Semaglutide

Week 26, higher-dose portion (Regeneron, 2025): lean mass fell 6.5% with semaglutide alone, versus 3.3% with trevogrumab 200 mg, 3.8% with 400 mg, and 2.0% with the three-drug arm. Fat mass fell 15.7%, 17.3%, 19.1% and 27.1%. Body weight fell 10.6%, 9.9%, 11.1% and 13.4%. Lower-dose portion (Regeneron, 2026): lean mass fell 6.7% at Week 26 and 7.3% at Week 52 with placebo plus semaglutide, versus 3.3% and 4.2% with trevogrumab 75 mg. In an MRI substudy of participants with usable scans, the sponsor reports that trevogrumab 75 mg preserved 72.7% (Week 26) and 68.9% (Week 52) of the thigh muscle volume lost with semaglutide alone. The higher-dose and lower-dose portions are separate groups, and Week 26 and Week 52 figures should not be combined.

• Results come from sponsor press releases; the ClinicalTrials.gov record has no posted results, and no peer-reviewed paper was reviewed (the sponsor says one is in press).
• Week-26 p-values for the primary endpoints were not corrected for multiple comparisons, according to the sponsor.
• The higher-dose (200/400 mg) and lower-dose (25/75 mg) portions are separate groups, so their numbers are not interchangeable. The sponsor’s 2025 release also calls the 200 mg arm its “lower-dose” arm, so “lower dose” means different things in the two releases.
• MRI results include only participants with usable scans, and the preservation percentages are the sponsor’s own calculations.
• The two ADA 2026 abstracts and the 10-Q were not used for figures; their text was not reviewed here.
• Lean mass measured by DXA is not the same as muscle strength or physical function.

By week 68, average body weight changed by -14.9% with semaglutide versus -2.4% with placebo (estimated difference -12.4 percentage points, 95% CI -13.4 to -11.5, P<0.001, journal abstract). The registry's observed in-trial means were -15.6% and -2.8%. Weight loss of at least 5% was reached by 1,047 people on semaglutide (86.4%) and 182 on placebo (31.5%). Loss of at least 10% was reached by 838 (69.1%) versus 69 (12.0%). Loss of at least 15% was reached by 612 (50.5%) versus 28 (4.9%). Waist circumference fell 14.1 cm versus 4.4 cm and systolic blood pressure 7 versus 1 mmHg.

• The registry's observed averages and the journal's model-based estimates differ slightly because they treat people who stopped treatment differently.
• Participants did not have diabetes, and about three quarters were women (1,453 of 1,961), so results may not apply to other groups.
• The shares reaching 10%, 15% and 20% weight loss are calculated among the people with week-68 data (1,212 on semaglutide, 577 on placebo), not among everyone randomized.
• The trial lasted 68 weeks and does not describe weight regain after stopping; follow-up results are in separate publications.
• The body-composition (DEXA) results come from a small subgroup of 83 and 39 people.
• The trial was run and funded by the drug's developer, and only the journal abstract was reviewed, not the full paper.

• Average change in body weight at week 68 with semaglutide 2.4 mg: ClinicalTrials.gov results (observed in-trial mean) reports -15.6%; NEJM abstract (primary estimand) reports -14.9%. 0.7 percentage points; the placebo averages also differ (-2.8% vs -2.4%). The registry presents observed means for the in-trial and on-treatment periods, while the journal abstract reports estimates under an estimand that assesses effects regardless of treatment discontinuation.

The main outcome occurred in 108 of 1,648 people (6.6%) on semaglutide and 146 of 1,649 (8.9%) on placebo (hazard ratio 0.74, 95% confidence interval 0.58 to 0.95). The result met the noninferiority test (P<0.001), and the registry also reports a test for superiority (P=0.0167). The journal reported that non-fatal heart attacks were not significantly different and non-fatal strokes were lower on semaglutide, while cardiovascular deaths were similar in the two groups. The registry reports that the expanded outcome, which adds procedures and hospital admissions, occurred in 12.1% versus 16.0%. Complications of diabetic eye disease (retinopathy) were more common on semaglutide (hazard ratio 1.76, 95% confidence interval 1.11 to 2.78).

• SUSTAIN-6 was designed first as a noninferiority safety trial; the registry also lists a superiority test, but the better-than-placebo finding is secondary to the safety design.
• The two semaglutide doses and the two placebo groups were pooled for the main analysis, so the result does not compare doses.
• Only the PubMed abstract of the journal report was reviewed, not the full paper, so the full list of secondary results and the eye-disease details are not covered.
• The journal and the registry give slightly different percentages for non-fatal heart attack and stroke, and the sources do not say why.
• Participants were adults aged 50 or older with established or likely cardiovascular disease, so results may not apply to younger or lower-risk people.
• More people stopped treatment early on semaglutide than on placebo, which can affect how results are interpreted.

• Share of people with a non-fatal heart attack or non-fatal stroke: NEJM abstract reports Non-fatal heart attack 2.9% vs 3.9%; non-fatal stroke 1.6% vs 2.7% (semaglutide vs placebo); ClinicalTrials.gov posted results reports Non-fatal MI 2.5% vs 3.7%; non-fatal stroke 1.5% vs 2.5%. Registry percentages are 0.1 to 0.4 points lower in each group; the hazard ratios (0.74 and 0.61) match. The reason for the difference is not established from the sources reviewed.