Recent Cholesterol-Lowering Drug Trials: New Data, New Questions

  • Michel de LorgerilEmail author
Part of the Nutrition and Health book series (NH)

Key Points

• The cholesterol-lowering drug trials recently published were either negative (ENHANCE, SEAS, GISSI-HF) or obviously biased and therefore not credible (JUPITER).

• New data strongly suggest that the results of previous, highly positive trials with statins in the secondary prevention of coronary heart disease published between 1994 and 2004 and that were used to issue guidelines for medical practitioners should be reviewed carefully and considered somewhat suspect.


Cholesterol-lowering drugs Heart disease Cholesterol Drug trials 


  1. 1.
    Kastelein JJ, Akdim F, Stroes ES, for ENHANCE investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358: 1431–1443.PubMedCrossRefGoogle Scholar
  2. 2.
    Mitka M. Controversies surround heart drug study. Questions about Vytorin and trial sponsors’ conduct. JAMA 2008; 299: 885–887.PubMedCrossRefGoogle Scholar
  3. 3.
    Greenland P, Lloyd-Jones D. Critical lessons from the ENHANCE trial. JAMA 2008; 299: 953–955.PubMedCrossRefGoogle Scholar
  4. 4.
    O’Riordan M. Congress continues to probe Merck and Shering-Plough: angry emails highlight ENHANCE controversy. http:
  5. 5.
    Stevermer J. ENHANCE study: ezetimibe lowers LDL, but does it matter? J Fam Pract 2008; 57: 436–437.Google Scholar
  6. 6.
    Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction. The Rotterdam Study. Circulation 1997; 96: 1432–1437.PubMedCrossRefGoogle Scholar
  7. 7.
    O’Leary DH, Polak JF, Kronmal RA et al. Carotid intima-media thickness as a risk factor of myocardial infarction and stroke in older adults. N Engl J Med 1999; 340: 14–22.PubMedCrossRefGoogle Scholar
  8. 8.
    Smilde TJ, van Wissen S, Wollersheim H et al. Effect of aggressive versus conventional lipid-lowering on Atherosclerosis Progression in Familial Hypercholesterolemia (ASAP): a prospective, randomized, double-blind trial. Lancet 2001; 357: 577–581.PubMedCrossRefGoogle Scholar
  9. 9.
    Taylor AJ, Kent SM, Flaherty PJ et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima media thickness. Circulation 2002; 106: 2055–2060.PubMedCrossRefGoogle Scholar
  10. 10.
    Toutouzas P, Richter D. Carotid intima-media thickness (cIMT): a useful clinic tool or research luxury? Another view of the ENHANCE trial. Angiology 2008; 59: 77S–79S.PubMedCrossRefGoogle Scholar
  11. 11.
    Stein EA. Additional lipid lowering trials using surrogate measurements of atherosclerosis by carotid intima-media thickness: more clarity or confusion? J Am Coll Cardiol 2008; 52: 2206–2209.PubMedCrossRefGoogle Scholar
  12. 12.
    Sudhop T, von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolemia. Drugs 2002; 62: 2333–2347.PubMedCrossRefGoogle Scholar
  13. 13.
    O’Riordan M. JUPITER halted: rosuvastatin significantly reduces cardiovascular morbidity and mortality. From Heartwire, a professional news service available at:
  14. 14.
    AstraZeneca. Crestor outcomes study JUPITER closes early due to unequivocal evidence of benefit.
  15. 15.
    Knopp RH. d‘Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006; 29: 1478–1485.PubMedCrossRefGoogle Scholar
  16. 16.
    Wanner C, Krane V, März W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238–248.PubMedCrossRefGoogle Scholar
  17. 17.
    Asselbergs FW, Diercks GFH, Hillege HL et al., for the Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) investigators. Effect of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110: 2809–2816.PubMedCrossRefGoogle Scholar
  18. 18.
    Pedersen TR, Faergeman O, Kastelein JJ et al. High-dose atorvastatin vs. usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study, a randomized controlled trial. JAMA 2005; 294: 2437–2445.PubMedCrossRefGoogle Scholar
  19. 19.
    Barter PJ, Caulfield M, Eriksson M et al., for the ILLUMINATE investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109–2122.PubMedCrossRefGoogle Scholar
  20. 20.
    O’Riordan M. CASHMERE: no IMT effect with atorvastatin over 12 months. http:
  21. 21.
    O’Riordan M. ACHIEVE stopped: IMT study with Niacin/Laropiprant halted by Merck & Co. http:
  22. 22.
    Topol EJ. Failing the public health. Rofecoxib, Merck and the FDA. N Engl J Med 2004; 315: 1707–1709.CrossRefGoogle Scholar
  23. 23.
    Bollapragada S, Norrie J, Norman J. Review of new regulations for the conduct of clinical trials of investigational medicinal products. BJOG 2007; 114: 917–921.PubMedCrossRefGoogle Scholar
  24. 24.
    Chalmers I. Proposal to outlaw the term “negative trial”. BMJ 1985; 290: 1002.CrossRefGoogle Scholar
  25. 25.
    Rossebø AB, Pedersen TR, Boman K et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359: 1343–1356.PubMedCrossRefGoogle Scholar
  26. 26.
    Tavazzi L, Maggioni AP, Marchioli R et al., GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet 2008; 372: 1231–1239.PubMedCrossRefGoogle Scholar
  27. 27.
    Palta S, Pai AM, Gill SK, Pai RG. New insights into the progression of aortic stenosis: implication for secondary prevention. Circulation 2000; 101: 2497–2502.PubMedCrossRefGoogle Scholar
  28. 28.
    Nassimiha D, Arronow WS, Ahn C, Goldman ME. Association of coronary risk factors with progression of valvular aortic stenosis in older persons. Am J Cardiol 2001; 87: 1313–1314.PubMedCrossRefGoogle Scholar
  29. 29.
    Mautner GC, Roberts WC. Reported frequency of coronary arterial narrowing by angiogram in patients with valvular aortic stenosis. Am J Cardiol 1992; 70: 539–540.PubMedCrossRefGoogle Scholar
  30. 30.
    Peltier M, Trojette F, Sarano ME et al. Relation between cardiovascular risk factors and non rheumatic severe calcific aortic stenosis among patients with a three-cuspid aortic valve. Am J Cardiol 2003; 91: 97–99.PubMedCrossRefGoogle Scholar
  31. 31.
    Davidson MH. Clinical significance of statin pleiotropic effects: hypotheses versus evidence. Circulation 2005; 111: 2280–2281.PubMedCrossRefGoogle Scholar
  32. 32.
    Nissen JE. Courage under fire: what is the optimal approach to initial treatment of stable angina? Curr Cardiol Rep 2008; 10: 79–80.PubMedCrossRefGoogle Scholar
  33. 33.
    Nissen SE, Tuzcu EM, Schoenhagen P et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291: 1071–1080.PubMedCrossRefGoogle Scholar
  34. 34.
    Cannon CB, Braunwald E, McCabe CH et al. Intensive versus moderate lipid-lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495–1504.PubMedCrossRefGoogle Scholar
  35. 35.
    Peto R, Emberson J, Landray M et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008; 359: 1357–1366.PubMedCrossRefGoogle Scholar
  36. 36.
    Collins R, Peto R. Analyses of cancer data from three ezetimibe trials: the authors reply. N Engl J Med 2009; 360: 86–87.CrossRefGoogle Scholar
  37. 37.
    Kjekshus J, Apetrei E, Barrios V et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: 2248–2261.PubMedCrossRefGoogle Scholar
  38. 38.
    Khush KK, Waters D. Lessons from the PROVE-IT trial. Higher dose of potent statin better for high-risk patients. Cleve Clin J Med 2004; 71: 609–616.PubMedCrossRefGoogle Scholar
  39. 39.
    Scirica BM, Morrow DA, Cannon CP et al. Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J Am Coll Cardiol 2006; 47: 2326–2331.PubMedCrossRefGoogle Scholar
  40. 40.
    Schwartz GG, Olsson AG, Ezekowitz MD et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285: 1711–1718.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    Ridker PM, Danielson E, Fonseca FA et al., for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-Reactive protein. N Engl J Med 2008; 359: 2195–2207.PubMedCrossRefGoogle Scholar
  43. 43.
    Mueller PS, Montori VM, Bassler D, Koenig BA, Guyatt GH. Ethical issues in stopping randomized trials early because of apparent benefit. Ann Intern Med 2007; 146: 878–881.PubMedGoogle Scholar
  44. 44.
    Montori VM, Devereaux PJ, Adhikari NK et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005; 294: 2203–2209.PubMedCrossRefGoogle Scholar
  45. 45.
    Tunstall-Pedoe H, Kuulasmaa K, Mähönen M, Tolonen H, Ruokokoski E, Amouyel P. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 1999; 353: 1547–1557.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Laboratoire TIMC-IMAG, UMR 5525, Cœur and Nutrition, Faculté de MédecineUniversité Joseph Fourier – Grenoble 1, CNRSGrenobleFrance
  2. 2.Domaine de la MerciLa TroncheFrance

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