Pharmacotherapy for dyslipidaemia--current therapies and future agents.
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.
L-MARC Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA. HBaysMD@aol.com
Harold
H
Bays
Evan A
EA
Stein
D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000493:pharmacokinetics; D008076:Cholesterol, HDL / Q000097:blood; D004338:Drug Combinations; D004764:Enterohepatic Circulation / Q000502:physiology; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D050356:Lipid Metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism
D019440:Anti-Obesity Agents; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D004338:Drug Combinations; D000960:Hypolipidemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL