Macrovascular Residual Risk Studies

COMMENT

The relevance of HDL-C as a modifiable cardiovascular risk factor – the ‘HDL hypothesis’ has long been a controversial issue.  It is now clear that while low plasma HDL-C concentration is undoubtedly a marker of cardiovascular risk, it is NOT a treatment target, supported by genetic and clinical trial data.1-3 The current study using a meta-regression analysis of clinical trials, a complementary approach to address this question empirically, is consistent with this view.

This conclusion is highly relevant in the context of two ongoing outcomes trials with the CETP inhibitors, anacetrapib and evacetrapib, which both lower plasma LDL-C concentration (by 25-35%) and raise HDL-C, on top of statin treatment.4,5 Given that pharmacological HDL-C raising is not associated with clinical benefit, is it therefore likely that any favourable effects from these trials could be driven by further LDL-C lowering (as these agents are given against a statin background), thus reinforcing the ‘lower is better’ LDL view?

Alternatively, there has been suggestion that HDL functionality may offer further insights into the role of HDL, although at the moment this remains within the research domain. However, there is also controversy with this parameter. In a recent study,6 very high HDL-C plasma levels (mean 86 mg/dL or 2.22 mmol/L) were shown to be associated with reduced cholesterol efflux capacity, a key functionality implicated in the putative antiatherogenic actions of HDL.  Alternatively, the composition of the HDL particle may be relevant. In experimental studies, cholesterol-overloaded HDL particles were shown to exert a negative impact on the antiatherogenic functionality of HDL. Moreover, in clinical studies HDL particle composition was shown to independently associate with progression of carotid atherosclerosis.7 This finding might suggest potential for a novel parameter, the HDL cholesterol/HDL particle ratio (i.e. the combination of the cholesterol content and number of HDL particles) as a determinant of the antiatherogenic function of HDL.

Whether HDL composition, particle number, the combination or HDL functionality is relevant to cardiovascular risk is still highly controversial. On the other hand, there is growing evidence to support triglyceride-rich remnant cholesterol (for which elevated nonfasting triglycerides are a marker) as a cardiovascular risk factor.8,9 Thus, while the jury appears to have spoken for HDL-C – and remains uncertain about HDL functionality -  the case for elevated triglycerides and cardiovascular risk continues to strengthen.