Should we target HDL cholesterol level in lowering cardiovascular risk?

In prospective observational studies and retrospective case control studies performed throughout the world, low serum levels of high-density lipoprotein cholesterol (HDL-C) are consistently associated with increased risk for all forms of atherosclerotic disease and its clinical sequelae, including myocardial infarction, stroke, and sudden death. In contrast, high serum levels of this lipoprotein are associated with reduced risk for these outcomes. The metabolism of high-density lipoproteins (HDLs) is complex, and a very large number of genetic polymorphisms influence the serum level of HDL particles in any given individual. A significant question in cardiovascular medicine is whether or not prospectively raising HDL in patients at risk is associated with significant reductions in cardiovascular events and rates of atherosclerotic disease progression. A recent comprehensive meta-analysis that incorporated the results of 108 prospective clinical trials suggests that the answer to this question is "no" with currently available lipid modifying therapies. However, a number of individual clinical trials and other meta-analyses suggest that, in fact, raising HDL does beneficially impact risk for cardiovascular events and slows progression or even reverses atherosclerosis. HDL appears to antagonize atherogenesis and drive a number of vasculoprotective phenomena. It has antioxidative, anti-proliferative, anti-thrombotic, and anti-inflammatory properties and potentiates reverse cholesterol transport. Under some conditions, the proteosome of HDL can change, rendering it pro-inflammatory and pro-oxidative. This paper explores many of the key questions surrounding HDL-C and why probing its efficacy may not be entirely amenable to a meta-analysis. Numerous drugs are in development which have the capacity to raise HDL-C dramatically. It is hoped that these agents will be able to provide us with a more definitive answer about the clinical efficacy of raising HDL-C, and what specific approaches will be necessary in patients with specific genetic and metabolic backgrounds in both the primary and secondary prevention settings.