The ESSENCE trial semaglutide results rest on something most weight-loss studies never collect: liver biopsies. In the first 800 adults checked at 72 weeks, the inflammation that defines a serious form of fatty liver disease cleared in 62.9% of people on weekly semaglutide against 34.3% on placebo, and liver scarring improved in 36.8% against 22.4%. Those biopsies earned Wegovy a U.S. liver indication in August 2025. Whether they mean fewer people ever reach cirrhosis is the question the trial is still running to answer.
What question did the ESSENCE trial ask?
ESSENCE is about MASH, short for metabolic dysfunction-associated steatohepatitis: fatty liver disease that has moved past stored fat into inflammation and damaged liver cells. It usually travels with extra weight, type 2 diabetes or high blood pressure. Its older name was NASH.
Over years, MASH can lay down fibrosis, which is scar tissue. Pathologists stage it from F0, no scarring, to F4, cirrhosis. ESSENCE enrolled people at F2 or F3: moderate to advanced scarring, but not cirrhosis.
The question: does semaglutide 2.4 mg once a week, the Wegovy dose, improve what a biopsy shows compared with a dummy injection? The wider question of semaglutide for fatty liver, including how doctors stage the liver without a needle, has its own page.
Who was enrolled, and for how long
ESSENCE is a phase 3 trial, the large, late-stage kind regulators rely on. It is randomized, meaning chance decided who got what, two people to semaglutide for every one to placebo, and double-blind, so neither participants nor staff knew. The paper reports 1,197 people randomized; the trial registry, NCT04822181, lists 1,205 enrolled.
The first 800 make up part 1. According to the trial's design paper, they joined between May 2021 and April 2023 at 253 sites in 37 countries. Their average age was 56, 57% were women, the average BMI was 34.6, and about 56% had type 2 diabetes. Roughly 7 in 10 were already at F3.
Everyone needed a biopsy showing active MASH with F2 or F3 scarring. Excluded were people whose liver damage had another cause, such as hepatitis B or C; people drinking more than 20 g of alcohol a day for women or 30 g for men, roughly one and a half to two standard U.S. drinks; anyone with signs of a failing liver or a past transplant; and anyone on a GLP-1 medicine in the previous 90 days.
What ESSENCE measured
Part 1 had two primary endpoints, the results the trial was built to judge.
The first was resolution of steatohepatitis without worsening of fibrosis: the follow-up biopsy no longer showed the inflammation and swollen, damaged cells that define MASH, and the scarring had not got worse. The second was fibrosis improvement without worsening of steatohepatitis: scarring dropped at least one stage, say from F3 to F2, while the inflammation held steady or eased.
Two pathologists read each biopsy independently, with a third settling disagreements, according to the Wegovy prescribing information. These are surrogate endpoints, measures expected to predict outcomes people actually feel, such as cirrhosis or a transplant, without being those outcomes.
ESSENCE trial semaglutide results: the numbers
At 72 weeks, Sanyal and colleagues reported in the New England Journal of Medicine that semaglutide beat placebo on both primary endpoints.
| Result at 72 weeks | Semaglutide (534 people) | Placebo (266 people) |
|---|---|---|
| MASH resolved, scarring not worse | 62.9% | 34.3% |
| Scarring improved at least one stage, MASH not worse | 36.8% | 22.4% |
| Both at once | 32.7% | 16.1% |
| Average change in body weight | −10.5% | −2.0% |
Put simply, about 6 in 10 people on semaglutide saw the liver inflammation clear, against about 1 in 3 on placebo. Scarring was the smaller effect: a little under 4 in 10 versus about 2 in 10.
A third of people on the dummy shot improved too. Everyone received standard care for diabetes, cholesterol and blood pressure, which is one reason the gap between the groups, not the raw percentage, is the result.
Side effects in the ESSENCE trial
An adverse event is any medical problem recorded during a study, whether or not the drug caused it. The AASLD's November 2025 practice guidance, drawing on the ESSENCE paper, reports them this way.
| Adverse event | Semaglutide | Placebo |
|---|---|---|
| Any adverse event | 86.2% | 79.7% |
| Nausea | 36.2% | 13.2% |
| Diarrhea | 26.9% | 12.2% |
| Constipation | 22.2% | 8.4% |
| Vomiting | 18.6% | 5.6% |
| Decreased appetite | 14.0% | 2.8% |
| Stopped treatment because of an adverse event | 2.6% | 3.3% |
The stomach was the story, and most of those effects were mild or moderate and faded with time. Stopping because of side effects was no more common than on placebo, and nobody on semaglutide stopped because of raised liver enzymes. Semaglutide side effects covers the wider picture.
What critics and later studies said
The sharpest criticism is about weight. A letter to the New England Journal of Medicine in August 2025 urged caution because substantial weight loss on its own, lifestyle change included, improves liver biopsies, and people on semaglutide lost about a tenth of their weight. How much of the benefit is the drug and how much is the weight loss is not settled.
The earlier phase 2 trial of 320 people explains why the scarring result mattered. Inflammation cleared in 59% at its highest daily dose versus 17% on placebo, but the scarring difference, 43% versus 33%, was not statistically significant. In ESSENCE it was.
The AASLD guidance also spells out the other side of the headline: 37.1% of people on semaglutide did not see their MASH resolve, and 63.2% did not see their scarring improve. No test yet predicts, person by person, who will respond.
As of September 22, 2026, the day this article was written, the newest ESSENCE analysis indexed in PubMed is an August 28 paper on the 116 Japanese participants. Inflammation cleared in 63.1% on semaglutide versus 36.8% on placebo, close to the overall result, but the scarring difference, 36.5% versus 28.9%, was too uncertain to call. Constipation, not nausea, was that group's most common side effect.
How ESSENCE led to Wegovy's MASH approval
On August 15, 2025, the FDA granted Wegovy accelerated approval for adults with noncirrhotic MASH and F2 to F3 fibrosis. Accelerated approval is a pathway for serious diseases that lets a drug reach patients on a surrogate result, here the biopsies, as long as a later trial confirms real clinical benefit.
The approval letter spells out that condition: Novo Nordisk must complete ESSENCE and show benefit on a combined measure of progression to cirrhosis, liver decompensation (the point where a scarred liver starts to fail), liver transplant and death.
As of September 22, 2026, the day this article was written, the FDA's list of ongoing accelerated approvals, current as of August 25, 2026, still shows that requirement open, with a final report due by December 31, 2029. The UK's medicines regulator authorised Wegovy for MASH on July 3, 2026, also conditionally, pending further results from the ongoing study.
What part 2 is still measuring
Part 1 asked what the biopsies looked like. Part 2 asks what matters to a person: over 240 weeks, about four and a half years, do fewer people on semaglutide go on to cirrhosis, a failing liver, a transplant or death? The design paper names cirrhosis-free survival as the primary endpoint, across an estimated 1,200 participants. The registry entry, last updated September 4, 2026, lists ESSENCE as active and no longer recruiting, with primary completion estimated for April 2029.
What ESSENCE means if you're weighing a prescription
ESSENCE is strong evidence for one product, one dose and one group: branded semaglutide 2.4 mg in adults with biopsy-proven MASH and F2 to F3 scarring. It says little about liver fat seen on an ultrasound without scarring, nothing about cirrhosis, and nothing about any one person's odds.
Tirzepatide has a smaller, earlier liver record. In the 190-person SYNERGY-NASH phase 2 trial, MASH resolved in 44% to 62% of people across three doses versus 10% on placebo at 52 weeks. That trial did not compare the two drugs, so it cannot say which is better for a liver; tirzepatide versus semaglutide compares them more broadly.
What ESSENCE cannot say about a compounded version
Through Promise, semaglutide is dispensed as a compounded medication, which is different from an FDA-approved product: the formulation offered here is not FDA-approved. ESSENCE tested branded Wegovy under a trial protocol, and neither its results nor its liver indication transfer to a compounded preparation. Compounded semaglutide explains that difference. A licensed provider may still prescribe a compounded formulation; that decision is between you and your doctor.
At Promise, a licensed provider reviews every request, and not everyone qualifies. Liver history, recent liver tests or scans, alcohol use and current medicines all belong in that review.
