Tirzepatide resolved MASH in up to 62% of patients in a 52-week phase 2 trial
A mid-stage trial found tirzepatide, sold as Mounjaro and Zepbound, cleared fatty liver inflammation better than placebo, but the drug is not approved for liver disease and larger trials are still needed.
Adults with a serious form of fatty liver disease were much more likely to have it resolve after a year of tirzepatide than after placebo, according to a phase 2 trial published in the New England Journal of Medicine and presented at the European Association for the Study of the Liver Congress 2024 [1][2].
The trial, called SYNERGY-NASH, randomly assigned 190 adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and stage F2 or F3 fibrosis — moderate or severe liver scarring — to weekly under-the-skin injections of tirzepatide at 5 mg, 10 mg or 15 mg, or to placebo, for 52 weeks [1][3]. Tirzepatide is a single molecule that activates the GIP and GLP-1 receptors; it is approved in the United States as Mounjaro for type 2 diabetes and as Zepbound for obesity, but not for liver disease [2].
The main goal was resolution of MASH without worsening of fibrosis at week 52. Among 157 participants who had a biopsy at week 52 that could be evaluated, that happened in 10% of the placebo group, 44% of the 5-mg group, 56% of the 10-mg group and 62% of the 15-mg group [1][3]. The differences from placebo ranged from 34 to 53 percentage points, and all three comparisons were statistically significant (P<0.001) [1][3]. Missing biopsy values were imputed under the assumption that they would follow the pattern seen in the placebo group [1][3].
Lilly, which funded the trial, reported somewhat higher figures for the same endpoint using a different statistical approach. Its "efficacy estimand" showed 51.8%, 62.8% and 73.3% for the 5-mg, 10-mg and 15-mg doses versus 13.2% for placebo, while its "treatment-regimen estimand" showed 43.6%, 55.5% and 62.4% versus 9.8% [2]. The peer-reviewed abstract reports 44%, 56% and 62% versus 10% [1][3].
On a secondary endpoint, at least a one-stage improvement in fibrosis without worsening of MASH occurred in 30% of the placebo group and 55%, 51% and 51% of the tirzepatide groups, depending on dose [1][3]. Lilly reported similar but slightly different figures — 29.7% on placebo and 54.9%, 51.3% and 51.0% on tirzepatide — and noted that these secondary comparisons were not adjusted for multiple testing [2]. The phase 2 study was not designed to prove that tirzepatide improves fibrosis, Lilly said, though the results suggested a potentially meaningful treatment effect across all doses [2].
The most common side effects in the tirzepatide groups were gastrointestinal, and most were mild or moderate in severity, the researchers reported [1][3]. Lilly said the overall safety profile was similar to what has been seen in its earlier tirzepatide trials in obesity and diabetes [2].
Why it matters for patients
There is no FDA-approved medicine for MASH, so this trial is one of the first randomized tests of a GLP-1-related drug in people whose livers already show inflammation and scarring rather than simple fat buildup. The participants all had F2 or F3 fibrosis, which means people with cirrhosis (F4) were not studied; no results for that group have been reported from this trial [1].
Fibrosis stage is what doctors watch most closely, because scarring is what drives the risk of liver complications. In this trial, roughly half of treated participants improved by at least one stage, versus about 30% on placebo — a smaller gap than the MASH resolution results, and one the investigators treat as a secondary, hypothesis-generating finding rather than proof [1][2].
Because tirzepatide is already on the market for other uses, some patients with MASH may be taking it or considering it. This trial does not establish that the drug is safe or effective for liver disease, and no dose for MASH has been approved. Lilly estimated that MASH will affect more than 19 million US adults by 2039, and a company official said MASH is the second most common contributor to liver transplantation in the U.S. [2].
What happens next
The researchers wrote that larger and longer trials are needed to further assess how well tirzepatide works, and how safe it is, in MASH [1][3]. Lilly said it is in discussions with regulatory authorities about next steps for tirzepatide in MASH, but has not disclosed a timeline, a filing date or details of any phase 3 program [2]. The trial is registered as NCT04166773 [1][3].
Sources
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