What Happened
The two medicines approved for metabolic dysfunction-associated steatohepatitis (MASH) have never faced each other in a randomized trial. An exploratory indirect comparison in October 2026 in Diabetes, Obesity and Metabolism is the closest thing yet: it puts semaglutide 2.4 mg ahead of resmetirom 80 mg on the liver endpoint regulators accepted.
Mantovani and Targher compared treatment effects versus placebo in MAESTRO-NASH (resmetirom) and ESSENCE (semaglutide).
For MASH resolution, semaglutide's effect exceeded resmetirom 80 mg by about 12.3 percentage points (risk difference -0.123; 95% CI -0.215 to -0.031), significant in patients under 65, women, those with BMI of 35 or higher, without type 2 diabetes, and with F3 fibrosis. Fibrosis improvement showed no overall difference.
Weight loss diverges sharply: semaglutide produced roughly 10-11% body-weight reduction at 72 weeks in ESSENCE against about 2% with placebo, while 17% and 22% of MAESTRO-NASH patients on resmetirom 80 mg and 100 mg lost at least 5%, versus 12% on placebo.
Who Is Affected
- Adults with MASH and F2-F3 fibrosis, the population both drugs are approved for, now have comparative data where months ago they had two labels.
- Clinicians choosing a first agent, and payers weighing injectable against oral costs.
- Patients who assumed both approvals meant equal protection. On histology, they do not.
Timeline
- March 2024 - FDA grants resmetirom accelerated approval on MAESTRO-NASH, the first MASH drug cleared in the U.S.
- August 2025 - Semaglutide 2.4 mg receives accelerated approval for the same population on ESSENCE part 1.
- October 2026 - The comparison appears in print; a real-world cardiovascular analysis of both drugs is presented at ACG.
What This Means for Researchers
The comparison is indirect. The trials enrolled different populations and produced very different placebo responses: 9.7% resolution on placebo in MAESTRO-NASH versus 34.3% in ESSENCE. Comparing each drug against its own placebo is right, but assumes the trials are exchangeable.
Weight loss is a surrogate. It predicts histologic improvement on average, not in every patient; a lean patient may get little weight benefit and still need liver-directed therapy.
The cardiovascular signal runs the other way. A TriNetX propensity-matched analysis at ACG 2026 (4,253 patients per arm) reported lower MACE with resmetirom at one year (HR 0.50; 95% CI 0.32-0.80) and two years (HR 0.61; 0.41-0.89), plus lower mortality (HR 0.29 and 0.33); myocardial infarction rates did not differ. The data are retrospective and cannot prove causation, but they cut against a simple "more weight loss wins" reading.
For a patient whose dominant risk is liver histology and who tolerates a GLP-1, the evidence favors semaglutide; for lean or GLP-1-intolerant patients, resmetirom remains defensible.
How to Verify Your Peptides
This story concerns approved medicines, not research compounds. An approved product has documented identity, purity, and fill weight; a vial sold as "semaglutide" has none.
If you work with research peptides, verify before use: a third-party certificate of analysis, HPLC purity, LC-MS identity, and a measured fill weight. See how testing works, HPLC versus LC-MS, and identity, purity and fill weight.
Safe Alternatives
For approved therapy, use a licensed prescriber and pharmacy. For research use, start from our peptide database and vendor directory, and treat unverified GLP-1 material as an unknown substance.
Sources
- Mantovani A, Targher G. Diabetes, Obesity and Metabolism. 2026;28(10):9707-9710.
- Sanyal AJ, et al. New England Journal of Medicine. 2025;392(21):2089-2099.
- Harrison SA, et al. New England Journal of Medicine. 2024;390(6):497-509.
- Samhoun J, et al. ACG 2026, Nashville.