Clinical benefits of tirzepatide in patients with steatotic liver disease and cardiometabolic dysfunction.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease affects more than 30% of adults globally, yet effective treatment options remain limited. Tirzepatide has shown promise in early clinical trials, but its real-world effectiveness with liver-related outcomes remains uncertain. METHODS: Using TriNetX Global Collaborative Network, adults with steatotic liver disease (SLD) and cardiometabolic dysfunction were identified between June 1, 2022, and April 25, 2025. Individuals newly prescribed tirzepatide were propensity score-matched 1:1 to controls not receiving tirzepatide. The primary outcome was major adverse liver outcomes (MALO), defined as decompensated liver events, hepatocellular carcinoma, or liver transplantation. RESULTS: Among 54,882 matched individuals, tirzepatide was associated with a lower incidence of MALO compared to the control group (HR, 0.32; 95% CI, 0.28-0.37). Tirzepatide use was associated with reductions in composite decompensated liver events (HR, 0.31; 95% CI, 0.26-0.36), esophageal variceal bleeding (HR, 0.39; 95% CI, 0.26-0.58), hepatic encephalopathy (HR, 0.27; 95% CI, 0.21-0.34), ascites-related complications (HR, 0.28; 95% CI, 0.23-0.33), hepatocellular carcinoma (HR, 0.36; 95% CI, 0.25-0.53), and liver transplantation (HR, 0.16; 95% CI, 0.08-0.33). Additionally, tirzepatide was associated with lower risks of all-cause mortality (HR, 0.22; 95% CI, 0.18-0.28), major adverse cardiac events (HR, 0.46; 95% CI, 0.40-0.52), and major adverse kidney events (HR, 0.26; 95% CI, 0.22-0.32). CONCLUSIONS: In this retrospective study, tirzepatide use was associated with substantially lower risks of liver-related complications among patients with SLD and cardiometabolic dysfunction, supporting the need for prospective validation of its potential hepatic benefits.