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.