TL;DR: Semaglutide is now the first drug approved for MASH, the fatty liver disease that used to be called NASH. In the ESSENCE phase 3 trial, 62.9% of patients achieved resolution of steatohepatitis without worsening fibrosis, versus 34.3% on placebo, and the FDA granted accelerated approval in August 2025 on the strength of that data. Tirzepatide (SYNERGY-NASH) and survodutide (Boehringer’s GLP-1/glucagon dual agonist) posted even larger phase 2 numbers, up to 73.3% and 83.0% respectively, and the glucagon-receptor piece those two drugs share is the most interesting open question in the field: does it act on the liver directly, on top of weight loss.
What MASH actually is
MASH stands for metabolic dysfunction-associated steatohepatitis. It’s the current name for a disease most people still know as NASH (non-alcoholic steatohepatitis); the field renamed it a few years ago to tie the disease more explicitly to the metabolic drivers behind it, rather than defining it by what it isn’t. The underlying biology didn’t change, just the label.
MASH develops in stages. It starts as simple fat accumulation in the liver, which on its own is common and often harmless. MASH is what happens when that fat is joined by inflammation and cell injury, and the combination starts to scar the liver over time. That scarring is called fibrosis, and it’s staged on a scale that every trial in this space reports against:
F0 and F1 are the earliest stages, where the liver is still largely functional and the scarring is limited. F2 and F3 are where the trials below concentrate their enrollment, because this is the window where fibrosis is advanced enough to matter clinically but the liver hasn’t yet crossed into cirrhosis. F4, cirrhosis, is a different disease state with its own trial programs and is generally excluded from these studies. The reason drug companies care so much about F2-F3 is straightforward: fibrosis stage is the single best predictor of whether someone with fatty liver disease eventually develops liver failure, needs a transplant, or dies from a liver-related cause. Reversing fibrosis at this stage, or at least stopping it from advancing, is the actual clinical goal behind every percentage in this article.
Semaglutide and the ESSENCE trial
ESSENCE is the phase 3 trial that got semaglutide approved. It randomized 1,197 adults with biopsy-confirmed MASH and F2-F3 fibrosis, 2:1, to once-weekly semaglutide 2.4 mg or placebo, with a planned interim analysis at week 72 in the first 800 patients enrolled. The trial itself runs for 240 weeks total; the interim analysis is what supported approval.
At week 72, 62.9% of the 534 patients on semaglutide achieved resolution of steatohepatitis with no worsening of fibrosis, compared with 34.3% of the 266 patients on placebo. A second measure, fibrosis improvement without worsening of steatohepatitis, was reached by 36.8% on semaglutide versus 22.4% on placebo. And the combined endpoint that both trial designers and regulators care about most, resolution of steatohepatitis together with fibrosis improvement in the same patient, was hit by 32.7% on semaglutide versus 16.1% on placebo. Average weight loss in the trial was 10.5% on semaglutide versus 2.0% on placebo, published in the New England Journal of Medicine in April 2025.
The FDA granted semaglutide (Wegovy) accelerated approval for noncirrhotic MASH with moderate to advanced fibrosis (F2-F3) in August 2025, making it the first drug approved specifically for this disease. Accelerated approval means the agency accepted the liver histology results as a reasonable stand-in for a longer-term outcome, with a confirmatory trial, ESSENCE Part 2, still running to show that semaglutide actually reduces liver-related clinical events like decompensation or transplant. That readout is expected around 2029. It’s worth saying plainly: this is a real approval based on a large, randomized, biopsy-confirmed phase 3 trial, not a preliminary signal. The confirmatory data is a formality of the accelerated pathway, not an asterisk on whether the drug works.
Tirzepatide: SYNERGY-NASH, phase 2
Tirzepatide’s liver data comes from SYNERGY-NASH, a phase 2 trial that randomized 190 adults with biopsy-confirmed MASH and F2-F3 fibrosis to tirzepatide 5 mg, 10 mg, 15 mg, or placebo for 52 weeks. At the 15 mg dose, 73.3% of participants achieved absence of MASH with no worsening of fibrosis, compared with 13.2% on placebo. On the fibrosis side, 54.2% of the 15 mg group achieved at least a 1-stage improvement in fibrosis without worsening of MASH, versus 32.8% on placebo. Both were statistically significant and met the trial’s primary and key secondary endpoints.
This is phase 2 data, meaningfully smaller and shorter than ESSENCE, and tirzepatide does not currently carry a MASH approval. But the magnitude of the resolution rate, more than seven in ten patients on the top dose, is the kind of number that tends to justify a phase 3 program, and it puts tirzepatide’s liver profile in the same conversation as semaglutide’s despite the different mechanism (GLP-1/GIP dual agonism versus GLP-1 alone).
Survodutide: a phase 2 dual agonist with a bigger number still
Survodutide, Boehringer Ingelheim’s GLP-1/glucagon dual agonist, posted the largest headline number of the three. In its phase 2 MASH trial, enrolling patients across fibrosis stages F1 through F3 over 48 weeks, up to 83.0% of participants on survodutide achieved a statistically significant improvement in MASH, versus 18.2% on placebo. In the same trial, up to 52.3% of participants across F1-F3 showed fibrosis improvement without worsening of MASH, and in the F2-F3 subgroup specifically, that fibrosis-improvement rate reached 64.5%. Survodutide has since received FDA Fast Track designation for MASH with fibrosis, and Boehringer has moved the compound into phase 3.
Survodutide is covered in more depth, including its obesity trial data and how it compares to a similar dual agonist, in our survodutide vs mazdutide comparison.
Three different trials, phases, populations, and endpoints — not a head-to-head comparison. Semaglutide: ESSENCE phase 3, 72 wk. Tirzepatide: SYNERGY-NASH phase 2, 15 mg, 52 wk. Survodutide: phase 2, highest dose, 48 wk.
The endpoints aren’t identical across trials either. Semaglutide’s headline figure is “resolution of steatohepatitis without worsening of fibrosis,” tirzepatide’s is “absence of MASH without worsening of fibrosis,” and survodutide’s is a broader “significant improvement in MASH.” They’re closely related but not interchangeable definitions, which is one more reason to read the chart above as three separate stories rather than a ranked leaderboard.
Why the liver might care about glucagon, not just weight loss
Here’s the mechanistic question that makes this space more interesting than another set of weight-loss trials. Every GLP-1 drug reduces hepatic fat indirectly, simply by producing weight loss: less overall fat mass generally means less fat stored in the liver. That alone explains a meaningful share of the histology improvement seen with semaglutide and tirzepatide.
But survodutide isn’t a pure GLP-1 drug. It also activates the glucagon receptor, and glucagon receptor signaling is understood to directly increase hepatic fat oxidation, the liver’s own process for burning through stored fat, independent of how much weight the patient has lost overall. That’s the mechanistic rationale for why dual agonists like survodutide, and triple agonists like retatrutide (which adds GIP receptor activity to the mix), are watched so closely for liver-specific effects. If glucagon-receptor activation is doing real, additive work on the liver rather than just riding on the coattails of weight loss, dual and triple agonists could end up outperforming single-target GLP-1 drugs on liver histology by a wider margin than their relative weight-loss numbers alone would predict.
Retatrutide, the GLP-1/GIP/glucagon triple agonist covered in our what is retatrutide explainer, sits in the same theoretical bucket as survodutide on this question, though its liver-specific trial data is earlier-stage than either drug discussed above.
Where the timeline stands
- 1
2024
Tirzepatide SYNERGY-NASH phase 2 and survodutide phase 2 both report results.
- 2
April 2025
ESSENCE phase 3 interim results (semaglutide) published in the New England Journal of Medicine.
- 3
August 2025
FDA grants semaglutide accelerated approval for noncirrhotic MASH with F2-F3 fibrosis, the first approval in the disease.
- 4
~2029
ESSENCE Part 2 confirmatory trial expected to read out on liver-related clinical events.
Semaglutide is, as of today, the only one of the three drugs discussed here with an actual approval. Tirzepatide and survodutide both have phase 2 data strong enough to justify phase 3 programs, and both are being tracked toward that next step. If you want the broader picture on how these three drugs (and retatrutide) compare on weight loss generally, not just liver outcomes, our GLP-1, tirzepatide, and retatrutide comparison lays out the full picture, and the what is semaglutide and what is tirzepatide explainers cover each drug’s mechanism from the ground up for anyone who wants that foundation first.
Frequently asked questions
What is MASH and how is it different from NASH?
MASH (metabolic dysfunction-associated steatohepatitis) is the current name for the disease previously called NASH (non-alcoholic steatohepatitis). The rename reflects a shift toward defining the disease by its metabolic drivers rather than by what it excludes. The underlying biology, fat accumulation plus inflammation plus liver scarring, is the same condition under both names.
Is semaglutide actually approved for fatty liver disease?
Yes. The FDA granted semaglutide (Wegovy) accelerated approval in August 2025 for noncirrhotic MASH with moderate to advanced fibrosis (stages F2-F3), based on the ESSENCE phase 3 trial. It’s the first drug approved specifically for this disease. A confirmatory trial tracking longer-term liver outcomes is expected to read out around 2029, which is a standard requirement of the accelerated approval pathway rather than a sign the current data is preliminary.
How much did semaglutide improve fatty liver disease in the ESSENCE trial?
At 72 weeks, 62.9% of patients on semaglutide achieved resolution of steatohepatitis without worsening of fibrosis, versus 34.3% on placebo. A combined endpoint, resolution plus fibrosis improvement in the same patient, was reached by 32.7% on semaglutide versus 16.1% on placebo, alongside average weight loss of 10.5%.
Are tirzepatide and survodutide approved for MASH?
No, not yet. Both have phase 2 data, tirzepatide’s SYNERGY-NASH trial and survodutide’s phase 2 MASH program, showing resolution or improvement rates of 73.3% and up to 83.0% respectively against their own placebo arms. Both are earlier in development than semaglutide and are being advanced toward phase 3 programs rather than currently approved for this indication.
Why does the glucagon receptor matter for liver fat specifically?
GLP-1 receptor activation helps the liver indirectly, mainly through overall weight loss. The glucagon receptor, which survodutide and retatrutide also activate, is understood to directly increase hepatic fat oxidation, the liver’s own fat-burning process, independent of total body weight change. That’s the working theory for why dual and triple agonists are of particular interest for liver-specific outcomes, though it hasn’t been isolated from the weight-loss effect in a human trial yet.
Can these trial results be compared directly to rank the three drugs?
Not reliably. The three trials differ in phase, duration, fibrosis-stage inclusion criteria, dose, and the exact histology endpoint measured, resolution versus absence of MASH versus significant improvement. The percentages are useful for seeing the direction and scale of each drug’s effect against its own placebo arm, but they aren’t head-to-head evidence of which drug performs best in the same population.