Tirzepatide resolves MASH without worsening fibrosis

Treatment with tirzepatide for 52 weeks resulted in MASH* resolution, with no worsening of fibrosis in patients with MASH and fibrosis in the phase II SYNERGY-NASH trial.

MASH is a progressive liver disease associated with liver-related complications and death.

In the trial, tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, resolved MASH without worsening of fibrosis in 44 percent of patients in the tirzepatide 5-mg group, 56 percent in the 10-mg group, and 62 percent in the 15-mg group compared with 10 percent in the placebo group (p<0.001 for all). [EASL 2024, abstract LBO-001]

“The study is significant, given the urgent need for treatment options that are capable of slowing MASH progression and potentially reducing serious health complications,” said study author Dr Rohit Loomba from the University of California San Diego School of Medicine, La Jolla, California, US.

SYNERGY-NASH population

The study was conducted between January 2020 and January 2023 at 130 sites in 10 countries and enrolled 190 patients with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Among the cohort, 57 percent were women, the median age was 54 years, and 86 percent were White. The mean BMI at baseline was 36 kg/m², 58 percent had T2D. Forty-three percent had F2 fibrosis, and 57 percent had F3 fibrosis. [N Engl J Med 2024; doi:10.1056/NEJMoa2401943]

Patients were randomly assigned in a 1:1:1:1 ratio to receive subcutaneous tirzepatide 5 mg, 10 mg, or 15 mg once weekly, or placebo, for 52 weeks, stratified by T2D status and geographic region.

The primary endpoint was the resolution of MASH, defined as no steatotic liver disease (NAFLD** activity steatosis score of 0) or simple steatosis (NAFLD activity steatosis score of 1, 2, or 3) without steatohepatitis, an inflammation score of 0 or 1, and a ballooning score of 0, without worsening of fibrosis at 52 weeks. A key secondary endpoint was an improvement of ≥1 fibrosis stage without worsening of MASH.

Other study endpoints

Among 190 patients who underwent randomization, 165 (87 percent) completed the trial, 161 (85 percent) completed the trial regimen, and 157 (83 percent) had liver biopsy results at week 52 that could be evaluated.

At week 52, a decrease of ≥2 points in the NAFLD activity score, with a reduction of ≥1 point in at least two NAFLD activity score components, occurred in 72–78 percent of patients across the three tirzepatide groups and 37 percent of those in the placebo group.

As for the secondary endpoint, the percentage of patients who had an improvement of at least 1 fibrosis stage without worsening of MASH was 55 percent, 51 percent, and 51 percent in those taking 5 mg-, 10 mg- and 15 mg tirzepatide, respectively, compared with 30 percent in the placebo group (p<0.05).

In addition, the mean percentage change in body weight was −10.7 percent, −13.3 percent, and −15.6 percent in the 5 mg, 10 mg, and 15 mg tirzepatide groups, respectively, compared with −0.8 percent in the placebo group.

Tyranny of small numbers

When asked during a Q&A session about the 30 percent response rate in the placebo group, Loomba said: “It’s a tyranny of small numbers.” The placebo group had 48 patients, whereas the total number of patients in the treatment groups was approximately thrice.

As for the apparent no-dose effect on fibrosis with terzipatide, Loomba explained that, again, that could be an effect of the small phase II trial design. “Typically, if we had 300 patients per arm, I think we would start seeing some dose response,” he pointed out. “It’s also possible that the peak effect is somewhere in the middle.”

The most common adverse events in the tirzepatide groups were gastrointestinal events, which were mostly mild or moderate.

Several study limitations included the small sample size, the short trial duration, the lack of safety and efficacy assessments in patients with MASH who had progressed to cirrhosis, and the lack of adjustment for multiplicity in calculating the sample size and confidence intervals.

“Larger and longer trials are needed to further assess tirzepatide for the treatment of MASH with liver fibrosis and determine whether tirzepatide treatment could reduce the risk of major adverse liver outcomes,” said Loomba.

Indicated as an adjunct to diet and exercise, tirzepatide was US FDA-approved for T2D in 2022 and for obesity and overweight in 2023.