Antibodies
11. The Bottom Line
12. Frequently Asked Questions
13. References

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Why Muscle Mass Matters During Weight Loss

Skeletal muscle is the body's largest glucose disposal site, a key driver of resting metabolic rate, and a reservoir of amino acids the immune system taps during illness. Lose too much of it and you get a metabolic profile that looks worse than where you started — lower energy expenditure, impaired insulin sensitivity, reduced functional capacity, and elevated fracture risk.

Semaglutide (Wegovy/Ozempic) and tirzepatide (Zepbound/Mounjaro) produce weight loss of 15-22% over 68-72 weeks. That magnitude will almost always involve some lean tissue. The question is whether GLP-1 drugs accelerate lean mass loss beyond what caloric restriction alone would produce, and whether that loss translates into functional impairment.

The Quarter Fat-Free Mass Rule

For decades, obesity researchers have used the "Quarter Fat-Free Mass Rule" as a benchmark: during weight loss, about 25% of the weight shed will be fat-free mass (FFM), while 75% will be fat (Heymsfield et al., 2014).

The rule traces back to Gilbert Forbes's work in the 1980s mapping the curvilinear relationship between fat mass and fat-free mass. The key insight: leaner people lose proportionally more lean tissue during weight loss, while those with higher starting body fat lose proportionally more fat.

The rule has limitations — it doesn't account well for exercise, protein intake, age, or the speed of weight loss, and it underestimates lean mass loss in bariatric surgery patients. Still, 25% remains the benchmark against which GLP-1 body composition data is judged.

STEP 1 Body Composition Data: Semaglutide Under the DXA Scanner

The STEP 1 trial randomized 1,961 adults with obesity (BMI 30+ or 27+ with comorbidities) to semaglutide 2.4 mg weekly or placebo for 68 weeks. The headline result: 14.9% mean weight loss with semaglutide versus 2.4% with placebo (Wilding et al., NEJM, 2021).

A subset of 140 participants (95 semaglutide, 45 placebo) from nine trial sites underwent dual-energy X-ray absorptiometry (DXA) scans at baseline and week 68. Here is what the body composition data showed:

Measurement	Semaglutide (n=95)	Placebo (n=45)
Total weight change	-15.0%	-3.6%
Total fat mass change	-19.3%	—
Visceral fat mass change	-27.4%	—
Total lean body mass change	-9.7%	—
Lean mass proportion of total weight	+3.0 percentage points	—

In absolute terms, semaglutide-treated participants lost approximately 10.4 kg of fat mass and 6.9 kg of lean mass. That puts lean mass at roughly 40% of total weight lost — well above the Quarter FFM benchmark (Wilding et al., J Endocrine Soc, 2021).

But there is a counterargument baked into the same data. Despite losing lean mass in absolute terms, the proportion of lean tissue relative to total body weight increased by 3 percentage points. The lean-to-fat mass ratio improved, and improvements were larger in participants who lost more weight. Body composition got better overall even though lean mass declined in absolute terms.

Novo Nordisk has emphasized this point. Critics counter that an improved ratio does not negate the absolute loss of metabolically active tissue — especially if functional strength and physical performance decline.

SURMOUNT-1: How Tirzepatide Compares

The SURMOUNT-1 trial tested tirzepatide (a dual GIP/GLP-1 receptor agonist) at three doses in 2,539 adults with obesity. At the highest dose (15 mg), participants lost an average of 22.5% body weight over 72 weeks.

A DXA substudy of 160 participants produced body composition data that looked more favorable for lean mass preservation:

Measurement	Tirzepatide (n=124)	Placebo (n=36)
Total weight change	-21.3%	-5.3%
Fat mass change	-33.9%	-8.2%
Lean mass change	-10.9%	-2.6%
Lean mass as % of weight lost	~26%	~25%

At roughly 26% of total weight lost, tirzepatide's lean mass reduction fell close to the Quarter FFM benchmark. That is a notable difference from semaglutide's 40% figure — though the two trials enrolled different patient populations and used DXA at different time points, making direct comparison imperfect.

In absolute terms, tirzepatide-treated participants lost approximately 5.6 kg of lean tissue alongside 15.9 kg of fat mass. The proportion of body weight consisting of lean tissue was preserved or slightly increased (Look et al., Diabetes Obes Metab, 2025).

Semaglutide vs. Tirzepatide: A Cross-Trial Body Composition Comparison

No head-to-head trial has directly compared semaglutide and tirzepatide on body composition using the same measurement protocol in the same patient population. The SURMOUNT-5 trial, which was the first direct comparison of the two drugs, showed tirzepatide produced 20.2% weight loss versus semaglutide's 13.7% over 72 weeks — but it did not include a DXA substudy.

Still, the cross-trial numbers are worth examining side by side:

Parameter	Semaglutide 2.4 mg (STEP 1)	Tirzepatide 15 mg (SURMOUNT-1)
Total weight loss	~15%	~21.3%
Lean mass lost (absolute)	~6.9 kg	~5.6 kg
Fat mass lost (absolute)	~10.4 kg	~15.9 kg
Lean mass as % of total weight lost	~40%	~26%
DXA substudy size	95 treated	124 treated

The pattern here is striking. Tirzepatide produced greater total weight loss, greater fat loss, and less lean mass loss in both absolute and proportional terms. Some researchers speculate that the GIP receptor component of tirzepatide may play a role in lean mass preservation, though the mechanism remains under investigation.

A post-hoc MRI analysis from the SURPASS-3 trial (tirzepatide in type 2 diabetes) provided additional detail. MRI — which is more accurate than DXA for distinguishing muscle from other lean tissue — showed reductions in total fat mass with relatively lower reductions in lean mass, and also measured changes in myosteatosis (fat infiltration within muscle), which DXA cannot capture (Lancet Diabetes Endocrinol, 2025).

The Sarcopenia Concern in Older Adults

The most alarming data comes from a 24-month retrospective cohort study published in Drug Design, Development and Therapy in 2025. Researchers compared 220 older adults with type 2 diabetes taking semaglutide against 212 matched controls, tracking appendicular skeletal muscle mass index (ASMI), grip strength, and gait speed.

The findings were sobering:

• Muscle mass: ASMI declined significantly in the semaglutide group versus controls
• Grip strength: Initially improved in men, then declined; continuously decreased in women
• Gait speed: Significantly reduced in both sexes
• Sarcopenia prevalence: 27.7% of participants met sarcopenia criteria
• Dose response: Higher semaglutide doses predicted greater muscle loss

Multivariable analysis identified semaglutide dosage, baseline ASMI, and gait speed as independent predictors of muscle loss. The authors warned that semaglutide may "paradoxically accelerate physiological muscle decline, particularly at higher doses and in individuals with pre-existing low muscle mass" (Wang et al., DDDT, 2025).

A separate case report in the Korean Journal of Family Medicine described a 74-year-old man who developed severe sarcopenia after starting semaglutide for type 2 diabetes. He lost 8 kg, and his appendicular muscle mass dropped to 6.78 kg/m2 (below the 7 kg/m2 threshold for sarcopenia). His grip strength fell to 20 kg (normal is above 28 kg) and his walking speed declined significantly. After reducing his semaglutide dose and starting a structured exercise program, his muscle mass recovered to 8.75 kg/m2 over four months (Korean J Fam Med, 2025).

These findings matter because older adults already lose roughly 1-2% of muscle mass per year after age 50. Layering GLP-1-induced lean mass loss on top of age-related sarcopenia creates a compounding problem. For a 70-year-old with borderline muscle mass, the difference between independence and frailty can be a few kilograms of skeletal muscle.

Is This Worse Than Normal Dieting?

This is the most contested question in the field. The short answer: probably not — but the evidence is not conclusive.

A primer in Circulation argued that muscle-related changes with GLP-1 receptor agonists appear to be "adaptive" — meaning the lean mass lost is roughly proportional to what you would expect for the degree of weight loss achieved through any method (Circulation, 2024). GLP-1 agonists work primarily by reducing appetite, creating a caloric deficit. Since caloric restriction invariably produces some lean mass loss, it would be surprising if these drugs didn't. A 2025 analysis stated it plainly: "GLP-1 receptor agonists induce loss of lean mass: so does caloric restriction" (PMC, 2025).

A network meta-analysis of 22 randomized controlled trials (2,258 participants) found GLP-1 RAs reduced lean mass by an average of 0.86 kg — with lean mass at about 25% of total weight lost, right at the FFM benchmark (ScienceDirect, 2024). The heterogeneity between trials was large, though. Some reported lean mass losses of 25%, others closer to 40-60%. Study design, patient characteristics, substudy sample sizes, and measurement timing all contribute to the spread.

The honest assessment: GLP-1 drugs probably do not cause disproportionate lean mass loss relative to the caloric deficit they create. But they produce weight loss at magnitudes — 15-22% — that most patients would never achieve through diet alone. At those magnitudes, even a proportional lean mass loss becomes clinically significant.

The Measurement Problem: Why DXA Doesn't Tell the Whole Story

A major limitation in the current evidence is reliance on DXA to measure "lean mass." DXA cannot distinguish skeletal muscle from water, organ mass, or connective tissue. It cannot measure muscle quality — intramuscular fat infiltration, fiber type composition, or mitochondrial function.

This matters for three reasons:

• Up to 15% of adipose tissue consists of fat-free/lean mass. When a patient loses large amounts of fat, the lean component within that fat tissue disappears too, inflating the apparent lean mass loss on DXA without any actual muscle loss.
• Water shifts confound DXA readings. GLP-1 agonists affect fluid balance. Changes in water content can register as lean mass changes even when muscle protein mass hasn't changed.
• Most Phase 3 trials don't include body composition substudies. The FDA does not require tests of muscle function, mobility, or strength.

As a Journal of the Endocrine Society analysis put it: "Many Phase 3 clinical trials of anti-obesity medications do not assess muscle/lean mass changes, and those that do use a less accurate tool (DXA) rather than MRI, in a subset of the overall trial population" (J Endocrine Soc, 2024).

MRI and CT provide far more accurate assessments of muscle volume and quality. The SURPASS-3 MRI substudy is one of the few to use gold-standard imaging. Future trials need to follow that example.

One counterpoint worth noting: a 2024 University of Utah study found semaglutide improved mitochondrial efficiency in skeletal muscle, measured as ATP produced per O2 consumed — suggesting that even as muscle mass decreases, the remaining muscle may function better (PubMed, 2024).

Mitigation Strategies: What the Evidence Supports

The good news is that lean mass loss during GLP-1 therapy is not inevitable. Multiple lines of evidence point to practical interventions that can dramatically improve body composition outcomes.

Resistance Training

The European Association for the Study of Obesity's Physical Activity Working Group has stated that resistance training — not aerobic exercise — is the primary countermeasure against lean mass loss during weight reduction. Several systematic reviews confirm this finding.

A 2025 case series published in SAGE Open Medical Case Reports examined three patients who prioritized lean mass preservation during GLP-1 treatment. Each patient performed resistance training 3-5 days per week and maintained protein intakes of 0.7-1.7 g/kg/day. The results:

Patient	Drug	Weight Change	Fat Mass Change	Lean Mass Change
Case 1	Semaglutide	-33.0%	-53.4%	-6.9%
Case 2	Tirzepatide	-26.8%	-61.6%	+2.5%
Case 3	Tirzepatide	-13.2%	-46.9%	+5.8%

Case 2 and Case 3 actually gained lean tissue while losing substantial weight — a result that is extremely difficult to achieve during caloric restriction without structured resistance training (Tinsley & Nadolsky, SAGE, 2025).

This is a case series, not a randomized trial. But the pattern aligns with decades of exercise physiology research showing resistance training is the most effective intervention for preserving lean mass during energy deficit. For patients using peptides for muscle growth or following bodybuilding-oriented protocols, combining a GLP-1 agonist with structured strength training appears to offer aggressive fat loss with minimal muscle compromise.

Protein Intake

A 2025 presentation at the Endocrine Society's annual meeting (ENDO 2025) reported that higher protein intake protected against semaglutide-associated muscle loss, particularly in older adults and women. After adjusting for total weight loss, researchers found that being older, female, or consuming less protein was independently associated with greater lean mass decline (Haines et al., ENDO 2025).

Current recommendations for patients on GLP-1 therapy:

• General target: 1.2-1.6 g protein/kg body weight per day
• For those doing resistance training: 1.6-2.2 g/kg/day
• Priority sources: Complete proteins (eggs, dairy, poultry, fish, soy)

The practical challenge: GLP-1 agonists suppress appetite, and many patients struggle to eat enough food in general — let alone hit high protein targets. Working with a dietitian to plan protein-dense, lower-volume meals becomes especially important.

Combined Approach

The best available evidence suggests that combining resistance training and adequate protein intake produces better lean mass outcomes than either strategy alone. A Mass General review concluded that "combining a high protein diet and consistent exercise with GLP-1 treatment has the greatest benefit in preserving bone and muscle mass, compared to diet alone or high protein diet alone" (Mass General Advances in Motion, 2024).

For practical guidance on maintaining weight loss after stopping GLP-1 therapy, resistance training and protein adequacy become even more important — they provide the metabolic infrastructure to sustain results after the drug is discontinued.

Next-Generation Approaches: CagriSema & Anti-Myostatin Antibodies

The pharmaceutical industry is not ignoring the muscle mass problem. Two major approaches are in clinical development.

CagriSema (Cagrilintide + Semaglutide)

CagriSema combines cagrilintide (a long-acting amylin analogue) with semaglutide in a single weekly injection. In the REDEFINE 1 trial, published in the New England Journal of Medicine in 2025, CagriSema produced 22.7% mean weight loss in adults with obesity over 68 weeks (NEJM, 2025).

A DXA substudy of 252 participants found:

Treatment	Fat Mass (% of weight lost)	Lean Soft Tissue (% of weight lost)
CagriSema	66.9%	33.1%
Semaglutide alone	69.7%	30.3%
Cagrilintide alone	62.9%	37.1%
Placebo	56.7%	43.3%

CagriSema's lean mass loss proportion (33.1%) sits between the semaglutide STEP 1 figure (~40%) and the tirzepatide SURMOUNT-1 figure (~26%). Among participants who lost 30% or more of body weight, lean tissue proportion rose from 51.3% at baseline to 63.2% at 68 weeks.

Preclinical rodent data suggested CagriSema would preferentially target fat mass while preserving lean mass. The human data partially supports this, though the improvement over semaglutide alone was more modest than hoped. Novo Nordisk has submitted a New Drug Application to the FDA, with a decision expected in 2026.

Regeneron's COURAGE Trial: Anti-Myostatin Antibodies

A more targeted approach comes from Regeneron's Phase 2 COURAGE trial, which tests whether blocking myostatin — a protein that inhibits muscle growth — can preserve lean mass during semaglutide treatment.

The trial enrolled 605 adults with obesity and tested semaglutide alone or in combination with trevogrumab (an anti-myostatin antibody), with or without garetosmab (an anti-activin A antibody). Results presented at EASD 2025 were striking:

Treatment Group	Lean Mass Change	Lean Mass as % of Weight Lost
Semaglutide alone	-6.5%	33%
Semaglutide + trevogrumab 200 mg	-3.3%	16.8%
Semaglutide + trevogrumab 400 mg	-3.8%	—
Triple combination (+ garetosmab)	-2.0%	7.4%

The triplet combination preserved roughly 80% of the lean mass that would have been lost with semaglutide alone — while simultaneously increasing fat loss from 15.7% to 27.1%. All combination groups showed statistically significant improvements over semaglutide monotherapy (P < .0001) (Regeneron, EASD 2025).

The triple combination did show a higher discontinuation rate due to tolerability issues, and two deaths occurred in that group (though no causal link was established). The doublet combination was generally well tolerated.

The trial's weight maintenance phase (weeks 26-52) is ongoing, with full results expected in late 2026. If confirmed, anti-myostatin antibodies could become a standard adjunct to GLP-1 therapy — particularly for older patients or those with limited ability to exercise. Eli Lilly had been developing bimagrumab (another anti-myostatin agent) with tirzepatide but halted its Phase 2b trial in September 2025 for "strategic business reasons."

The Bottom Line

GLP-1 receptor agonists produce real lean mass loss. That is not in dispute. What is disputed is whether that loss is disproportionate (probably not for most patients), whether it impairs function (the evidence is mixed, but concerning in older adults), and whether it can be mitigated (yes, substantially).

Here is what the evidence supports as of early 2026:

1. Semaglutide-induced weight loss includes roughly 33-40% lean mass based on DXA substudies — above the traditional 25% FFM benchmark, though this figure varies by study and population.

2. Tirzepatide appears to preserve lean mass somewhat better at roughly 26% of weight lost — closer to the expected benchmark — but no head-to-head body composition trial exists.

3. Older adults, women, and those with low baseline muscle mass are at highest risk for clinically meaningful lean mass loss and functional decline.

4. Resistance training is the single most effective countermeasure. Case series data show that patients who train 3-5 days per week with resistance exercises can maintain — or even gain — lean tissue during GLP-1-induced weight loss.

5. Protein intake of 1.2-1.6 g/kg/day (or higher for active individuals) provides additional protection against muscle loss.

6. The measurement tools used in most trials (DXA) overestimate true muscle loss by conflating water, organ tissue, and lean components of adipose tissue with skeletal muscle.

7. Next-generation therapies — CagriSema and anti-myostatin antibodies — show early promise in shifting the ratio of weight loss further toward fat.

For patients currently on or considering GLP-1 therapy: talk to your doctor about body composition monitoring, start or maintain a resistance training program, and prioritize protein intake. The drugs work. The question is whether you are doing the ancillary work to ensure the weight you lose is the weight you want to lose.

Frequently Asked Questions

Does semaglutide cause muscle loss?

Yes. Clinical trial data from the STEP 1 DXA substudy shows semaglutide-induced weight loss includes approximately 40% lean body mass. However, lean mass is not the same as muscle mass — DXA cannot distinguish between muscle, water, and organ tissue. The proportion of lean tissue relative to total body weight actually improves during treatment.

How much muscle do you lose on Ozempic or Wegovy?

In STEP 1, participants taking semaglutide 2.4 mg lost approximately 6.9 kg of lean mass over 68 weeks, alongside 10.4 kg of fat mass. This represents about a 9.7% reduction from baseline lean mass. Individual results vary significantly based on exercise habits, protein intake, and starting body composition.

Is tirzepatide better than semaglutide for preserving muscle?

Cross-trial comparisons suggest tirzepatide may preserve lean mass better than semaglutide. In SURMOUNT-1, roughly 26% of tirzepatide-induced weight loss was lean mass, versus approximately 40% in STEP 1 for semaglutide. However, no head-to-head body composition trial has been conducted, so this comparison should be interpreted cautiously.

Can you prevent muscle loss while taking a GLP-1 agonist?

Evidence strongly supports that resistance training (3-5 days per week) and adequate protein intake (1.2-1.6 g/kg/day or higher) can substantially reduce or even eliminate lean mass loss during GLP-1 therapy. One case series documented patients who gained lean tissue while losing 13-33% of body weight on semaglutide or tirzepatide.

Are older adults at greater risk for GLP-1-related muscle loss?

Yes. A 24-month retrospective study found semaglutide was associated with accelerated sarcopenia in older adults with type 2 diabetes, including declining grip strength and gait speed. Higher doses and lower baseline muscle mass predicted greater loss. Older adults should discuss muscle preservation strategies with their healthcare provider before starting GLP-1 therapy.

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References

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2. Wilding JPH, Batterham RL, Calanna S, et al. Impact of semaglutide on body composition in adults with overweight or obesity: exploratory analysis of the STEP 1 study. J Endocrine Soc. 2021;5(Suppl 1):A16. PMC8089287

3. Look M, Tronieri JS, Engel S, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study. Diabetes Obes Metab. 2025. doi:10.1111/dom.16275

4. Heymsfield SB, Gonzalez MC, Shen W, et al. Weight loss composition is one-fourth fat-free mass: a critical review and critique of this widely cited rule. Obes Rev. 2014;15(4):310-321. PMC3970209

5. Neeland IJ, Linge J, Birkenfeld AL. Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024;26(Suppl 4):40-51. doi:10.1111/dom.15728

6. Heymsfield SB, Coleman LA, Miller R, et al. Fundamental body composition principles provide context for fat-free and skeletal muscle loss with GLP-1 RA treatments. J Endocrine Soc. 2024;8(11):bvae164. doi:10.1093/jes/bvae164

7. Wang Y, et al. Semaglutide therapy and accelerated sarcopenia in older adults with type 2 diabetes: a 24-month retrospective cohort study. Drug Des Devel Ther. 2025. PMC12235021

8. Sargeant JA, et al. GLP-1 receptor agonists and muscle mass effects. Circulation. 2024. doi:10.1161/CIRCULATIONAHA.124.067676

9. Tinsley GM, Nadolsky S. Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: a case series. SAGE Open Med Case Rep. 2025. PMC12536186

10. Regeneron Pharmaceuticals. Results from Phase 2 COURAGE trial demonstrating potential to improve quality of GLP-1 receptor agonist-induced weight loss by preserving lean mass. Presented at EASD 2025. Press release

11. Novo Nordisk. CagriSema 2.4 mg/2.4 mg demonstrated 22.7% mean weight reduction in adults with overweight or obesity in REDEFINE 1. N Engl J Med. 2025. doi:10.1056/NEJMoa2502081

12. Haines M, et al. Consuming more protein may protect patients taking anti-obesity drug from muscle loss. Presented at ENDO 2025. Endocrine Society

13. Sargeant JA, et al. GLP-1 agonists and exercise: the future of lifestyle prioritization. Front Clin Diabetes Healthc. 2025. PMC12683586

14. Tanaka K, et al. Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle. 2024. PubMed: 39605484

15. Park S, et al. A case report of semaglutide-induced sarcopenia: causes of fatigue in older adults. Korean J Fam Med. 2025. PMC12301675

16. Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: systematic review and network meta-analysis. Obesity. 2024. doi:10.1016/j.jcjo.2024.10.010

17. Tirzepatide and muscle composition changes in people with type 2 diabetes (SURPASS-3 MRI). Lancet Diabetes Endocrinol. 2025. doi:10.1016/S2213-8587(25)00027-0

18. Preserving lean body mass in patients taking GLP-1 for weight loss. Mass General Advances in Motion. 2024. Link

This article is for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare provider before starting or modifying any medication regimen.