Plasma lipoproteins can be separated by ultracentrifugation based on their physical properties, without direct reference to their composition, with ‘high-density’ lipoproteins (HDL) comprising those with density greater than 1.063 g/ml. HDL lipoprotein particles should be explicitly distinguished from HDL-cholesterol, which is but one of the constituents of HDL. Apolipoprotein A-I is the major structural protein of HDL and comprises 70% of total HDL protein. In addition, there is a large number of protein constituents, the functions of which broadly span lipid transport, inflammation, immune function, hormone binding, haemostasis and antioxidant functions.1 Our appreciation of the context-specific roles of these proteins remains rudimentary, and tools to quantify their putative contributions still more so. On the other hand, measurement of HDL-cholesterol is relatively straightforward and has been undertaken widely.

HDL has come to be regarded as atheroprotective, based on three lines of evidence: (1) the inverse relationship between cardiovascular event rates and HDL-cholesterol that is seen in epidemiological studies; (2) animal data showing that the administration of apolipoprotein AI and/or HDL particles reduce atherosclerosis and (favourably remodel atherosclerotic plaques); and (3) a small number of clinical trials suggesting that some drugs that elevate HDL-cholesterol also reduce cardiovascular events or result in plaque regression, assessed by ultrasound or MRI. These observations have raised the possibility that interventions that increase HDL-cholesterol might reduce cardiovascular risk. However, several recent findings have challenged this notion. First, alterations of HDL-cholesterol that are associated with naturally occurring, genetic polymorphisms allow the effects of changes in HDL-cholesterol due to Mendelian randomisation to be mapped to cardiovascular risk. Alterations in HDL-cholesterol by these means do not track with predicted cardiovascular risk. Secondly, niacin (nicotinic acid) is the most efficacious of clinically available drugs to elevate HDL-cholesterol. The AIM–HIGH trial of niacin in patients with low HDL-cholesterol was abandoned due to …