Lipoprotein(a) and Risk Stratification for Atherosclerotic Cardiovascular Disease Across the Cardiovascular‐Kidney‐Metabolic Continuum

Background Lp(a) (lipoprotein(a)) is an established risk factor for atherosclerotic cardiovascular disease (ASCVD), but its prognostic relevance across the cardiovascular‐kidney‐metabolic (CKM) continuum remains uncertain. We examined whether Lp(a) was associated with incident ASCVD across CKM stages and whether it provided complementary risk stratification beyond CKM staging. Methods We included 333 321 UK Biobank participants free of clinical cardiovascular disease at baseline and classified them into CKM stages 0 to 3. Elevated Lp(a) was defined as ≥125 nmol/L. The primary outcome was incident ASCVD, defined as coronary artery disease or ischemic stroke. Cox proportional hazards models were used to estimate hazard ratios (HRs), and 10‐year absolute risks were estimated using Kaplan–Meier methods. Results During a median follow‐up of 15.3 years, 17 581 incident ASCVD events occurred. After adjustment for demographic characteristics, socioeconomic factors, lifestyle factors, low‐density lipoprotein cholesterol, medications, and CKM stage, elevated Lp(a) was associated with higher ASCVD risk (HR, 1.31 [95% CI, 1.25–1.36]). In joint analyses, risk increased progressively across combined CKM–Lp(a) categories, with the highest risk observed in participants with CKM stage 3 and elevated Lp(a) versus CKM stage 0 and lower Lp(a) (HR, 3.43 [95% CI, 2.74–4.31]). Ten‐year ASCVD risk ranged from 0.64% to 16.30%, and the absolute risk difference associated with elevated Lp(a) increased from 0.23% in stage 0 to 2.20% in stage 3. Conclusions Elevated Lp(a) was associated with higher incident ASCVD risk across the CKM continuum. Although relative associations were broadly consistent across CKM stages, absolute risk increments associated with elevated Lp(a) were greater at more advanced CKM stages, supporting the integration of Lp(a) into CKM‐based risk stratification for primary prevention.