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20-06-2024 | Non-Alcoholic Fatty Liver Disease | Editor's Choice | News

Tirzepatide shows promise for metabolic dysfunction-associated steatohepatitis

Author: Laura Cowen

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medwireNews: Patients with metabolic dysfunction-associated steatohepatitis (MASH) and moderate or severe fibrosis have significantly higher rates of disease resolution, without worsening fibrosis, when given tirzepatide rather than placebo, show data from the phase 2 SYNERGY-NASH trial.

Rohit Loomba (University of California at San Diego, USA) and co-investigators explain that tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist that is known to “induce substantial weight reduction” in people with type 2 diabetes and/or obesity.

In addition, treatment with tirzepatide led to a reduction in liver fat and an improvement in biomarkers of MASH and fibrosis in a trial among people with type 2 diabetes, but its efficacy in people with MASH and moderate or severe fibrosis is unclear.

To investigate, Loomba and team randomly assigned 190 people with biopsy-confirmed MASH and moderate or severe (stage F2 or F3) fibrosis to receive once-weekly subcutaneous tirzepatide 5 mg (n=47), 10 mg (n=47), or 15 mg (n=48), or placebo (n=48) for 52 weeks. The participants had a mean age of 54.4 years and a mean BMI of 36.1 kg/m2. Over half (57%) were women and 58% had type 2 diabetes.

The researchers report in The New England Journal of Medicine that, at 52 weeks, participants given tirzepatide had significantly higher rates of MASH resolution without worsening of fibrosis than those given placebo. The rates were 44%, 56%, and 62% in the tirzepatide 5 mg, 10 mg, and 15 mg groups, respectively, compared with 10% in the placebo group.

In addition, people given tirzepatide 5 mg, 10 mg, and 15 mg were more likely to have an improvement of at least one fibrosis stage without worsening of MASH at 52 weeks than those given placebo, at rates of 55%, 51%, and 51%, respectively, versus 30%.

Loomba and co-authors comment: “The relatively short duration of the SYNERGY-NASH trial (52 weeks) may account for the similar incidence of improvement in fibrosis (51 to 55%) across the three doses of tirzepatide. Alternatively, fibrosis regression of approximately 50% may be the ceiling effect with weight reduction.”

Tirzepatide treatment was also associated with greater improvements in several secondary outcomes versus placebo including the overall nonalcoholic fatty liver disease activity score and its subscores for steatosis, lobular inflammation, and hepatocellular ballooning, as well as blood markers of liver injury.

Participants in the tirzepatide 5 mg, 10 mg, and 15 mg arms had a greater mean percentage reduction in bodyweight during the study than those in the placebo arm, at a respective 10.7%, 13.3%, and 15.6% versus 0.8%. Furthermore, Loomba et al say that “[t]here appeared to be an association between greater degrees of weight reduction and higher incidences of MASH resolution without worsening of fibrosis, but the relationship with weight reduction was less apparent for reduction in fibrosis without worsening of MASH.”

There were no unexpected adverse events (AEs) and those that did occur typically involved mild or moderate nausea, diarrhea, or constipation. Serious AEs occurred in 6% of participants given tirzepatide and 6% of those given placebo.

The researchers conclude: “Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH with liver fibrosis and to determine whether tirzepatide treatment could reduce the risk of major adverse liver outcomes.”

The study findings were simultaneously presented at the EASL Congress 2024 in Milan, Italy.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

N Engl J Med 2024; doi:10.1056/NEJMoa2401943
EASL Congress 2024; Milan, Italy: 6–8 June

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