Multiple Trials Show Lean Mass Loss Alongside Fat Reduction in Obesity Treatments

By Helen Whitaker, Senior Editor

Three trials published in The New England Journal of Medicine tracked body composition changes during treatment with semaglutide or tirzepatide. Participants lost 9 to 21 percent of their body weight over periods of 68 to 104 weeks. Scans showed fat mass accounted for 60 to 75 percent of that reduction while lean mass made up the rest.

The studies focused on adults with overweight or obesity. One trial included people with cardiovascular disease but not diabetes. These reports shift attention from total scale weight to the makeup of tissue lost.

The STEP 1 trial tested semaglutide 2.4 mg given once weekly. Adults lost a mean 14.9 percent of body weight at 68 weeks versus 2.4 percent on placebo [1]. A DEXA substudy linked the reduction mostly to fat mass loss.

Tirzepatide produced larger average losses in the SURMOUNT-1 trial. Doses of 5 mg, 10 mg and 15 mg led to 15 to 21 percent weight reduction at 72 weeks [2]. The highest dose reached 20.9 percent loss against 3.1 percent on placebo. Roughly 75 percent of the weight lost came from fat mass.

The SELECT trial examined semaglutide in a broader group. Adults with obesity and cardiovascular disease but no diabetes showed a mean weight change of minus 9.4 percent at 104 weeks compared with minus 0.9 percent on placebo [3]. The pattern matched earlier body composition findings from dedicated trials.

What this means

Trial data indicate that substantial weight reduction with these agents includes meaningful lean mass loss in addition to fat loss. The ratio appears consistent at 25 to 40 percent lean mass across the studies reviewed. Longer term effects on physical function or muscle strength stay unmeasured in these protocols.

Key takeaways

• Semaglutide 2.4 mg produced mean weight loss of 14.9 percent at 68 weeks versus 2.4 percent on placebo in adults with overweight or obesity [1].
• Tirzepatide 15 mg produced mean weight loss of 20.9 percent at 72 weeks with about 75 percent of loss as fat mass [2].
• Semaglutide 2.4 mg produced mean weight change of minus 9.4 percent versus minus 0.9 percent on placebo at 104 weeks in the SELECT trial [3].
• Body composition substudies using DEXA showed lean mass loss typically accounts for 25 to 40 percent of total weight lost.
• Trial evidence remains limited to 68 to 104 weeks and to secondary endpoints measured in participant subsets.

Limitations

Body composition endpoints were secondary or exploratory. Many relied on DEXA scans in small subsets of participants. Trial durations reached at most 104 weeks so trajectories beyond two years stay uncharted. No large studies mandated resistance training so direct evidence on mitigation remains sparse. Populations were mostly White adults without baseline sarcopenia which limits generalizability to older adults or diverse groups.

FAQ

What proportion of total weight lost with semaglutide or tirzepatide is fat mass versus lean mass?
Data from the trials show fat mass makes up roughly 60 to 75 percent of total loss while lean mass accounts for the remaining 25 to 40 percent.

How do dedicated body-composition assessments (DEXA, MRI) in GLP-1 trials compare across agents and doses?
DEXA substudies in the STEP 1 and SURMOUNT-1 trials found similar predominance of fat mass loss for both semaglutide and tirzepatide though exact ratios varied modestly by dose.

Does combining GLP-1 therapy with resistance exercise alter the ratio of fat-to-lean loss?
The trials did not require structured resistance training so few data exist on whether exercise changes the ratio.

What do FDA and EMA labels state regarding monitoring of body composition or muscle health?
Approvals for these agents cite the overall benefit-risk profile from the trials. Labeling describes metabolic effects but does not require routine body-composition scans.

Sources / References

1. Once-Weekly Semaglutide in Adults with Overweight or Obesity. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

2. Tirzepatide Once Weekly for the Treatment of Obesity. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

3. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2307563