Does Retatrutide Cause Muscle Loss?

DXA measures fat, lean soft tissue and bone mineral. Lean tissue includes muscle, organs and body water; a scan alone does not measure strength or diagnose sarcopenia. The useful questions are how body composition changes, whether strength and function are maintained, and whether nutrition and activity remain adequate.

The Phase 2 Body Composition Sub-Study

Study design

• Sub-study within the Phase 2 T2D trial (NCT04867785)
• Body composition measured by DXA scans (dual-energy X-ray absorptiometry) — the clinical gold standard for distinguishing fat mass from lean mass
• 36 weeks of treatment
• Primary endpoint: percent change in total fat mass at 36 weeks vs. placebo and dulaglutide (an existing GLP-1 drug)
• Comparators: placebo and dulaglutide 1.5mg

Who was actually scanned

56% of sub-study participants were female; 85% were White, 13% Black, and 3% Asian.

Why this data matters

This is the first time retatrutide's effect on body composition has been measured with DXA, providing objective data on how much of the weight lost is fat versus lean tissue. Prior to this, all retatrutide weight loss data reported only total body weight — we could not determine the composition of that weight loss.

What the sub-study reported

A percentage reduction in starting fat mass is not the percentage of total weight loss that was fat. For example, the table’s 26.1% is a change in the 8 mg group’s fat mass, not a claim that 26.1% of its weight loss was fat or muscle. Nor does the finding establish that retatrutide preserves all muscle or causes muscle growth.

Caveats: only 103 of the 189 enrolled participants completed treatment and both DXA scans. Total fat-mass change was the substudy’s prespecified primary endpoint, but the small sample and missing scans limit interpretation. The lower point estimate at 12 mg than 8 mg does not establish a dose plateau or its cause. Results in adults with type 2 diabetes may not generalize to everyone with obesity.

The Muscle Loss Question in Context

Why muscle loss matters during weight loss

When the body is in caloric deficit — whether from a drug that reduces appetite or from eating less — it draws energy from both fat stores and lean tissue. The consequences of excessive lean mass loss include:

• Reduced resting metabolic rate — muscle is metabolically active tissue, so losing it lowers the number of calories your body burns at rest
• Impaired physical function — particularly concerning in older adults, where sarcopenia (age-related muscle loss) is already a risk
• Potential for weight regain — a lower metabolic rate after weight loss can create conditions favorable for regaining weight if the drug is stopped
• Bone density reduction — significant weight loss can also reduce bone mineral density, increasing fracture risk

What we know from other GLP-1 drugs

Other weight-management studies also report lean-mass loss alongside fat loss. Comparing percentages across studies requires care: age, diabetes status, baseline composition, duration and measurement methods differ.

Why Retatrutide Might Differ

The glucagon hypothesis

Retatrutide’s glucagon activity is a reason to study body composition, not a guarantee of muscle preservation. The DXA paper notes both preclinical fat-loss findings and a potential concern: chronic glucagon activity can lower circulating amino acids, which could affect muscle protein synthesis.

Important caveats

The clinical substudy found a proportion of lean-mass loss broadly consistent with other weight treatments. It did not show that glucagon caused a better ratio. Glucagon agonism is also not unique to retatrutide: mazdutide and survodutide target that receptor too. Direct comparisons and measurements of strength and function are needed before claiming a muscle-preserving advantage.

Preserving Muscle During Weight Loss

Planning Nutrition and Exercise

Exercise and nutrition plans should match physical capacity, medical conditions and dietary needs. The advisory emphasizes individualized assessment, especially when baseline muscle reserve is low.

Why Resistance Training Matters

The advisory recommends combining adequate protein with structured resistance exercise; protein alone is unlikely to preserve muscle without that training stimulus. It suggests strength work at least three times weekly and at least 150 minutes of moderate aerobic activity, adapted to ability. These are general GLP-1-care recommendations, not a tested retatrutide-specific muscle-preservation regimen.

Hitting the protein target is harder on retatrutide

Reduced appetite can make eating enough difficult. The advisory suggests eating protein-rich foods first and considering nutrient-dense options such as eggs, yogurt, fish, legumes or a supplement when needed. Ongoing inability to eat adequately calls for clinical assessment; changing an investigational dose is not a nutrition plan.

How much of the loss is muscle?

A scan-based lean-mass estimate cannot answer this precisely because it includes more than skeletal muscle. Strength and physical function deserve attention alongside body composition. The advisory discusses repeat measurements and practical functional assessments; a clinician can choose an approach that fits the person rather than relying only on a scale or percentage.

What We Do Not Know Yet

• Larger body-composition datasets: the Phase 3 releases reviewed here do not settle the detailed fat, lean tissue and muscle-function questions raised by the small DXA substudy.
• Long-term muscle function: 36-week body composition does not establish what happens to strength, mobility or lean tissue over years.
• Direct comparison: the cited substudy does not establish a muscle-preserving advantage over semaglutide or tirzepatide.
• Bone and frailty outcomes: weight loss and lean-mass measurements alone cannot determine fracture risk or outcomes in older adults with limited muscle reserve.

Frequently Asked Questions

Sources

• Phase 2 Body Composition Sub-Study. The Lancet Diabetes & Endocrinology. June 2025. (NCT04867785 sub-study)
• Coskun, T., Wu, Q., Schloot, N.C., Haupt, A., Milicevic, Z., Khouli, C., Harris, C. (2025). Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial. The Lancet Diabetes & Endocrinology. DOI: 10.1016/S2213-8587(25)00092-0
• Rosenstock, J., et al. (2023). Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes. The Lancet. DOI: 10.1016/S0140-6736(23)01053-X
• Wilding, J.P.H., et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). New England Journal of Medicine. DOI: 10.1056/NEJMoa2032183
• Mozaffarian, D., et al. (2025). Nutritional priorities to support GLP-1 therapy for obesity: a joint advisory from the ACLM, ASN, OMA, and TOS. Obesity Pillars. PMC12264624
• ClinicalTrials.gov: NCT04867785