Association Between HDL Cholesterol Changes and Cardiovascular Event Risk: A Nationwide Health Screening Cohort in Japan

Background: Low high-density lipoprotein cholesterol (HDL-C) is an established marker of cardiovascular risk. However, HDL-C levels may change over time in relation to metabolic status, lifestyle factors, and medication use, and the cardiovascular implications of longitudinal HDL-C changes remain incompletely understood. Methods: We conducted a retrospective cohort study using the JMDC Claims Database, including 3,387,924 adults who underwent at least two health checkups between 2005 and 2021. Participants were categorized into four groups based on HDL-C changes between two time points: persistently low, low to normal, normal to low, and persistently normal. The primary outcome was incident composite cardiovascular disease (CVD), including myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. Cox proportional hazards models were used to estimate hazard ratios (HRs) with adjustment for demographic and clinical covariates. Results: During a mean follow-up of 4.3 years, persistently low HDL-C was associated with the highest risk of composite CVD compared with persistently normal HDL-C (HR 1.15, 95% CI 1.12–1.19). Both Low-to-Normal and Normal-to-Low groups also showed elevated risks (HR 1.10, 95% CI 1.06–1.14; HR 1.14, 95% CI 1.10–1.19, respectively). The strongest association was observed for myocardial infarction, whereas the association with stroke was modest and less consistent after full adjustment. Conclusions: Longitudinal changes in HDL-C were associated with cardiovascular risk after adjustment for cardiometabolic factors and medication use. Persistently low HDL-C conferred the greatest risk, and serial HDL-C patterns may provide additional information for cardiovascular risk assessment beyond a single baseline measurement.