Macrovascular Residual Risk Studies

COMMENT

There is indisputable epidemiologic evidence that a low plasma level of HDL cholesterol is associated with increased risk of cardiovascular disease complications.1 There is also evidence that low plasma HDL cholesterol is a predictor for the risk of recurrent cardiovascular events in the short-term in patients with ACS.2 Such findings underlie thinking that specifically targeting HDL may offer potential for reducing the high level of residual cardiovascular risk that persists in high-risk individuals receiving best evidence-based treatment.

ACS patients are at highest residual cardiovascular risk, with ~10% of recurrent events occurring within the first 6‚Äì12 months, and ~20‚Äì30% within 2 years.3-5 There is some evidence to suggest that HDL infusions may have favourable effects on atherosclerotic burden in such high-risk patients.6-8  Based on these findings, the current study investigated the potential of CER-001, an HDL mimetic, for reducing atherosclerosis or atheroma progression in ACS patients receiving best evidence-based treatment, including statins.

Yet despite a large prospective placebo-controlled design, the study failed to show any benefit with any dose of CER-001 on coronary atherosclerosis. These findings are consistent with other imaging studies in ACS patients which have so far failed to show significant benefit versus placebo on coronary atherosclerosis burden.6,7 The authors have questioned whether the dosing regimen, composition of the investigational treatment, or patient population may have been limiting factors. Indeed, in the dal-OUTCOMES study,9 there was no significant benefit on major cardiovascular events with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib, which specifically targeted HDL. Given that there was also no evidence of any association between baseline plasma HDL-C concentration and risk for major cardiovascular events in this patient population, has led some to postulate that the potentially atheroprotective activities of HDL are functionally defective in the inflammatory ACS setting, and therefore HDL may be less able to prevent coronary atherosclerosis progression and the ensuing clinical events. However, such speculation is based on in vitro experimental findings.

So what do the results of this study mean for the potential role of HDL in residual risk?
First, it must be noted that there were no specific inclusion criteria regarding plasma HDL-C levels in CHI-SQUARE. Therefore, such a question cannot be answered by this study. Furthermore, the lack of benefit on coronary atherosclerosis observed in CHI-SQUARE implicates other factors in residual cardiovascular risk. A low plasma HDL cholesterol concentration is also commonly associated with elevated triglycerides; this dyslipidaemic profile is a key driver of atherogenic risk in individuals with metabolic syndrome and/or type 2 diabetes.10 Indeed, as discussed in this month’s Focus article, there is renewed enthusiasm for a role for triglyceride-rich lipoproteins and their remnants in the high level of persistent residual cardiovascular risk in high-risk patients.