Impact of Mean and Variability of High‐Density Lipoprotein‐Cholesterol on the Risk of Myocardial Infarction, Stroke, and Mortality in the General Population

BACKGROUND: A low level of high‐density lipoprotein‐cholesterol (HDL‐C) is a well‐known risk factor for cardiovascular events. Recent studies have also suggested that HDL‐C variability has a predictive role in patients with coronary artery disease. We investigated the combined effect of the mean and variability of HDL‐C on the risk of myocardial infarction (MI), stroke, and mortality in the general population. METHODS AND RESULTS: We selected 5 433 098 subjects in the Korean National Health Insurance System cohort who had no history of MI or stroke and who underwent ≥3 health examinations between 2009 and 2013. Visit‐to‐visit HDL‐C variability was calculated using the coefficient of variation, variability independent of the mean and average real variability. The low‐mean and high‐variability groups were defined as the lowest and highest quartiles of HDL‐C mean and variability, respectively. There were 27 605 cases of MI, 31 162 cases of stroke, and 50 959 deaths during the median follow‐up of 5.1±0.6 years. A lower mean or higher variability (coefficient of variation) of HDL‐C was associated with a higher risk of adverse outcomes, and the 2 measures had an additive effect. In the multivariable‐adjusted model, the hazard ratios (95% CIs) of the low‐mean/high‐variability group compared with the high‐mean/low‐variability group were 1.47 (1.41–1.54) for MI, 1.23 (1.18–1.28) for stroke, and 1.41 (1.36–1.45) for all‐cause mortality. Results were consistent when variability was modeled using variability independent of the mean or average real variability, and in various sensitivity and subgroup analyses. CONCLUSIONS: Low mean and high variability of HDL‐C is associated with an increased risk of MI, stroke, and mortality.