Is an extremely high-density lipoprotein cholesterol concentration associated with an increased risk of cardiovascular disease and mortality in adult men and women?

This observational cohort study found a U-shaped association between high-density lipoprotein (HDL) cholesterol levels and all-cause and cardiovascular mortality in both men and women. See the Synopsis for specific HDL concentration levels and corresponding hazard ratios. (LOE = 2b)

Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: Two prospective cohort studies. Eur Heart J 2017;38(32):2478-2486.  [PMID:28419274]

Cohort (prospective)

Foundation

Population-based

These investigators analyzed data obtained from 2 prospective cohorts of adults, aged 20 years to 100 years, in Denmark. Information on health, lifestyle, and HDL concentration level was compared with cause of death (cardiovascular, cancer, or other), ischemic heart disease, myocardial infarction, and ischemic stroke. Multiple adjustments were made for other covariates including age, body mass index, smoking status, alcohol consumption, physical activity, blood pressure, diabetes, medications, low-density lipoprotein cholesterol and triglyceride levelss, and (for women) menopausal status and hormone replacement therapy. A total of 52,268 men and 64,240 women were followed up for a median of 6.0 years (range: 0 - 23 years). The association between HDL cholesterol level and all-cause mortality was U-shaped for both men and women, with both low and high concentrations being associated with excess all-cause mortality. In particular, after multifactorial adjustment, men with an HDL cholesterol level of 97 mg/dL to 115 mg/dL (2.5 - 2.99 mmol/L) and equal to or greater than 116 mg/dL (3.0 mmol/L) had an increased risk of all-cause mortality (hazard ratio [HR] = 1.36, 95% CI 1.09 - 1.70; and HR = 2.06, 1.44 - 2.95, respectively) compared with men in the reference group (HDL level 58 - 76 mg/dL [1.5-1.99 mmol/L]. As expected, men with a low HDL cholesterol level (< 39 mg/dL [1.0 mmol/L] also had an increased risk of all-cause mortality. Similarly, women with an HDL cholesterol level of at least 135 mg/dL (3.5 mmol/L) had an increased risk of all-cause mortality (HR = 1.68; 1.09 - 2.58). A similar U-shaped association was also seen between HDL cholesterol level and cardiovascular mortality in both men and women.