Large reductions in body weight almost never come entirely from body fat.
Some fat-free mass is usually lost as well. That has made muscle loss an important question for newer incretin-based drugs, especially retatrutide, which has produced particularly large weight reductions in clinical trials.
The good news is that researchers now have direct body-composition data for retatrutide. The less satisfying part is that the data do not answer every question people often ask about “muscle loss.”
A 2025 body-composition substudy published in The Lancet Diabetes & Endocrinology found that retatrutide produced large reductions in fat mass while also reducing lean mass. Importantly, the proportion of weight lost as lean tissue was broadly similar to what has been reported with other obesity treatments.
That does not mean retatrutide prevents muscle loss. It also does not mean the treatment disproportionately destroys muscle.
The real answer is more nuanced.
TL;DR
Retatrutide does reduce lean mass during weight loss.
In the main published body-composition substudy:
- 189 adults with type 2 diabetes entered the substudy.
- 103 had usable DXA measurements at both baseline and week 36.
- Total fat mass fell by as much as 26.1% in the retatrutide groups.
- Exploratory analyses found losses of up to 10.9 kg of fat mass.
- Lean mass declined by as much as 6.5 kg in a treatment group.
- The investigators concluded that the proportion of lean mass lost relative to total weight loss was similar to other obesity treatments.
But DXA-measured lean mass is not the same thing as skeletal muscle. It also includes water, organs, connective tissue, and other non-fat tissues.
So the current evidence supports saying that retatrutide causes some lean-mass loss during substantial weight reduction. It does not yet establish exactly how much functional skeletal muscle is lost over the long term.
Why Muscle Loss Comes Up With Retatrutide
Retatrutide is a single peptide that activates three hormone receptors:
- GLP-1 receptor
- GIP receptor
- glucagon receptor
It remains investigational and is not currently approved by the FDA or any other regulatory agency. Lilly is continuing Phase 3 development across obesity, type 2 diabetes, cardiovascular disease, sleep apnea, osteoarthritis, and other conditions.
The reason body composition has attracted so much attention is simple: retatrutide has produced very large changes in body weight.
In the Phase 2 obesity trial, the 12 mg group lost an average of about 24.2% of body weight at 48 weeks. More recent Phase 3 TRIUMPH-1 results reported average weight reductions as high as 28.3% at 80 weeks under the efficacy estimand.
When total weight loss reaches that magnitude, researchers want to know where the lost mass came from.
Was it mostly fat?
Was a large amount lean tissue?
And how much of that lean tissue was actually skeletal muscle?
The Retatrutide Body-Composition Substudy
The most important evidence comes from a prespecified substudy of the Phase 2 retatrutide trial in adults with type 2 diabetes.
The analysis was published in 2025 in The Lancet Diabetes & Endocrinology.
The main diabetes trial enrolled 281 participants.
Of those, 189 participated in the body-composition substudy.
Researchers used dual-energy X-ray absorptiometry, or DXA, to measure changes in body composition.
The substudy included:
- 29 participants assigned to placebo
- 32 receiving retatrutide 0.5 mg
- 31 in pooled 4 mg groups
- 33 in pooled 8 mg groups
- 30 receiving 12 mg
- 34 receiving dulaglutide 1.5 mg
However, not every participant had complete imaging.
Of the 189 people enrolled in the substudy:
- 155 had a baseline DXA scan
- 103 completed treatment and had both baseline and week-36 scans.
That smaller number is important when judging how confidently the results can be generalized.
Most of the Change Was Fat Mass
The clearest finding was substantial fat loss.
At week 36, mean reductions in total fat mass were:
| Group | Change in Total Fat Mass |
|---|---|
| Retatrutide 0.5 mg | -4.9% |
| Retatrutide 4 mg | -15.2% |
| Retatrutide 8 mg | -26.1% |
| Retatrutide 12 mg | -23.2% |
| Dulaglutide | -2.6% |
| Placebo | -4.5% |
The 4 mg, 8 mg, and 12 mg groups showed significantly greater fat-mass reductions than placebo.
Exploratory analyses went further.
Researchers reported reductions of up to approximately:
- 10.9 kg in total fat mass
- 0.6 kg in android visceral fat mass.
So the weight reduction clearly was not being driven primarily by loss of lean tissue.
A large amount of adipose tissue was lost.
Retatrutide Also Reduced Lean Mass
Fat was not the only tissue that changed.
The study reported decreases in lean mass of as much as 6.5 kg in a retatrutide group.
That sounds substantial when considered by itself.
But interpreting lean-mass loss requires comparing it with the much larger total body-weight reduction occurring at the same time.
The authors’ conclusion was that the proportion of lean mass lost relative to total weight lost was similar to what has been observed with other obesity treatments.
In other words, retatrutide produced more overall weight loss, but the available data did not suggest that an unusually high percentage of that weight came from lean tissue.
Lean Mass Is Not the Same as Muscle Mass
This is probably the most important limitation of the phrase “retatrutide muscle loss.”
DXA does not directly measure skeletal muscle.
DXA broadly separates the body into:
- fat mass
- lean soft tissue
- bone mineral.
Lean soft tissue includes skeletal muscle, but it also contains:
- organs
- connective tissue
- body water
- glycogen-associated water
- other non-fat tissue.
So a decrease in DXA-measured lean mass cannot automatically be translated into an equal decrease in skeletal muscle.
A 2024 review of GLP-1-based therapies made this same point. The authors described DXA-measured fat-free mass as only a crude surrogate for skeletal muscle and noted that more advanced imaging and functional testing are needed to understand muscle changes properly.
That distinction becomes particularly important during rapid weight loss because changes in glycogen and associated water can alter lean-mass measurements.
How Does Retatrutide Compare With Other Incretin Drugs?
Lean-mass loss is not unique to retatrutide.
It occurs with many forms of significant weight reduction.
A 2026 systematic review and meta-analysis examining incretin therapies found that lean mass accounted for approximately:
- 35.2% of weight lost with semaglutide
- 25.4% with tirzepatide
- 26.8% with liraglutide
Across the included studies, roughly 25% to 39% of total weight loss with incretin therapies came from lean mass.
Lifestyle-induced weight loss also produced lean-mass reduction.
In that analysis, intensive lifestyle interventions produced a broadly comparable proportional reduction in lean mass, while lifestyle programs that incorporated resistance training produced a more favorable body-composition profile.
That puts the retatrutide findings into context.
The current concern is not that retatrutide appears to produce a completely different type of tissue loss. It is that very large total weight reductions can translate into substantial absolute changes in both fat and lean mass.
Tirzepatide Shows a Similar Pattern
The SURMOUNT-1 body-composition substudy provides another useful comparison.
In 160 participants with DXA data, tirzepatide produced a:
- 21.3% reduction in body weight
- 33.9% reduction in fat mass
- 10.9% reduction in lean mass
over 72 weeks.
Again, lean mass decreased.
But fat mass decreased much more.
This general pattern is common during effective weight reduction.
Does Losing Lean Mass Mean Someone Is Developing Sarcopenia?
Not necessarily.
Sarcopenia is not defined simply as losing kilograms of lean tissue.
Modern definitions of sarcopenia also consider factors such as:
- muscle strength
- muscle quantity
- physical performance
- functional ability.
Someone with obesity can lose some lean tissue while still improving the proportion of lean tissue relative to total body weight.
That is one reason a single DXA number does not fully describe skeletal muscle health.
The retatrutide substudy did not provide the kind of long-term muscle-function data needed to determine whether treatment meaningfully increases or decreases sarcopenia risk.
Absolute Muscle Loss May Still Matter
There is an important reason researchers continue to study this issue.
Even if the percentage of weight lost as lean mass is normal for weight reduction, extremely large total weight loss can still mean a meaningful absolute amount of lean tissue is lost.
For example, losing one-third of a relatively small amount of weight is very different from losing one-third of a much larger amount.
This issue may be especially relevant for:
- older adults
- people with low baseline muscle mass
- people with frailty
- people with physical disabilities
- people with chronic disease.
A recent scientific review noted that clinical weight-loss studies often report approximately 20% to 40% of total weight reduction coming from fat-free mass, which has increased interest in evaluating skeletal muscle more directly as anti-obesity drugs become more effective.
What We Still Do Not Know
The retatrutide body-composition data are useful, but there are major unanswered questions.
There Is Only One Published DXA Substudy
The key body-composition evidence comes from 189 adults enrolled in a Phase 2 type 2 diabetes substudy, with only 103 completing both baseline and week-36 DXA measurements.
That is much smaller than the full Phase 3 retatrutide program.
The Population Had Type 2 Diabetes
The results may not perfectly represent people with obesity who do not have diabetes.
DXA Does Not Directly Measure Skeletal Muscle
MRI or CT can provide more direct information about specific muscle compartments.
Muscle Quality Was Not Fully Characterized
Muscle quantity and muscle quality are different concepts.
Intramuscular fat, strength, power, and physical function may change differently from total lean mass.
Phase 3 Body-Composition Results Have Not Yet Been Published
Phase 3 trials have greatly expanded the retatrutide safety and efficacy database, but detailed Phase 3 DXA muscle-composition results have not yet become a central part of the published evidence.
So, Does Retatrutide Cause Muscle Loss?
The most scientifically accurate answer is:
Retatrutide causes some loss of lean mass during substantial weight reduction, but current evidence does not show that an unusually large proportion of the weight lost comes from lean tissue compared with other effective obesity treatments.
And “lean mass loss” should not automatically be translated into “skeletal muscle loss.”
The 2025 body-composition substudy showed dramatic reductions in fat mass alongside measurable decreases in lean mass. Investigators concluded that the overall composition of the weight loss was broadly comparable with other obesity treatments.
What remains uncertain is the effect of very large, sustained retatrutide-associated weight loss on actual skeletal muscle quantity, muscle quality, strength, and physical function across different patient populations.
Those questions will require more detailed and longer-term studies.
Retatrutide remains an investigational drug and has not been approved for medical use.
References
Coskun T, et al. Effects of retatrutide on body composition in people with type 2 diabetes. The Lancet Diabetes & Endocrinology. 2025. PubMed
Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial. New England Journal of Medicine. 2023. NEJM study
Look M, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study. PubMed
Lean Mass Changes With Incretin Therapy Versus Lifestyle Intervention: A Systematic Review and Meta-Analysis. 2026. PubMed
GLP-1 receptor agonist-based agents and weight loss composition: Filling the gaps. PubMed