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Causes Underlying the Reduced Response to Simvastatin Treatment in Hypercholesterolemic Patients

  • Alberto Corsini
  • Maria Mazzotti
  • Tiziano Zanelli
  • Patrizia Uboldi
  • Domenico Sommariva
  • Franco Pazzucconi
  • Cesare R. Sirtori
  • Antonio Gaddi
  • Giancarlo Descovish
  • Agnese Granata
  • Remo Fumagalli
  • Alberico L. Catapano
Conference paper
Part of the NATO ASI Series book series (volume 73)

Abstract

Simvastatin, a competitive inhibitor of HMG-CoA reductase, effectively reduces elevated plasma cholesterol levels by up regulating the LDL receptor expression. Therefore in patients whose hypercholesterolemia (HC) is due to a defective LDL-receptor interaction vastatins may not be as effective as expected. To verify this hypothesis we studied the possible causes for the poor response (<15% decrease of LDL cholesterol) to simvastatin (40 mg/die) in 11 HC patients. Biochemical defects were identified in 5 patients. Three patients presented with binding-defective LDL, without the 3500 mutation, and the remaining two had normal LDL but their serum contained factors interfering with the LDL-receptor interaction. From these results we conclude that distinct biochemical defects might contribute to the poor response to simvastatin in hypercholesterolemic patients.

Key words

LDL receptor binding defective LDL hypolipidaemic drugs apolipoprotein B probucol 

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References

  1. Beaumont JL, Beaumont V (1977) Autoimmune hyperlipidemia. Atherosclerosis 26: 405–418.PubMedCrossRefGoogle Scholar
  2. Bilheimer DW, Eisenberg S, Levy RI (1972) The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 260: 212–221.Google Scholar
  3. Bilheimer DW, Grundy SM, Brown MS, Goldstein JL (1983) Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci USA 80: 4124–4128.PubMedCrossRefGoogle Scholar
  4. Brown MS, Faust JR, Goldstein JL, Kaneko I, Endo A (1978) 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 253: 1121–1128.PubMedGoogle Scholar
  5. Brown MS, Goldstein JL (1981) Lowering plasma cholesterol by raising LDL receptors. N Engl J Med 305: 515–517.PubMedCrossRefGoogle Scholar
  6. Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47.PubMedCrossRefGoogle Scholar
  7. Brown MS, Goldstein JL (1987) The hyperlipoproteinemias and other disorders of lipid metabolism. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS (eds) Harrison’s Principles of Internal Medicine. McGraw-Hill, New York, llth Edition, 16501661.Google Scholar
  8. Brown G, Albers JJ, Fisher LD, et al (1990) Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 323: 1289–1298.PubMedCrossRefGoogle Scholar
  9. Corsini A, Roma P, Sommariva D, Fumagalli R, Catapano AL (1986) Autoantibodies to the low density lipoprotein receptor in a subject affected by severe hypercholesterolemia. J Clin Invest 78: 940–946.PubMedCrossRefGoogle Scholar
  10. Corsini A, McCarthy BJ, Granata A, et al (1991) Familial defective apo B-100, characterization of an Italian family. Eur J Clin Invest 21: 389–397.PubMedCrossRefGoogle Scholar
  11. Endo A, Tsujita Y, Kuroda M, Tanzawa K (1979) Effects of ML-236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals. Biochim Biophys Abta 575: 266–276.Google Scholar
  12. Feingold KR, Castro GR, Ishikawa Y, Fielding PE, Fielding CR (1989) Cutaneous xanthoma in association with paraproteinemia in the absence of hyperlipidemia. J Clin Invest 83: 796–802.PubMedCrossRefGoogle Scholar
  13. Fisher RA, Yates F (1953) In: Oliver and Boyd (eds) Statistical Tables for Biological, Agricultural and Medical Research, 4th Edition, 60.Google Scholar
  14. Grundy SM (1988) HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 319: 24–33.PubMedCrossRefGoogle Scholar
  15. Grundy SM, Vega GL (1990) Causes of high blood cholesterol.Circulation 81: 412–427.Google Scholar
  16. Grundy SM, Vega GL, Garg A (1990) Use of 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors in various forms of dyslipidemia. Am J Cardiol 66: 31B - 38B.PubMedCrossRefGoogle Scholar
  17. Goldstein JL, Basu SK, Brown MS (1983) Receptor-mediated endocytosis of the low density lipoproteins in cultured cells. Methods Enzymol 98: 241–260.PubMedCrossRefGoogle Scholar
  18. Goldstein JL, Brown MS (1989) Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic Basis of Inherited Disease. McGraw-Hill, New York, 6th Edition, 1: 1215–1250.Google Scholar
  19. Hagemenas FC, Pappu AS, Illingworth DR (1990) The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolaemia. Eur J Clin Invest 20: 150–157.PubMedCrossRefGoogle Scholar
  20. Havel RJ, Eder HA, Bragdon JH (1955) The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest 34: 1345–1354.PubMedCrossRefGoogle Scholar
  21. Havel RJ, Hunninghake DB, Illingworth DR, et al (1987) A multicenter study of lovastatin (mevinolin) in the therapy of heterozygous familial hypercholesterolemia. Ann Intern Med 107: 609–615.PubMedGoogle Scholar
  22. Illingworth D, Sexton G (1984) Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia. J Clin Invest 74: 1972–1978.PubMedCrossRefGoogle Scholar
  23. Innerarity TL, Mahley RW (1978) Enhanced binding by cultured human fibroblasts of apo E-containing lipoproteins as compared with low density lipoproteins. Biochemistry 17: 1440–1447.PubMedCrossRefGoogle Scholar
  24. Innerarity TL, Weisgraber KH, Arnold KS, et al (1987) Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 84: 1650–1661.CrossRefGoogle Scholar
  25. Innerarity TL, Mahley RW, Weisgraber KH, et al (1990) Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res 31: 1337–1349.PubMedGoogle Scholar
  26. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ (1990) Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 264: 3007–3012.PubMedCrossRefGoogle Scholar
  27. Kleinman Y, Eisenberg S, Oschry Y, Gavish D, Stein O, Stein Y (1985) Defective metabolism of hypertriglyceridemic low density lipoprotein in cultured human skin fibroblasts: J Clin Invest 75: 1796–1803.PubMedGoogle Scholar
  28. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680.PubMedCrossRefGoogle Scholar
  29. Lewis LA, De Wolfe VG, Butkus A, Page IH (1975) Autoimmunehyperlipidemia in a patient. Am J Med 59: 208–218. Lipid Research Clinics Program (1984) Reduction in incidenceGoogle Scholar
  30. of coronary heart disease. JAMA 251: 31–364.Google Scholar
  31. Lowering Blood Cholesterol to Prevent Heart Disease. Consensus Conference (1985) JAMA 253: 2080–2086.CrossRefGoogle Scholar
  32. Naruszewicz M, Carew TE, Pittman RC, Witztum JL, Steinberg D (1984) A novel mechanism by which probucol lowers low density lipoprotein levels demonstrated in the LDL receptor-deficient rabbit. J Lipid Res 25: 1206–1213.PubMedGoogle Scholar
  33. Raveh D, Israeli A, Arnon R, Eisenberg S (1990) Effects of lovastatin therapy on LDL receptor activity in circulating monocytes and on structure and composition of plasma lipoproteins. Atherosclerosis 82: 19–26.PubMedCrossRefGoogle Scholar
  34. Reihner E, Rudling M, Stahlberg D, et al (1990) Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med 323: 224–228.PubMedCrossRefGoogle Scholar
  35. Riesen W, Noseda G (1975) Antibodies against lipoproteins in man, occurence and biological significance. Klin Wochenschr 53: 353–361.PubMedCrossRefGoogle Scholar
  36. Saiki RK, Gelfand DH, Stoffel S, et al (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239: 487–491.PubMedCrossRefGoogle Scholar
  37. Stamler J (1979) Population studies. In: Levy R, Rifkind B, Dennis B, Ernst N (eds) Nutrition, Lipids, and Coronary Heart Disease. Raven Press, New York, 25–88Google Scholar
  38. Stossel TP (1988) A multicenter comparison of lovastatin and cholestyramine therapy for severe primary hypercholesterolemia. JAMA 260: 359–366.CrossRefGoogle Scholar
  39. The Lovastatin Study Group IV (1990) A multicenter comparison of lovastatin and probucol for treatment of severe primary hypercholesterolemia. Am J Cardiol 66: 22B - 30B.CrossRefGoogle Scholar
  40. Trezzi E, Roma P, Bernini F, Fumagalli R, Catapano AL (1984) Effects of probucol on the in vivo plasma clearance of human low density lipoprotein receptors in vitro. Atherosclerosis 52: 309–316.PubMedCrossRefGoogle Scholar
  41. Vega GL, Grundy SM (1986) In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 78: 1410–1414.PubMedCrossRefGoogle Scholar
  42. Yamamoto A, Yokoyama S, Yamamura T (1988) Escape phenomenon occurs by lowering cholesterol with a hydroxymethylglutaryl coenzyme A ( HMG-CoA) reductase inhibitor in patients with familial hypercholesterolemia. Atherosclerosis 71: 257–260.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • Alberto Corsini
    • 1
  • Maria Mazzotti
    • 1
  • Tiziano Zanelli
    • 1
  • Patrizia Uboldi
    • 1
  • Domenico Sommariva
    • 2
  • Franco Pazzucconi
    • 3
  • Cesare R. Sirtori
    • 3
  • Antonio Gaddi
    • 4
  • Giancarlo Descovish
    • 1
  • Agnese Granata
    • 1
  • Remo Fumagalli
    • 1
  • Alberico L. Catapano
    • 4
  1. 1.Institute of Pharmacological SciencesUniversity of MilanMilanItaly
  2. 2.Bollate HospitalMilanItaly
  3. 3.Center E. Grossi PaolettiUniversity of MilanItaly
  4. 4.Atherosclerosis Center and Department of Internal MedicineS. Orsola Hospital, University of BolognaItaly

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