Future of High-Density Lipoprotein Infusion Therapies

Abstract

The field of high-density lipoprotein (HDL) therapeutics is broadly aimed at combating the significant residual cardiovascular risk remaining after effective low-density lipoprotein (LDL) cholesterol reduction.1 After the recent failure of 3 orally active HDL-raising agents in prospective intervention trials, including 2 in the cholesteryl ester transfer protein (CETP) inhibitor class2,3 and niacin,4,5 the goals of HDL therapy are currently undergoing reassessment. Key opinion leaders are advocating a shift in the target of HDL therapy from elevation in circulating HDL cholesterol levels to enhancement of the functional properties of HDL, especially HDL-mediated reverse cholesterol transport and cellular cholesterol efflux.6,7 These events have focused the spotlight on HDL infusion therapies that transiently increase HDL particle number and enhance efflux capacity for cellular cholesterol; other defective features of HDL functionality may potentially be normalized.8 However, evaluation of HDL infusion therapies has been limited to date to small surrogate end-point trials; indeed, large phase 3 outcome trials to test the efficacy of these agents in reducing definitive morbidity and mortality end points are eagerly awaited. If proven effective, HDL infusion agents would have potential application across a wide range of vascular diseases but would be particularly amenable to delivery in the context of acute coronary syndromes. Coronary artery disease morbidity and mortality relate largely to either physical disruption or endothelial erosion of the fibrous cap of atherosclerotic plaques in the coronary arteries, triggering luminal or intraplaque thrombus formation.9 An acute or unstable coronary syndrome (sudden death, nonfatal myocardial infarction, or unstable angina) results, the nature of which depends in large part on the degree of vessel occlusion. Plaques at greatest risk for rupture are characterized by a marked abundance of both extracellular and intracellular lipid (cholesterol); immunoinflammatory cells, including monocyte-macrophages and T …