0
December 25, 1987, Vol 258, No. 24 >
ARTICLE | December 25, 1987

3-Hydroxy-3-Methylglutaryl—Coenzyme A Reductase Inhibitors in the Treatment of Hypercholesterolemia FREE

Jeffrey M. Hoeg, MD; H. Bryan Brewer, Jr, MD
[+] Author Affiliations

Reprint requests to Bldg 10, Room 7N117, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892 (Dr Hoeg).


JAMA. 1987;258(24):3532-3536. doi:10.1001/jama.1987.03400240064025
Text Size: A A A
Published online
Article
References

A new class of drugs, which inhibit de novo cholesterol biosynthesis, significantly reduces the blood cholesterol concentrations in hypercholesterolemic patients. Four separate inhibitors have lowered plasma total cholesterol and low-density lipoprotein (LDL) levels in humans by 20% to 40%: mevastatin (Compactin), lovastatin (mevinolin), pravastatin (CS-514, Eptastatin, and SQ 31 000), and simvastatin (Synvinolin, MK-733). In addition to lowering total and LDL cholesterol concentrations, the plasma concentration of the potentially atherogenic B apolipoprotein is also reduced by 20% to 40%. The reduction in the levels of circulating atherogenic lipoprotein particles occurs as a result of decreased synthesis and enhanced removal of LDLs by the LDL receptor pathway in hepatocytes. Moreover, the levels of high-density lipoprotein cholesterol, which are inversely related to atherosclerosis, increase in concentration with treatment by these drugs. If the short-term safety of these drugs extends to ongoing long-term studies and if cardiovascular morbidity and mortality are affected by their use, this class of hypolipidemic agent will markedly facilitate the effective treatment of hypercholesterolemia.

(JAMA 1987;258:3532-3536)

REFERENCES

1 +
 Lipid Research Clinics Coronary Primary Prevention Trial: Results: I. Reduction in incidence of coronary heart disease . JAMA 1984;;251:251-264.
2 +
 Lipid Research Clinics Coronary Primary Prevention Trial: Results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering . JAMA 1984;;251:365-374.
3 +
Hoeg JM, Gregg RE, Brewer HB Jr:  An approach to the management of hyperlipoproteinemia . JAMA 1986;;255:512-521.
4 +
Avigan J, Steinberg D, Vroman HE, et al:  Studies of cholesterol biosynthesis: I. The identification of desmosterol in serum and tissues of animals and man treated with MER-29 . J Biol Chem 1960;;235:3123-3126.
5 +
Dvornik D, Kraml M, Dubuc J, et al:  A novel mode of inhibition of cholesterol biosynthesis . J Am Chem Soc 1963;;85:3309.
6 +
Anchor RWP, Winkelmann RK, Perry HO:  Cutaneous side effects from use of triparanol (MER-29): Preliminary data on ichthyosis and loss of hair . Mayo Clin Proc 1961;;36:217-228.
7 +
Laughlin RC, Carey TF:  Cataracts in patients treated with triparanol . JAMA 1962;;181:339-340.
8 +
Endo A, Kuroda M, Tanazawa K:  Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B, fungal metabolites having hypocholesterolemic activity . FEBS Lett 1976;;72:323-326.
9 +
Mabuchi H, Haba T, Tatami R, et al:  Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase on serum lipoproteins and ubiquinone-10 levels in patients with familial hypercholesterolemia . N Engl J Med 1981;;305:478-482.
10 +
Mabuchi H, Sakai T, Sakai Y, et al:  Reduction of serum cholesterol in heterozygous patients with familial hypercholesterolemia: Additive effects of Compactin and cholestyramine . N Engl J Med 1983;;308:609-613.
11 +
Yamamoto A, Yamamura T, Yokoyama S, et al:  Combined drug therapy—cholestyramine and Compactin—for familial hypercholesterolemia . Int J Clin Pharmacol Ther Toxicol 1984;;22:493-497.
12 +
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 1980;;77:3957-3961.
13 +
Illingworth DR, Sexton GJ:  Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia . J Clin Invest 1984;;74:1972-1978.
14 +
Hoeg JM, Maher MB, Zech LA, et al:  Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinemia . Am J Cardiol 1986;;57:933-939.
15 +
Grundy SM, Bilheimer DW:  Inhibition of 3-hydroxy-3-methylglutaryl-3-methylglutaryl CoA reductase by mevinolin in familial hypercholesterolemia heterozygotes: Effects on cholesterol balance . Proc Natl Acad Sci USA 1984;;81:2538-2542.
16 +
Illingworth DR:  Mevinolin plus colestipol in therapy for severe heterozygous familial hypercholesterolemia . Ann Intern Med 1984;;101:598-604.
17 +
Grundy SM, Vega GL, 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 1985;;103:339-343.
18 +
Illingworth DR, Connor WE:  Hypercholesterolemia persisting after distal ileal bypass: Responses to mevinolin . Ann Intern Med 1984;;100:850-851.
19 +
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 1986;;60:209-214.
20 +
Laue L, Hoeg JM, Barnes K, et al:  The effect of mevinolin on steroidogenesis in patients with defects in the LDL receptor pathway . J Clin Endocrinol Metab 1987;;64:531-535.
21 +
Grundy SM, Vega GL:  Influence of mevinolin on metabolism of low density lipoproteins in primary moderate hypercholesterolemia . J Lipid Res 1985;;26:1464-1475.
22 +
Hunninghake DB, Miller VT, Palmer RH, et al:  Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolemia . JAMA 1986;;256:2829-2834.
23 +
East CA, Grundy SM, Bilheimer DW:  Preliminary report: Treatment of type 3 hyperlipoproteinemia with mevinolin . Metabolism 1986;;35:97-98.
24 +
Tobert JA, Bell GD, 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 1982;;69:913-919.
25 +
Tobert JA, Hitzenberger G, Kukoveta WR, et al:  Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl coenzyme A reductase . Atherosclerosis 1982;;41:61-65.
26 +
Brown MS, Goldstein JL:  Lowering plasma cholesterol by raising LDL receptors . N Engl J Med 1981;;305:515-517.
27 +
Hoeg JM, Brewer HB Jr:  Human lipoprotein metabolism and the liver , in Popper H, Schaffner F (eds): Progress in Liver Diseases . New York, Grune & Stratton, 1986;, vol 3, pp 51-64.
28 +
Monge JC, Hoeg JM, Law SW, et al:  Low density lipoproteins (LDL) induce coordinate regulation of human apolipoproteins (apo)A and B-100 biosynthesis in HepG2 cells , abstracted. Clin Res 1986;;34:443A.
29 +
Nakaya N, Houima Y, Tanrachi H, et al:  The effect of CS-J14 on serum lipids and apolipoproteins in hypercholesterolemic subjects . JAMA 1987;;257:3088-3093.
30 +
Yamamoto A, Sudo H, Endo A:  Therapeutic effects of MLL-236B in primary hypercholesterolemia . Atherosclerosis 1980;;35:259-266.
31 +
Yoshino G, Kazumi T, Uenoyama R, et al:  Probucol versus Eptastatin in hypercholesterolaemic diabetics . Lancet 1986;;2:740-741.
32 +
Nakay N, Homma Y, Tamachi H, et al:  The effect of CS-514, an inhibitor of HMG-CoA reductase, on serum lipids in healthy volunteers . Atherosclerosis 1986;;61:125-128.
33 +
Olsson AG, Morelgaard J, von Scheink H:  Synvinolin in hypercholesterolaemia . Lancet 1986;;2:390-391.
34 +
Mol MJTM, Erkelens DW, Gevers Leuven JA, et al:  Effects of Synvinolin (MK-733) on plasma lipids in familial hypercholesterolaemia . Lancet 1986;;2:936-939.
35 +
Minsker DH, MacDonald JS, Robertson RT, et al:  Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase . Teratology 1983;;28:449-456.
36 +
Illingworth DR, Corbin D:  The influence of mevinolin on the adrenal cortical response to corticotropin in heterozygous familial hypercholesterolemia . Proc Natl Acad Sci USA 1985;;82:6291-6294.
37 +
Thompson GR, Ford J, Jenkinson M, et al:  Efficacy of mevinolin as adjuvant therapy for refractory familial hypercholesterolemia . Q J Med 1986;;232:803-811.
38 +
Fojo SS, Hoeg JM, Lackner KJ, et al:  The effects of lovastatin (mevinolin) treatment on adrenal steroidogenesis in type II hyperlipoproteinemia . Horm Metab Res , in press.
39 +
Farnsworth WH, Hoeg JM, Maher MB, et al:  Testicular function in type II hyperlipoproteinemic patients treated with lovastatin (mevinolin) or neomycin . J Clin Endocrinol Metab 1987;;65:546-550.
40 +
Laue L, Hoeg JM, Barnes K, et al:  Abnormal growth hormone secretory dynamics in children with familial hypercholesterolemia . Horm Res , in press.
41 +
Hoeg JM, Maher MB, Bailey KR, et al:  Comparison of six pharmacological regimens for hypercholesterolemia . Am J Cardiol 1987;;59:812-815.
42 +
Canner PL, Berge KG, Wenger NK, et al:  Fifteen-year mortality in coronary drug project patients: Long-term benefit with niacin . J Am Coll Cardiol 1986;;8:1245-1255.

Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
 Lipid Research Clinics Coronary Primary Prevention Trial: Results: I. Reduction in incidence of coronary heart disease . JAMA 1984;;251:251-264.
2 +
 Lipid Research Clinics Coronary Primary Prevention Trial: Results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering . JAMA 1984;;251:365-374.
3 +
Hoeg JM, Gregg RE, Brewer HB Jr:  An approach to the management of hyperlipoproteinemia . JAMA 1986;;255:512-521.
4 +
Avigan J, Steinberg D, Vroman HE, et al:  Studies of cholesterol biosynthesis: I. The identification of desmosterol in serum and tissues of animals and man treated with MER-29 . J Biol Chem 1960;;235:3123-3126.
5 +
Dvornik D, Kraml M, Dubuc J, et al:  A novel mode of inhibition of cholesterol biosynthesis . J Am Chem Soc 1963;;85:3309.
6 +
Anchor RWP, Winkelmann RK, Perry HO:  Cutaneous side effects from use of triparanol (MER-29): Preliminary data on ichthyosis and loss of hair . Mayo Clin Proc 1961;;36:217-228.
7 +
Laughlin RC, Carey TF:  Cataracts in patients treated with triparanol . JAMA 1962;;181:339-340.
8 +
Endo A, Kuroda M, Tanazawa K:  Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B, fungal metabolites having hypocholesterolemic activity . FEBS Lett 1976;;72:323-326.
9 +
Mabuchi H, Haba T, Tatami R, et al:  Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase on serum lipoproteins and ubiquinone-10 levels in patients with familial hypercholesterolemia . N Engl J Med 1981;;305:478-482.
10 +
Mabuchi H, Sakai T, Sakai Y, et al:  Reduction of serum cholesterol in heterozygous patients with familial hypercholesterolemia: Additive effects of Compactin and cholestyramine . N Engl J Med 1983;;308:609-613.
11 +
Yamamoto A, Yamamura T, Yokoyama S, et al:  Combined drug therapy—cholestyramine and Compactin—for familial hypercholesterolemia . Int J Clin Pharmacol Ther Toxicol 1984;;22:493-497.
12 +
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 1980;;77:3957-3961.
13 +
Illingworth DR, Sexton GJ:  Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia . J Clin Invest 1984;;74:1972-1978.
14 +
Hoeg JM, Maher MB, Zech LA, et al:  Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinemia . Am J Cardiol 1986;;57:933-939.
15 +
Grundy SM, Bilheimer DW:  Inhibition of 3-hydroxy-3-methylglutaryl-3-methylglutaryl CoA reductase by mevinolin in familial hypercholesterolemia heterozygotes: Effects on cholesterol balance . Proc Natl Acad Sci USA 1984;;81:2538-2542.
16 +
Illingworth DR:  Mevinolin plus colestipol in therapy for severe heterozygous familial hypercholesterolemia . Ann Intern Med 1984;;101:598-604.
17 +
Grundy SM, Vega GL, 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 1985;;103:339-343.
18 +
Illingworth DR, Connor WE:  Hypercholesterolemia persisting after distal ileal bypass: Responses to mevinolin . Ann Intern Med 1984;;100:850-851.
19 +
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 1986;;60:209-214.
20 +
Laue L, Hoeg JM, Barnes K, et al:  The effect of mevinolin on steroidogenesis in patients with defects in the LDL receptor pathway . J Clin Endocrinol Metab 1987;;64:531-535.
21 +
Grundy SM, Vega GL:  Influence of mevinolin on metabolism of low density lipoproteins in primary moderate hypercholesterolemia . J Lipid Res 1985;;26:1464-1475.
22 +
Hunninghake DB, Miller VT, Palmer RH, et al:  Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolemia . JAMA 1986;;256:2829-2834.
23 +
East CA, Grundy SM, Bilheimer DW:  Preliminary report: Treatment of type 3 hyperlipoproteinemia with mevinolin . Metabolism 1986;;35:97-98.
24 +
Tobert JA, Bell GD, 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 1982;;69:913-919.
25 +
Tobert JA, Hitzenberger G, Kukoveta WR, et al:  Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl coenzyme A reductase . Atherosclerosis 1982;;41:61-65.
26 +
Brown MS, Goldstein JL:  Lowering plasma cholesterol by raising LDL receptors . N Engl J Med 1981;;305:515-517.
27 +
Hoeg JM, Brewer HB Jr:  Human lipoprotein metabolism and the liver , in Popper H, Schaffner F (eds): Progress in Liver Diseases . New York, Grune & Stratton, 1986;, vol 3, pp 51-64.
28 +
Monge JC, Hoeg JM, Law SW, et al:  Low density lipoproteins (LDL) induce coordinate regulation of human apolipoproteins (apo)A and B-100 biosynthesis in HepG2 cells , abstracted. Clin Res 1986;;34:443A.
29 +
Nakaya N, Houima Y, Tanrachi H, et al:  The effect of CS-J14 on serum lipids and apolipoproteins in hypercholesterolemic subjects . JAMA 1987;;257:3088-3093.
30 +
Yamamoto A, Sudo H, Endo A:  Therapeutic effects of MLL-236B in primary hypercholesterolemia . Atherosclerosis 1980;;35:259-266.
31 +
Yoshino G, Kazumi T, Uenoyama R, et al:  Probucol versus Eptastatin in hypercholesterolaemic diabetics . Lancet 1986;;2:740-741.
32 +
Nakay N, Homma Y, Tamachi H, et al:  The effect of CS-514, an inhibitor of HMG-CoA reductase, on serum lipids in healthy volunteers . Atherosclerosis 1986;;61:125-128.
33 +
Olsson AG, Morelgaard J, von Scheink H:  Synvinolin in hypercholesterolaemia . Lancet 1986;;2:390-391.
34 +
Mol MJTM, Erkelens DW, Gevers Leuven JA, et al:  Effects of Synvinolin (MK-733) on plasma lipids in familial hypercholesterolaemia . Lancet 1986;;2:936-939.
35 +
Minsker DH, MacDonald JS, Robertson RT, et al:  Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase . Teratology 1983;;28:449-456.
36 +
Illingworth DR, Corbin D:  The influence of mevinolin on the adrenal cortical response to corticotropin in heterozygous familial hypercholesterolemia . Proc Natl Acad Sci USA 1985;;82:6291-6294.
37 +
Thompson GR, Ford J, Jenkinson M, et al:  Efficacy of mevinolin as adjuvant therapy for refractory familial hypercholesterolemia . Q J Med 1986;;232:803-811.
38 +
Fojo SS, Hoeg JM, Lackner KJ, et al:  The effects of lovastatin (mevinolin) treatment on adrenal steroidogenesis in type II hyperlipoproteinemia . Horm Metab Res , in press.
39 +
Farnsworth WH, Hoeg JM, Maher MB, et al:  Testicular function in type II hyperlipoproteinemic patients treated with lovastatin (mevinolin) or neomycin . J Clin Endocrinol Metab 1987;;65:546-550.
40 +
Laue L, Hoeg JM, Barnes K, et al:  Abnormal growth hormone secretory dynamics in children with familial hypercholesterolemia . Horm Res , in press.
41 +
Hoeg JM, Maher MB, Bailey KR, et al:  Comparison of six pharmacological regimens for hypercholesterolemia . Am J Cardiol 1987;;59:812-815.
42 +
Canner PL, Berge KG, Wenger NK, et al:  Fifteen-year mortality in coronary drug project patients: Long-term benefit with niacin . J Am Coll Cardiol 1986;;8:1245-1255.

Letters

Submit a Letter
CME Course for:


You need to register in order to view this quiz.


To understand the clinical management of acute heart failure syndromes.
Accreditation Information The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
To view and print your certificate and access a summary of your CME courses go to My CME.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
Submit a Response

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

© 2012 American Medical Association. All Rights Reserved.
Powered bySilverchair Information Systems