Bays Harold, Stein Evan A
L-MARC Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA.
Expert Opin Pharmacother. 2003 Nov;4(11):1901-38. doi: 10.1517/14656566.4.11.1901.
Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and soy proteins; those currently in development include newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP cleavage-activating protein (SCAP) activating ligands. Other current agents that affect lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils, antioxidants and policosanol, whilst those in development include microsomal triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2) antagonists and AGI1067) and functional oils. Current agents that affect nuclear receptors include PPAR-alpha and -gamma agonists, while in development are newer PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and 'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also nuclear receptor targets of investigational agents. Agents in development also may affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination lipid-altering drugs are currently available such as extended-release niacin/lovastatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin and pravastatin/aspirin are under development. Finally, current and future lipid-altering drugs may include anti-obesity agents which could favourably affect lipid levels.
目前主要通过增加肝脏低密度脂蛋白受体活性来降低低密度脂蛋白胆固醇（LDL-C）的调脂药物包括他汀类药物、胆汁酸螯合剂/树脂以及胆固醇吸收抑制剂（如依泽替米贝）、植物甾烷醇/甾醇、多酚类物质，还有营养保健品（如燕麦麸、车前子和大豆蛋白）；目前正在研发的药物包括新型他汀类药物、植物甾烷醇类似物、角鲨烯合酶抑制剂、胆汁酸转运抑制剂以及固醇调节元件结合蛋白（SREBP）裂解激活蛋白（SCAP）激活配体。其他目前影响脂质代谢的药物包括烟酸、阿西莫司、高剂量鱼油、抗氧化剂和聚多卡醇，而正在研发的药物包括微粒体甘油三酯转运蛋白（MTP）抑制剂、酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂、吉卡贝尼、利非波罗、泛酸类似物、烟酸受体激动剂、抗炎药（如脂蛋白相关磷脂酶A2拮抗剂和AGI1067）以及功能性油脂。目前影响核受体的药物包括PPAR-α和-γ激动剂，而正在研发的是新型PPAR-α、-γ和-δ激动剂，以及双重PPAR-α/γ和“泛”PPAR-α/γ/δ激动剂。肝脏X受体（LXR）、法尼醇X受体（FXR）和固醇调节元件结合蛋白（SREBP）也是研究药物的核受体靶点。正在研发的药物也可能影响高密度脂蛋白胆固醇（HDL-C）的血液水平或通量，包括胆固醇酯转运蛋白（CETP）抑制剂（如托彻普）、CETP疫苗、各种HDL“疗法”以及ATP结合盒转运蛋白（ABC）A1、卵磷脂胆固醇酰基转移酶（LCAT）和B1型清道夫受体（SRB1）的上调剂，还有合成载脂蛋白（Apo）E相关肽。目前已有固定剂量复方调脂药物，如缓释烟酸/洛伐他汀，而阿托伐他汀/氨氯地平、依泽替米贝/辛伐他汀、阿托伐他汀/CETP抑制剂、他汀/PPAR激动剂、缓释烟酸/辛伐他汀和普伐他汀/阿司匹林正在研发中。最后，目前和未来的调脂药物可能包括对脂质水平有有利影响的抗肥胖药物。
