Retatrutide vs CagriSema Muscle Loss: Which Preserves More Muscle During Weight Loss?
Last updated: October 2026
Retatrutide and CagriSema are investigational obesity treatments that can produce substantial weight loss through different hormonal mechanisms. But for people who want to reduce body fat without sacrificing muscle, the scale alone does not tell the whole story.
The critical question is not simply which treatment produces the greatest weight reduction. It is how much of that reduction comes from fat, how much comes from lean tissue, and whether the treatment helps people maintain muscle strength and physical function throughout the process.
Existing clinical evidence provides some insight into body-composition changes with both treatments. However, there is currently insufficient evidence to establish that retatrutide or CagriSema preserves more muscle than the other.
This review examines the published clinical evidence, explains what body-composition measurements can and cannot tell us, and outlines practical strategies for protecting muscle during substantial weight loss.
Key Takeaways
- Retatrutide: A Phase 2 body-composition substudy published in The Lancet Diabetes & Endocrinology in 2025 found substantial fat-mass reductions alongside lean-mass reductions. The investigators reported that the proportion of weight loss attributable to lean mass was similar to that observed with other obesity treatments.
- CagriSema: The Phase 3a REDEFINE 1 trial demonstrated substantial weight loss over 68 weeks. Exploratory DXA body-composition findings presented by Novo Nordisk indicated that most measured weight loss came from fat mass, with a proportion also attributable to lean soft tissue.
- No valid head-to-head muscle comparison exists: The studies differed in population, duration, treatment protocol and body-composition reporting. Their results cannot reliably establish which treatment is more muscle-sparing.
- Lean mass is not synonymous with skeletal muscle: DXA measures lean soft tissue and fat mass, not isolated contractile muscle. Strength and physical function are also important outcomes.
- Muscle preservation requires a broader strategy: Progressive resistance training, adequate protein, appropriate energy intake and clinical monitoring matter regardless of the treatment used.
1. What Are Retatrutide and CagriSema?
Retatrutide
Retatrutide is an investigational triple hormone receptor agonist developed by Eli Lilly. It activates receptors for:
- Glucose-dependent insulinotropic polypeptide (GIP)
- Glucagon-like peptide-1 (GLP-1)
- Glucagon
Its combined activity affects appetite regulation, glucose metabolism, energy balance and body weight.
CagriSema
CagriSema is an investigational fixed-dose combination developed by Novo Nordisk. It combines:
- Cagrilintide: A long-acting amylin analogue.
- Semaglutide: A GLP-1 receptor agonist.
The two components act through complementary pathways involved in appetite, satiety and food intake.
Although these treatments use different mechanisms, both can generate substantial energy deficits through reduced appetite and food intake. When energy intake falls considerably, the body may lose both fat and lean tissue.
The practical challenge is to maximise fat loss while retaining as much muscle, strength and physical function as possible.
2. Retatrutide: What Does the Muscle-Loss Evidence Show?
The 2025 Phase 2 body-composition substudy
The most directly relevant published evidence is the study by Coskun and colleagues, published in The Lancet Diabetes & Endocrinology in August 2025.
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The research was a substudy of a randomised, double-blind Phase 2 trial involving adults with type 2 diabetes. Participants received different retatrutide doses, placebo or dulaglutide. Body composition was assessed using dual-energy X-ray absorptiometry (DXA).
Retatrutide body-composition findings
Source: Coskun et al., The Lancet Diabetes & Endocrinology, 2025. These are reported maximum findings across dose groups and analyses, not a matched estimate for every participant or a head-to-head comparison with CagriSema.
The primary body-composition endpoint was percentage change in total fat mass. Retatrutide produced substantial reductions in fat mass compared with placebo at several doses.
The investigators also assessed lean-mass changes. Their interpretation was that the proportion of weight loss attributable to lean mass was similar to that reported with other obesity treatments, despite the substantial overall weight loss observed with retatrutide.
This is an important distinction. A drug can produce greater absolute lean-mass loss because it produces greater total weight loss, without necessarily causing a larger proportion of weight lost to come from lean tissue.
Important limitations of the retatrutide study
- The body-composition findings came from a Phase 2 substudy involving people with type 2 diabetes, rather than a dedicated muscle-preservation trial in the general obesity population.
- Although 189 participants entered the body-composition substudy, 155 had a baseline DXA scan and 103 completed treatment with both baseline and week-36 scans.
- The maximum fat-mass and lean-mass changes should not automatically be treated as results from the same dose group or as a ratio that applies to every patient.
- DXA-derived lean mass includes lean soft tissue beyond skeletal muscle and can be affected by changes in body water.
- The study was funded by Eli Lilly, and the authors disclosed employment and shareholding relationships with the company.
Consequently, the evidence supports the conclusion that retatrutide can reduce fat mass substantially while also reducing lean mass. It does not establish that retatrutide has a unique muscle-preserving effect.
Primary reference: Coskun T, et al. Effects of retatrutide on body composition in people with type 2 diabetes. The Lancet Diabetes & Endocrinology. 2025;13:674–684.
3. Retatrutide Phase 3 Results: Does Greater Weight Loss Mean Greater Muscle Loss?
In September 2026, the Phase 3 TRIUMPH-1 trial of retatrutide was published in the New England Journal of Medicine. This trial evaluated adults with obesity without diabetes over 80 weeks.
TRIUMPH-1: Mean percentage change in body weight at week 80
Source: Jastreboff et al., New England Journal of Medicine, September 29, 2026. These are the published treatment-regimen estimates and are not body-composition or muscle-loss measurements.
The results demonstrate substantial weight-loss efficacy. However, total weight reduction cannot tell us how much weight was lost from body fat, skeletal muscle, other lean tissues or body water.
The key evidence gap remains: the Phase 3 weight-loss result does not, by itself, demonstrate superior muscle preservation. A dedicated, adequately powered body-composition assessment with measures of muscle strength and function would be needed to answer that question reliably.
4. CagriSema: What Does the Muscle-Loss Evidence Show?
The Phase 3a REDEFINE 1 trial
REDEFINE 1 evaluated CagriSema in adults with overweight or obesity who did not have diabetes. The 68-week trial compared CagriSema with semaglutide, cagrilintide and placebo.
In the primary publication, the mean percentage change in body weight at week 68 was:
- CagriSema: −20.4%
- Placebo: −3.0%
These figures use the treatment-policy estimand, which includes outcomes regardless of treatment discontinuation or other events handled under the study's analysis plan. The investigators also reported a 22.7% reduction under the trial-product estimand, which estimates the treatment effect under a scenario in which participants remained on treatment without specified rescue interventions.
These two estimates answer slightly different statistical questions and should not be used interchangeably.
What do the DXA body-composition findings show?
Additional REDEFINE 1 body-composition findings were presented by Novo Nordisk at the American Diabetes Association's 2025 Scientific Sessions. The analysis used DXA to assess changes in total body fat mass and total body lean soft-tissue mass at week 68.
CagriSema: Reported DXA findings
Source: Novo Nordisk, REDEFINE 1 scientific-session presentation, ADA 2025. These are exploratory body-composition findings from a DXA subgroup, not a dedicated muscle-strength study or proof that CagriSema preserves more muscle than another treatment.
The findings suggest that the majority of measured weight reduction came from body fat. They also indicate that a proportion came from lean soft tissue.
However, these results require careful interpretation for three reasons.
- Lean soft tissue is not the same as skeletal muscle. DXA measurements include water and other lean tissues.
- The analysis was a subgroup assessment. It should not be treated as a definitive demonstration of muscle preservation for every person receiving CagriSema.
- The findings do not establish superiority over retatrutide. The trials had different populations, duration, protocols and reporting methods.
The results support the view that substantial fat loss can occur with CagriSema, alongside measurable lean-tissue changes. They do not establish that CagriSema prevents muscle loss.
Source: Novo Nordisk, REDEFINE 1 and REDEFINE 2 scientific-session presentation, ADA 2025.
5. Retatrutide vs CagriSema: Side-by-Side Evidence Comparison
Retatrutide
Mechanism: GIP, GLP-1 and glucagon receptor agonism.
Relevant body-composition evidence: A peer-reviewed Phase 2 DXA substudy in people with type 2 diabetes, published in 2025.
Study duration: 36 weeks for the body-composition substudy.
Finding: Substantial fat-mass reductions alongside lean-mass reductions. Investigators reported that the proportion of weight lost as lean mass was similar to that with other obesity treatments.
Limitation: No direct head-to-head trial establishes better muscle preservation than CagriSema.
CagriSema
Mechanism: Amylin analogue plus GLP-1 receptor agonism.
Relevant body-composition evidence: Exploratory DXA subgroup findings presented from REDEFINE 1.
Study duration: 68 weeks for REDEFINE 1.
Finding: Most measured weight reduction came from fat mass, with a reported proportion coming from lean soft tissue.
Limitation: The DXA findings are not proof of superior skeletal-muscle preservation and cannot be directly compared with retatrutide's Phase 2 substudy.
The comparison above deliberately avoids ranking the treatments by absolute kilograms of lean mass lost. Those figures are influenced by baseline body composition, total weight reduction, treatment duration, participant characteristics and study methods.
6. Why You Cannot Rank Them by Muscle Loss Yet
There are several methodological problems with comparing the available numbers as though both medicines were tested in the same trial.
Different populations
The retatrutide body-composition substudy included participants with type 2 diabetes. REDEFINE 1 enrolled adults with overweight or obesity without diabetes. Differences in age, baseline body composition, metabolic status and other characteristics can affect the response to weight-loss treatment.
Different treatment durations
The retatrutide substudy measured changes through week 36, whereas the REDEFINE 1 body-composition analysis assessed changes through week 68. Longer exposure and greater total weight loss can produce different absolute changes in fat and lean tissue.
Different doses and analyses
Neither treatment's results should be interpreted as though every participant received the same dose, achieved the same weight reduction or completed treatment. Estimated treatment effects also depend on how trial discontinuation, missing measurements and other events are handled statistically.
Lean mass is not identical to muscle
DXA separates body composition into bone mineral, fat mass and lean soft tissue. Although lean soft tissue includes skeletal muscle, it also includes organs, connective tissue and body water.
During rapid weight loss, changes in hydration and glycogen stores can affect lean-mass estimates. A reduction in DXA-derived lean mass therefore does not necessarily represent an equivalent loss of muscle protein or contractile muscle tissue.
Muscle quality matters
Preserving muscle is not only about retaining kilograms of lean tissue. Muscle strength, physical performance and the ability to perform everyday activities are also clinically meaningful.
A treatment that produces a favourable fat-to-lean-mass change does not automatically preserve strength. Conversely, a change in lean mass does not automatically demonstrate clinically important muscle weakness.
7. Does Retatrutide's Glucagon Activity Cause More Muscle Loss?
This is a reasonable scientific question, but it cannot be answered from the mechanism alone.
Retatrutide activates the glucagon receptor in addition to the GIP and GLP-1 receptors. Glucagon signalling affects energy metabolism, and researchers have examined potential interactions between glucagon activity, amino-acid metabolism and protein balance.
However, a theoretical mechanism does not demonstrate that a medicine causes more clinically important muscle loss in humans.
The published Phase 2 retatrutide body-composition study found substantial fat-mass reductions and reported that the proportion of weight loss attributable to lean mass was similar to that seen with other obesity treatments.
That evidence does not support describing retatrutide as inherently muscle-wasting. Equally, it does not establish that the drug is muscle-sparing.
The clinically relevant question is the overall effect on fat mass, lean tissue, strength, physical function, nutrition and long-term health—not whether a single receptor pathway could theoretically influence muscle metabolism.
8. How to Preserve Muscle During Treatment With Either Drug
Until comparative evidence becomes available, the most defensible strategy is to protect muscle during weight loss regardless of which treatment is eventually prescribed.
1. Prioritise progressive resistance training
Resistance exercise provides a mechanical stimulus that helps the body maintain muscle during periods of reduced energy intake.
A practical programme may include two or three resistance-training sessions per week, covering major muscle groups and progressing according to ability, recovery and experience.
Exercises may include squats or sit-to-stand movements, hip hinges, pushing and pulling exercises, step-ups and other movements appropriate to the individual's physical condition.
People with substantial mobility limitations, joint pain, cardiovascular disease or frailty should work with an appropriately qualified clinician or exercise professional to adapt the programme safely.
2. Consume adequate protein
Protein provides amino acids needed for muscle maintenance and repair. During active weight loss, adequate protein intake is especially important when appetite suppression makes it difficult to consume sufficient food.
A commonly used planning range for many adults undergoing weight reduction is approximately 1.2–1.6 grams of protein per kilogram of body weight per day. This is a starting point for individual assessment, not a universal prescription.
In people with obesity, calculating a protein target directly from actual body weight may overestimate requirements. A dietitian may use target, ideal or adjusted body weight, alongside age, activity level, body composition and medical history.
People with chronic kidney disease or other conditions that require protein restriction should obtain individualised advice before increasing protein intake.
3. Avoid excessive calorie restriction
Strong appetite suppression can make it difficult to eat enough to support training and maintain adequate nutrition.
Rather than pursuing the fastest possible weight reduction, the goal should be a sustainable energy deficit that supports fat loss while allowing sufficient protein, essential fats, vitamins, minerals and overall food intake.
Persistent nausea, vomiting, difficulty eating or an inability to maintain adequate fluid intake warrants medical review, particularly during dose escalation.
4. Distribute protein across meals
Spreading protein across several meals can make nutritional targets easier to achieve. Depending on dietary preferences, options include eggs, fish, poultry, dairy products, tofu, tempeh, legumes and other protein-rich foods.
Smaller meals may be more tolerable for people experiencing early fullness. Meal size and composition should be adjusted to individual symptoms and nutritional needs.
5. Monitor strength as well as body weight
Scale weight is useful, but it is an incomplete measure of treatment success.
Other measures may include:
- Waist circumference and changes in clothing fit.
- Strength during resistance exercises and the ability to perform daily activities.
- Walking speed, chair-rise performance or other appropriate functional measures.
- Body-composition measurements when clinically indicated and performed consistently.
- Dietary intake, hydration, fatigue and recovery from exercise.
Serial DXA scans may help assess body-composition trends in selected situations, but changes should be interpreted in context. Routine repeated scans are not necessary for everyone, and bioelectrical impedance devices can also be affected by hydration and measurement conditions.
6. Review treatment with a clinician
A healthcare professional can help determine whether the rate of weight loss, adverse effects, nutritional intake or changes in physical function require intervention.
Medication dosing should not be increased, reduced or combined with other treatments solely to manipulate muscle loss without medical supervision.
9. Safety and Regulatory Status
As of October 27, 2026, both treatments remain investigational in the United States.
- Retatrutide: It has not been approved by the FDA or any other regulatory agency, according to the developer's current public information. It remains under clinical investigation.
- CagriSema: Novo Nordisk submitted a New Drug Application to the FDA in December 2025. The company stated on October 20, 2026, that a regulatory decision was expected in the fourth quarter of 2026. The medicine was still described as investigational in that announcement.
Regulatory status can change, so current authorisation should be checked with the relevant national medicines regulator before publication or clinical decision-making.
Neither investigational treatment should be obtained from unregulated online sellers or used as a research peptide outside authorised clinical trials. Products sold outside regulated clinical channels may have uncertain identity, purity, concentration, storage conditions or contamination risks.
For official status updates, consult the developers' information:
10. Final Verdict: Which Is Better for Muscle Preservation?
Neither retatrutide nor CagriSema can currently be declared the winner for muscle preservation.
Retatrutide has a published Phase 2 body-composition substudy demonstrating substantial fat loss alongside lean-mass loss. The study's investigators reported that the proportion of weight lost as lean mass was similar to that seen with other obesity treatments.
CagriSema has Phase 3 weight-loss evidence and exploratory DXA findings showing that most measured weight reduction in the reported analysis came from fat mass, although a proportion came from lean soft tissue.
These findings are informative, but they do not establish which treatment preserves more skeletal muscle. The trials differed in population, duration, endpoints and reporting methods, and neither set of measurements is equivalent to a direct assessment of muscle strength and function.
The most evidence-based conclusion is that greater weight-loss efficacy should not automatically be interpreted as better—or worse—muscle preservation.
For anyone pursuing substantial weight reduction, the priority should be to lose excess fat while maintaining strength, adequate nutrition and physical function. Resistance training, sufficient protein, a sustainable energy deficit and appropriate clinical monitoring are central to that objective.
Frequently Asked Questions
Does retatrutide cause muscle loss?
The published Phase 2 body-composition study reported lean-mass reductions alongside substantial fat-mass reductions. However, lean-mass change is not equivalent to measured skeletal-muscle loss, and the study did not establish that retatrutide causes more clinically important muscle loss than other obesity treatments.
Does CagriSema preserve muscle better than retatrutide?
This has not been established. CagriSema has exploratory DXA body-composition findings from REDEFINE 1, while retatrutide has a published Phase 2 body-composition substudy. Differences between those studies prevent a valid ranking of their muscle-preservation effects.
What percentage of weight loss is lean mass with these treatments?
The reported CagriSema DXA analysis indicated that approximately 33% of measured weight reduction came from lean soft tissue and 67% from fat mass. Retatrutide's investigators reported that the proportion of weight lost as lean mass was similar to that seen with other obesity treatments. These findings were obtained using different study designs and should not be compared as though they came from a single trial.
Is lean-mass loss the same as muscle loss?
No. DXA-derived lean soft tissue includes skeletal muscle, organs, connective tissue and body water. A decline in lean mass does not necessarily represent an equivalent loss of skeletal muscle or muscle strength.
Can protein supplements prevent muscle loss during weight reduction?
Adequate protein intake can support muscle maintenance, especially alongside resistance training, but protein supplements alone cannot guarantee preservation of muscle. Total energy intake, training, age, baseline health, treatment-related appetite suppression and other factors also matter.
What is the best way to monitor muscle preservation?
Use a combination of functional strength, exercise performance, dietary assessment, clinical evaluation and, when appropriate, body-composition measurements. Body weight alone cannot distinguish fat loss from lean-tissue loss.
Can retatrutide and CagriSema be combined?
There is no established clinical evidence supporting the combination of these investigational treatments to improve muscle preservation. Combining them could introduce additional safety risks and should not be attempted outside an appropriately authorised clinical research setting.
References and Further Reading
-
Coskun T, Wu Q, Schloot NC, et al.
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. 2025;13(8):674–684.
https://doi.org/10.1016/S2213-8587(25)00092-0 -
Garvey WT, Blüher M, Osorto Contreras CK, et al.
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.
New England Journal of Medicine. 2025;393:635–647.
https://doi.org/10.1056/NEJMoa2502081 -
Jastreboff AM, Kaplan LM, Davies MJ, et al.
Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity.
New England Journal of Medicine. Published September 29, 2026.
https://doi.org/10.1056/NEJMoa2604169 -
Novo Nordisk.
REDEFINE 1 and REDEFINE 2 scientific-session results, American Diabetes Association Scientific Sessions, 2025.
View the scientific-session presentation -
Eli Lilly.
What to know about retatrutide. Updated September 2026.
Official retatrutide information -
Novo Nordisk.
CagriSema updates and REDEFINE 1 analyses, October 2026.
Official CagriSema information
Medical Disclaimer
This article is for educational and informational purposes only. It is not personal medical advice, a prescription or a substitute for consultation with a qualified healthcare professional. Clinical trial findings do not guarantee individual results. Investigational treatments should only be used in appropriately authorised clinical trials until they receive the relevant regulatory approvals.
Editorial note: This review evaluates the available evidence independently of commercial claims. Funding sources, study limitations and the distinction between lean mass and skeletal muscle are considered when interpreting the findings.
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