Tirzepatide Found Superior to Placebo in MASH Resolution, Fibrosis Improvement

More than 50% of patients with metabolic dysfunction-associated steatohepatitis (MASH), with or without type 2 diabetes (T2D), receiving 1 of 3 doses of tirzepatide (Eli Lilly and Company) achieved an absence of MASH with no worsening of fibrosis compared to placebo, according to data from the phase 2 SYNERGY-NASH study.

Results of the dose-finding study were presented at the European Association for the Study of the Liver Congress 2024, held June 5-8, in Milan, Italy, and simultaneously published in NEJM.

SYNERGY-NASH participants, who had MASH with stage 2 or 3 fibrosis, were randomly assigned to receive tirzepatide 5 mg, 10 mg, or 10 mg, via subcutaneous administration once a week for 52 weeks.

Among the 190 participants, the efficacy estimand showed that 51.8%, 62.8%, and 73.3% of those who received 5 mg, 10 mg, and 15 mg doses of tirzepatide, respectively, achieved MASH resolution without worsening of fibrosis compared to 13.2% of those who received placebo at 52 weeks, meeting the study’s primary endpoint.

Researchers also reported that 59.1%, 53.3%, and 54.2% of participants who received 5 mg, 10 mg, or 15 mg of tirzepatide, respectively, had a 1-stage or greater improvement in fibrosis without worsening of MASH compared to 32.8% of those who received placebo, satisfying the study’s secondary endpoint.

Tirzepatide was also associated with improvements in body weight, blood markers of liver injury, and biomarkers of liver fat, inflammation, and fibrosis, according to an Eli Lilly press release.

Although the SYNERGY-NASH study was not designed to confirm whether or not tirzepatide improves fibrosis, the results demonstrate its potential for a clinically meaningful treatment effect across all doses, Eli Lilly noted.

"MASH is the second most common contributor to liver transplantation in the US, highlighting the need for novel therapies," first author Rohit Loomba, MD, MHSc, chief of the division of gastroenterology and hepatology at University of California San Diego School of Medicine, said in the release. "The study is significant, given the urgent need for treatment options that are capable of slowing the progression of the disease and potentially reducing serious health complications."

When Loomba and colleagues assessed the safety of tirzepatide, they found that the overall safety profile was similar to that observed in the SURMOUNT and SURPASS clinical trials. The most commonly reported adverse events were gastrointestinal-related, including nausea, diarrhea, constipation, weight loss, decreased appetite, which were generally mild-to-moderate in severity.

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to reduce hyperglycemia in adults with T2D (Mounjaro) and for chronic weight management in adults who with obesity or with overweight and related comorbid conditions (Zepbound).

Reference: Lilly's tirzepatide was superior to placebo for MASH resolution, and more than half of patients achieved improvement in fibrosis at 52 weeks. News item. Eli Lilly and Company. June 8, 2024. Accessed June 13, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-was-superior-placebo-mash-resolution-and-more