Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive disease with substantial morbidity and mortality and no approved treatments. Observational studies have linked aspirin use to reduced prevalence and progression of MASLD. However, the efficacy and safety of aspirin for reducing hepatic steatosis, inflammation, and fibrosis in patients with MASLD are unknown.

Methods: In a 6-month, randomized, double-blind, placebo-controlled trial, we assigned 80 adults aged 18-70 years with established MASLD (without cirrhosis) to receive daily aspirin 81mg daily or placebo in a 1:1 ratio. The primary endpoint was mean change in intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS); secondary endpoints included mean changes in alanine aminotransferase (ALT), IHL by MRI proton density fat fraction (MRI-PDFF), and the combined inflammation and fibrosis cT1 score. Treatment effects were assessed from the intention-to-treat population.

Results: Between September 2019 and November 2022, 80 participants were randomized, and 71 completed the trial. At baseline, mean age (47.9±12.1), BMI (33.7±6.0 kg/m²), sex distribution (56.3% female), and IHL (37.6±18.4%) did not differ between groups. Absolute IHL change at month 6 was -7.3% (95% CI: -14.3 to -0.3) with aspirin and 3.0% (95% CI: -4.4 to 10.5) with placebo (P=0.009), yielding a relative IHL reduction of 10.3% with aspirin compared to placebo (95% CI: -17.9 to -2.8; P=0.011). The percent change in IHL was -17.3% (95% CI: -30.3 to -3.7) with aspirin and 30.3% (95% CI: 5.4 to 56.1) with placebo (P=0.007). Improvements in all prespecified secondary hepatic endpoints were observed in the aspirin group, including a reduction in mean cT1 score (-18.8, 95% CI: -50.7 to 13.0) vs. placebo (29.2, 95% CI: -2.3 to 60.7, p=0.011). The mean absolute weight change did not differ between groups (0.1kg for aspirin vs. 0.4kg for placebo, P=0.80), nor did the proportion of patients with ≥3% weight loss (12.5% for aspirin vs. 10% for placebo, P=0.66). The only drug-related adverse event in the aspirin group was heartburn in 1 participant. Adverse events led to discontinuation in 1 participant per group.

Conclusion: In this 6-month trial in adults with MASLD, aspirin 81mg daily substantially reduced hepatic steatosis and markers of hepatic inflammation and fibrosis. These findings support larger, long-term trials assessing the effects of aspirin on MASLD histological and clinical endpoints.