Lovastatin: An HMG-CoA Reductase Inhibitor for Lowering Cholesterol

Cardiovascular Pharmacotherapy III

0025-7125/89 $0.00 + .20

Lovastatin: An HMG-CoA Reductase Inhibitor for lowering Cholesterol

William H. Frishman, MD,* and Roderick C. Rapier, MD,t

Increased levels of total cholesterol, low-density lipoprotein (LDL)cholesterol, and very low-density lipoprotein (VLDL)-cholesterol are identified as risk factors for the development of coronary artery disease. 6. 30. 32. 33 An inverse relationship between high density lipoprotein (HDL)-cholesterol levels and coronary disease risk also has been established. 6, 30. 32. 33 A recent report describing 356,222 screenees of the Multiple Risk Factor Intervention Trial (MRFIT) showed that a 10 per cent reduction in cholesterol led to an 11.3 per cent reduction in the mortality rate from coronary artery disease and a 4.4 per cent decrease from all causes. 31 The Lipid Research Clinics Program demonstrated that a reduction in total cholesterol of 9 per cent (compared to diet/placebo) and LDL-cholesterol of 13 per cent (compared to diet/placebo) led to a 19 per cent (statistically significant) reduction in coronary heart disease death and nonfatal myocardial infarction. 34 This study also demonstrated that a small increase in HDLcholesterol could lead to a 2 per cent reduction in the coronary heart disease rate. 34 This observation has been confirmed in the recent Helsinki Heart Study.9a The National Institutes of Health issued a consensus report based on the available data, suggesting that for every 1 per cent reduction in serum cholesterol, there is a 2 per cent reduction in coronary heart disease morbidity and mortality over the entire distribution of cholesterol values studied. 27 They recommended recently that all individuals over the age of 30 years have cholesterol values below 200 mg per dl. 27 For individuals with cholesterol values above 240 mg per dl and LDL-cholesterol values 'Professor of Medicine, Epidemiology, and Social Medicine, Albert Einstein College of Medicine; and Director of Medicine, Hospital of the Albert Einstein College of Medicine, Bronx, New York tDepartment of Medicine, University of California School of Medicine-San Diego, San Diego, California

Medical Clinics of North America-Vo!' 73, No. 2, March 1989

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over 160 mg per dl, the panel recommended diet therapy, with the addition of drug therapy, if necessary.27a Patients with past histories of coronary artery disease or those with increased risk for coronary artery disease may require instruction at even lower LDL values. 27a The initial step in lowering cholesterol is a special diet, which should be low in fat, and with saturated fatty acids replaced by polyunsaturated fattv acids. Cholesterol intake also should be reduced. Total calories should not' be excessive because obesity is associated with increased production of triglycerides and VLDL-cholesterol. Because lipid levels may be reduced only minimally by special diets in certain patients,l1 drug therapy is the next step. There are multiple drugs that can be used. In 1987, the Food and Drug Administration approved the marketing of lovastatin, a competitive inhibitor of 3-hydroxy3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme step in cholesterol synthesis in the body. The pharmacology of this novel cholesterol-lowering drug is discussed in this article.

CHOLESTEROL AND LIPOPROTEIN METABOLISM Adequate levels of cholesterol are essential for moderating the membrane fluidity of all cells. This is accomplished by cholesterol molecules interacting with fatty acyl chains that otherwise would crystallize and lead to a rigid membrane. Cholesterol also is a precursor in human steroid hormone production. The body obtains its cholesterol from two sources. Given a typical Western diet, an individual obtains about one third of his or her daily cholesterol from ingested foodstuffs, and produces two thirds de novo in the liver and intestines. 36 Most of the cholesterol synthesized in the body comes from the liver. The level of cholesterol synthesis is not constant, but peaks at midnight. The process begins (Fig. 1) with acetyl co enzyme A, from which all 27 carbon atoms in cholesterol are obtained. After a series of reactions, 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) is produced. The ratelimiting step in cholesterol production is controlled by the enzyme, 3hydroxy-methylglutaryl coenzyme A reductase, which produces mevalonate from HMG-CoA. This is the point at which lovastatin has its effect by competitively inhibiting the catalyst for this irreversible step. This inhibition of the reductase is followed directly by lower levels of mevalonate in the plasma and the urine. 28 Cholesterol, proteins, and triglycerides are transported in the plasma as lipoproteins. The average American adult absorbs approximately 100 mg of triglyceride and 250 mg of cholesterol in the diet. 4 The intestine is the site where these dietary lipids are incorporated into triglyceride-rich chylomicrons. Chylomicrons interact with lipoprotein lipase found in capillary beds, causing the release of free fatty acids. The chylomicron is depleted of triglycerides, forming a remnant. The liver takes up the remnant and disposes of the cholesterol in this form or as bile acids. In the bile, much of the cholesterol and bile acids are reabsorbed from the intestines. The liver also forms a cholesterol-triglyceride-rich lipoprotein (VLDL)

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Acetoacetyl CoA + Acetyl CoA + H20

l

o 11

C-S-CoA I

CH2 I

OH-C-CH3 I

I HMG CoAl

CH2 I

COOHMG CoA Reductase in Cytosol (Enzyme offected by lovostotin)

Cleavage Enzyme / in Mitochondr/ Acetyl CoA + Acetoacetate (Precursors of Ketone Bodies)

CH20H I

CH2 I

OH-C-CH3 (Mevolonote) I

CH2 I

COO-

l

Mevalonote (yrOPhosPhote

Isopentenyl Pyrophosphate

I Ubiquinone

l l

Geranyl Pyrophosphate

!

Farnesyl Pyrophosphate

l

Squalene Synthetase

S'T' Cholesterol

Dolichol

Figure 1. Branched pathway of cholesterol synthesis.

for tissue transport. In the plasma, the VLDL interacts with lipoprotein lipase at capillary beds and loses most of its triglyceride. The remaining particles are intermediate-density lipoprotein (IDL) or VLDL remnants. The IDL either is taken up by LDL receptors or converted to LDL. 4.5 The main carrier of cholesterol is LDL. The LDL delivers cholesterol to hepatic and extrahepatic cells by binding to LDL receptors found on cell membranes. LDL is taken into the cell and cholesterol is released for use in membrane synthesis. When LDL releases its cholesterol into cells, cholesterol homeostasis is maintained by suppression of HMG-CoA reductase, acyl CoA-acyl transferase (ACAT), down-regulation ofLDL receptors, and activation for re-esterifying excess cholesterol for storage.

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H

Figure 2. Structural formula of lovastatin.

HC' 3 Cholesterol also can be bound to HDL in the plasma. Produced in the liver and intestine, HDL can bind free cholesterol from various tissues.

LOVASTATIN Chemistry Lovastatin (mevinolin, MK-B03, Mevacor) is a fermentation production of the fungus Aspergillus terreus. I It is similar in structure to an earlier compound, compactin, a less potent inhibitor of HMG-CoA reductase, whose clinical development was limited by possible cardiogenicity in animals. 8 The chemical structure of lovastatin is shown in Figure 2. There are other HMG-CoA reductase inhibitors currently under investigation: simvastatin, pravastatin, and mevastatin. 12a Pharmacology Lovastatin is an inhibitor of HMG-CoA reductase, interfering with the formation of mevalonate, a precursor of cholesterol. Mevalonate also is a precursor of ubiquinone and dolichol, non sterol substances essential for cell growth (see Fig. 2).3 It initially was thought that an HMG-CoA reductase inhibitor may inhibit formation of these substances, but this is not the case. 3 It appears that when HMG-CoA reductase is inhibited and mevalonate formation is decreased, a latter enzyme in cholesterol synthesis, squalene synthetase, also is inhibited, allowing sufficient farnesyl pyrophosphate for nonsterol production. Nonsterol synthesis does not appear to be inhibited by HMG-CoA reductase. Pharmacokinetics Lovastatin is an inactive lactone (prodrug) that is hydrolyzed in the liver to an active f3-hydroxyacid form. This principal metabolite is the

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inhibitor of the enzyme HMG-CoA reductase. The dissociation constant of the enzyme inhibitor complex (K 1) is approximately 10- 9 M.2~, 36 An oral lovastatin dose is absorbed from the gastrointestinal tract, with greater absorption at meals. The drug undergoes extensive first-pass metabolism in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile, It is estimated that only 5 per cent of an oral dose reaches the general circulation as an active enzyme inhibitor. Eighty-three per cent of the drug is excreted in the bile and 10 per cent in the urine. 22, 23 Lovastatin and its ~-hydroxyacid metabolite are highly bound to human plasma proteins. 22 Lovastatin crosses the blood-brain and placental barriers. The major active metabolites present in human plasma are the ~-hydroxy­ acid of lovastatin, its 6' -hydroxy derivative, and two unidentified metabolites. Peak plasma levels of both active and total inhibitors are attained 2 to 4 hours after lovastatin ingestion. The half-life of the ~-hydroxyacid is approximately 1 to 2 hours. This rapid metabolism would seem to necessitate multiple doses per day. Clinical trials, however, have indicated once or twice daily dosaging is optimum. With a once-a-day dosing regimen, within the therapeutic range of 20 to 80 mg per day, steady-state plasma concentrations of total inhibitors after 2 to 3 days were about 1.5 times that of a single dose. 22 Single daily doses administered in the evening are more effective than the same dose given in the morning, perhaps because cholesterol mainly is synthesized at night. 29 A substantial clinical effect of lovastatin is noted within 2 weeks, a maximal effect at 4 to 6 weeks, and the effect completely dissipates 4 to 6 weeks after stopping the drug.

CLINICAL EXPERIENCES Several investigators have demonstrated that lovastatin lowers the cholesterol levels of normal and hypercholesterolemic animals. 1, 12., 12b, 19-21 These studies demonstrate that the increased LDL-receptor activity and decreased LDL synthesis are responsible for the hypocholesterolemic effect of the drug. Several studies in humans have confirmed this observation. 2, 12, 39 This increase in LDL-receptor activity occurs in response to a decrement in cholesterol synthesis by HMG-CoA reductase inhibition. LDL may be reduced by either its increased clearance from the plasma or its decreased production. Human Volunteers Tobert and associates 38 conducted the first clinical studies with lovastatin in normal male volunteers on normal diets. The cholesterol values of the subject group ranged between 150 and 300 mg per dl. Using a placebocontrol design, these investigators demonstrated that cholesterol levels were reduced significantly with active lovastatin therapy (14.6 per cent reduction with 5 mg of the drug twice daily for 11 days, 24.5 per cent reduction with 15 mg used twice daily for 9 days, and 21.5 per cent with 50 mg used twice daily for 7 days). Serum triglycerides were not changed. In a follow-up study, dosages of the drug ranging from 6.25 to 50 mg twice

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Table 1. Effects of Lovastatin in Patients with Familial Hypercholesterolemia 16, 1735 CHANGE FROM BASELINE (DOSE RANGE.

Total-C

LDL-C

HDL-C

t -

LDL-CI HDL-C

t t

20-80

MG/DAY)

Total-Cl HDL-C

Triglycerides

t t

Total-C = total cholesterol; LDL-C = low-density lipoprotein-cholesterol; HDL-C high-density lipoprotein-cholesterol; t t = 2:25% change from baseline at maximal doses; t or t = 0-25% change from baseline at maximal doses; - = no apparent effect.

daily were administered for 4 weeks. 37 Clinical effects were observed by 3 days and, after 4 weeks, cholesterol was reduced significantly, as well as the LDL-cholesterol and apolipoprotein B levels in plasma. No adverse effects were reported. Heterozygous Familial Hypercholesterolemia Bilheimer and Grundy studied six patients with familial heterozygous hypercholesterolemia, using radiolabeled LDL-cholesterol and its disappearance to calculate a fractional catabolic rate (FCR) and transport rate. 2 The FCR is used to approximate LDL-receptor activity2, 19,39; the transport rate is indicative of LDL synthesis. Using 20-mg lovastatin administered twice daily, a 27 per cent decrease in total cholesterol and a 30 per cent reduction in LDL-cholesterol were observed, resulting from an increase in the FCR. This study suggested a direct stimulatory effect on LDL-receptor activity by lovastatin, perhaps related to a stimulation of the gene for LDLreceptor synthesis by the drug, 2 Subsequent studies evaluating lovastatin's efficacy in heterozygous familial hypercholesterolemia showed that lovastatin, in doses of 5 mg twice daily, produced decreases in total serum cholesterol and LDL-cholesterol.17 Doses of 10, 20, and 40 mg twice daily were even more effective. 16, 17,35 The effects oflovastatin in these studies are summarized in Table 1. Patients in these studies were maintained on low-cholesterol diets (equal to or less than 300 mg per day) and had serum cholesterol values greater than 300 mg per dl prior to treatment. Homozygous Familial Hypercholesterolemia Lovastatin appears to be less effective in reducing cholesterol for this condition than for heterozygous familial and nonfamilial hypercholesterolemia, 25, 35 The drug may not be very effective in a condition where patients have few or no LDL-receptors, East and colleagues7 tested this hypothesis in a child with familial homozygous hypercholesterolemia who was relatively unresponsive to lovastatin, but became extremely responsive to the drug after liver transplant. Nonfamilial (Polygenic) Hypercholesterolemia Similar to the findings in patients with familial heterozygous hypercholesterolemia, lovastatin is effective in patients with nonfamilial hypercholesterolemia. 14, 17, 24 Lovastatin may be more effective in normalizing cholesterol values in the nonfamilial hypercholesterolemia patient, although

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the reduction in LDL-cholesterol may be greater in the familial hypercholesterolemia patient. 22 The largest lovastatin study to date was the multicenter trial involving 264 patients who had primary hypercholesterolemia with an elevated LDLcholesterol and normal triglycerides (type IIa) or mild hypertriglyceridemia (type IIb).24a All subjects were felt to be at high risk for coronary disease on the basis of a variety of risk factors; all were on an American Heart Association phase I diet that was continued during the study. Patients were randomized to therapy with lovastatin (20 mg or 40 mg twice daily for 12 weeks) or cholestyramine (doses escalating from 4 to 8 to 12 mg daily over 3 weeks and then continued at 12 mg daily for the remaining 9 weeks of the 12-week treatment period). Cholesterol fell by 27 per cent in the 20mg lovastatin group and by 34 per cent in the 40-mg group, versus a 12 per cent reduction in the cholestyramine-treated group. In addition, LDLcholesterol was reduced by 32 per cent and 42 per cent, respectively, versus 23 per cent, and apolipoprotein B by 28 per cent and 33 per cent, versus 21 per cent. Both drugs produced similar mean increases in HDLs. Although cholestyramine had no significant effect on VLDL-cholesterol and apolipoprotein levels, and was associated with an 11 per cent increase in plasma triglycerides, lovastatin was associated with reduction of VLDLcholesterol by 34 per cent and 31 per cent and plasma triglycerides by 21 per cent and 27 per cent, with median increases in apolipoprotein A II of 8 per cent and 13 per cent. Adverse effects reported in the two groups were primarily gastrointestinal intolerance: 13 per cent in the low-dose lovastatin, 14 per cent in the higher dose, and 58 per cent in the cholestyramine group. Constipation was reported by 28 per cent of those on cholestyramine, versus 2 per cent and 6 per cent, respectively on low- and high-dose lovastatin. Dyspepsia occurred in 17 per cent on cholestyramine versus 1 per cent on lovastatin. One patient on 40 mg of lovastatin developed a myositis that reversed with discontinuation of the drug. Ophthalmologic examination showed no consistent changes, and both drugs raised transaminase levels, particularly aminotransaminase levels. Increases to more than twice normal were actually more common in the cholestyramine than in the lovastatin group. The authors concluded that lovastatin is more effective and better tolerated in the short-term treatment of primary hypercholesterolemia. The effects of lovastatin in nonfamilial hypercholesterolemia are summarized in Table 2. Combination Therapy The rationale for using lovastatin in combination with other cholesterollowering drugs is to cause an additive or synergistic reduction in total and LDL-cholesterol through complementary effects on LDL-receptor function, and other mechanisms. In several studies, lovastatin has been combined with bile acid binding resins l2 , 15, 39 and neomycin. 13 In studies evaluating the efficacy of colestipol (10 to 20 mg per day), a bile acid sequestrant, plus lovastatin (20 to 40 mg twice daily),12, 14,39 there were greater reductions in total cholesterol and LDL-cholesterol than with single-drug therapy. 22

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Table 2. Effects of Lovastatin in Patients with Nonfamilial (Polygenic) H ypercholesterolemia 14 CHANCE FROM BASELINE (DOSE RAt-;CE

Total-C

LDL-C

HDL-C

i

<->

LDL-CI HDL-C

tt

10-80 Mc/DAY)

Total-Cl HDL-C

VLDL-C

Triglycerides

t t

Total-C = total cholesterol; LDL-C = low-density lipoprotein-cholesterol; HDL-C high-density lipoprotein-cholesterol; VLDL-C = very-Iow-density lipoprotein-cholesterol; t t = 225% change from baseline at maximal doses; i = 0-25% change from baseline at maximal doses; <-> = no apparent effect.

Hoeg and coworkers13 investigated the combination of neomycin, the aminoglycoside antibiotic that inhibits the absorption of cholesterol, with lovastatin. Lovastatin, 20 mg twice daily, was administered for 1 month, followed by neomycin, 1 g twice daily, for 2 months, then the combination for 1 month. Lovastatin alone reduced total cholesterol and LDL-cholesterol significantly, whereas the effect of neomycin alone was negligible. There was no further decrement in total cholesterol and LDL-cholesterol with combination therapy compared with lovastatin alone. In this study, combination therapy was associated with a significant reduction in HDLcholesterol. It was concluded that there was no advantage in combining neomycin with lovastatin. Diabetes Mellitus The onset of noninsulin-dependent diabetes commonly is associated with a decrease in HDL-cholesterol and increases in plasma VLDL triglycerides, VLDL-cholesterol, and LDL-cholesterol. In a placebo-controlled studylO involving 16 patients with non insulin-dependent diabetes, lovastatin, 20 mg twice daily, reduced total plasma cholesterol by 26 per cent. In addition, glycemic control was maintained, and there were reductions in LDL-cholesterol of 28 per cent; apolipoprotein B, 26 per cent; VLDLcholesterol, 42 per cent; and triglycerides, 31 per cent. Plasma levels of HDL-cholesterol did not change with lovastatin treatment but the ratio of total to HDL-cholesterol fell by 29 per cent. Nephrotic Syndrome The nephrotic syndrome is associated with increased levels of cholesterol and triglycerides. These lipid disorders are difficult to treat and they predispose patients to early-onset coronary artery disease. Lovastatin has been shown to reduce plasma concentrations of VLDL- and LDL-cholesterol in patients with nephrotic syndrome with kinetic evidence of enhanced LDL-receptor activity. 40 Effects on Triglycerides and High-density Lipoproteins Lovastatin appears to have variable effects, with most studies showing a reduction in triglycerides 15. 17. 24 ..35 and an increase in HDL-cholesterol. 7. 13. 14. 17. 24. 25

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CLINICAL USE Lovastatin has been shown to be effective in lowering serum cholesterol in familial heterozygous and nonfamilial hypercholesterolemia. 12a Lovastatin dosages as low as 5 mg twice daily produce significant reductions in serum cholesterol. Patients should be placed on a standard cholesterol-lowering diet prior to drug treatment. The recommended starting dose is 20 mg once daily, given with the evening meal. The recommended dosing range is 20 to 80 mg per day in single or divided doses. Adjustments should be made at intervals of 4 weeks or more. A dosage of 40 mg per day can be initiated in patients with cholesterol levels over 300 mg per dl. Twice daily dosing appears to be the most effective treatment regimen, with daily evening doses being slightly less effective and daily morning doses least effective. Maximal and stable cholesterol reduction typically is achieved within 4 to 6 weeks of treatment initiation. In patients with high cholesterol, diet and lovastatin may not reduce cholesterol to the desired level. Colestipol, in combination with lovastatin, may provide additional efficacy. Studies have been done comparing lovastatin in doses of 40 to 80 mg daily versus cholestyramine, 12 g twice daily, and probocol, 500 mg twice daily, with greater efficacy of lovastatin being seen. 26 Adverse Effects Several hypercholesterolemic agents are available, each having a significant side effect profile. 18 Lovastatin has an acceptable rate of adverse reactions, but needs to be used with some caution. 22 In the published trials, approximately 2 per cent of patients were withdrawn from treatment because of adverse reactions. Gastrointestinal side effects (diarrhea, abdominal pain, constipation, flatulence) are the most commonly reported adverse side effects. Marked, persistent but asymptomatic increases (to more than three times the upper limit of normal) in serum transaminases have been reported in 2 per cent of patients receiving the drug for 1 year. These abnormalities rapidly return to normal after the discontinuation of the drug, and no permanent liver damage has been reported with the drug. 14, 24 It is recommended that liver function tests be performed every 4 to 6 weeks during the first 15 months of therapy with lovastatin, and periodically thereafter. Skeletal muscle abnormalities have been described with the drug. Myositis has been noted in 0.5 per cent of patients and may be of more concern in patients concurrently receiving gemfibrozil. 22, 26 Therapy should be withheld or discontinued in patients with risk factors for rhabdomyolysis such as heart transplant patients receiving cyclosporine,12a Investigators testing lovastatin have noted cataracts in dogs given at least 50 times the maximum human dosage in long-term studies. 9 Concern over cataracts dates from some 25 years ago, when an unrelated antihyperlipidemic agent, ctriparazel, was removed from the market after many new lens opacities were found in patients who took it,9 It still is controversial

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whether or not lovastatin can produce cataracts. 36 Although new lens opacities have been described with lovastatin, it is not known whether this incidence differs in an untreated control population. 12c Because it will take years to reach a firm conclusion about lovastatin and cataracts, individuals taking the drug must be followed closely. A slit-lamp eye examination, with dilated pupils and retroillumination, should be performed at baseline and repeated annually, as long as lovastatin treatment continues. Any shagreen (grayish-green discoloration) in the subcapsular cortical region of the lens should be noted; vacuoles should be counted and the number recorded. 9 No changes in visual acuity have been described with the drug. An extensive multicenter trial is in progress that was designed to resolve this controversy in a large population of patients treated with either lovastatin or placebo, long-term. No effects of lovastatin on normal steroidogenesis have been described. 36

CONCLUSION Lovastatin is the first in the class of HMG-CoA reductase inhibitors with therapeutic effects similar to the bile acid sequestrants and nicotinic acid in reducing total cholesterol and LDL-cholestero}.22.36 Although the drug is tolerated well, its long-term safety profile needs to be established before it can be recommended as a first-line treatment of elevated cholesterol, either alone or in combination. Its effect in modifying the risk of cardiovascular morbidity and mortality also needs to be established.

REFERENCES 1. Alberts AW, Chen J, Kuron G, et al: Mevinolin: A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77:3957-3961, 1980 2. Bilheimer OW, Grundy SM, Brown MS, et al: Mevinolin and colestipol stimulate receptormediated clearance of low-density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci USA 80:4124-4128, 1983 3. Brown MS, Goldstein JL: Multivalent feedback regulation of HMG-CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res 21:505-517, 1980 4. Brown MS, Kovanen PT, Goldstein JL: Regulation of plasma cholesterol by lipoprotein receptors. Science 212:628-635, 1981 5. Brunzell JO, Chait A, Bierman EL: Pathophysiology of lipoprotein transport. Metabolism 27:1109-1127, 1978 6. Castelli WP, Garrison RJ, Wilson PW: Incidence of coronary heart disease and lipoprotein cholesterol levels: The Framingham Study. JAMA 256(20):2835-2838, 1986 7. East C, Grundy SM, Bilheimer OW: Normal cholesterol levels with lovastatin (mevinolin) therapy in a child with homozygous familial hypercholesterolemia following liver transplantation. JAMA 256(20):2843-2848, 1986 8. Endo A, Kuroda M, Tsijita Y: ML-236B and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrium. J Antibiot 29:1346-1348, 1976 9. Fraunfelder F: Ocular examination before initiation oflovastatin (Mevacor) tberapy [letter]. Am J Ophthalmol 105:91-92, 1988 9a. Frick MH, Elo 0, Happa K, et al: Helsinki Heart Study: Primary prevention trial with

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genfibrozil in middle-aged men with dyslipidemia: Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317:1237-1451, 1987 10. Carg A, Crundy S: Lovastatin for lowering cholesterol values in noninsulin-dependent diabetes mellitus. N Engl J Med 318:81-86, 1988 11. Crundy SM: Dietary therapy for different forms of hyperlipoproteinemia. Circulation 76:523-528, 1987 12. Crundy SM, Vega CL, Bilheimer DW: Influence of combined therapy with mevinolin and interruption of bile-acid reabsorption on low-density lipoproteins in heterozygous familial hypercholesterolemia. Ann Intern Med 103:339-343, 1985 12a. Crundy SM: HMC-CoA reductase inhibitors for treatment of hypercholesteremia. N Engl J Med 319:24--33, 1988 12b. Henwood JM, Heel AC: Lovastatin. Drugs 36:429-454, 1988 12c. Hunninghake DB, Miller VT, Coldbert I, et al: Lovastatin: Follow-up ophthalmologic data. JAMA 259:354--355, 1988 13. Hoeg JM, Maher MB, Bailey KR, et al: The effects of mevinolin and neomycin alone and in combination on plasma lipid and lipoprotein concentrations in type II hyperlipoproteinemia. Atherosclerosis 60:209-214, 1986 14. Hoeg JM, Maher MB, Zech AL, et al: Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinemia. Am J Cardiol 57:933-939, 1986 15. Illingworth DR: Mevinolin plus colestipol in therapy for severe heterozygous familial hypercholesterolemia. Ann Intern Med 101:598-604, 1984 16. Illingworth DR: Comparative efficacy oeonce versus twice daily mevinolin in the therapy of familial hypercholesterolemia. Clin Pharmacol Ther 40:338-343, 1986 17. Illingworth DR, Sexton CJ: Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia. J Clin Invest 74:1972-1978, 1984 18. Knodel LC, Talbert RL: Adverse effects of hypolipidaemic drugs. Med Toxicol 2:10-32, 1987 19. Kovanen PT, Bilheimer DW, Coldstein JL, et al: Regulatory role for hepatic low-density lipoprotein receptors in vivo in the dog. Proc Natl Acad Sci USA 78:1194-1198, 1981 20. Kritchevsky D, Tepper SA, Klurfeld DM: Influence of mevinolin on experimental atherosclerosis in rabbits. Pharmacol Res Commun 13:921-925, 1981 21. Kroon PA, Hand KM, Huff JW, et al: The effects of mevinolin on serum cholesterol levels of rabbits with endogenous hypercholesterolemia. Atherosclerosis 44:41-48, 1982 22. Krukemyer JJ, Talbert RL: Lovastatin: A new cholesterol-lowering agent. Pharmacotherapy 7:198-210, 1987 23. Lovastatin for Hypercholesterolemia. The Medical Letter on Drugs and Therapeutics. 29:99-101, 1987 24. Lovastatin Study Croup ll: Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolemia. A Multicenter Study. JAMA 256:2829-2834, 1986 24a. Lovastatin Study Croup Ill: Multicenter comparison of lovastatin and cholestyramine therapy for severe primary hypercholesterolemia. JAMA 260:359--366, 1988 25. Luae L, Hoeg JM, Barnes K, et al: The effect of mevinolin on steroidogenesis in patients with defects in the low-density lipoprotein receptor pathway. J Clin Endocrinol Metab 64:531-535, 1987 26. Merck Sharp & Dohme: Mevacor package insert. West Point, PA, August 1987 27. NIH Consensus Conference: Lowering blood cholesterol to prevent heart disease. JAMA 253:2080-2086, 1985 27a. NIH Expert Panel: Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 148:36--69, 1988 28. Parker TS, Cordon BR, Saal SD: Plasma mevalonate as a measure of cholesterol synthesis in man. J Clin Invest 74:795, 1984 29. Parker TS, McNamara DJ, Brown C: Mevalonic acid in human plasma: Relationship of concentration and circadian rhythm to cholesterol synthesis rates in man. Proc Natl Acad Sci USA 79:3037, 1982 30. Schaefer EJ, Levy RI: Pathogenesis and management of lipoprotein disorders. N Engl J Med 312:1300-1310, 1985 31. Stamler J, Wentworth D, Neaton JD: Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings

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in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial. JAMA 256:2823-2828, 1986 Steinberg 0: Lipoproteins and the pathogenesis of atherosclerosis. Circulation 76:508514, 1987 Steinberg D: Cholesterol and cardiovascular disease: Current perspectives. Circulation 76:501-503, 1987 The Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial Results. 1. Reduction in incidence of coronary heart disease. JAMA 251:351-364, 1984 Thompson CR, Ford J, Jenkinson M, et al: Efficacy of mevinolin as adjuvant therapy for refractory familial hypercholesterolemia. Q J Med 60:803-811, 1986 Tobert JA: New developments in lipid-lowering therapy: The role of inhibitors of hydroxymethylglutaryl coenzyme A reductase. Circulation 76:534-538, 1987 Tobert JA, Bell CD, Birtwell J, et al: Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in healthy volunteers. J Clin Invest 69:913-919, 1982 Tobert JA, Hitzenberger C, Kukovetz WR, et al: Rapid and substantial lowering of human serum cholesterol by mevinolin (MK 803), an inhibitor of hydroxymethylglutaryl co enzyme A reductase. Atherosclerosis 41:61-65, 1982 Vega CL, Crundy SM: Treatment of primary moderate hypercholesterolemia with lovastatin (mevinolin) and colestipol. JAMA 257:33-38, 1987 Vega CL, Crundy SM: Lovastatin therapy in nephrotic hyperlipidemia: Effects on lipoprotein metabolism. Kidney lnt 33:1160-1168, 1988

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