HDL Elevators and Mimetics - Emerging Therapies for Atherosclerosis

Manojit      Pal; Sivaram      Pillarisetti

Abstract

High plasma levels of LDL cholesterol, triglycerides and low levels of HDL cholesterol are strong and independent risk factors of coronary heart disease (CHD). The first two abnormalities are addressed by a variety of drugs including statins, cholesterol absorption inhibitors, fibrates and niacin. Some of these drugs also elevate HDL albeit weakly. Thus treatments optimized for HDL elevation are still an unmet medical need. Low HDL-C is the most common lipoprotein abnormality in patients with CHD and the body of evidence showing an inverse relationship between HDL-C levels and risk for CHD has grown large. Research in the past decade not only greatly enhanced our understanding of HDL metabolism but also offered potential therapeutic targets to address low HDL syndrome. There are two classes of these ‘HDL drugs’ - those that elevate plasma HDL (e.g. cholesteryl ester transfer protein - CETP and ligands of transcription factors such as peroxisome proliferator activated receptor PPAR α/δ, liver X receptor (LXR)) and those that mimic HDL and facilitate reverse cholesterol transport (RCT) a key function of plasma HDL. HDL mimetics, which include ApoA1 mutants and peptide mimetics of ApoA1, are thought to be ‘fast acting’ and may show greater benefits especially in acute coronary syndromes. The purpose of this review is to examine key players in HDL metabolism and therapeutics that modulate/ mimic these targets. The prospect of these approaches in the prevention of cardiovascular disease is also discussed.

Keywords: coronary heart disease (CHD), reverse cholesterol transport (RCT), VLDL, apoA-I, peroxisome proliferator-activated receptors, LXR-Ligands

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