The New England Journal of MedicineTirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis

Potential Role of Tirzepatide in Addressing Metabolic Liver Disease and Fibrosis

Tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, was assessed for its efficacy and safety in patients with metabolic dysfunction-associated steatohepatitis (MASH) and moderate or severe fibrosis in a phase 2 trial. This study compared various doses of tirzepatide to a placebo over a 52-week period, focusing on the resolution of MASH and improvement in fibrosis stages.

Study Design:

• Participants: 190 participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis.
• Study Type: Phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial.
• Intervention: Once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks.
• Primary Endpoint: Resolution of MASH without worsening of fibrosis at 52 weeks.
• Key Secondary Endpoint: Improvement (decrease) of at least one fibrosis stage without worsening of MASH.

Key Findings:

• Resolution of MASH without worsening of fibrosis:
  • Placebo: 10%
  • 5 mg tirzepatide: 44% (Difference: 34 percentage points; 95% CI: 17 to 50)
  • 10 mg tirzepatide: 56% (Difference: 46 percentage points; 95% CI: 29 to 62)
  • 15 mg tirzepatide: 62% (Difference: 53 percentage points; 95% CI: 37 to 69)
  • (P<0.001 for all comparisons)
• Improvement of at least one fibrosis stage without worsening of MASH:
  • Placebo: 30%
  • 5 mg tirzepatide: 55% (Difference: 25 percentage points; 95% CI: 5 to 46)
  • 10 mg tirzepatide: 51% (Difference: 22 percentage points; 95% CI: 1 to 42)
  • 15 mg tirzepatide: 51% (Difference: 21 percentage points; 95% CI: 1 to 42)
• Adverse Events: Most common in tirzepatide groups were gastrointestinal events, which were mostly mild or moderate in severity.

HCN Medical Memo
Tirzepatide demonstrated significant efficacy in resolving MASH and improving liver fibrosis stages over a 52-week period compared to placebo. This suggests a potential new therapeutic option for patients with MASH and moderate to severe fibrosis, pending further larger and longer trials to confirm these findings and ensure safety.

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