Stratified Burden of MASLD in Cardiovascular Kidney Metabolic syndrome: Stage-Dependent Prevalence and Insulin Resistance-Driven Cardiovascular Mortality

ObjectiveThis study aimed to investigate the epidemiological burden of metabolic dysfunction-associated steatotic liver disease (MASLD) across Cardiovascular-Kidney-Metabolic syndrome (CKM) stages and evaluate its association with cardiovascular mortality, while exploring the mediating role of insulin resistance (IR). MethodsUsing data from the National Health and Nutrition Examination Survey (NHANES, 2009-2018), we included 9,093 adults with CKM stages 1-4. MASLD was defined by validated indices (usFLI [&ge;] 30). Weighted Cox regression assessed MASLD-associated cardiovascular mortality risk. Restricted cubic splines (RCS) modeled dose-response relationships. Causal mediation analysis quantified TyG indexs contribution to MASLD-related mortality. Sensitivity analyses included subgroup stratification, missing data deleting and alternative MASLD definitions. ResultsMASLD prevalence increased significantly across advancing CKM stages (stage 1: 8.04%, stage 2:32.78%, stage 3: 41.90% and stage 4: 42.55%; P < 0.001). RCS revealed linear mortality risk escalation with rising usFLI scores (Non-line P < 0.05). MASLD independently predicted 63% higher cardiovascular mortality risk (adjusted HR=1.63, 95% CI:1.05-2.52). Stratify analyses revealed heterogeneity in associations by diabetes, CKD, CVD, and CKM stages (P for interaction < 0.05), stronger risks were observed in non-diabetic, non-CKD, non-CVD and early-stage (1-2) CKM. TyG-mediated IR explained 40.5% of MASLD-associated mortality. Sensitivity analyses confirmed robustness across MASLD definitions (FLI-based HR = 1.68, 95% CI, 1.07 - 2.63, P = 0.025). ConclusionMASLD exhibits a stage-dependent escalation in CKM populations and independently drives CVD mortality, with insulin resistance mediating 40% of this risk. Integrating MASLD screening into CKM risk stratification may enhance early intervention, particularly in early-stage patients.