Tirzepatide for metabolic dysfunction-associated steatohepatitis: results from phase II clinical trials and perspectives.

Tirzepatide is a once-weekly injectable dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. GIP and GLP-1 are incretins promoting insulin release from pancreatic β-cells. Results from clinical trials have confirmed that tirzepatide exerts favorable effects on glucose metabolism and insulin resistance, reduces food intake and has been approved for the treatment of adults with type 2 diabetes, and who are overweight/obese or who have weight-related comorbidities. Results from SYNERGY-NASH, a phase 2 study involving patients with biopsy-proven MASH and stage 2 or 3 fibrosis, have shown that tirzepatide achieved MASH resolution with no worsening of fibrosis in a significantly higher percentage of patients than placebo. Additionally, more patients in the tirzepatide group in comparison to placebo achieved a 1-stage or greater fibrosis improvement without worsening of MASH, but the study was not powered to detect this change, and noninvasive biomarkers of fibrosis were not significantly improved. While these results suggest a potential role for tirzepatide in MASH treatment given its ability to improve insulin sensitivity and reduce food intake, factors already shown to be beneficial in reducing livers steatosis and fibrosis, larger clinical trials are needed.