High-density lipoprotein (HDL) cholesterol concentrations are inversely associated with cardiovascular disease and mortality across a range of concentrations, but genetic evidence suggest that extreme high concentrations may paradoxically lead to more cardiovascular disease. We tested the hypothesis that extreme high concentrations of HDL cholesterol are associated with high all-cause mortality in men and women.

A total of 52 268 men and 64 240 women were included from the two prospective population-based studies, the Copenhagen City Heart Study and the Copenhagen General Population Study. During 745 452 person-years of follow-up, number of deaths from any cause were 5619 (mortality rate, 17.1/1000 person-years (95% confidence interval (CI): 16.7–17.6)) in men and 5059 (mortality rate, 12.1/1000 person-years (11.8–12.4)) in women. The association between HDL cholesterol concentrations and all-cause mortality was U-shaped for both men and women, with both extreme high and low concentrations being associated with high all-cause mortality risk. The concentration of HDL cholesterol associated with the lowest all-cause mortality was 1.9 mmol/L (95% CI: 1.4–2.0) (73 mg/dL (54–77)) in men and 2.4 mmol/L (1.8–2.5) (93 mg/dL (69–97)) in women. When compared with the groups with the lowest risk, the multifactorially adjusted hazard ratios for all-cause mortality were 1.36 (95% CI: 1.09–1.70) for men with HDL cholesterol of 2.5–2.99 mmol/L (97–115 mg/dL) and 2.06 (1.44–2.95) for men with HDL cholesterol ≥3.0 mmol/L (116 mg/dL). For women, corresponding hazard ratios were 1.10 (0.83–1.46) for HDL cholesterol of 3.0–3.49 mmol/L (116–134 mg/dL) and 1.68 (1.09–2.58) for HDL cholesterol ≥3.5 mmol/L (135 mg/dL).

Men and women in the general population with extreme high HDL cholesterol paradoxically have high all-cause mortality. These findings need confirmation in other studies.