Emerging high-density lipoprotein infusion therapies: fulfilling the promise of epidemiology?

Abstract

High-density lipoprotein (HDL) plays a key role in reverse cholesterol transport but also activates nitric oxide synthase and stimulates prostacyclin release, enhances endothelial repair, inhibits cell adhesion molecule expression on vascular endothelium and monocyte recruitment into the arterial wall, and exerts antithrombotic effects. In experimental animals, infusions of HDL or apolipoprotein A-1 (apoA-1) halt the progression or induce regression of atherosclerosis, with favorable effects on plaque composition. Remarkably, a benefit is observed after a single infusion. In a pilot study, weekly infusions of ETC-216, a formulation of recombinant apoA-1 Milano, were administered at two doses for 5 weeks to patients beginning within 2 weeks of an acute coronary syndrome (ACS). Among the 47 patients completing the study, percent atheroma volume by intracoronary ultrasound was reduced in the combined active treatment groups but not in the placebo group. In a larger trial, the Effect of rHDL on Atherosclerosis-Safety and efficacy (ERASE), 183 post-ACS patients were randomized to 4 weekly infusions of placebo or one of two doses of CSL-111, which consists of apoA-1 derived from human plasma and combined with soybean phosphatidylcholine. The greater dose was discontinued because of a high incidence of hepatic enzyme elevation. Among the 136 patients with evaluable end point data, percent change in atheroma volume, the primary endpoint, improved significantly in the CSL-111 group but not in the placebo group. The secondary end points of plaque characterization indices and quantitative coronary angiographic changes both improved significantly in the CSL-111 group compared with the group receiving placebo. Taken together, this evidence suggests that infusions of HDL or apoA-1 may reduce events, particularly among patients with ACS.