Apolipoprotein A-I Therapy

Since 1988, with the release of the National Cholesterol Education Panel (NCEP) Adult Treatment Panel I, lowdensity lipoprotein cholesterol (LDL-C) has been the primary focus of therapy (1). Although the total cholesterol to high-density lipoprotein cholesterol (HDL-C) ratio is a better cardiovascular risk predictor (2), the consensus at the time was that the clinical evidence only supported LDL-C reduction to improve outcomes. For the past 20 years, targeting LDL-C has yielded impressive results, especially with statins, yet low HDL-C continues to predict increased cardiovascular events, even in conjunction with low LDL-C levels (3). High LDL-C and low HDL-C are approximately equal risk factors in population studies, and both lipoproteins are causally linked to atherosclerosis (4). Severe apolipoprotein (apo) A-I deficiency (familial hypoalphalipoproteinemia) is associated with very premature coronary heart disease similar to heterozygous familial hypercholesterolemia (5). However, unlike LDL metabolism, in which the cellular regulation is well understood, HDL and the process of reverse cholesterol transport remain complex and elusive targets of drug development (6).