The High-Density Lipoprotein Puzzle

Classic Epidemiology: High-Density Lipoprotein Cholesterol Is a Biomarker of Atherogenic Lipoproteins and Other Major Cardiovascular Risk Factors High-density lipoprotein (HDL) cholesterol is a robust biomarker of atherosclerotic cardiovascular disease (CVD) events. In observational studies and many clinical trials of statin therapy, HDL cholesterol levels are inversely associated with CVD events. In the Emerging Risk Factors Collaboration that included 302,430 participants enrolled in 68 long-term prospective studies, for every 15 mg/dL increase in HDL cholesterol, the hazard ratio for coronary heart disease (CHD) events was 0.71 (95% confidence interval: 0.68–0.75) in models that were stratified by sex and trial group and further adjusted for age, systolic blood pressure, smoking status, history of diabetes mellitus, and body mass index. These associations remained significant in models that included triglycerides and non-HDL cholesterol. Low levels of HDL cholesterol are inversely associated with apolipoprotein B–containing lipoproteins; thus, HDL cholesterol has been considered no more than a biomarker for atherogenic lipoproteins. Several studies have investigated the association between HDL cholesterol, atherogenic lipoproteins, and CVD. In multivariate models that include apolipoprotein B or low-density lipoprotein (LDL) particle concentration, HDL cholesterol was not associated with increased cardiovascular risk. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) that included study participants with low levels of HDL cholesterol (men <45 mg/dL and women <47 mg/dL) and nonelevated triglycerides (<400 mg/dL), the risk of future CHD events was linearly associated with baseline and 6-month levels of apolipoprotein B but not with HDL cholesterol. These analyses indicate that low levels of HDL cholesterol are not associated with CVD events after adjustment for atherogenic lipoprotein concentrations. Clinical trials of high-intensity statin therapy have not confirmed the prognostic importance of HDL cholesterol in the prediction of CVD events. In the Treating to New Targets (TNT) trial, HDL cholesterol was not associated with future