SYNERGY-NASH shows tirzepatide resolves fatty liver disease in a phase 2 trial

Eli Lilly reported detailed results on June 8, 2024, from SYNERGY-NASH, a phase 2 trial testing tirzepatide — the molecule sold as Mounjaro for type 2 diabetes and Zepbound for obesity — in adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and moderate or severe liver scarring ^[2]. The results were presented at the European Association for the Study of the Liver (EASL) Congress 2024 and published the same day in the New England Journal of Medicine ^[2][1].

The trial randomly assigned 190 participants, with or without type 2 diabetes, to once-weekly injections of tirzepatide at 5 mg, 10 mg or 15 mg, or to placebo, for 52 weeks ^[1][2]. All had MASH confirmed by liver biopsy with stage F2 or F3 fibrosis — meaning scarring that has advanced beyond the earliest stage but has not reached cirrhosis ^[1]. The main question was whether MASH would resolve on a repeat biopsy without fibrosis getting worse ^[1].

What the numbers showed

In the published analysis, 157 of the 190 participants had week-52 biopsy results that could be evaluated; missing results were filled in as if they had followed the placebo group's pattern ^[1][3]. Under that conservative approach, MASH resolved without worsening fibrosis in 10% of the placebo group, 44% at 5 mg, 56% at 10 mg and 62% at 15 mg ^[1][3]. The differences versus placebo were 34, 46 and 53 percentage points, with P<0.001 for all three comparisons ^[1][3].

On the key secondary endpoint — improving fibrosis by at least one stage without MASH getting worse — 30% of the placebo group improved, compared with 55% at 5 mg, 51% at 10 mg and 51% at 15 mg ^[1][3]. The confidence intervals for those fibrosis differences were wide and reached close to zero at the lower end (95% CI, 5 to 46; 1 to 42; and 1 to 42) ^[1][3]. Lilly said the study was not designed to prove that tirzepatide improves fibrosis, though the company described the results as showing "the potential for a clinically meaningful treatment effect across all doses" ^[2].

Lilly's press release also reported a second way of counting, called the efficacy estimand, which looks at results among people who stayed on treatment: 51.8%, 62.8% and 73.3% at 5 mg, 10 mg and 15 mg versus 13.2% on placebo for the primary endpoint, and 59.1%, 53.3% and 54.2% versus 32.8% for fibrosis improvement ^[2]. These numbers are higher than the ones in the journal, which used the treatment-regimen estimand ^[2][1]. Both sets come from the same trial; they differ because of how dropouts and treatment discontinuations are handled ^[2].

The most common side effects in the tirzepatide groups were gastrointestinal — nausea, diarrhea, decreased appetite and constipation — and most were mild or moderate ^[1][2]. Lilly said the overall safety profile matched what was seen in the earlier SURMOUNT and SURPASS programs ^[2]. Secondary endpoints also showed improvements in body weight, blood markers of liver injury, and biomarkers of liver fat, inflammation and fibrosis ^[2].

Why it matters for patients

MASH is the fatty liver disease formerly called NASH, and it can progress to cirrhosis. Lilly cited it as the second most common contributor to liver transplantation in the U.S. and said MASH is expected to affect more than 19 million U.S. adults by 2039 ^[2]. Many people with MASH also have obesity or type 2 diabetes, so they may already be candidates for a GLP-1 or dual-agonist drug for another reason.

But this was a phase 2, dose-finding study of 190 people over one year, and the authors wrote that "larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH" ^[1][3]. Tirzepatide is approved only as Mounjaro for type 2 diabetes (May 13, 2022) and as Zepbound for obesity or overweight with a weight-related condition (November 8, 2023), both as an adjunct to diet and exercise ^[2]. Use for MASH is investigational ^[2]. The trial also did not measure whether liver-related complications or deaths were reduced.

What happens next

Lilly said on June 8, 2024, that it was "engaged with regulatory authorities on the next steps for tirzepatide for the treatment of MASH" ^[2]. No timeline for a phase 3 MASH trial or a regulatory filing was given in these sources. The NEJM article appeared in the July 25, 2024 print issue, was updated on September 4, 2025, and an erratum was published in March 2026 ^[1][3]; the content of that correction is not described in the sources available here.