Decreasing low-density lipoprotein cholesterol (LDL-C) concentrations with statin treatment represents a key therapeutic strategy for primary and secondary prevention of cardiovascular disease, as summarised in the Joint British Societies 2 guidelines.1 However, the relative risk reduction for major vascular events for each mmol/l reduction in LDL-C associated with use of statins is only approximately 20%2 and many people treated with statins will go on to have their first or subsequent cardiovascular disease event. Consequently, there is a pressing need to develop alternative strategies to decrease risk of vascular disease.

A wealth of epidemiological observational data suggests there is a strong inverse causal relation between concentrations of high-density lipoprotein cholesterol (HDL-C) and risk of cardiovascular disease. For example, a review of four large prospective studies suggests that every increase of 0.03 mmol/l in HDL-C is associated with a 2–3% decreased risk of cardiovascular disease.3 This suggests that raising HDL-C could be a promising approach to reduce cardiovascular disease risk and a review in this issue of Heart by Hausenloy and Yellon considers this topic in detail (see page 706).4

However, there are some challenges to the conventional viewpoint that low HDL-C is a cardiovascular risk factor and that increasing HDL-C will be beneficial. For example, some genetic mutations that cause low HDL-C have not been associated with increased risk of cardiovascular disease.5 It is possible that the close association between HDL-C and other factors such as triglyceride levels, insulin sensitivity and a pro-inflammatory phenotype may contribute to the apparent relation between HDL-C and cardiovascular risk rather than HDL-C concentrations alone being the sole explanation. Plasma triglyceride concentrations have relatively large inter-individual and intra-individual variability and this makes it more difficult to establish associations with outcomes of interest than for more stable potential risk factors such …