Effect of Semaglutide on Thigh Skeletal Muscle Volume, Fat Infiltration and Physical Function in People With Obesity: Secondary Analysis of STEP UP
- Design
- Randomized trial · 55 participants · Intermediate outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all participants had obesity (BMI ≥ 30 kg/m2; mean BMI 39.3) and mean age was 45; diabetes was excluded.
- Could weight loss explain it?
- Not applicableThe outcomes are body composition measures (with a sit-to-stand test), so weight-loss mediation is not applicable. The semaglutide group lost 19.5 kg against 0.4 kg on placebo; the authors note sit-to-stand change may reflect body-weight loss more than muscle function.
- Study tier
- Study tier 3LOW: randomized, double-blind and prespecified, but the analysis covers 55 of 1407 trial participants with only 6 on placebo, outcomes are intermediate (MRI body composition, sit-to-stand), and the authors call the results exploratory and hypothesis generating: a small randomized comparison.
- Assessment
- Version 3 · Two independent AI reviews agreed · Nov 11, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
In an MRI substudy of the randomised STEP UP trial, 55 adults with obesity (mean age 45) received weekly semaglutide (7.2 mg or 2.4 mg) or placebo, alongside diet and activity advice, for 72 weeks. Compared with placebo, semaglutide was linked to larger falls in body fat, visceral fat and fat within the thigh muscle. Lean tissue and thigh muscle volume also fell, but the differences from placebo were not statistically significant, and sit-to-stand repetitions were similar in both groups. Only 6 people were on placebo, so the authors treat the results as exploratory.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 7.2 mg or 2.4 mg once weekly (pooled for the main analysis)
- Route
- subcutaneous
- Comparator
- placebo (both groups with lifestyle intervention)
- Treatment duration
- 72 weeks
- Primary outcome
- changes in MRI body composition (adipose, lean, visceral fat, thigh muscle volume and fat infiltration) and sit-to-stand repetitions
- Effect
- Pooled semaglutide vs placebo: adipose body tissue -11.1 L (p < 0.0001), visceral adipose tissue -1.5 L (p = 0.04), thigh muscle fat infiltration -0.92%-points (p = 0.001); lean body tissue -1.7 L (p = 0.16) and thigh skeletal muscle volume -1.1 L (p = 0.07), not significant; sit-to-stand repetitions similar in both groups (13 at baseline, 15 at Week 72)
- 95% confidence interval
- 95% CIs: adipose body tissue -16.5 to -5.7; visceral adipose tissue -2.9 to -0.1; lean body tissue -4.0 to 0.7; thigh skeletal muscle volume -2.3 to 0.1; thigh muscle fat infiltration -1.41 to -0.42
- P value
- p < 0.0001 (adipose body tissue); p = 0.04 (visceral adipose tissue); p = 0.16 (lean body tissue); p = 0.07 (thigh skeletal muscle volume); p = 0.001 (thigh muscle fat infiltration)
- Follow-up
- 72 weeks
- Adverse events
- Adverse events in 95.3% (7.2 mg), 83.3% (2.4 mg) and 66.7% (placebo); gastrointestinal events in 86.0%, 50.0% and 33.3%; musculoskeletal and connective tissue events in 7.0% of the 7.2 mg group and none in the other groups
- Limitations
- A small secondary analysis of one trial's MRI subgroup (only 6 on placebo) with limited power, which the authors call exploratory; participants were mostly female, White and relatively young, and MRI covered only T9 to the knees, so lean mass loss is likely underestimated.
Who was studied
- Mean age
- 45 (SD 12) years
- Age min
- 18
- Sex distribution
- 78.2% female (43 of 55)
- Bmi mean
- 39.3
- Bmi min
- 30
- Obesity status
- obesity required (BMI ≥ 30 kg/m2)
- Diabetes status
- excluded (history of type 1 or type 2 diabetes, or HbA1c ≥ 6.5%); 38.2% had prediabetes
- Baseline condition
- obesity (BMI ≥ 30 kg/m2)
- Sample size
- 55
- Inclusion exclusion
- adults with BMI ≥ 30 and at least one unsuccessful dietary weight-loss effort; diabetes excluded; MRI subpopulation: bodyweight < 149 kg, no metal implants, suitable for MRI
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 55
- Randomization
- yes
- Blinding
- double-blind
- Comparator
- placebo (both groups with lifestyle intervention)
- Follow up duration
- 72 weeks
- Outcome type
- intermediate
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- 95% CIs reported; 55 analysed (pooled semaglutide n = 49, placebo n = 6); the authors call the analyses exploratory owing to the small placebo group
- Risk of bias
- not assessed
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- Novo Nordisk A/S
- Industry funded
- Yes
- Manufacturer
- Novo Nordisk A/S
- Sponsor role
- Novo Nordisk A/S funded the study and paid for medical writing; the data analysis was performed by an author (S.B.) who is a Novo Nordisk employee; all authors had full data access and final responsibility for submission.
- Author conflicts
- Three authors are Novo Nordisk employees (two also hold shares); one is an employee and shareholder of AMRA Medical; the others report grants, honoraria, advisory or consulting fees from Novo Nordisk, Eli Lilly and many other companies.
- Independent replication
- unknown
- Notes
- Authors declare relationships with the drug's manufacturer: Novo Nordisk
Funding is shown on every study and never used to score it.
03Claims
Claims this study bears on
- GLP-1-induced weight loss causes clinically meaningful loss of muscle mass or function.Mixed
STEP UP MRI substudy, 55 of 1407 adults with obesity (6 on placebo), 72 weeks: against placebo, thigh skeletal muscle volume (-1.1 L; -2.3 to 0.1; p = 0.07) and lean body tissue (-1.7 L; -4.0 to 0.7; p = 0.16) did not differ significantly, thigh muscle fat infiltration fell (-0.92%-points; p = 0.001), and sit-to-stand repetitions were a mean of 13 at baseline and 15 at Week 72 in both groups. Exploratory; industry funded.
04Source
The source, as retrieved
Abstract
[AIMS] To assess the effect of semaglutide on body composition and physical function. [MATERIALS AND METHODS] The phase 3b STEP UP trial randomised adults with body mass index ≥ 30 kg/m2 to once-weekly subcutaneous semaglutide 7.2 mg, semaglutide 2.4 mg or placebo for 72 weeks. This prespecified secondary analysis assessed changes in MRI body composition and physical function. [RESULTS] Of 1407 participants, 55 with a valid baseline scan were included (semaglutide 7.2 mg, n = 43, 2.4 mg, n = 6 [pooled semaglutide group, n = 49]; placebo, n = 6). Estimated treatment differences (95% confidence intervals; p-values) for absolute changes in adipose/muscle compartment volumes for the pooled semaglutide versus placebo group, respectively, were: -11.1 L (-16.5 to -5.7; p < 0.0001) for adipose body tissue, -1.5 L (-2.9 to -0.1; p = 0.04) for visceral adipose tissue, -1.7 L (-4.0 to 0.7; p = 0.16) for lean body tissue, -1.1 L (-2.3 to 0.1; p = 0.07) for thigh skeletal muscle volume and -0.92%-points (-1.41 to -0.42; p = 0.001) for thigh muscle fat infiltration. Similar results were seen for relative changes in adipose/muscle compartment volumes. A sensitivity analysis for the semaglutide 7.2 mg group versus placebo showed similar results. A mean of 13 sit-to-stand repetitions in 30 s at baseline, and 15 repetitions at Week 72, was observed in the pooled semaglutide and placebo groups. [CONCLUSIONS] Semaglutide plus lifestyle intervention was associated with reductions in adipose tissue volume, skeletal muscle volume and skeletal muscle fat infiltration, with a preserved number of sit-to-stand repetitions. Further research to assess the impact of weight loss on skeletal muscle composition and function should be explored in the future. [TRIAL REGISTRATION] ClinicalTrials.gov identifier NCT05646706.