Cardiovascular-kidney-metabolic syndrome and the risk of liver-related and cardiovascular events across the steatotic liver disease spectrum.

BACKGROUND: Steatotic liver disease (SLD) is closely associated with cardiometabolic factors, but whether the cardiovascular-kidney-metabolic (CKM) stage stratifies risk for major adverse cardiovascular events (MACEs) and liver-related events (LREs) across SLD subtypes remains unclear. METHODS: In the UK Biobank study, participants with SLD were classified into subtypes of metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD), and alcohol-related liver disease (ALD). The primary outcomes were incident MACEs and LREs, assessed overall and by subtype. Associations were evaluated using Cox models, Kaplan-Meier curves, and population-attributable risks (PARs). FINDINGS: Over 14.7 years of follow-up, 17,973 MACEs (14.0%) and 2,742 LREs (2.0%) occurred among 142,564 individuals with SLD. Higher CKM stage was associated with graded increases in both outcomes (CKM stages 2-4 vs. 0-1: adjusted HRs 1.51 [95% CI 1.43-1.59] to 3.62 [3.31-3.97] for MACEs and 1.28 [1.11-1.48] to 2.32 [1.95-2.75] for LREs), with similar trends across subtypes. Obesity and hypertension were the leading contributors to both outcomes (PARs of up to 19.0% and 22.8% for LREs), whereas diabetes contributed more prominently to LREs than to MACEs (17.5% vs. 7.9%). CONCLUSIONS: A higher CKM stage is associated with an increased long-term risk of MACEs and LREs across the SLD spectrum. Obesity and hypertension are the primary contributors to both outcomes, and diabetes additionally contributes to LREs. FUNDING: Supported by the National Science and Technology Major Project, the National Key R&D Program of China, and the National Natural Science Foundation of China.