Targeting High Density Lipoproteins in the Prevention of Cardiovascular Disease?

Abstract

Recent studies involving HDL-raising therapeutics have greatly changed our understanding of this field. Despite effectively raising HDL-C levels, niacin remains of uncertain clinical benefit. Synthetic niacin receptor agonists are unlikely to raise HDL-C or have other beneficial effects on plasma lipids. Despite the failure in phase 3 of two CETP inhibitors, two potent CETP inhibitors that raise HDL-C levels by > 100% (and reduce LDL-C substantially) are in late stage clinical development. Infusions of recombinant HDL containing ‘wild-type’ apoA-I or apoA-I Milano, as well as autologous delipidated HDL, all demonstrated promising early results and remain in clinical development. A small molecule that causes upregulation of endogenous apoA-I production is also in clinical development. Finally, upregulation of macrophage cholesterol efflux pathways through agonism of liver X receptors or antagonism of miR-33 remains of substantial interest. The field of HDL therapeutics is poised to transition from the ‘HDL-cholesterol hypothesis’ to the ‘HDL flux hypothesis’ in which the impact on flux from macrophage to feces is deemed to be of greater therapeutic benefit than the increase in steady-state concentrations of HDL cholesterol.

Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond

“…Indeed, the "HDL-cholesterol hypothesis" has begun to be replaced by the "HDL function/fl ux hypothesis" ( 106 ), refl ecting the growing consensus that measurement of one minor HDL component (i.e., cholesterol) is not suffi cient to capture the cardioprotective potential of HDL. Recent studies have clearly shown that specifi c functional readouts, such as capacity for cholesterol effl ux ( 107 ) or anti-inflammatory index ( 108 ), may be better indicators than the HDL-C number for predicting CAD risk in an individual.…”

Liver-specific transgenic expression of cholesteryl ester hydrolase reduces atherosclerosis in Ldlr−/− mice

“…However, in contrast to liver-specifi c Ces defi ciency, which did not alter plasma lipoprotein profi les, transgenic expression of hCEH signifi cantly reduced total plasma and VLDL cholesterol levels and these effects were more pronounced in males. Although these changes in the plasma cholesterol levels can be viewed as anti-atherogenic, it needs to be emphasized that increasing evidence, however, points to an apparent lack of correlation between plasma lipid profi les and atherogenesis (22)(23)(24)(25), and fl ux of cholesterol from the peripheral tissue, including the artery wallassociated macrophage foam cells, to feces is a more relevant parameter for predicting the risk for the development of atherosclerosis ( 26 ). In addition, Rowlan et al ( 27 ) have recently demonstrated that most atherosclerosis susceptibility loci are distinct from those for plasma lipids.…”

Effects of HDL-modifiers on cardiovascular outcomes: A meta-analysis of randomized trials

“…However, till now, the pharmacological strategies to rise HDL-C have demonstrated only weak benefits in cardiovascular prevention. In particular, niacin, a vitamin with a broad-spectrum effect on lipid metabolism, showed promising results in initial trials and a subsequent metaanalysis [18e20], although more recent trials, conducted in the years of high dose statins, failed to demonstrate any benefit of niacin supplementation [21,22]. Furthermore, large interests have been focused on the new pharmacological class of cholesteryl ester transfer protein (CETP) inhibitors that, by blocking HDL degradation, may provide a remarkable increase in HDL.…”