Estimated sdLDL‐C/LDL‐C Discordance Is Associated With Advanced Cardiovascular–Kidney–Metabolic Syndrome, Incident Cardiovascular Disease and Mortality: Evidence From Two Population‐Based Cohorts

Background sdLDL‐C is a more atherogenic subfraction of LDL particles. We aimed to investigate the associations of sdLDL‐C and its discordance with LDL‐C with advanced stages, incident cardiovascular disease (CVD) and mortality among adults across the cardiovascular–kidney–metabolic (CKM) syndrome spectrum. Methods This study included adults from two cohorts: 16 992 participants from the National Health and Nutrition Examination Survey (NHANES, 1999–2018) and 8252 from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2020) across CKM Stages 0–4. sdLDL‐C was estimated (E‐sdLDL‐C) via Sampson's equation. Discordance was defined as an absolute E‐sdLDL‐C/LDL‐C percentile difference of ≥ 10 percentiles. Logistic regression assessed advanced CKM, and Cox models evaluated associations with incident CVD in CHARLS and mortality in both cohorts. Survey‐weighted analyses were applied in NHANES, and CHARLS models were fitted with community‐level cluster‐robust standard errors. Results Higher E‐sdLDL‐C at a given level of E‐lbLDL‐C and greater E‐sdLDL‐C/LDL‐C discordance were each associated with increased advanced CKM prevalence across both cohorts (discordantly high vs. low in NHANES: OR: 2.89, 95% CI: 2.39–3.50). E‐sdLDL‐C at a given level of E‐lbLDL‐C was positively associated with incident CVD risk in CHARLS, whereas the discordance associations were attenuated after adjustment for baseline CKM stage. Each SD increment in discordance was associated with 15% higher all‐cause and 20% higher cardiovascular mortality in NHANES, and 23% higher all‐cause mortality in CHARLS. Conclusions E‐sdLDL‐C and its discordance with LDL‐C are associated with advanced CKM, incident CVD and mortality, suggesting that E‐sdLDL‐C/LDL‐C discordance may reflect LDL‐related lipid heterogeneity associated with adverse CKM outcomes.