What were the main results of the ESSENCE trial?

At the 72-week interim analysis, 62.9% of patients on once-weekly semaglutide 2.4 mg had resolution of steatohepatitis without worsening of fibrosis versus 34.3% on placebo, and 36.8% had improvement in liver fibrosis without worsening of steatohepatitis versus 22.4% on placebo. About 32.7% achieved both endpoints versus 16.1% on placebo, and weight fell 10.5% vs 2.0%. All comparisons were highly statistically significant (P<0.001).

Did ESSENCE prove semaglutide improves liver fibrosis?

Yes, at 72 weeks on biopsy. ESSENCE is the first phase 3 trial in which a GLP-1 drug significantly improved fibrosis stage — 36.8% of semaglutide patients improved by at least one stage without worsening of steatohepatitis, versus 22.4% on placebo. This is notable because the earlier phase 2 semaglutide trial cleared MASH but missed the fibrosis endpoint. The 72-week improvement is a histologic surrogate; longer-term durability is still being measured.

Is there 2-year or longer-term ESSENCE fibrosis data?

Not yet published. The headline ESSENCE results are from Part 1, the week-72 (about 17-month) interim. The trial is designed to run to week 240 (about 4.6 years) in Part 2, with a primary outcome of progression to cirrhosis and liver-related clinical events plus a planned week-240 biopsy. As of mid-2026 that longer-term readout has not reported, so any claim of a 2-year ESSENCE fibrosis result should be treated cautiously.

Why did the FDA approve Wegovy for MASH on 72-week data?

It was an accelerated approval (August 2025), the pathway used when a drug improves a surrogate endpoint reasonably likely to predict clinical benefit, with confirmation deferred. The 72-week biopsy histology in ESSENCE was the surrogate; the confirmation — fewer cirrhosis and liver-related events — is built into ESSENCE Part 2 at week 240. The approval covers noncirrhotic MASH with moderate-to-advanced (F2-F3) fibrosis.

How does semaglutide for MASH compare to resmetirom (Rezdiffra)?

Resmetirom was the first MASH drug approved (2024, MAESTRO-NASH trial), an oral liver-targeted thyroid-receptor agonist with roughly 26-30% MASH resolution and 24-26% fibrosis improvement at 52 weeks. Semaglutide is an injectable with larger MASH-resolution and fibrosis numbers at 72 weeks plus substantial weight loss, but the trials and timepoints differ and there are no head-to-head data. Both are approved options for F2-F3 MASH; the choice is individualized with a hepatologist.

ESSENCE: Semaglutide for MASH Fibrosis (2026)

36.8% vs 22.4% fibrosis improvementPatients with improved liver fibrosis and no worsening of steatohepatitis at 72 weeks — semaglutide 2.4 mg vs placebo (ESSENCE Part 1, Sanyal 2025)

ESSENCE is the phase 3 trial that made semaglutide (the molecule in Wegovy and Ozempic) the first GLP-1 medicine — and the first injectable — ever shown in a large randomized trial to improve liver fibrosis, the scarring that actually determines whether MASH (metabolic dysfunction–associated steatohepatitis, formerly NASH) progresses to cirrhosis. At the pre-specified 72-week interim analysis, 62.9% of patients on once-weekly semaglutide 2.4 mg had resolution of steatohepatitis without worsening of fibrosis versus 34.3% on placebo, and 36.8% had an improvement in fibrosis without worsening of steatohepatitis versus 22.4% on placebo (Sanyal 2025 ^[1]). Those results, published in the New England Journal of Medicine on June 5, 2025, drove the FDA's August 2025 accelerated approval of Wegovy for noncirrhotic MASH with F2–F3 fibrosis ^[3]. But there is a crucial detail the headlines skip: 72 weeks is only Part 1. The trial is designed to run to week 240 — about 4.6 years — and the longer-term “2-year-plus” fibrosis and hard-outcome data are not yet published. This deep-dive walks through exactly what ESSENCE has shown, what it has not shown yet, and why the difference matters. For the broader patient picture, see Wegovy for MASH and fatty liver and whether GLP-1 drugs damage the liver.

The honest summary

ESSENCE is the trial behind the approval. A phase 3, double-blind, placebo-controlled trial of once-weekly semaglutide 2.4 mg in 1,197 adults with biopsy-confirmed MASH and fibrosis stage F2 or F3, randomized 2:1 to drug or placebo, planned to run 240 weeks (Sanyal 2025^[1]; Newsome 2024^[2]).
72-week MASH resolution: 62.9% vs 34.3%. The estimated treatment difference was 28.7 percentage points (95% CI 21.1–36.2; P<0.001) for resolution of steatohepatitis without worsening of fibrosis (Sanyal 2025^[1]).
72-week fibrosis improvement: 36.8% vs 22.4%. Difference 14.4 percentage points (95% CI 7.5–21.3; P<0.001) for improvement in fibrosis with no worsening of steatohepatitis — the first time a GLP-1 hit this endpoint in phase 3 (Sanyal 2025^[1]).
Both endpoints together: 32.7% vs 16.1%. Roughly twice as many semaglutide patients achieved both MASH resolution and fibrosis improvement (Sanyal 2025^[1]).
The "2-year" / longer-term fibrosis readout is NOT published yet. The histologic data above are from the week-72 interim of Part 1. Part 2 continues to week 240, with a primary endpoint of progression to cirrhosis / liver-related clinical events — that readout has not reported (Newsome 2024^[2]; Sanyal 2025^[1]).
FDA accelerated approval, August 2025. Wegovy (semaglutide 2.4 mg) was approved for noncirrhotic MASH with moderate-to-advanced (F2–F3) fibrosis on the strength of the surrogate histology — “accelerated” precisely because the hard-outcome data are still pending ^[3]; AASLD issued matching practice guidance in November 2025 (Bansal 2026^[4]).

Why fibrosis — not fat — is the number that matters

In MASH, the liver accumulates fat, becomes inflamed, and the inflammation drives fibrosis — scar tissue that is staged from F0 (none) to F4 (cirrhosis). Decades of natural-history data show that it is the fibrosis stage, not the amount of fat or even the degree of inflammation, that predicts liver-related death, cirrhosis, and the need for a transplant. That is why modern MASH trials are judged on two histologic endpoints scored from liver biopsy: (1) resolution of steatohepatitis without worsening of fibrosis, and (2) improvement in fibrosis by at least one stage without worsening of steatohepatitis. A drug can clear fat and calm inflammation yet leave the scar untouched — which is exactly why the fibrosis endpoint is the harder, more clinically meaningful one to hit.

This is the context that makes ESSENCE notable. The earlier phase 2 trial of semaglutide in NASH (Newsome 2021^[5]) had already shown impressive MASH resolution — up to 59% at the 0.4 mg daily dose versus 17% on placebo — but it failed the fibrosis endpoint: the proportion with fibrosis improvement was not significantly different from placebo. For four years that left an open question: could a GLP-1 actually move the scar, or only the fat? ESSENCE answered it.

How ESSENCE was built

ESSENCE (trial identifier NCT04822181) is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. It enrolled 1,197 adults with biopsy-confirmed MASH and fibrosis stage F2 or F3 (moderate to advanced, but pre-cirrhotic), randomizing them 2:1 to once-weekly subcutaneous semaglutide 2.4 mg (the Wegovy dose, titrated up over 16 weeks) or matching placebo, on top of lifestyle advice (Newsome 2024^[2]). Crucially, the trial is structured in two parts on the same 240-week backbone: histology endpoints are read at the week-72 biopsy (Part 1), and the trial then continues to week 240 for clinical outcomes (Part 2).

The week-72 primary analysis was pre-specified to be performed on the first 800 randomized patients who had reached that timepoint with paired baseline-and-72-week biopsies — 534 on semaglutide and 266 on placebo. Both primary endpoints were scored by blinded central pathologists. The two endpoints were tested hierarchically, so a positive result on the first protected the statistical validity of the second (Sanyal 2025^[1]).

“Part 1” vs “Part 2” — read this before quoting ESSENCE

Everything you have seen in the press — 62.9% resolution, 36.8% fibrosis improvement, the FDA approval — comes from Part 1, the week-72 interim. Part 2 of the very same trial runs to week 240 and is powered for a different, harder question: does semaglutide reduce progression to cirrhosis and liver-related clinical events? When someone says “the 2-year ESSENCE fibrosis data,” pause: as of mid-2026 the only published histology is the 72-week (~17-month) readout. The longer-term biopsy and clinical-event data have not reported.

The 72-week results, walked through number by number

Primary endpoint 1 — resolution of steatohepatitis

Resolution of steatohepatitis (clearance of the inflammatory MASH activity) without any worsening of fibrosis occurred in 62.9% of the semaglutide group versus 34.3% of the placebo group. The estimated treatment difference was 28.7 percentage points (95% CI 21.1 to 36.2; P<0.001) (Sanyal 2025^[1]). Put plainly: nearly two-thirds of patients on semaglutide cleared their steatohepatitis without their scarring getting worse — almost double the placebo rate, and the placebo rate itself is high because all participants received lifestyle counseling.

Primary endpoint 2 — improvement in liver fibrosis

This is the historic one. Improvement in liver fibrosis by at least one stage, with no worsening of steatohepatitis, occurred in 36.8% of the semaglutide group versus 22.4% of placebo — a treatment difference of 14.4 percentage points (95% CI 7.5 to 21.3; P<0.001) (Sanyal 2025^[1]). That is the endpoint the phase 2 trial had missed (Newsome 2021^[5]). Note the size of the effect honestly: it is real and statistically robust, but the absolute gap is about 14 points, and more than a third of placebo patients also showed fibrosis improvement on biopsy — a reminder of both biopsy sampling variability and the genuine benefit of lifestyle change.

Combined endpoint and weight

Achieving both primary endpoints — MASH resolution and fibrosis improvement — happened in 32.7% on semaglutide versus 16.1% on placebo (difference 16.5 percentage points; 95% CI 10.2 to 22.8; P<0.001). Body weight fell 10.5% on semaglutide versus 2.0% on placebo (difference −8.5 percentage points; 95% CI −9.6 to −7.4; P<0.001) (Sanyal 2025^[1]). The weight loss is the presumed engine of the liver benefit, though semaglutide also has metabolic effects on the liver independent of weight.

ESSENCE Part 1 — week-72 histologic outcomes (first 800 patients)

Endpoint	Semaglutide 2.4 mg	Placebo	Difference (95% CI)
Resolution of steatohepatitis, no worsening of fibrosis	62.9%	34.3%	28.7 pp (21.1 to 36.2)
Fibrosis improvement ≥1 stage, no worsening of MASH	36.8%	22.4%	14.4 pp (7.5 to 21.3)
Both endpoints achieved	32.7%	16.1%	16.5 pp (10.2 to 22.8)
Mean body-weight change	−10.5%	−2.0%	−8.5 pp (−9.6 to −7.4)

All four comparisons were P<0.001 (Sanyal 2025^[1]). “pp” = percentage points.

Safety at 72 weeks

The safety profile was the familiar GLP-1 one — gastrointestinal and dose-related, not a new liver signal. The most common adverse events on semaglutide versus placebo were nausea (36.3% vs 13.2%), diarrhea (26.9% vs 12.2%), constipation (22.3% vs 8.4%), and vomiting (18.6% vs 5.6%); 88% of patients reached and maintained the full 2.4 mg target dose by week 72 (Sanyal 2025^[1]). Importantly, there was no evidence that semaglutide caused liver injury — consistent with the broader GLP-1 hepatic-safety literature reviewed in does a GLP-1 damage the liver. One caveat relevant to MASH patients specifically: appetite-suppressing therapy can accelerate loss of lean mass, which matters in a population at risk of sarcopenia — see semaglutide and muscle-mass loss.

What the longer-term (week-240) data will — and won't — tell us

Here is the part that the “2-year fibrosis” framing gets wrong. The FDA granted Wegovy accelerated approval for MASH in August 2025 ^[3]. Accelerated approval is the pathway used when a drug improves a surrogate endpoint — here, the 72-week biopsy histology — that is “reasonably likely” to predict clinical benefit, with the confirmation deferred to a later trial. In ESSENCE, that confirmation is built into Part 2: the trial continues to week 240 with a primary outcome of cirrhosis-free survival / progression to liver-related clinical events (decompensation, liver failure, hepatocellular carcinoma, transplant), plus a planned week-240 biopsy (Newsome 2024^[2]).

As of this writing (mid-2026), that longer-term readout has not been published. So the honest state of the evidence is: semaglutide demonstrably improves MASH histology and fibrosis stage at ~17 months, and it is biologically and statistically reasonable to expect that durable fibrosis regression would translate into fewer cirrhosis events — but that clinical-outcome benefit has not yet been proven, and the durability of the fibrosis improvement beyond 72 weeks is not yet reported from ESSENCE itself. Anyone citing a “2-year” or “240-week” ESSENCE fibrosis result should be treated with skepticism until the Part 2 paper appears.

Why the gap between “72 weeks” and “240 weeks” is the whole story

A one-stage fibrosis improvement on a single biopsy is a strong surrogate, but it is not the same as preventing cirrhosis. Two things could still happen on longer follow-up: the fibrosis benefit could deepen with continued treatment (the optimistic case), or some patients could plateau or regress toward baseline. ESSENCE Part 2 is the experiment that will tell us. Until then, the approval rests on the 72-week surrogate — which is appropriate for a disease with no other approved injectable, but is not the final word.

How ESSENCE fits with the other MASH drugs

ESSENCE did not happen in a vacuum. The first drug ever approved for MASH was resmetirom (Rezdiffra), a thyroid-hormone-receptor-β agonist, approved in 2024 on the strength of the MAESTRO-NASH trial: at 52 weeks, MASH resolution reached 26–30% and fibrosis improvement 24–26% versus 9–14% and 14–15% on placebo (Harrison 2024^[6]). Resmetirom is an oral pill that is liver-targeted; semaglutide is an injectable that also drives large weight loss and cardiometabolic benefit. They are not interchangeable, and head-to-head data do not exist.

The other GLP-1-class entrant is tirzepatide (the dual GIP/GLP-1 agonist in Mounjaro/Zepbound), studied in the phase 2 SYNERGY-NASH trial: at 52 weeks, MASH resolution without worsening fibrosis reached up to 62% versus 10% on placebo, with a favorable but phase-2-sized fibrosis signal (Loomba 2024^[7]). Tirzepatide is not yet approved for MASH; its phase 3 fibrosis program is ongoing. The practical landscape, then: as of 2026, semaglutide and resmetirom are the approved options for F2–F3 MASH, and AASLD's November 2025 guidance update folded semaglutide into the treatment algorithm (Bansal 2026^[4]). A separate strand of ESSENCE-adjacent work — the SAMARA trial — is testing whether noninvasive tests can replace biopsy for tracking MASH response (Ajmera 2026^[8]), which matters because the biopsy requirement is the biggest barrier to treating MASH at scale.

What this means if you have MASH

Fibrosis stage is the thing to ask about. ESSENCE enrolled F2–F3, and the FDA label is for noncirrhotic MASH with moderate-to-advanced fibrosis ^[3]. If you have MASH, your hepatologist will stage your fibrosis (biopsy, or increasingly FibroScan/MRI-based tools) before deciding on therapy.
The proven benefit is histologic, at ~17 months. Semaglutide clears MASH and improves fibrosis on biopsy at 72 weeks. It is reasonable to expect this lowers long-term liver risk, but the cirrhosis-prevention data are still being collected in ESSENCE Part 2 (Sanyal 2025^[1]; Newsome 2024^[2]).
This is a treatment decision for a hepatologist, not a self-prescription. MASH staging, drug choice (semaglutide vs resmetirom), and monitoring all require specialist input — see the patient-action guidance in Wegovy for MASH and fatty liver.
Watch lean mass and GI tolerance. The side-effect profile is GI-dominant and dose-related, and rapid weight loss can cost muscle (Sanyal 2025^[1]; muscle-mass loss).

Bottom line

ESSENCE is a landmark trial: at 72 weeks, once-weekly semaglutide 2.4 mg resolved steatohepatitis in 62.9% of patients (vs 34.3% on placebo) and — the historic part — improved liver fibrosis in 36.8% (vs 22.4%), the first GLP-1 to hit the fibrosis endpoint in phase 3 (Sanyal 2025^[1]). That surrogate-endpoint win earned Wegovy an FDA accelerated approval for F2–F3 MASH in August 2025 ^[3] and a place in AASLD guidance (Bansal 2026^[4]). But the trial is explicitly a two-part, 240-week design: the longer-term “2-year-plus” fibrosis durability and the hard cirrhosis/clinical-event outcomes are from Part 2, and as of mid-2026 they have not been published. The accurate way to describe ESSENCE today is: proven histologic and fibrosis benefit at 72 weeks, with the clinical-outcome confirmation still pending — exactly the situation accelerated approval is designed for.

This article is educational and is not medical advice. Every percentage, confidence interval, and PMID above was verified against the live PubMed database and the New England Journal of Medicine 2025 publication of ESSENCE before posting. MASH staging and treatment decisions belong with a hepatologist.

References

1.Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. New England Journal of Medicine. 2025. PMID: 40305708.
2.Newsome PN, Sanyal AJ, Engebretsen KA, et al. Semaglutide 2.4 mg in Participants With Metabolic Dysfunction-Associated Steatohepatitis: Baseline Characteristics and Design of the Phase 3 ESSENCE Trial. Alimentary Pharmacology & Therapeutics. 2024. PMID: 39412509.
3.U.S. Food and Drug Administration. FDA grants accelerated approval of semaglutide (Wegovy) for noncirrhotic MASH with moderate-to-advanced (F2-F3) liver fibrosis (NDA 215256/S-024 approval letter), August 15, 2025. FDA Drugs@FDA. 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/215256Orig1s024ltr.pdf
4.Bansal MB, Sanyal AJ, Cusi K, et al. Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: November 2025 updates to AASLD Practice Guidance. Hepatology. 2026. PMID: 41201884.
5.Newsome PN, Buchholtz K, Cusi K, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. New England Journal of Medicine. 2021. PMID: 33185364.
6.Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. New England Journal of Medicine. 2024. PMID: 38324483.
7.Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. New England Journal of Medicine. 2024. PMID: 38856224.
8.Ajmera V, Loomba R, et al. Clinical Trial: Semaglutide Versus Placebo in NIT-Assessed MASH - A Multicenter Randomised Placebo-Controlled Trial (SAMARA). Alimentary Pharmacology & Therapeutics. 2026. PMID: 41527269.