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Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis With Liver Fibrosis
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- This phase II, multicenter randomized controlled trial examined the efficacy and safety of tirzepatide in patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or severe fibrosis. Resolution of MASH without worsening of fibrosis occurred 44% in the 5-mg group, 56% in the 10-mg group, and 62% in the 15-mg group, compared with 10% in the placebo group. Improvement of at least one fibrosis stage without worsening of MASH occurred in 55% in the 5-mg group, 51% in the 10-mg group, and 51% in the 15-mg group, compared with 30% in the placebo group. Most of the adverse effects in the tirzepatide groups were gastrointestinal, but with mild-to-moderate severity.
- In this phase II trial, treatment with tirzepatide for 52 weeks improves MASH and, in some cases, resolves MASH without worsening fibrosis.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
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
We 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 one 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 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one 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 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 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 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. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).
Additional Info
Disclosure statements are available on the authors' profiles:
Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis
N. Engl. J. Med 2024 Jun 08;[EPub Ahead of Print], R Loomba, ML Hartman, EJ Lawitz, R Vuppalanchi, J Boursier, E Bugianesi, M Yoneda, C Behling, OW Cummings, Y Tang, B Brouwers, DA Robins, A Nikooie, MC Bunck, A Haupt, AJ SanyalFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Tirzepatide is a glucagon-like peptide (GLP-1) agonist and a glucose-dependent insulinotropic polypeptide (GIP) agonist associated with weight loss and blood sugar reduction, likely due to slowed gastric emptying and increased insulin sensitivity.1
Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is the second most common indication for liver transplantation and the fastest-increasing indication, surpassing alcohol-related liver disease.2 Lifestyle changes are the primary intervention, especially with the goal being weight loss for individuals with an elevated body mass index, and, if needed, bariatric surgery or drug therapy.3
This study, sponsored by the manufacturer of tirzepatide, intended to evaluate the effect of tirzepatide on inflammation and fibrosis based on labwork, ultrasound, and biopsy, with the primary endpoint of MASH resolution without worsening of fibrosis. Participants (N = 190) were predominately White (86%) and Hispanic/Latino (36%), with a mean BMI of 36 kg/m2 and type 2 diabetes present in 58%. The participants all had biopsy-confirmed MASH with stage 2 to 3 (F2-3) fibrosis. The exclusion criteria included other chronic liver diseases, cirrhosis, excess alcohol intake, uncontrolled diabetes, and prior GLP-1 or weight-loss medication use. Participants were randomized to four equal groups: placebo or 5-, 10-, or 15-mg dose of tirzepatide. They were followed for 52 weeks, and the biopsy was repeated. Overall, 157 participants (83%) had an end-of-treatment liver biopsy that could be evaluated. Notably, fewer than 5% of patients discontinued tirzepatide due to adverse events, mostly gastrointestinal.
Resolution of MASH without worsening fibrosis seemed to follow a dose-responsive significant effect over placebo. Similar benefits can be seen with nonpharmacologic weight loss, pioglitazone, and other GLP-1 agonists, although head-to-head comparisons are lacking.4
The secondary endpoint was a decrease in the fibrosis stage and no worsening of MASH. Presumably, this was chosen as prior studies of semaglutide and weight loss failed to show liver biopsy fibrosis improvement over placebo, although there is some variation in the metrics measured.5
Although encouraging, this study was relatively small, short in duration, and included few Black participants. Furthermore, data regarding tirzepatide being associated with a reduction in cirrhosis or major adverse liver outcomes, such as decompensated cirrhosis or liver transplantation are lacking — especially as MASH represents a chronic condition likely necessitating many years of treatment — as are data relative to the associated costs and risks.
We continue to find potential benefits of the GLP-1 agonist class, including this relatively novel GLP-1/GIP agonist, but it is premature to recommend these drugs for patients with MASH who do not have another appropriate indication for tirzepatide therapy. We all anxiously await more data concerning long-term safety and improved access to this class of medications.
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