New developments in lipid-lowering therapy: the role of inhibitors of hydroxymethylglutaryl-coenzyme A reductase.

Abstract

HMG-CoA reductase catalyzes the conversion of hydroxymethylglutarate to mevalonate, an important early rate-limiting step in the cholesterol biosynthesis pathway. Since the discovery of compactin, the first HMG-CoA reductase inhibitor, by Endo et al. in 1976, several other inhibitors have been described. Those that have been investigated in the clinic include mevastatin (compactin), lovastatin (mevinolin), simvastatin (synvinolin), eptastatin (CS-514, SQ-31,000), and SRI-62320. These compounds are competitive inhibitors, with Ki values of the hydroxyacid forms of around 10(-9) M. Lovastatin (mevinolin, Mevacor), which is in the late stages of clinical development and has been administered to over 1000 subjects for up to 4 years, is the inhibitor on which the most information is available. It is given in single or divided doses of 20 to 80 mg/day, and is a very effective and usually well-tolerated lipid-lowering agent. At 40 mg bid, lovastatin produces the following approximate mean changes: total plasma cholesterol, -33%; low-density lipoprotein (LDL) cholesterol, -40%; very low-density lipoprotein cholesterol, -35%; plasma triglycerides, -25%; high-density lipoprotein cholesterol, +10%; apolipoprotein B, -20%. The substantial reduction in both LDL cholesterol and apolipoprotein B (the principal protein component of LDL) indicates a reduction in the number of circulating LDL particles. The mechanism probably involves both decreased LDL production and increased LDL clearance.