Tirzepatide Shows Potential to Improve Fatty Liver Associated Fibrosis in Diabetes: Insights from the SYNERGY-NASH trial

Review by Dr. Cinthia Reyes Cruz (Dominican Republic)

Study Summary 

We already know that nonalcoholic fatty liver disease (NAFLD), now known as Metabolic dysfunction-associated steatohepatitis (MASH) is common in people with type 2 diabetes (T2DM), but treatment options specifically targeting liver fat and fibrosis are still lacking. GLP-1 receptor agonists have shown some promise in reducing liver fat, but their effects on liver fibrosis aren’t well established. The SYNERGY-NASH trial evaluated the effect of tirzepatide in controlling liver fat deposits and its implications on liver fibrosis.

In this study, 190 adults with biopsy-confirmed MASH and F2-F3 fibrosis were randomized to receive tirzepatide (5mg, 10mg, 15mg) or placebo once weekly. MASH resolution without fibrosis worsening was achieved in 10% of placebo patients, compared with 44%, 56% and 62% in the tirzepatide 5mg, 10mg and 15mg groups, respectively. Also, improvement of more than 1 stage of fibrosis without MASH worsening was observed in 30% of placebo patients versus 51-55% among the tirzepatide groups. This tirzepatide effect was even more pronounced when evaluated in terms of a more than 2-point reduction in NAFLD Activity Score (NAS) which was achieved in 72-78% in the tirzepatide groups, versus 37% in the placebo group. Side effects were minimal, including nausea, diarrhea, constipation and were similarly frequent across all patient groups.

Commentary 

This randomized, multicenter, dose-ranging study delivers exciting histologic outcomes, showing that tirzepatide can resolve MASH without worsening fibrosis. And, adding to this, even improve fibrosis stage. Strengths include biopsy-confirmed endpoints, and the consistency of effect across various doses. Limitations include the exclusion of cirrhosis (F4 stage), which potentially limits use in advanced disease. There was also limited diversity in terms of the ethnic groups included.

Overall, these findings are promising. Especially in the setting of early disease, in which clinicians should consider these GLP-1/GIP therapies. Although, longer-term studies with broader populations would be warranted to confirm fibrosis reversal in MASH.

Citation

Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis - PubMed

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