New prospects for lipid-lowering drugs.
The advent of 3-hydroxy-methylglutaryl Co-enzyme A (HMG-CoA) reductase inhibitors has dramatically improved the treatment of dyslipidaemia and the prevention of atherosclerosis over the past 10 years. Similar but less marked benefit had previously been demonstrated for fibrates and bile acid sequestrants, which were first introduced over 30 years ago and are still in use. The discovery that fibrates are ligands for peroxisome proliferator activated receptors (PPARs) may lead to innovations in the future. However, most of the compounds now undergoing clinical trials are either HMG-CoA reductase inhibitors or bile acid sequestrants, which is indicative of the current emphasis on lowering low density lipoprotein (LDL) cholesterol. Drugs in an earlier stage of development include inhibitors of squalene synthase, which have yet to fulfil their initial promise, and of acylcholesterolacyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). Most of the earlier ACAT inhibitors were poorly absorbed, but compounds with better bioavailability hold considerable promise by virtue of their ability to inhibit ACAT in liver and arterial wall macrophages. MTP inhibitors have the potential to drastically reduce apolipoprotein B (apoB) secretion, but safety issues could negate this advantage. Thus, despite the impact of statins, the development of new lipid-modulating drugs continues to be a dynamic field of research.
MRC Lipoprotein Team, Clinical Sciences Centre, Imperial College School of Medicine, London, UK.
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Naoumova