Background: The relationship between baseline low-density lipoprotein cholesterol (LDL-C) levels and mortality risk is complex, with both high and low LDL-C levels linked to increased mortality risk. Addressing sex differences in this association has gained attention in clinical practice; nonetheless, the interplay between LDL-C levels, mortality risk, and sex remains unclear.
Objective: To investigate sex differences in baseline LDL-C levels and their association with all-cause mortality and disease risk.
Methods: Data from the Japan Medical Data Center claims database (January 1, 2005 to April 30, 2021) were analyzed. This study included 3,898,594 individuals without a history of cardiovascular or cerebrovascular disease or lipid-lowering medication use. The primary outcome was all-cause mortality, with secondary outcomes including myocardial infarction, heart failure, ischemic stroke, cerebral hemorrhage, and malignancy incidence.
Results: At lower LDL-C levels (<50 mg/dL), all-cause mortality exhibited a stronger sex dependency, with a hazard ratio of 2.16 (95% CI, 1.19-3.91) for males compared with females. While males with higher LDL-C levels had a greater risk of myocardial infarction, those with an LDL-C level <50 mg/dL showed higher risks of heart failure, ischemic stroke, and hemorrhagic stroke than those shown by females.
Conclusion: The association between LDL-C levels and cardiovascular disease risk varies by sex and risk type. These findings emphasize the need for nuanced interpretation of sex differences in LDL-C levels to guide risk assessment, as well as the need to account for population-specific heterogeneity.
Keywords: Cardiovascular disease risk; LDL paradox; Low-density lipoprotein cholesterol; Mortality; Sex differences.
Copyright © 2025. Published by Elsevier Inc.