HDL Particle Functionality As a Primary Pharmacological Target for HDL-based Therapies

Despite all existing pharmaceuticals aiming at effectively reducing LDL cholesterol, the steadily increasing prevalence of coronary heart disease (CHD) worldwide shifted focus on HDL as an alternative therapeutic target for the treatment of CHD. Indeed, based on the results from epidemiological studies, high HDL cholesterol (HDL-C) levels have been traditionally associated to atheroprotection. Therefore, current drug design considers plasma HDL-C levels as a primary pharmacological target for combating CHD. However, this approach does not take into consideration the fact that HDL is a rather heterogeneous mixture of lipoprotein particles with distinct apolipoprotein and lipid composition that dictate their atheroprotective or proatherogenic function. This may explain why simply raising HDL-C levels by pharmacological means has yet to yield the expected atheroprotection in recent clinical trials. In this review we argue that HDL particle functionality rather than HDL-C levels should be the primary target in the rational design of new HDL-based pharmaceuticals aiming at successfully treating CHD.