HPS2-THRIVE, AIM-HIGH and dal-OUTCOMES: HDL-cholesterol under attack.

Abstract

A low level of high-density lipoprotein cholesterol (HDL-C) is an established predictor of the risk of coronary heart disease (CHD).1 HDL promotes cellular cholesterol efflux and reverse cholesterol transport from lipid-laden macrophages (Figure 1), and prevents lipoprotein oxidation. A linear inverse relation has been reported in many observational studies between plasma HDL-C level and incident CHD events, with a plateau effect at HDL-C values >90 mg/dL in men and 75 mg/dL in women.2 However, it remains uncertain whether raising HDL-C levels therapeutically (by either niacin or cholesterol ester transfer protein “CETP” inhibitors) would reduce subsequent cardiovascular (CV) events beyond that achieved with intensive statin therapy. Figure 1. Reverse Cholesterol Transport. ABCA1, ATP binding cassette A1 transporter; ABCG1, ATP binding cassette G1 transporter; CETP, cholesterol ester transfer protein; SR-B1: Scavenger receptor-B1; LDLR, low density lipoprotein receptor. Niacin has multiple beneficial effects on serum lipoproteins;3 (1) it raises HDL-C level primarily by promoting the production and retarding the catabolism of Apo A1 in the liver, and also by stimulating ATP-binding cassette transporter A1 which augments reverse cholesterol transport. (2) It decreases the secretion of very low density lipoprotein (VLDL) particles from the liver with subsequent reduction of both intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles; an effect mediated by inhibition of hormone-sensitive lipase in the adipose tissue, and hepatocyte diacylglycerol acyltransferase-2 (DGAT-2). (3) It is unique in lowering lipoprotein (a) levels by up to 30%. (4) It inhibits oxidative stress, key inflammatory genes, cytokines involved in atherosclerosis. Inhibition of CETP by torcetrapib, dalcetrapib, anacetrapib, and evacetrapib is another attractive strategy to raise plasma HDL-C level.4,5 CETP promotes the transfer of cholesterol esters from HDL to triglyceride-rich lipoprotein particles, in exchange for triglyceride, thereby reducing the circulating HDL-C concentration. Over the past years, numerous randomized clinical studies have been conducted to assess the clinical efficacy and safety of these drugs.