HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease – Insights from randomized clinical trials and human genetics.

Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial. These HDL cholesterol increasing trials were launched without conclusive evidence from human genetics, and despite discrepant species dependent evidence from animal studies. Evidence from human genetics and from randomized clinical trials over the last 13 years now point in the direction that concentrations of HDL cholesterol, do not appear to be a viable future path to target therapeutically for prevention of ASCVD. A likely explanation for the strong observational association between low HDL cholesterol and high ASCVD risk is the concomitant inverse association between HDL cholesterol and atherogenic triglyceride-rich lipoproteins. The purpose of the present review is to bring HDL cholesterol increasing trials into a human genetics context exemplified by candidate gene studies of key players in HDL biogenesis as well as by HDL cholesterol related genome-wide association studies. Graphical abstract summarizing conclusions: Observational epidemiology, randomized clinical trials and human genetics suggesting noncausality between low HDL cholesterol concentrations and increased ASCVD risk. Left upper image: 1. Low HDL cholesterol is associated with increased risk of ASCVD, confirmed in numerous case-control and prospective studies. Right upper image: 2. Genetic evidence from consortia and candidate gene studies have shown that the inverse association between HDL cholesterol concentrations and risk of ASCVD may not be of a causal nature. Left lower image: 3. HDL cholesterol concentration increasing trials have so far not shown to reduce risk of ASCVD. Right lower image: 4. Despite lack of support of a causal role, the HDL cholesterol concentration can be used as a biomarker for ASCVD risk prediction. ASCVD = atherosclerotic cardiovascular disease; HDL = high-density lipoprotein. [Display omitted] [ABSTRACT FROM AUTHOR]