Perelman School of Medicine at the University of Pennsylvania, Philadelphia, 19104, USA.
Curr Cardiol Rep. 2012 Dec;14(6):684-91. doi: 10.1007/s11886-012-0317-3.
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 2 CETP inhibitors, 2 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.
最近涉及升高 HDL 的治疗方法的研究极大地改变了我们对这一领域的认识。尽管烟酸能有效升高 HDL-C 水平，但临床获益仍不确定。合成烟酸受体激动剂不太可能升高 HDL-C 或对血浆脂质有其他有益作用。尽管 CETP 抑制剂的 3 期临床试验失败，但 2 种强效的 CETP 抑制剂可使 HDL-C 水平升高 >100%（并显著降低 LDL-C），目前处于临床开发后期。含有“野生型”载脂蛋白 A-I 或载脂蛋白 A-I 米兰的重组 HDL 输注，以及自体去脂 HDL，所有这些都显示出有希望的早期结果，并仍在临床开发中。一种能引起内源性载脂蛋白 A-I 产生上调的小分子也正在临床开发中。最后，通过激活肝 X 受体或拮抗 miR-33 上调巨噬细胞胆固醇流出途径仍然具有重要意义。HDL 治疗学领域正从“HDL-胆固醇假说”向“HDL 通量假说”转变，人们认为从巨噬细胞到粪便的通量变化比 HDL 胆固醇稳态浓度的升高具有更大的治疗益处。
