Abstract 4140119: Liver Steatosis and Liver Fibrosis Predict Major Adverse Cardiovascular Events in the CLEAR Outcomes Trial

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), and progressive stages accompanied by liver fibrosis (LF), have been associated with liver-related and CV complications in middle-aged patients, although data on the latter is limited. Objectives: We evaluated whether liver steatosis (LS) or LF are associated with CV outcomes in a large clinical trial that included patients at high CV risk who were statin intolerant (SI), and if so, whether bempedoic acid (BA) treatment reduces observed increases in CV risk. Methods: CLEAR Outcomes evaluated the efficacy of BA in 13,970 SI patients randomized to BA (180 mg daily) or placebo and followed for a median of 40.6 months. The primary outcome was a 4-component major adverse CV event (MACE4: nonfatal MI, nonfatal stroke, coronary revascularization, or CV death). This post-hoc analysis used the following non-invasive algorithms to estimate the presence of LS and LF at baseline: Framingham Steatosis Index (FSI), Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Score (NFS). Continuous variables were reported as mean±SD, categorical variables as proportion. Time-to-event data were analysed using a Cox proportional hazards model. Adjusted hazard ratios (aHR) for every 1 unit increase in score, while holding every other variable constant, and corresponding 95% CI were reported. Results: The mean age of included participants was 66±9 years, 48% were female, mean BMI was 30±5 kg/m 2 , and characteristics were balanced over the treatment arms. Baseline FSI was 0.2±1.5, FIB-4 1.3±0.6 and NFS -0.6±1.2. LS was associated with an increased incidence of MACE4 in the whole study population, as indicated by the aHR of 1.09 (1.06-1.12) for 1 unit of FSI increase. LF was also associated with increased risk of MACE4 in the overall population, aHR 1.19 (1.11-1.28) for 1 unit of FIB-4 increase, and aHR 1.14 (1.10-1.19) for 1 unit of NFS increase. For LS, per 1 unit of FSI increase the aHR for MACE4 was lower in the treatment group: aHR of 1.04 (0.99-1.09) for BA vs 1.14 (1.09-1.18) for placebo, interaction p=0.004. For LF, aHR did not differ between groups and no significant interaction with treatment was observed. Conclusion: Both LS and LF are associated with an increased risk of MACE4. Overall, BA was associated with lower rates of MACE4 across categories of LS and LF (data not shown). A lower risk of LS-associated MACE4 was observed in the BA group. These benefits are less clear regarding the MACE4 risk driven by LF.