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A strong inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and coronary heart disease (CHD) has been recognised from epidemiological studies for over 30 years.1 However, it has been difficult to show that increasing HDL-cholesterol by lifestyle or pharmacological means reduces the risk of CHD. A recent meta-regression analysis found no relationship between the drug-induced increases in HDL-cholesterol and CHD events or death after adjusting for changes in low-density lipoprotein (LDL) cholesterol.2 There are various reasons why such analyses may fail to provide a true picture of the benefit of raising HDL-cholesterol, as discussed by Chapman et al.3 The amount of cholesterol associated with HDL particles may be a poor marker of the many functions of HDL, the most obvious being reverse cholesterol transport with the indirect pathway through lipoproteins containing apolipoprotein B mediated by cholesteryl ester transfer protein (CETP) making a major contribution. Other potentially anti-atherosclerotic actions of HDL include anti-oxidative, anti-inflammatory, anti-apoptotic, anti-thrombotic, anti-infectious and vasodilatory activities.3 Moreover, HDL particles are highly heterogeneous in their physicochemical properties and content of apolipoproteins and other associated proteins, and different interventions are likely to alter these in different ways.
The Investigation of Lipid Level Management to Understand its Impact in Atherosclerosis Events (ILLUMINATE) trial with the CETP inhibitor torcetrapib was terminated prematurely because of an increased risk of total mortality and cardiac events in patients receiving torcetrapib, despite a 72% increase in HDL-cholesterol and 25% reduction in LDL-cholesterol with torcetrapib.4 New studies to elucidate the mechanisms of these adverse effects identified that torcetrapib stimulates the release of …
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