<International Circulation>: Possible new targets in lipid therapies will be proposed at this meeting. Can you tell us the latest progress in this area? Is HDL a hopeful target for atherosclerosis therapy?

    Prof. Libby: HDL， in my reading of the literature， is an undisputed biomarker of prospective coronary vascular risk. Many studies have replicated this association. But HDL is more complicated than LDL. The steady state measurement of HDL in plasma does not tell us about the flux of cholesterol from the lesion， for example， through to the bile and the feces. We are much less certain that a change in HDL associated with an intervention will translate into a change in benefit. There are several avenues toward modulating HDL that are under intense investigation. There was the unfortunate and disappointing experience with torcetrapib， a cholesteryl ester transfer protein inhibitor that seemed to have off-target effects that actually increased complications in treated patients. However， two agents targeting the same enzyme are currently in advanced clinical investigation. In the coming years， we will have more evidence about whether increases in HDL mediated by inhibition of CETP will confer clinical benefit. Several strategies using protein therapy or small peptide mimetics of the major apolipoprotein of HDL， apolipoprotein A-I， are currently under consideration for clinical utility. There are also two major clinical trials that will be reporting results in the next few years — the HPS-THRIVE and the AIM-HIGH study， examining whether nicotinic acid， including in combination with a prostaglandin D inhibitor that may reduce some of the unwanted actions of niacin， will confer clinical benefit. Certainly， from my reading of the literature， nicotinic acid is the best substantiated drug therapy for raising HDL and conferring clinical benefit. We have had a great disappointment with the fibrate drugs in the last few years， with the FIELD trial not showing clinical benefit in diabetic patients with fenofibrate and with the ACCORD trial also not demonstrating positive outcomes. There are a few points about the fibrates that merit mention: One is that gemfibrozil， which reduced events in the VA-HIT trial and the Helsinki Heart Study， is not compatible with statin therapy because of a well-understood drug–drug interaction. The only other fibrate available in the United States is fenofibrate， for which we really don’t have evidence of clinical benefit. The second point for consideration is that post hoc sub-group analyses in several fibrate trials have suggested benefit in the subset of patients who have high triglycerides and low HDL. This is a proposition that requires formal testing prospectively in a clinical trial. So today， from my own personal practice perspective， I would use lifestyle change first in dealing with atherosclerotic risk， but then I would use nicotinic acid as the next step in trying to address low HDL. I also use fish oil with omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) as a strategy for patients with higher triglycerides， once I have addressed the usual secondary causes of hypertriglyceridemia — such as poorly controlled diabetes or hypothyroidism. Nicotinic acid requires a committed patient and a committed doctor in many cases because of the commonly encountered flushing it produces.