Purpose of review: Epidemiological and clinical studies link low levels of HDL cholesterol (HDL-C) with increased risk of atherosclerotic cardiovascular disease (CVD). However, genetic polymorphisms linked to HDL-C do not associate consistently with CVD risk, and randomized clinical studies of drugs that elevate HDL-C via different mechanisms failed to reduce CVD risk in statin-treated patients with established CVD. New metrics that capture HDL's proposed cardioprotective effects are therefore urgently needed.
Recent findings: Recent studies demonstrate cholesterol efflux capacity (CEC) of serum HDL (serum depleted of cholesterol-rich atherogenic lipoproteins) is an independent and better predictor of incident and prevalent CVD risk than HDL-C. However, it remains unclear whether therapies that increase CEC are cardioprotective. Other key issues are the impact of HDL-targeted therapies on HDL particle size and concentration and the relationship of those changes to CEC and cardioprotection.
Summary: It is time to end the clinical focus on HDL-C and to understand how HDL's function, protein composition and size contribute to CVD risk. It will also be important to link variations in function and size to HDL-targeted therapies. Developing new metrics for quantifying HDL function, based on better understanding HDL metabolism and macrophage CEC, is critical for achieving these goals.