Effect of bempedoic acid on cardiovascular risk in patients with metabolic dysfunction-associated steatotic liver disease

AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of disease starting with liver steatosis and progressing to fibrosis. We evaluated whether non-invasive tests of steatosis and fibrosis are associated with cardiovascular outcomes, and whether bempedoic acid treatment reduced cardiovascular risk. METHODS: A post-hoc exploratory analysis of CLEAR Outcomes (n=13,970, median follow-up 40·6 months) was carried out using non-invasive tests to estimate liver steatosis and fibrosis: Framingham Steatosis Index (FSI), Fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS). The endpoint was a 4-component major adverse cardiovascular event. Time-to-event was analyzed using Cox proportional hazards models. RESULTS: The mean (±SD) age was 66 ±9 years and BMI 30 ±5 kg/m2. Adjusted for other risk factors, liver steatosis was associated with an increased incidence of MACE4 in the placebo group, with hazard ratio (HRFSI) 1·13 (95%CI 1·08-1·18) for 1 unit of FSI increase. Similarly, liver fibrosis was associated with increased risk of MACE4, HRFIB4 1·21 (95%CI 1·09-1·34) and HRNFS 1·16 (95%CI 1·10-1·23) for 1 unit of increase in score. In patients at risk for liver steatosis, the HR for MACE4 associated with 1-unit of FSI increase was lower in the bempedoic acid group: HRFSI_BA 1·04 (95%CI 0·99-1·09) vs. HRFSI_PBO 1·14 (95%CI 1·09-1·18). Treatment effect was not related to the degree of fibrosis. CONCLUSION: Liver steatosis and fibrosis assessed with non-invasive tests are associated with an increased risk of MACE4. Bempedoic acid reduced MACE4 risk, with an additional benefit in patients with elevated steatosis scores.