Weight loss and diabetes medications have positive therapeutic effects on MASH

MILAN — The weight loss and diabetes drug tirzepatide reversed metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, according to results from the SYNERGY-NASH Phase 2 trial.

Among 190 participants with biopsy-confirmed MASH and fibrosis, estimates of treatment regimens showed that 44% of patients in the weekly 5 mg tirzepatide group, 50% in the 10 mg group, and 62% in the 15 mg group experienced resolution of MASH without worsening of fibrosis, compared with 10% in the placebo group (P“Overall, it’s less than 0.001,” Rohit Loomba, MD, of the University of California, San Diego, reported at the European Society for the Study of the Liver annual meeting.

The test results are New England Journal of Medicine.

“MASH is the second leading cause of liver transplants in the United States, highlighting the need for new therapies,” Loumba said in a press release from tirzepatide manufacturer Eli Lilly. “This study is significant given the urgent need for treatment options that may slow disease progression and reduce serious health complications.”

A combination glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist received FDA approval for the treatment of type 2 diabetes (Mounjaro) in 2022, followed by FDA approval for the treatment of obesity or overweight management (Zepbound) in 2023.

Lomba also presented an efficacy analysis that included all randomized participants, excluding data available after permanently discontinuing tirzepatide or placebo. In that analysis, efficacy estimates showed that 51.8% of patients in the 5 mg tirzepatide group, 62.8% of patients in the 10 mg group, and 73.3% of patients in the 15 mg group achieved resolution of MASH without worsening of fibrosis, compared with 13.2% in the placebo group.

In the key secondary endpoint, the proportion of participants who achieved a reduction in at least one fibrosis stage without worsening of MASH was 55%, 51%, and 51% in participants taking 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, compared with 30% in the placebo group (P<0.05).

When asked during the Q&A about the 30% response rate in the placebo group, Loomba surmised that “that’s a real tyranny of small numbers.” There were 48 patients in total in the placebo group, but about three times as many total participants in the treatment group. “That’s why I think the precision estimates are not clear,” he explained.

Laurent Castella, MD, PhD, of the University of Paris Cité in Clichy, France, wanted to know why tirzepatide appeared to have “no dose effect on fibrosis” in the trial. Loumba replied that this, too, was likely an artifact of the small Phase II study design. “Typically, with 300 patients in each arm, I would say you start to see a dose response,” he noted. “It’s also possible that the peak effect is somewhere in the middle.”

Among all study participants, the percentage of participants who achieved a 2-point or greater reduction in their NAFLD Activity Score and a 1-point reduction in at least two components of that score at week 52 showed significant improvement in approximately 72% to 78% of participants in the treatment group compared with approximately 37% in the placebo group (P<0.001 in all cases).

Significant reductions were also observed in liver fat content and liver fibroinflammation assessed by MRI, and liver stiffness assessed by vibration-controlled transient elastography.

“The histologic findings are supported by changes in biomarkers of fibrosis,” Lomba told attendees. Evaluation of serum biomarkers revealed a significant decrease in NIS4, a biomarker for MASH in patients with NAS ≥ 4 (PThe fibrosis marker ELF and the fibrosis biomarker Pro-C3 were also significantly reduced in the active drug group (PBoth were <0.001. ALT and AST also showed significant reductions by week 26 and were maintained through week 52.

In safety analyses, adverse events were reported in 92% of patients receiving tirzepatide and 83% of patients receiving placebo. The most common adverse event in the tirzepatide group was gastrointestinal disorders, with 96% of events being mild to moderate in severity. Discontinuations were similar in the treatment and placebo groups, occurring in approximately 4% of patients in each group.

The rate of serious adverse events was similar in both groups, about 6.2 percent. Progression to cirrhosis occurred in 2.8 percent of patients receiving tirzepatide compared with 4.2 percent in the placebo group. Loomba noted that no participants experienced liver dysfunction or evidence of drug-induced liver damage. The major adjudicated cardiovascular adverse event was a transient ischemic attack, which occurred in the tirzepatide 5 mg group. Gallbladder-related adverse events occurred in 2.8 percent of patients in the tirzepatide group and 2.1 percent in the placebo group. No cases of acute pancreatitis were reported.

SYNERGY-NASH is a dose-finding, multicenter, randomized trial that enrolled 190 participants between January 2020 and January 2023. Of the participants, 57% were female, the median age was approximately 54 years, and 86% were white. The mean body mass index (BMI) at baseline was 36, and 58% had type 2 diabetes. At baseline, 43% of participants had F2 liver fibrosis and 57% had F3 fibrosis.