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Newer pharmaceutical agents to treat lipid disorders

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Abstract

The National Cholesterol Education Program Adult Treatment Panel III guidelines and the results of the Heart Protection Study have provided a stronger rationale to more aggressively treat high-risk patients to a low-density (LDL) cholesterol goal of less than 100 mL/dL. Two new therapies, ezetimibe and rosuvastatin, have recently been added to the lipid-lowering armamentarium to improve guideline adherence. Ezetimibe, a novel cholesterol absorption inhibitor, lowers LDL by 18% to 20% and can be used safely in combination with statins. Adding ezetimibe to a statin is comparable with the LDL-lowering efficacy of tripling the dose of the statin. Rosuvastatin is a highly efficacious statin providing 8% greater LDL reduction than equivalent doses of atorvastatin, and the starting dose of 10 mg/d provides nearly a 50% reduction in LDL cholesterol. There are several investigational drugs in development for the prevention and treatment of atherosclerosis. Of these investigational drugs, the most promising are the cholesterol ester transfer protein inhibitors, which have the potential to significantly raise high-density lipoprotein cholesterol and acetyl-coenzyme A: cholesterol acyltransferase inhibitors, which may directly inhibit the progression of atherosclerosis.

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References and Recommended Reading

  1. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adult (Adult Treatment Panel III). J Am Med Assoc 2001, 285:2486–2497.

  2. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebocontrolled trial. Lancet 2002, 360:7–22.

    Article  Google Scholar 

  3. Collins R, Armitage J, Parish S, et al.: Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003, 361:2005–2016.

    Article  PubMed  Google Scholar 

  4. Catapano AL: Ezetimibe: a selective inhibitor of cholesterol absorption. Eur Heart J Suppl 2001, 3(Suppl E):E6-E10. An early review of ezetimibe.

    Article  CAS  Google Scholar 

  5. Davis HR, Compton DS, Hoos L, et al.: Ezetimibe (SCH58235) localizes to the brush border of small intestinal enterocyte and inhibits enterocyte cholesterol uptake and absorption [abstract]. Eur Heart J 2000, 21(Suppl):636.

    Google Scholar 

  6. Knopp RH, Bays H, Manion CV, et al.: Effect of ezetimibe on serum concentrations of lipid-soluble vitamins [abstract]. Atherosclerosis 2001, 2(Suppl):90.

    Google Scholar 

  7. van Heek M, Farley C, Compton DS, et al.: Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 2000, 129:1748–1754.

    Article  PubMed  Google Scholar 

  8. Zetia [prescribing information]. North Wales, PA: Merck/Schering-Plough Pharmaceuticals; 2002.

  9. Bays HE, Moore PB, Drehobl MA et al.: Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther 2001, 23:1209–1230. The first phase II trial of ezetimibe.

    Article  PubMed  CAS  Google Scholar 

  10. Punwani N, Pai S, Bach C, et al.: Effect of food on oral bioavailability of SCH58235 in healthy male volunteers [abstract]. AAPS Pharm Sci [serial online] 1998, 1(Suppl):S486.

    Google Scholar 

  11. fnvan Heek M, France CF, Compton DS, et al.: In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461. J Pharmacol Exp Ther 1997, 283:157–163.

    PubMed  Google Scholar 

  12. Rosenblum SB, Huynh T, Alfonso A, et al.: Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH58235): a designed, potent, orally active inhibitor of cholesterol absorption. J Med Chem 1998, 41:973–980.

    Article  PubMed  CAS  Google Scholar 

  13. van Heek M, Farley C, Compton DS, et al.: Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function. Br J Pharmacol 2001, 134:409–417.

    Article  PubMed  Google Scholar 

  14. van Heek M, Compton DS, Davis HR: The cholesterol absorption inhibitor, ezetimibe, decreases diet-induced hypercholesterolemia in monkeys. Eur J Pharmacol 2001, 415:79–84.

    Article  PubMed  Google Scholar 

  15. Sudhop T, Lutjohann D, Kodal A, et al.: Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002, 106:1943–1948.

    Article  PubMed  CAS  Google Scholar 

  16. Zhu Y, Statkevich P, Kosoglou T, et al.: Effect of SCH 58235 on the activity of drug metabolizing enzymes in vivo. Clin Pharmacol Ther 2000, 67:152.

    Google Scholar 

  17. Zhu Y, Statkevich P, Kosoglou T, et al.: Lack of a pharmacokinetic interaction between ezetimibe and atorvastatin. Clin Pharmacol Ther 2001, 69:P68.

    Google Scholar 

  18. Kosoglou T, Meyer I, Veltri EP, Statkevich P, et al.: Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol 2002, 54:309–319.

    Article  PubMed  CAS  Google Scholar 

  19. Reyderman L, Kosoglou T, Statkevich P, et al.: No pharmacokinetic drug interaction between ezetimibe and lovastatin [abstract]. Clin Pharmacol Ther 2001, 69:P66.

    Article  Google Scholar 

  20. Reyderman L, Statkevich P, Kosoglou T, et al.: No pharmacokinetic drug interaction between ezetimibe and either cerivastatin or fluvastatin [abstract]. AAPS Pharm Sci 2001, 3(Suppl 3). http://www.aapspharmceutica.com.

  21. Statkevich P, Reyderman L, Kosoglou T, et al.: Ezetimibe does not affect the pharmacokinetics and pharmacodynamics of glipizide [abstract]. Clin Pharmacol Ther 2001, 69:P67.

    Google Scholar 

  22. Kosoglou T, Statkevich P, Bauer KS et al.: Ezetimibe does not affect the pharmacokinetics and pharmacodynamics of digoxin [abstract]. AAPS Pharm Sci 2001, 3 (Suppl 3). http://www.aapspharmceutica.com.

  23. Keung AC, Kosoglou T, Statkevich P, et al.: Ezetimibe does not affect the pharmacokinetics of oral contraceptives [abstract]. Clin Pharmacol Ther 2001, 69:P55.

    Google Scholar 

  24. Bauer KS, Kosoglou T, Statkevich P, et al.: Ezetimibe does not affect the pharmacokinetics or pharmacodynamics of warfarin [abstract]. Clin Pharmacol Ther 2001, 69:P5.

    Google Scholar 

  25. Kosoglou T, Guillaume M, Sun S, et al.: Pharmacodynamic interaction between fenofibrate and the cholesterol absorption inhibitor ezetimibe. Atherosclerosis 2001, 2(Suppl):38.

    Google Scholar 

  26. Krishna G, Kosoglou T, Ezzet F, et al.: Effect of cimetidine on the pharmacokinetics of ezetimibe [abstract]. AAPS Pharm Sci [serial online] 2001, 3(Suppl 3). http://www.aapspharmceutica. com.

  27. Courtney RD, Kosoglou T, Statkevich P, et al.: Effect of antacid on the pharmacokinetics of ezetimibe. Clin Pharmacol Ther 2002, 71:80.

    Google Scholar 

  28. Dujovne CA, Ettinger MP, McNeer JF, et al.: Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 2002, 90:1092–1097.

    Article  PubMed  CAS  Google Scholar 

  29. Knopp RH, Gitter H, Truitt T, et al.: Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003, 8:729–741.

    Article  CAS  Google Scholar 

  30. Davidson MH, McGarry T, Bettis R, et al.: Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002, 40:2125–2134. This trial demonstrates the additive beneficial effects of ezetimibe to simvastatin on LDL, HDL, and triglycerides.

    Article  PubMed  CAS  Google Scholar 

  31. Ballantyne C, Houri J, Notarbartolo A, et al.: Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003, 19:e9043-e9044. This trial demonstrates the additive effects of ezetimibe to atorvastatin.

    Google Scholar 

  32. Kerzner B, Corbelli J, Sharp S, et al.: Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003, 91:418–424.

    Article  PubMed  CAS  Google Scholar 

  33. Melani L, Mills R, Hassman D, et al.: Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Eur Heart J 2003, 8:685–689.

    Google Scholar 

  34. Gagné C, Bays HE, Weiss Sir, et al.: Efficay and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002, 90:1084–1091. Demonstrates the additive effects of ezetimibe to ongoing statin therapy including reduction in hs-CRP.

    Article  PubMed  Google Scholar 

  35. Tolleshaug H, Hobgood KK, Brown MS, et al.: The LDL receptor locus in familial hypercholesterolemia: multiple mutations disrupt transport and processing of a membrane receptor. Cell 1983, 32:941–951.

    Article  PubMed  CAS  Google Scholar 

  36. Glueck CJ, Spiers J, Tracy T, et al.: Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives. Metabolism 1991, 40:842–848.

    Article  PubMed  CAS  Google Scholar 

  37. Davidson MH: Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia. Expert Opin Investig Drugs 2002, 11:125–141.

    Article  CAS  Google Scholar 

  38. Jones PH, Davidson MH, Stein EA, et al.: Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol 2003, 92:152–160. A large comparative trial that demonstrates the greater efficacy of rosuvastatin on LDL reduction and increases in HDL.

    Article  PubMed  CAS  Google Scholar 

  39. Stein EA: Introduction: rosuvastatin-an efficacy assessment based on pooled trial data. Am J Cardiol 2003, 91:1C-2C.

    Article  PubMed  Google Scholar 

  40. Crestor; rosuvastatin calcium: IPR (trade) 630100, IPR (sample) 630200, API (sample) 23073-00. Package insert. Wilmington: AstraZeneca; 2003.

  41. Davidson MH: Introduction: utilization of surrogate markers of atherosclerosis for the clinical development of pharmaceutical agents. Am J Cardiol 2001, 87:1A-7A.

    Article  PubMed  CAS  Google Scholar 

  42. Tall AR: An overview of reverse cholesterol transport. Eur Heart J 1998, 19(Suppl A):A31-A35.

    PubMed  CAS  Google Scholar 

  43. Whitlock ME, Swenson TL, Ramakrishman R, et al.: Monoclonal antibody inhibition of cholesteryl ester transfer protein activity in the rabbit Effects on lipoprotein composition and high density lipoprotein cholesteryl ester metabolism. J Clin Invest 1989, 84:129–137.

    Article  PubMed  CAS  Google Scholar 

  44. Brown ML, Inazu A, Hesler CB, et al.: Molecular basis of lipid transfer protein deficiency in a family with increased highdensity lipoproteins. Nature 1989, 342:448–451.

    Article  PubMed  CAS  Google Scholar 

  45. Riyama Y, Okamura T, Inazu A, et al.: A low prevalence of coronary heart disease among subjects with increased high density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med 1998, 27:659–687.

    Article  Google Scholar 

  46. Irano K, Yamashita S, Nakajima N, et al.: Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity. Arterioscler Thromb Vasc Biol 1997, 17:1053–1059.

    Google Scholar 

  47. Stein O, Stein Y: Atheroprotective mechanisms of HDL [review. Atherosclerosis 1999, 144:285–301.

    Article  PubMed  CAS  Google Scholar 

  48. Rittershaus CW, Miller DP, Thomas LJ, et al.: Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol 2000, 20:2106–2112.

    PubMed  CAS  Google Scholar 

  49. Davidson MH, Maki K, Umporowicz D, et al.: The safety and immunogenicity of a CETP vaccine in healthy adults. Atherosclerosis 2003, 169:113–120. The first phase I study of the CETP vaccine.

    Article  PubMed  CAS  Google Scholar 

  50. Datamonitor. London; 2003. http://datamonitor.com.

  51. Rudell LL, Lee RG, Cockman TL: Acyl coenzyme A: cholesterol acyltransferase types 1 and 2: structure and function in atherosclerosis. Curr Opin Lipidol 2001, 12:121–127.

    Article  Google Scholar 

  52. Insull W, Koren M, Davignon J, et al.: Efficacy and short-term safety of a new ACAT inhibitor, avasimibe, on lipids, l ipoproteins, and apolipoproteins, in patients with combined hyperlipidemia. Atherosclerosis 2001, 157:137–144.

    Article  PubMed  CAS  Google Scholar 

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Davidson, M.H. Newer pharmaceutical agents to treat lipid disorders. Curr Cardiol Rep 5, 463–469 (2003). https://doi.org/10.1007/s11886-003-0108-y

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  • DOI: https://doi.org/10.1007/s11886-003-0108-y

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