MASH Trials: Resmetirom and Semaglutide

A 2026 expert review places resmetirom and semaglutide together as the first medicines approved for metabolic dysfunction-associated steatohepatitis, or MASH, with moderate-to-severe fibrosis. Its central caution is as important as the approval milestone: the evidence rests on liver-biopsy endpoints measured over a relatively short period, while effects on later hepatic and systemic outcomes remain unresolved^[1]. The two medicines were not tested against each other. Their phase 3 results answer separate questions in different programs, so percentages should not be ranked as if they came from one head-to-head trial.

Why the review links these medicines

The review describes different biological routes. Resmetirom is a liver-directed thyroid hormone receptor beta agonist. Semaglutide is a GLP-1 receptor agonist that acts systemically and produces weight and metabolic effects. The authors report that both can produce MASH resolution and fibrosis improvement in a proportion of treated patients, while also identifying open questions about patient selection, noninvasive assessment, monitoring, treatment duration and equitable access^[1].

That shared clinical setting does not make the drugs interchangeable. The review does not report a randomized comparison, a sequencing trial or evidence for using the medicines together. A fair read therefore starts with each phase 3 study on its own terms before considering what remains unknown across both programs.

What MAESTRO-NASH tested

MAESTRO-NASH is an ongoing phase 3 randomized trial in adults with biopsy-confirmed steatohepatitis and fibrosis stages F1B, F2 or F3. Participants were assigned equally to 80 mg resmetirom, 100 mg resmetirom or placebo once daily. The published week 52 analysis included 966 participants. It evaluated two biopsy-based primary outcomes: steatohepatitis resolution without fibrosis worsening, and improvement in fibrosis by at least one stage without worsening of the disease-activity score^[2].

Steatohepatitis resolution without worsening fibrosis occurred in 25.9% of the 80 mg group and 29.9% of the 100 mg group, compared with 9.7% on placebo. Fibrosis improved by at least one stage without worsening disease activity in 24.2% and 25.9% of the two resmetirom groups, respectively, compared with 14.2% on placebo. Both dose comparisons met the reported statistical threshold for both primary outcomes^[2]. These are group-level biopsy results, not a guarantee that an individual liver will respond.

Low-density lipoprotein cholesterol fell by 13.6% and 16.3% in the resmetirom groups by week 24, compared with a 0.1% increase on placebo. Diarrhea and nausea were more frequent with resmetirom. Serious adverse events occurred in 10.9% of the 80 mg group, 12.7% of the 100 mg group and 11.5% of the placebo group^[2]. The abstract supports those trial-level safety observations but does not replace current prescribing information or individual clinical review.

What ESSENCE tested

ESSENCE is an ongoing phase 3, double-blind trial in people with biopsy-defined MASH and F2 or F3 fibrosis. The full program assigned 1,197 participants in a two-to-one ratio to weekly semaglutide 2.4 mg or placebo for 240 weeks. The published report is a planned interim analysis at week 72 in the first 800 participants, not the completed 240-week trial^[3]. That timing distinction limits what the report can say about durability and clinical events.

At week 72, steatohepatitis resolution without worsening fibrosis occurred in 62.9% of the semaglutide group and 34.3% of the placebo group, an estimated difference of 28.7 percentage points. Fibrosis reduction without worsening steatohepatitis occurred in 36.8% and 22.4%, respectively, an estimated difference of 14.4 points. Both primary comparisons met the trial's reported statistical threshold^[3].

The combined outcome of steatohepatitis resolution and fibrosis reduction was reported in 32.7% with semaglutide and 16.1% with placebo. Mean body weight changed by -10.5% and -2.0%, respectively. Gastrointestinal adverse events were more common with semaglutide, while the planned bodily-pain comparison did not differ significantly between groups^[3]. The interim analysis reports histology and selected secondary outcomes; it does not complete the longer clinical-outcomes question.

Why the percentages cannot be ranked

The studies differed in enrolled fibrosis stages, treatment duration, allocation ratio, medicine, route and analysis populations. Their placebo response rates also differed. Even similarly worded biopsy outcomes were measured inside separate protocols at week 52 and week 72. Comparing 29.9% in one active group with 62.9% in another ignores those design differences and cannot establish relative efficacy.

Both reports were industry-funded. Madrigal Pharmaceuticals funded MAESTRO-NASH, and Novo Nordisk funded ESSENCE^[2][3]. Funding does not erase randomization or placebo control, but it belongs beside the results when readers assess protocol choices, analysis and reporting. A direct comparative trial would be needed to answer which option performs better in the same eligible population.

What remains unresolved

The 2026 review highlights the main evidence gap: approval relied on histological changes over periods that are short relative to the course of chronic liver disease. It calls out unresolved questions about noninvasive tests, monitoring, duration of treatment, hepatic outcomes, systemic outcomes and fair access^[1]. A biopsy improvement can support efficacy without yet proving how much a therapy changes later decompensation, transplantation, cardiovascular events or survival.

This is also not a self-selection guide. Trial eligibility depended on confirmed disease and fibrosis criteria, and each medicine has its own approved population, contraindications, interactions, warnings and monitoring requirements. The reported dose groups describe controlled research and should not be copied or combined outside clinical care. Decisions require a clinician to confirm diagnosis, stage fibrosis and use current product information.

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