Abstract
BACKGROUND: Previous studies have shown that extremely high levels of high-density lipoprotein (HDL) cholesterol are paradoxically associated with adverse outcomes in certain clinical settings. We aimed to test the hypothesis that extremely high levels of HDL cholesterol are associated with increased all-cause and cause-specific mortality in the general population. METHODS: We included 51,235 individuals from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2018 with a median follow-up of 9.3 years. Baseline HDL cholesterol levels were measured, and mortality data were ascertained from National Death Index (NDI) records through December 31, 2019. Weighted Cox proportional hazards regression, restricted cubic spline curves, and cumulative incidence analyses were performed. RESULTS: A U-shaped association was observed between HDL cholesterol levels and all-cause, cardiovascular and non-cardiovascular mortality in the general population. Compared with individuals with HDL cholesterol levels between 50 and 59 mg/dL, the adjusted hazard ratios (95% CIs) for those with extremely high HDL cholesterol levels (≥ 80 mg/dL) were 1.24 (1.08-1.43), 1.18 (1.03-1.36) and 1.27 (1.09-1.49) for all-cause, cardiovascular and non-cardiovascular mortality, respectively. Similar U-shaped patterns were replicated in both men and women. Further analyses of cause-specific mortality subcategories showed that extremely high HDL cholesterol levels were also associated with increased mortality from heart disease, respiratory disease, endocrine disease, and cancer. CONCLUSION: Extremely high levels of HDL cholesterol were associated with an increased risk of all-cause, cardiovascular, and non-cardiovascular mortality in the general population. Future studies should investigate the causal factors leading to the association of elevated HDL cholesterol and mortality.