Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport

Numerous prospective epidemiological studies have shown a strong inverse relationship between HDL cholesterol (HDL-C) levels and coronary heart disease (CHD).1 Many controlled clinical trials also demonstrate that treating patients who have low HDL-C with various lipid-modifying therapies, including statins, fibrates, niacin, or combination therapy, can reduce major coronary events.2–12 The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines recognize low HDL-C (<40 mg/dL) as an independent major risk factor for CHD, as a component of the metabolic syndrome, and as a potential target for therapeutic intervention.13 However, the primary target of the NCEP ATP III guidelines is to lower LDL cholesterol (LDL-C), given the strong and abundant clinical trial data for both primary and secondary prevention of adverse coronary events by lowering LDL-C. The recent update to the ATP III guidelines recommends even more aggressive treatment of LDL-C given new clinical trial data.14 However, even in patients treated to aggressive LDL-C goals, coronary events still occur,15,16 and low HDL-C is a major risk factor in this group. Therefore, a natural next step in the search for therapies to further reduce cardiovascular morbidity and mortality leads to raising HDL-C levels and/or improving HDL function. An important concept with regard to HDL-based therapies is that the plasma HDL-C level per se may not reflect the functionality of HDL or the impact of a specific HDL-targeted therapy on atherosclerosis or cardiovascular risk. In this review we focus on the concepts underlying the therapeutic targeting of HDL metabolism and the specific areas and compounds in clinical and preclinical development.Therapeutic lifestyle changes are currently recommended as first-line therapy in patients with low HDL-C levels. Smoking depresses HDL-C levels, and cessation is associated with modest increases in HDL-C.17,18 Aerobic exercise can raise HDL-C levels, but in …