Time to ditch HDL-C as a measure of HDL function?

Abstract

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.

Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review

“…Because of this relationship, pharmaceutical companies developed several drugs designed to raise HDL-C concentrations through inhibition of cholesteryl ester transfer protein (CETP) activity. Several CETP inhibitors including torcetrapib, dalcetrapib, and evacetrapib progressed to clinical trials [14]. In the case of torcetrapib, an increase in HDL-C of 72% was observed in study participants [15].…”

“…Human genetics studies demonstrate that extremely low and high HDL-C levels are not necessarily linked to increased risk or protection from CVD, and suggest that the HDL-C level alone is not the causal factor [18,19]. Taken together, these clinical trial results have led to the re-examination of HDL metabolism with an increased focus on the function, composition, size, and number of circulating HDL particles, rather than the amount of cholesterol carried by HDL particles, which makes up a relatively small proportion of the cargo [14,16,17]. The athero-protection associated with HDL-C depends on the functional abilities of the HDL particle itself, not on the plasma levels of HDL-C [20].…”

Changes in High-Density Lipoproteins Related to Outcomes in Patients with Acute Stroke

“…High-density lipoproteins (HDL) are highly heterogeneous in size, shape and composition [ 1 , 2 ]. HDL-cholesterol concentration remains a biomarker to assess cardiovascular risk.…”

The High Density Lipoprotein Cholesterol Hypothesis Revisited

“…(13,14,24) In vitro assays of CEC of HDL may include four possible pathways: aqueous diffusion, scavenger receptor class B type I (SR-B1) receptor, and ATP binding cassette transporter A-1 (ABCA1), and ATP-binding cassette sub-family G member 1 (ABCG1) transporters. (27) Genetic epidemiology does not support a causal relationship between HDL cholesterol and future risk of myocardial infarction. In a Mendelian randomization study that included 20 studies (12,482 myocardial infarction cases and 95,407 controls), single nucleotide polymorphisms in the endothelial lipase gene (LIPG Asn396Ser) had higher HDL-C levels and similar nonlipid and other lipid risk factors for myocardial infarction.…”

“…(26) Therefore, evaluating changes in HDL subpopulations in response to therapy might be a better metric than HDL-C levels for predicting risk. (27) As well as varying in size, HDL particles vary in protein content, as HDL's proteome is very rich. Alterations in protein cargo have been associated with pathological states, such as inflammation (28), poor response to therapy (29), autoimmune disease (30), and diabetes (31).…”