CHOLESTEROL AND CARDIOVASCULAR DISEASE New developments in lipid-lowering therapy: the role of inhibitors of hydroxymethylglutaryl-

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 ofaround 10-9M. 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. Circulation 76, No. 3, 534-538, 1987. THE ROLE OF hypercholesterolemia, or more accurately hyperbetalipoproteinemia, as a risk factor for atherosclerosis in general and ischemic heart disease in particular is supported by a wealth of clinical, epidemiologic, and pathologic studies. A National Institutes of Health Consensus Development Panel recently concluded' that the ideal blood cholesterol for all Americans over the age of 30 is 200 mg/dl or less, and that attempts should be made to lower blood cholesterol when it exceeds the 75th percentile, or approximately 240 mg/dl, in middle-aged American men. Therapy should always start with a lipid-lowering diet, but diets acceptable to most patients typically lower blood cholesterol by 10% or less. Drug therapy has been limited by insufficient efficacy at tolerated doses, and in some cases a high instance of side effects and/or significant safety problems.2 In individuals eating a typical Western diet, approximately one-third of total body cholesterol is derived From the Department of Clinical Research, Merck Sharp & Dohme Research Laboratories, Rahway, NJ. Address for correspondence: J. A. Tobert, M. B., Ph.D., Department of Clinical Research, Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065. *Registered trademark of Merck & Co., Inc. from the diet, and two-thirds is synthesized, mainly by the liver and intestine. The biosynthetic pathway for cholesterol involves more than 25 different enzymes, and is summarized in figure 1. An important ratelimiting step in this pathway is the conversion of hydroxymethylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is catalyzed by HMG-CoA reductase. Early attempts to inhibit cholesterol synthesis were centered on the late stages of the pathway. One such inhibitor, triparanol (MER/29), was used briefly in the clinic, but was withdrawn in 1962 after reports of serious toxicity, including cataracts, ichthyosis, and alopecia. Triparanol inhibited the conversion of desmosterol to cholesterol, and consequently caused the buildup of desmosterol in plasma and tissues.5 It is believed that the toxicity of triparanol and other latestage inhibitors can be attributed, at least in part, to the accumulation of abnormal sterols in tissues. Inhibitors of HMG-CoA reductase inhibit the pathway at a much earlier stage, and therefore cannot cause buildup of sterol intermediates. Five inhibitors have been studied in the clinic: mevastatin (compactin), lovastatin (mevinolin, Mevacor*), simvastatin (synvi*Registered trademark of Merck & Co., Inc. CIRCULATION 534 by gest on N ovem er 8, 2017 http://ciajournals.org/ D ow nladed from CHOLESTEROL AND CARDIOVASCULAR DISEASE