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Treatment of hypercholesterolemia with the HMG CoA reductase inhibitor, simvastatin

  • Hyperlipidemias
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Summary

We report the results of a two center study on the use of the HMG Co A reductase inhibitor, simvastatin, in 44 patients suffering from familial hypercholesterolemia or from primary hypercholesterolemia of unknown etiology. The study included two separate phases: Phase I was part of a multicenter, 4-week, placebo-controlled trial; phase II was a 6-month, open extension trial, the object of which was to reduce low density lipoprotein (LDL) cholesterol levels to below the 50th percentile by increasing the dose of simvastatin, by the use of additional lipid-lowering medication, or both. Our phase I results were commensurate with those reported for the entire international cohort of 272 patients, indicating a clear dose-response relationship, with approximately 75% of the maximum reduction in LDL-C levels being achieved with 20 mg/day and over 90% of the maximum being achieved with 40 mg of simvastatin per day. In the open extension trial, the results from the 2 centers were essentially similar. Total cholesterol fell by 29% on the 20 mg/day dose and by 34% on the full dose of 40 mg/day. LDL-C levels were reduced by 40% on the 40 mg/day schedule, and triglycerides also fell to between 20% and 40% below baseline values. HDL-C concentration rose by 14% and 17.6%. The effects of simvastatin were uniform, both within and between the two cohorts. The addition of cholestyramine caused a further substantial reduction in LDL-cholesterol to below 55% of the initial value in four patients, whereas bezafibrate further enhanced the fall in triglycerides and the increase in high-density lipoprotein cholesterol, but had only a slight effect on LDL-C levels. Adverse reactions included asymptomatic increases in plasma creatine kinase activity, generally associated with previous physical exertion, and transient rises in transaminase levels. In one patient with a history of alcoholic excess, transaminase levels were persistently greater than normal. These results indicate that the HMG Co A reductase inhibitor, simvastatin, is a powerful therapeutic agent for the lowering of plasma cholesterol levels in patients with genetic hypercholesterolemia.

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References

  1. Lipid Clinics Research Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in the incidence of coronary heart disease.JAMA 1984; 257:351–364.

    Google Scholar 

  2. Lipid Research Clinics Program. The Lipid Research Clinics Primary Prevention Trial results. II. The relationship of reduction in incidence to coronary heart disease to cholesterol-loweringJAMA 1984; 257:365–374.

    Google Scholar 

  3. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia: Safety of treatment, changes in risk factors and incidence of coronary heart disease.N Engl J Med 1987; 317:1237–1245.

    PubMed  Google Scholar 

  4. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in coronary drug project patients: Long term benefits with niacin.J Am Coll Cardiol 1986; 8:1245–1255.

    PubMed  Google Scholar 

  5. Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs.Med Toxicol 1987; 2:10–32.

    PubMed  Google Scholar 

  6. Endo A, Kurdo M, Tanzawa K, et al. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholsterolaemic activity.FEBS Letters 1976; 72:323–326.

    Google Scholar 

  7. Kaneko I, Hazama-Shimada Y, Endo A. Inhibitory effects on lipid metabolism in cultured cells of ML-236B, a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase.Eur J Biochem 1978; 87:313–321.

    PubMed  Google Scholar 

  8. Brown MS, Faust JR, Goldstein JL. Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase.J Biol Chem 1978; 253:1121–1128.

    PubMed  Google Scholar 

  9. Faust JR, Goldstein JL, Brown MS. Synthesis of ubiquinone and cholesterol in human fibroblasts: Regulation of a branched pathway.Arch Biochem Biophys 1979; 192:86–99.

    PubMed  Google Scholar 

  10. Brown MS, Goldstein JL. Mutivalent feedback regulation of HMG Co A reductase, a control mechanism coordinating isoprenoid synthesis and cell growth.J Lipid Res 1980; 21:505–517.

    PubMed  Google Scholar 

  11. Tsujita Y, Kuroda M, Tanzawa K, et al. Hypolipidemic effects in dogs of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.Atherosclerosis 1979; 32:307–313.

    PubMed  Google Scholar 

  12. Kuroda M, Tsujita Y, Tanzawa K, et al. Hypolipidemic effects in monkeys of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.Lipids 1979; 14:585–589.

    PubMed  Google Scholar 

  13. Kita T, Brown MS, Goldstein JL. Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A livers of mice treated with mevinolin, a competitive inhibitor of the reductase.J Clin Invest 1980; 66:1094–1100.

    PubMed  Google Scholar 

  14. Yamamoto A, Sudo H, Endo A. Therapeutic effects of ML-236B in primary hypercholesterolaemia.Atherosclerosis 1980; 35:259–266.

    PubMed  Google Scholar 

  15. Mabuchi H, Haba T, Tatami R, et al. Effects of an inhibitor of 3-hydroxy-3-methylgltaryl coenzyme A reductase on serum lipoproteins and ubiquinone-10 levels in patients with familial hypercholesterolaemia.N Engl J Med 1981; 305: 478–482.

    PubMed  Google Scholar 

  16. Mabuchi H, Sakai T, Sakai Y, et al. Reduction of serum cholesterol in heterozygous patients with familial hypercholesterolaemia.N Engl J Med 1983; 308:609–613.

    PubMed  Google Scholar 

  17. Bilheimer DW, Grundy SM, Brown MS, et al. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolaemia heterozygotes.Proc Natl Acad Sci 1983; 80:4124–4128.

    PubMed  Google Scholar 

  18. Illingworth DR, Sexton GJ. hypocholesterolaemic effects of mevinolin inpatients with heterozygous familial hypercholesterolaemia.J Clin Invest 1984; 74:1972–1978.

    PubMed  Google Scholar 

  19. Grundy SM, Vega GL, Bilheimer DW. Influence of combined therapy with mevinolin and interruption of bile-acid reabsorption of low density lipoproteins in heterozygous familial hypercholesterolaemia.Ann Intern Med 1985; 103:339–343.

    PubMed  Google Scholar 

  20. The Lovastatin Study Group II. Therapeutic response to lovastatin (mevinolin) in non-familial hypercholesterolaemia. A multicenter study.JAMA 1986; 256:2829–2834.

    Google Scholar 

  21. Havel RJ, Hunninghake DB, Illingworth R, et al. Lovastatin (mevinolin) in the treatment of heterozygous familial hypercholesterolaemia. A multicenter study.Ann Int Med 1987; 107:609–615.

    PubMed  Google Scholar 

  22. Hoskin PJ, Yarnold JR, Easton D. Synvinolin in hypercholesterolaemia.Lancet 1987; II:390–391.

    Google Scholar 

  23. Mol MJTM, Erkelens DW, Gevers Leuven JA, et al. Effects of synvinolin (MK-733) on plasma lipids in familial hypercholesterolaemia.Lancet 1986; II:936–938.

    Google Scholar 

  24. Thompson GR, Ford J, Jenkinson M, et al. Efficacy of mevinolin as adjuvant therapy for refractory familial hypercholesterolaemia.Quart J Med 1986; 60:803–811.

    PubMed  Google Scholar 

  25. Hoeg JM, Maher MB, Zech LA, et al. Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinaemia.Am J Cardiol 1986; 57:933–939.

    PubMed  Google Scholar 

  26. Vega GL, Grundy SM. Treatment of primary moderate hypercholesterolaemia with lovastatin (mevinolin) and colestipol.JAMA 1987; 257:33–38.

    PubMed  Google Scholar 

  27. Yoshino G, Kazumi T, Inui A, et al. Probucol versus eptastatin in hypercholesterolaemic diabetics.Lancet 1986; II: 740–741.

    Google Scholar 

  28. Nakaya N, Homma Y, Tamachi H, et al. The effects of CS-514 on serum lipids and apolipoproteins in hypercholesterolaemic subjects.JAMA 1987; 257:3088–3093.

    PubMed  Google Scholar 

  29. Rifkind BM, Segal P. Lipid Research Clinics Program reference for hyperlipidemia and hypolipidemia.JAMA 1983; 250:1869–1872.

    PubMed  Google Scholar 

  30. Lipid Research Clinics Program. Manual of Laboratory Operations.Lipid and Lipoprotein Analysis Revised, U.S. Department of Health and Human Services. Bethesda, Maryland, 1982.

    Google Scholar 

  31. Friedewald WT, Levy RI, Frederickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge.Clin Chem 1972; 18:499–592.

    PubMed  Google Scholar 

  32. Bernstein M, Scholnick HR, Morfin B. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions.J Lipid Res 1970; 11:583–595.

    PubMed  Google Scholar 

  33. Wiebe DA, Smith SY. Six methods for isolating high-density lipoprotein compared with the use of the reference method for quantifying cholesterol in serum.Clin Chem 1985; 31:746–750.

    PubMed  Google Scholar 

  34. Brown MS, Goldstein JL. Lowering plasma cholesterol by raising LDL receptors.N Eng J Med 1981; 305:515–517.

    Google Scholar 

  35. Alberts AW, Chen J, Kuran G, et al. Mevinolin: A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.Proc Natl Acad Sci 1980; 77:3957–3961.

    PubMed  Google Scholar 

  36. Hoeg JM, Brewer HB Jr. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in the treatment of hypercholesterolaemia.JAMA 1987; 258:3532–3536.

    PubMed  Google Scholar 

  37. Grundy SM. HMG Co A reductase inhibitors for treatment of hypercholesterolaemia.N Eng J Med 1988; 319:24–33.

    Google Scholar 

  38. Kovanen PT, Bilheimer DW, Goldstein JL, et al. Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog.Proc Natl Acad Sci 1981; 78:1194–1198.

    PubMed  Google Scholar 

  39. Bilheimer DW, Grundy SM, Brown MS, et al. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolaemia heterozygotes.Proc Natl Acad Sci 1983; 80:4124–4128.

    PubMed  Google Scholar 

  40. Hoeg JM, Maker MB, Bailey KR, Brewer HB Jr. Comparison of six pharmacologic regimens for hypercholesterolaemia.Am J Med 1987; 59:812–815.

    Google Scholar 

  41. Hunninghake DB, Miller VT, Goldberg I, et al. Lovastatin: Follow-up ophthalmic data.JAMA 1988; 259:354–355.

    Google Scholar 

  42. Norman DJ, Illingworth DR, Munson J, Hosenpud J. Myositis and acute renal failure in a heart-transplant recipient receiving lovastatin.N Engl J Med 1988; 318:46–47.

    PubMed  Google Scholar 

  43. East C, Alivizatos PA, Grundy SM, et al. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation.N Engl J Med 1988; 318:47–48.

    PubMed  Google Scholar 

  44. Tobert JA. Reply.N Engl J Med 1988; 318:48.

    PubMed  Google Scholar 

  45. Malloy MJ, Kane JP, Kunitake ST, Tun P. Complementarity of colestipol, niacin and lovastatin in treatment of severe familial hypercholesterolaemia.Ann Int Med 1987; 107:616–623.

    PubMed  Google Scholar 

  46. East CA, Grundy SM, Bilheimer DW. Preliminary report: Treatment of type 3 hyperlipoproteinaemia with mevinolin.Metabolism 1986; 35:97–98.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Biochemistry, University of Cape Town Medical School, Cape Town, South Africa

    AD Marais

  2. Carbohydrate and Lipid Metabolism Research Group, Department of Medicine, University of the Witwatersrand Medical School, Johannesburg, South Africa

    HC Seftel, SG Baker & BI Joffe

  3. Department of Chemical Pathology, School of Pathology University of the Witwatersrand, South Africa

    D Mendelsohn

  4. South African Institute for Medical Research, Johannesburg, South Africa

    D Mendelsohn

  5. Department of Ophthalmology, University of the Witwatersrand Medical School, Johannesburg, South Africa

    NH Welsh

  6. Department of Chemical Pathology, Red Cross War Memorial Children's Hospital, Rondebosch 7700, Cape Town, South Africa

    GMB Berger

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Berger, G., Marais, A., Seftel, H. et al. Treatment of hypercholesterolemia with the HMG CoA reductase inhibitor, simvastatin. Cardiovasc Drug Ther 3, 219–227 (1989). https://doi.org/10.1007/BF01883868

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