Global 
Deutschland 
Italia Liver and Bile
N Engl J Med. 2024;391(4):299–310
Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis
Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.
Methods: The authors conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least 1 fibrosis stage without worsening of MASH.
Results: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI]: 17–50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI: 29–62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI: 37–69) (p < 0.001 for all 3 comparisons). The percentage of participants who had an improvement of at least 1 fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI: 5–46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI: 1–42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI: 1–42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.
Conclusions: In this phase 2 trial involving participants with metabolic dysfunction-associated steatohepatitis (MASH) and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH.
Dr. Dr. Natascha Röhlen
Functional Senior Physician MASLD Outpatient Clinic, Department of Internal Medicine II, University Medical Center Freiburg (Germany)
GLP-1 receptor agonists as a therapeutic approach for MASH treatment
Metabolic dysfunction-associated steatohepatitis (MASH) is one of the leading causes of liver fibrosis and cirrhosis in western countries. In March 2024, resmetirom, a liver-selective thyroid hormone receptor beta (TRH-β) agonist, became the first drug approved for the treatment of patients with MASH and moderate to advanced fibrosis in the United States. Approval by the European Medicines Agency is still pending, but is expected by early 2025.
In addition to resmetirom, incretins in particular have been tested for the treatment of MASH in recent years. Incretins have already been well-established in the treatment of obesity and type 2 diabetes. By mimicking the effects of the endogenous hormones glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), or glucagon, incretins lead to weight loss and increased insulin sensitivity. While Newsome et al. already described protective effects of the GLP-1 receptor analogue semaglutide on histologically detectable inflammation and hepatocyte ballooning in 2021, current clinical studies are primarily investigating the effects of GLP-1/GIP and GLP-1/glucagon receptor agonists, which are associated with particularly effective weight loss.
In their phase 2 study, Loomba et al. investigated the effects of the GLP-1/GIP agonist tirzepatide in 190 MASH patients with moderate (F2) or severe fibrosis (F3). In the same issue of the New England Journal of Medicine, Sanyal et al. published a paper investigating the efficacy of the GLP-1/glucagon receptor agonist survodutide in 293 MASH patients with stage F1–F3 fibrosis. Both tirzepatide and survodutide were injected subcutaneously once a week with a dose-escalation phase of 1–6 months. Both studies showed a significant reduction in histological MASH activity without worsening of fibrosis after 52 or 48 weeks of therapy with tirzepatide or survodutide compared to the placebo group. In both studies, the verum group further showed a decrease in transaminases and a reduction in the liver fat content, as measured by magnetic resonance imaging. Treatment with a GLP-1 receptor agonist further tended to be associated with a higher percentage of patients with histologically detectable fibrosis regression (tirzepatide: +21%, survodutide: +14% compared to the placebo group). Both studies observed a higher incidence of gastrointestinal adverse events such as nausea and diarrhea under the respective therapy. However, serious adverse events did not occur more frequently than with placebo in either study.
While differences in the study design (different end points, differences in the degree of fibrosis, the patient cohort and the statistical analyses) do not allow a comparison of the efficacy of the 2 substances, both studies indicate a potential role for GLP-1 receptor agonists in the treatment of obese MASH patients. However, it remains unclear whether the observed effects on histological MASH activity are directly mediated by tirzepatide or survodutide, or whether they primarily reflect indirect effects of weight loss. In both studies, there was an average weight loss of 10–16% over the approximately 1-year therapy with a GLP-1 receptor agonist. With regard to fibrosis, the study durations of 48–52 weeks were most likely too short and the sample size too small to assess the long-term antifibrotic efficacy of GLP-1 receptor agonists. If the potential therapeutic effect is mainly mediated by weight loss, the maximum fibrosis regression can be expected after a treatment duration of > 1 year, according to published data from bariatric studies.
Patients with MASH cirrhosis were excluded from both studies. However, Loomba et al. published a phase 2 study in 2023 that indicated that the GLP-1 agonist semaglutide was safe for the treatment of compensated MASH cirrhosis. The already planned phase 3 studies with cirrhosis patients, as well as long-term data, are urgently needed not only to validate the short-term effect on MASH inflammation and fibrosis but also to assess the effect of GLP-1 receptor agonists on clinical end points such as decompensation events and the incidence of hepatocellular carcinoma (HCC).