High Density Lipoproteins: Is There a Comeback as a Therapeutic Target?

Low plasma levels of High Density Lipoprotein (HDL) cholesterol (HDL-C) are associated with increased risks of atherosclerotic cardiovascular disease (ASCVD). In cell culture and animal models, HDL particles exert multiple potentially anti-atherogenic effects. However, drugs increasing HDL-C have failed to prevent cardiovascular endpoints. Mendelian Randomization studies neither found any genetic causality for the associations of HDL-C levels with differences in cardiovascular risk. Therefore, the causal role and, hence, utility as a therapeutic target of HDL has been questioned. However, the biomarker "HDL-C" as well as the interpretation of previous data has several important limitations: First, the inverse relationship of HDL-C with risk of ASCVD is neither linear nor continuous. Hence, neither the-higher-the-better strategies of previous drug developments nor previous linear cause-effect relationships assuming Mendelian randomization approaches appear appropriate. Second, most of the drugs previously tested do not target HDL metabolism specifically so that the futile trials question the clinical utility of the investigated drugs rather than the causal role of HDL in ASCVD. Third, the cholesterol of HDL measured as HDL-C neither exerts nor reports any HDL function. Comprehensive knowledge of structure-function-disease relationships of HDL particles and associated molecules will be a pre-requisite, to test them for their physiological and pathogenic relevance and exploit them for the diagnostic and therapeutic management of individuals at HDL-associated risk of ASCVD but also other diseases, for example diabetes, chronic kidney disease, infections, autoimmune and neurodegenerative diseases.