Sex-Specific U-Shaped Relationships Between High-Density Lipoprotein Cholesterol Levels and 10-year Major Adverse Cardiovascular Events: A Nationwide Cohort Study of 5.7 Million South Koreans

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) is a well-known predictor of atherosclerotic cardiovascular diseases (ASCVD). We explored the relationships between HDL-C levels and 10-year major adverse cardiovascular events (MACE) and provided sex-specific upper reference limits for HDL-C levels. METHODS: Based on the Korean National Health Insurance Sharing Service, we identified 5,703,897 subjects (women, 48%) with age ≥40 years, eligible HDL-C results, and no prior ASCVD in 2009. We investigated the distribution of 10-year MACE according to HDL-C levels in 10 mg/dL (0.26 mmol/L) intervals and in three HDL-C groups (low men <40 mg/dL [1.03 mmol/L], women <50 mg/dL [1.29 mmol/L]; high between low and extremely high levels; and extremely high >90 mg/dL [2.33 mmol/L]). RESULTS: There were U-shaped relationships between HDL-C levels and 10-year MACE with later inflection in women than in men (nadir 80-99 mg/dL [2.07-2.56 mmol/L] and 50-59 mg/dL [1.29-1.53 mmol/L], respectively). In men, the extremely high HDL-C group showed significantly higher 10-year MACE than the high group (28.1% vs. 24.6%, P<0.0001). In women, the extremely high group showed the lowest 10-year MACE; if the extremely high starting point was raised to 130 mg/dL, it became similar to that in men and showed higher 10-year MACE than the high group (25.6% vs. 20.1%, P<0.0001). CONCLUSIONS: The 10-year MACE showed U-shaped relationships with HDL-C levels, and extremely high HDL-C level at 90 mg/dL (2.33 mmol/L) in men was corresponding in risk to 130 mg/dL (3.36 mmol/L) in women.