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. 2007 Jul 5;26(Suppl 1):21–28. doi: 10.1002/clc.4960261307

Treating hypercholesterolemia: Looking forward

Antonio M Gotto Jr 1,✉
PMCID: PMC6653980  PMID: 12539819

Abstract

Despite important advances in the management of hypercholesterolemia in recent decades, many patients with lipid disorders remain unidentified or undertreated and so continue to have unfavorable levels of low‐density lipoprotein (LDL) cholesterol and an increased risk for coronary events. The statins—which inhibit 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, the rate‐limiting enzyme in cholesterol biosynthesis—have proved to be the most powerful pharmacologic agents for lowering serum lipids, and newer statins offer even greater efficacy than the agents introduced 10 to 15 years ago. Studies have shown that rosuvastatin, in late‐stage development, is a very potent agent for the treatment of primary hypercholesterolemia, and that relatively low doses decrease LDL cholesterol levels to a greater extent than do similar doses of pravastatin, simvastatin, or atorvastatin as evaluated in separate clinical trials. Pitavastatin, in phase II trials, also has promise as a more potent drug than currently available statins. Because neither of these drugs has been approved for use in the United States, clinical trial results should be considered preliminary. In the future, agents that combine the actions of statins and nicotinic acid may achieve still greater LDL cholesterol reductions. Drugs that lower lipids via mechanisms other than inhibition of HMG‐CoA reductase also offer promise. The newest addition to the roster of lipid‐regulating agents is ezetimibe, a cholesterol absorption inhibitor that has been approved for use either alone or in combination with a statin. Agents in development include bile acid transport inhibitors and inhibitors of acyl CoA: cholesterol acyltransferase. More research will be needed to determine the full clinical potential of such approaches to the management of hypercholesterolemia.

Keywords: hypercholesterolemia, lipoprotein, low‐density lipoprotein cholesterol, coronary disease, hydroxymethylglutaryl‐CoA reductase inhibitors, investigational drugs

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References

  • 1. Summary of the second report of the National Cholesterol Education Program (NECP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) J Am Med Assoc 1993; 269: 3015–3023 [PubMed] [Google Scholar]
  • 2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: 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 Adults (Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2486–2457 [DOI] [PubMed] [Google Scholar]
  • 3. Yarzebski J, Spencer F, Goldberg RJ, Lessard D, Gore JM: Temporal trends (1986–1997) in cholesterol level assessment and management practices in patients with acute myocardial infarction. A population‐based perspective. Arch Intern Med 2001; 161: 1521–1528 [DOI] [PubMed] [Google Scholar]
  • 4. Sueta CA, Chowdhury M, Boccuzzi SJ, Smith SC Jr, Alexander CM, Londhe A, Lulla A, Simpson RJ Jr: Analysis of the degree of undertreatment of hyperlipidemia and congestive heart failure secondary to coronary artery disease. Am J Cardiol 1999; 83: 1303–1307 [DOI] [PubMed] [Google Scholar]
  • 5. Pearson TA, Laurora I, Chu H, Kafonek S: The Lipid Treatment Assessment Project (L‐TAP): A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid‐lowering therapy and achieving low‐density lipoprotein cholesterol goals. Arch Intern Med 2000; 160: 459–467 [DOI] [PubMed] [Google Scholar]
  • 6. Fonarow GC, French WJ, Parsons LS, Sun H, Malmgren JA: Use of lipid‐lowering medications at discharge in patients with acute myocardial infarction: Data from the National Registry of Myocardial Infarction 3. Circulation 2001; 103: 38–44 [DOI] [PubMed] [Google Scholar]
  • 7. Qureshi AI, Suri FK, Guterman LR, Hopkins LN: Ineffective secondary prevention in survivors of cardiovascular events in the US population: Report from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2001; 161: 1621–1628 [DOI] [PubMed] [Google Scholar]
  • 8. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. J Am Med Assoc 1998; 279: 1615–1622 [DOI] [PubMed] [Google Scholar]
  • 9. Scandinavian Simvastatin Survival Study Group : Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–1389 [PubMed] [Google Scholar]
  • 10. Long‐Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group : Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–1357 [DOI] [PubMed] [Google Scholar]
  • 11. Sacks FM, Pfeffer MA, Moyé LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–1009 [DOI] [PubMed] [Google Scholar]
  • 12. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333: 1301–1307 [DOI] [PubMed] [Google Scholar]
  • 13. Heart Protection Study Collaborative Group : MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high‐risk individuals: A randomised placebo‐controlled trial. Lancet 2002; 360: 7–22 12114036 [Google Scholar]
  • 14. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG: Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomized controlled trial. Lancet 2002; 360: 1623–1630 [DOI] [PubMed] [Google Scholar]
  • 15. Collins R, Armitage J: High‐risk elderly patients PROSPER from cholesterol‐lowering therapy (commentary). Lancet 2002; 360: 1618–1619 [DOI] [PubMed] [Google Scholar]
  • 16. Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart JC, Najib‐Fruchart J, Glineur C, Staels B: Statin‐induced inhibition of the Rho‐signaling pathway activates PPARalpha and induces HDL apoA‐I. J Clin Invest 2001; 107: 1423–1432 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Simes J, Furberg CD, Braunwald E, Davis BR, Ford I, Tonkin A, Shepherd J: Effects of pravastatin on mortality in patients with and without coronary heart disease across a broad range of cholesterol levels. The Prospective Pravastatin Pooling Project. Eur Heart J 2002; 23: 207–215 [DOI] [PubMed] [Google Scholar]
  • 18. Pfeffer MA, Keech A, Sacks FM, Cobbe SM, Tonkin A, Byington RP, Davis BR, Friedman CP, Braunwald E: Safety and tolerability of pravastatin in long‐term clinical trials: Prospective Pravastatin Pooling (PPP) Project. Circulation 2002; 105: 2341–2346 [DOI] [PubMed] [Google Scholar]
  • 19. Black DM, Bakker‐Arkema R, Nawrocki JW: An overview of the clinical safety profile of atorvastatin (Lipitor), a new HMG‐CoA reductase inhibitor. Arch Intern Med 1998; 158: 577–584 [DOI] [PubMed] [Google Scholar]
  • 20. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JD: Statin‐associated myopathy with normal creatine kinase levels. Ann Intern Med 2002; 137: 581–585 [DOI] [PubMed] [Google Scholar]
  • 21. Extending benefits of pravastatin to the elderly : Results of the PROSPER study. Available at: http://www.forhealthyaging.com/results. Accessed December 5, 2002.
  • 22. Yano K, Reed D, MacLean CJ: Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989; 20: 1460–1465 [DOI] [PubMed] [Google Scholar]
  • 23. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD: Serum cholesterol levels and six‐year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med 1989; 320: 904–910 [DOI] [PubMed] [Google Scholar]
  • 24. Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J: Reduction of stroke events with pravastatin. The Prospective Pravastatin Pooling (PPP) Project. Circulation 2001; 103: 387–392 [DOI] [PubMed] [Google Scholar]
  • 25. Paoletti R, Fahmy M, Mahla G, Mizan J, Southworth H: Rosuvastatin demonstrates greater reduction of low‐density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: A randomized, double‐blind study. J Cardiovasc Risk 2001; 8: 383–390 [DOI] [PubMed] [Google Scholar]
  • 26. Davidson M, Ma P, Stein EA, Gotto AM Jr, Raza A, Chitra R, Hutchinson H: Comparison of effects on low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 2002; 89: 268–275 [DOI] [PubMed] [Google Scholar]
  • 27. Brown WV, Chitra RR, Zedler BK, Bays HE, Hassman HA: Long‐term efficacy and safety of rosuvastatin: Results of a 52‐week comparator‐controlled trial versus pravastatin and simvastatin (abstr P1526). Eur Heart J 2001; 22 (suppl): 270 [Google Scholar]
  • 28. Olsson A, Southworth H, Wilpshaar JW: Long‐term efficacy and safety of rosuvastatin: Results of a 52‐week comparator‐controlled trial versus atorvastatin (abstr 1410). Eur Heart J 2001; 22 (suppl): 253 [Google Scholar]
  • 29. Olsson AG, Pears J, McKellar J, Mizan J, Raza A: Effect of rosuvastatin on low‐density lipoprotein cholesterol in patients with hypercholesterolemia. Am J Cardiol 2001; 88: 504–508 [DOI] [PubMed] [Google Scholar]
  • 30. Lipitor® (atorvastatin calcium) tablets . Prescribing information. Parke‐Davis, division of Pfizer Inc. Revised April 2002.
  • 31. Pravachol® (pravastatin sodium) tablets . Prescribing information. Bristol‐Myers Squibb Company; Revised May 2002. [Google Scholar]
  • 32. Zocor® (simvastatin) tablets . Prescribing information. Merck & Co., Inc. Issued May 2002. [Google Scholar]
  • 33. Kajinami K, Koizumi J, Ueda K, Miyamoto S, Takegoshi T, Mabuchi H: Effects of NK‐104, a new hydroxymethylglutaryl‐coenzyme reductase inhibitor, on low‐density lipoprotein cholesterol in heterozygous familial hypercholesterolemia. Hokuriku NK‐104 Study Group. Am J Cardiol 2000; 85: 178–183 [DOI] [PubMed] [Google Scholar]
  • 34. Noji Y, Higashikata T, Inazu A, Nohara A, Ueda K, Miyamoto S, Kajinami K, Takegoshi T, Koizumi J, Mabuchi H: Long‐term treatment with pitavastatin (NK‐104), a new HMG‐CoA reductase inhibitor, of patients with heterozygous familial hypercholesterolemia. Atherosclerosis 2002; 163: 157–164 [DOI] [PubMed] [Google Scholar]
  • 35. Saito Y, Yamada N, Teramoto T, Itakura H, Hata Y, Nakaya N, Mabuchi H, Tushima M, Sasaki J, Goto Y, Ogawa N: Clinical efficacy of pitavastatin, a new 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, in patients with hyperlipidemia. Arzneim‐Forsch/Drug Res 2002; 52: 251–255 [DOI] [PubMed] [Google Scholar]
  • 36. Saito Y, Yamada N, Teramoto T, Itakura H, Hata Y, Nakaya N, Mabuchi H, Tushima M, Sasaki J, Ogawa N, Goto Y: A randomized, double‐blind trial comparing the efficacy and safety of pitavastatin versus pravastatin in patients with primary hypercholesterolemia. Atherosclerosis 2002; 162: 373–379 [DOI] [PubMed] [Google Scholar]
  • 37. Istvan ES, Deisenhofer J: Structural mechanism for statin inhibition of HMG‐CoA reductase. Science 2001; 292: 1160–1164 [DOI] [PubMed] [Google Scholar]
  • 38. Zetia™ (ezetimibe) tablets . Prescribing information. Copyright© Merck/Schering‐Plough Pharmaceuticals, 2001, 2002
  • 39. Bays HE, Moore PB, Drehobl MA, Rosenblatt S, Toth PD, Dujovne CA, Knopp RH, Lipka LJ, Lebeaut AP, Yang B, Mellars LE, Cuffie‐Jackson C, Veltri EP: Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: Pooled analysis of two phase II studies. Clin Ther 2001; 23: 1209–1230 [DOI] [PubMed] [Google Scholar]
  • 40. Gagné C, Gaudet D, Bruckert E, for the Ezetimibe Study Group : Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002; 105: 2469–2475 [DOI] [PubMed] [Google Scholar]
  • 41. Ballantyne C, Houri J, Notarbartolo A, Melani L, Lipka L, LeBeaut A, Suresh R, Sun S, Veltri E, for the Ezetimibe Study Group : Ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia (abstr 1084–91). American College of Cardiology 51st Annual Scientific Session. J Am Coll Cardiol 2002; 39 (5 suppl A ): 227A [Google Scholar]
  • 42. Davidson M, McGarry T, Bettis R, Melani L, Lipka L, LeBeaut A, Suresh R, Sun S, Veltri E, for the Ezetimibe Study Group : Ezetimibe coadministered with simvastatin in 668 patients with primary hypercholesterolemia (abstr 1084–90). American College of Cardiology 51st Annual Scientific Session. J Am Coll Cardiol 2002b; 39 (5 suppl A ): 226A–227A (in press) [DOI] [PubMed] [Google Scholar]
  • 43. Kosoglou T, Fruchart J‐C, Guillaume M, Pember LJC, Sun S, Picard G, Affrime MB, Veltri EP: Coadministration of ezetimibe and fenofibrate leads to favorable effects on apo CIII and LDL sub‐fractions (poster 172). 72nd European Atherosclerosis Society Congress. Atherosclerosis 2001; (suppl) 2: 89 [Google Scholar]
  • 44. Brown WV: Novel approaches to lipid lowering: What is on the horizon? Am J Cardiol 2001; 87 (suppl): 23B–27B [DOI] [PubMed] [Google Scholar]
  • 45. Booker ML: S‐8921 (Shionogi). Curr Opin Investig Drugs 2001; 2: 393–395 [PubMed] [Google Scholar]
  • 46. Higaki J, Hara S, Takasu N, Tonda K, Miyata K, Shike T, Nagata K, Misui T: Inhibition of ileal Na+/bile acid cotransporter by S‐8291 reduces serum cholesterol and prevents atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 1998; 18: 1304–1311 [DOI] [PubMed] [Google Scholar]
  • 47. Bocan TM, Krause BR, Rosebury WS, Mueller SB, Lu X, Dagle C, Major T, Lathia C, Lee H: The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol 2000; 20: 70–79 [DOI] [PubMed] [Google Scholar]
  • 48. Insull W Jr, Koren M, Davignon J, Sprecher D, Schrott H, Keilson LM, Brown AS, Dujovne CA, Davidson MH, McLain R, Heinonen T: Efficacy and short‐term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins, and apolipoproteins, in patients with combined hyperlipidemia. Atherosclerosis 2001; 157: 137–144 [DOI] [PubMed] [Google Scholar]
  • 49. Tardif J‐C, Grégoire J, Lespérance J, Lambert J, L'Allier PL, Rodés J, Anderson T, Blue JW, Imus J, Heinonen T: Design features of the Avasimibe and Progression of coronary Lesions assessed by intravascular UltraSound (A‐PLUS) clinical trial. Am Heart J 2002; 144: 589–596 [DOI] [PubMed] [Google Scholar]
  • 50. Asami Y, Yamagishi I, Akiyoshi K, Tomoike H, Tsuchida K, Higuchi S: Inhibitory effect of TS‐962 on the formation of early atherosclerotic lesions in high fat‐fed hyperlipidemic hamsters. Atherosclerosis 1999; 146: 237–242 [DOI] [PubMed] [Google Scholar]
  • 51. Junquero D, Bruniquel F, N'Guyen X, Autin JM, Patoiseau JF, Degryse AD, Colpaert FC, Delhon A: F 12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in New Zealand rabbits fed a casein‐enriched diet. Atherosclerosis 2001; 155: 131–142 [DOI] [PubMed] [Google Scholar]

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