Estimated small dense low-density lipoprotein cholesterol in predicting atherosclerotic cardiovascular disease: longitudinal evidence from over one million Japanese adults

Background Small dense low-density lipoprotein cholesterol (sdLDL-C) is an atherogenic LDL-C subfraction associated with atherosclerotic cardiovascular disease (ASCVD). Although sdLDL-C integration into major routine risk assessments remains limited partly due to requiring additional lipid tests, a more implementable estimated sdLDL-C equation was recently developed. Objective This study aimed to evaluate the association between estimated sdLDL-C and incident ASCVD in a health checkup population of Japanese adults. Methods Using the DeSC database in Japan, this study included adults aged 40-74 years who underwent health checkups between April 2014 and March 2023. Estimated sdLDL-C was calculated via the Sampson formula, and the primary outcome was first incident ASCVD hospitalization via claims data. Estimated sdLDL-C was categorized into quartiles, and associations with incident ASCVD were evaluated using Cox regression models adjusted for sex, age, BMI, hypertension, diabetes, smoking, alcohol, low HDL-C, high LDL-C, lipid-lowering medication, and fasting time. Subgroup analyses were conducted by LDL-C, sex, age, and ASCVD subtypes. Results Among 1,884,758 participants, 22,596 incident ASCVD events were observed. The Cox model showed ASCVD risk increased across estimated sdLDL-C quartiles, with a hazard ratio of 1.25 [1.20-1.31] for Q4. This association largely continued across sex, age, LDL-C, and ASCVD subtype subgroups, with stronger associations observed in male participants, for CAD than ischemic stroke, among younger individuals, and those with higher LDL-C. Conclusion Higher estimated sdLDL-C was associated with increased ASCVD risk, including among individuals with low LDL-C. Estimated sdLDL-C may improve ASCVD risk stratification beyond LDL-C and inform further primary prevention strategies.