Skip to main content
SpringerLink
Log in

A Reappraisal of the Risks and Benefits of Treating to Target with Cholesterol Lowering Drugs

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Atherosclerotic cardiovascular disease (CVD) is the number one cause of death globally, and lipid modification, particularly lowering of low density lipoprotein cholesterol (LDLc), is one of the cornerstones of prevention and treatment. However, even after lowering of LDLc to conventional goals, a sizeable number of patients continue to suffer cardiovascular events. More aggressive lowering of LDLc and optimization of other lipid parameters like triglycerides (TG) and high density lipoprotein cholesterol (HDLc) have been proposed as two potential strategies to address this residual risk. These strategies entail use of maximal doses of highly potent HMG CoA reductase inhibitors (statins) and combination therapy with other lipid modifying agents. Though statins in general are fairly well tolerated, adverse events like myopathy are dose related. There are further risks with combination therapy. In this article, we review the adverse effects of lipid modifying agents used alone and in combination and weigh these effects against the evidence demonstrating their efficacy in reducing cardiovascular events, cardiovascular mortality, and all cause mortality. For patients with established CVD, statins are the only group of drugs that have shown consistent reductions in hard outcomes. Though more aggressive lipid lowering with high dose potent statins can reduce rates of non fatal events and need for interventions, the incremental mortality benefits remain unclear, and their use is associated with a higher rate of drug related adverse effects. Myopathy and renal events have been a significant concern with the use of high potency statin drugs, in particular simvastatin and rosuvastatin. For patients who have not reached target LDL levels or have residual lipid abnormalities on maximal doses of statins, the addition of other agents has not been shown to improve clinical outcomes and carries an increased risk of adverse events. The clinical benefits of drugs to raise HDLc remain unproven. In patients without known cardiovascular disease, there is conflicting evidence as to the benefits of aggressive pursuit of numerical lipid targets, particularly with respect to all cause mortality. Certainly, in statin intolerant patients, alternative agents with a low side effect profile are desirable. Bile acid sequestrants are an effective and safe choice for decreasing LDLc, and omega-3 fatty acids are safe agents to decrease TG. There remains an obvious need to design and carry out large scale studies to help determine which agents, when combined with statins, have the greatest benefit on cardiovascular disease with the least added risk. These studies should be designed to assess the impact on clinical outcomes rather than surrogate endpoints, and require a comprehensive assessment and reporting of safety outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. WHO | cardiovascular diseases (CVDs). http://www.who.int/mediacentre/factsheets/fs317/en/index.html. Accessed 5 August 2012.

  2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2–220.

    PubMed  Google Scholar 

  3. Kannel WB, Dawber TR, Kagan A, et al. Factors of risk in the development of coronary heart disease—six year follow-up experience: the Framingham Study. Ann Intern Med. 1961;55:33–50.

    PubMed  CAS  Google Scholar 

  4. Lipid Research Clinics Program. The lipid research clinics coronary primary prevention trial result. J Am Med Assoc. 1984; 251(3):351–64.

    Google Scholar 

  5. The Expert Panel. Report of the National Cholesterol Education Program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med. 1988;148(1):36–69.

    Google Scholar 

  6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II) (1993). J Am Med Assoc. 1993; 269(23), 3015–23.

    Google Scholar 

  7. 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(19):2486–97.

    Google Scholar 

  8. Grundy SM, Cleeman JI, Merz CN, National Heart, Lung, and Blood Institute; American College of Cardiology Foundation, American Heart Association, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227–39.

    PubMed  Google Scholar 

  9. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2007;28(19):2375–414.

    PubMed  Google Scholar 

  10. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–504.

    PubMed  CAS  Google Scholar 

  11. Waters DD, Guyton JR, Herrington DM, et al. Treating to new targets (TNT) study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004;93(2):154–8.

    PubMed  Google Scholar 

  12. Pedersen TR, Faergeman O, Kastelein JJ, et al. Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. J Am Med Assoc. 2005;294(19):2437–45.

    CAS  Google Scholar 

  13. LaRosa J, Grundy SM, Waters DD, for the Treating to New Targets (TNT) Investigators, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425–35.

    PubMed  CAS  Google Scholar 

  14. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81.

    PubMed  CAS  Google Scholar 

  15. Alla VM, Kaushik M, Mooss A. Targeting residual risk: the rationale for the use of non-HDL cholesterol. South Med J. 2010;103(5):434–7.

    PubMed  Google Scholar 

  16. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: Population based cohort study using the QResearch database. BMJ. 2010;340:c2197.

    PubMed  Google Scholar 

  17. Foody J. Statin use associated with increased risk of cataract, myopathy, liver dysfunction and acute renal failure with varying numbers needed to harm. Evid Based Med. 2010;15(6):187–8.

    PubMed  Google Scholar 

  18. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42.

    PubMed  CAS  Google Scholar 

  19. Ray KK, Seshasai SR, Erqou S, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010;170(12):1024–31.

    PubMed  CAS  Google Scholar 

  20. McClure DL, Valuck RJ, Glanz M, et al. Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiol Drug Saf. 2007;16(2):132–43.

    PubMed  CAS  Google Scholar 

  21. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Stroke. 2002;33(9):2337–41.

    PubMed  Google Scholar 

  22. McKenney JM, Davidson MH, Jacobson TA, National Lipid Association Statin Safety Assessment Task Force, et al. Final conclusions and recommendations of the national lipid association statin safety assessment task force. Am J Cardiol. 2006;97(8A):89C–94C.

    PubMed  CAS  Google Scholar 

  23. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–78.

    PubMed  CAS  Google Scholar 

  24. Taylor F, Ward K, Moore Theresa HM, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011;(1):CD004816.

  25. Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med. 1998;128(4):262–9.

    PubMed  CAS  Google Scholar 

  26. Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001;357(9256):577–81.

    PubMed  CAS  Google Scholar 

  27. 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 medial thickness. Circulation. 2002;106(16):2055–60.

    PubMed  CAS  Google Scholar 

  28. Nohara R, Daida H, Hata M, Justification for Atherosclerosis Regression Treatment (JART) Investigators, et al. Effect of intensive lipid-lowering therapy with rosuvastatin on progression of carotid intima-media thickness in Japanese patients: Justification for Atherosclerosis Regression Treatment (JART) study. Circ J. 2012;76(1):221–9.

    PubMed  CAS  Google Scholar 

  29. Nissen SE, Tuzcu EM, Schoenhagen P, REVERSAL Investigators, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. J Am Med Assoc. 2004;291(9):1071–80.

    CAS  Google Scholar 

  30. Nissen SE, Nicholls SJ, Sipahi I, ASTEROID Investigators, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. J Am Med Assoc. 2006;295(13):1556–65.

    CAS  Google Scholar 

  31. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365(22):2078–87.

    PubMed  CAS  Google Scholar 

  32. Houslay ES, Cowell SJ, Prescott RJ, the Scottish Aortic Stenosis and Lipid Lowering Therapy, Impact on Regression (SALTIRE) trial Investigators, Impact on Regression (SALTIRE) trial, et al. Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial. Heart. 2006;92(9):1207–12.

    PubMed  CAS  Google Scholar 

  33. Schmermund A, Achenbach S, Budde T, et al. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial. Circulation. 2006;113:427–37.

    PubMed  CAS  Google Scholar 

  34. Raggi P, Davidson M, Callister TQ, et al. Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic postmenopausal women beyond endorsed lipid lowering with EBT scanning (BELLES). Circulation. 2005;112:563–71.

    PubMed  CAS  Google Scholar 

  35. Hong MK, Park DW, Lee CW, et al. Effects of statin treatments on coronary plaques assessed by volumetric virtual histology intravascular ultrasound analysis. JACC Cardiovasc Interv. 2009;2(7):679–88.

    PubMed  Google Scholar 

  36. Hiro T, Kimura T, Morimoto T, JAPAN-ACS Investigators, et al. Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study). J Am Coll Cardiol. 2009;54(4):293–302.

    PubMed  Google Scholar 

  37. Fleg JL, Mete M, Howard BV, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol. 2008;52(25):2198–205.

    PubMed  CAS  Google Scholar 

  38. Kastelein JJ, Akdim F, Stroes ES, for the ENHANCE Investigators, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431–43.

    PubMed  CAS  Google Scholar 

  39. Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol. 2010;55(24):2721–6.

    PubMed  Google Scholar 

  40. Zhu S, Su G, Meng QH. Inhibitory effects of micronized fenofibrate on carotid atherosclerosis in patients with essential hypertension. Clin Chem. 2006;52:2036–42.

    PubMed  CAS  Google Scholar 

  41. Hiukka A, Westerbacka J, Leinonen ES, et al. Long-term effects of fenofibrate on carotid intima-media thickness and augmentation index in subjects with type 2 diabetes mellitus. J Am Coll Cardiol. 2008;52(25):2190–7.

    PubMed  CAS  Google Scholar 

  42. Ericsson CG, Nilsson J, Grip L, et al. Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing (The Bezafibrate Coronary Atherosclerosis Intervention Trial [BECAIT]). Am J Cardiol. 1997;80(9):1125–9.

    PubMed  CAS  Google Scholar 

  43. Davidson M, Rosenson RS, Maki KC, et al. Study design, rationale, and baseline characteristics: evaluation of fenofibric acid on carotid intima-media thickness in patients with type IIb dyslipidemia with residual risk in addition to atorvastatin therapy (FIRST) trial. Cardiovasc Drugs Ther. 2012;26(4):349–58.

    PubMed  CAS  Google Scholar 

  44. Hjerkinn EM, Abdelnoor M, Breivik L, et al. Effect of diet or very long chain omega-3 fatty acids on progression of atherosclerosis, evaluated by carotid plaques, intima-media thickness and by pulse wave propagation in elderly men with hypercholesterolaemia. Eur J Cardiovasc Prev Rehabil. 2006;13(3):325–33.

    PubMed  Google Scholar 

  45. Sacks FM, Stone PH, Gibson CM, et al. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. J Am Coll Cardiol. 1995;25(7):1492–8.

    PubMed  CAS  Google Scholar 

  46. Balk EM, Lichtenstein AH, Chung M, et al. Effects of omega-3 fatty acids on coronary restenosis, intima-media thickness, and exercise tolerance: a systematic review. Atherosclerosis. 2006;184(2):237–46.

    PubMed  CAS  Google Scholar 

  47. Von Schacky C, Angerer P, Kothny W, et al. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;130(7):554–62.

    Google Scholar 

  48. Nissen SE, Tardif JC, Nicholls SJ, ILLUSTRATE Investigators, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13):1304–16.

    PubMed  CAS  Google Scholar 

  49. Kastelein JJ, van Leuven SI, Burgess L, RADIANCE 1 Investigators, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007;356(16):1620–30.

    PubMed  CAS  Google Scholar 

  50. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2): a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110(23):3512–7.

    PubMed  CAS  Google Scholar 

  51. Lee JM, Robson MD, Yu LM, et al. Effects of high dose modified release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo controlled, magnetic resonance imaging study. J Am Coll Cardiol. 2009;54(19):1787–94.

    PubMed  CAS  Google Scholar 

  52. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361(22):2113–22.

    PubMed  CAS  Google Scholar 

  53. Lee K, Ahn TH, Kang WC, et al. The effects of statin and niacin on plaque stability, plaque regression, inflammation and oxidative stress in patients with mild to moderate coronary artery stenosis. Korean Circ J. 2011;41(11):641–8.

    PubMed  CAS  Google Scholar 

  54. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361(9364):1149–58.

    PubMed  CAS  Google Scholar 

  55. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. J Am Med Assoc. 2002;288(23):2998–3007.

    Google Scholar 

  56. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301–7.

    PubMed  CAS  Google Scholar 

  57. Downs JR, Clearfield M, Weis S, et al. 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(20):1615–22.

    CAS  Google Scholar 

  58. 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(8934):1383–89.

    Google Scholar 

  59. The Long-Term Intervention with Pravastatin in Ischemic 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. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study group. N Engl J Med. 1998;339(19):1349–57.

    Google Scholar 

  60. 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(9326):7–22.

    Google Scholar 

  61. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.

    PubMed  CAS  Google Scholar 

  62. Smith SC Jr, Allen J, Blair SN, the AHA/ACC; National Heart, Lung, and Blood Institute, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363–72.

    PubMed  Google Scholar 

  63. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375(9729):1875–84.

    PubMed  CAS  Google Scholar 

  64. Probstfield JL, Rifkind BM. The lipid research clinics coronary primary prevention trial: design, results, and implications. Eur J Clin Pharmacol. 1991;40(Suppl 1):S69–75.

    PubMed  Google Scholar 

  65. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. J Am Med Assoc. 1975;231(4):360–81.

    Google Scholar 

  66. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8(6):1245–55.

    PubMed  CAS  Google Scholar 

  67. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67.

    PubMed  Google Scholar 

  68. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–92.

    PubMed  CAS  Google Scholar 

  69. Marchioli R, Barzi F, Bomba E, GISSI-Prevenzione Investigators, et al. Early protection against sudden death by ω-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105(16):1897–903.

    PubMed  CAS  Google Scholar 

  70. Filion KB, El Khoury F, Bielinski M, et al. Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2010;10:24.

    PubMed  Google Scholar 

  71. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109–22.

    PubMed  CAS  Google Scholar 

  72. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150(12):858–68.

    PubMed  Google Scholar 

  73. Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf. 2011;10(3):373–87.

    PubMed  CAS  Google Scholar 

  74. Holbrook A, Wright M, Sung M, Ribic C, Baker S. Statin-associated rhabdomyolysis: is there a dose-response relationship? Can J Cardiol. 2011;27(2):146–51.

    PubMed  CAS  Google Scholar 

  75. Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr Opin Lipidol. 2007;18(4):401–8.

    PubMed  CAS  Google Scholar 

  76. Garcia Rodriguez LA, Herings R, Johansson S. Use of multiple international healthcare databases for the detection of rare drug-associated outcomes: a pharmacoepidemiological programme comparing rosuvastatin with other marketed statins. Pharmacoepidemiol Drug Saf. 2010;19(12):1218–24.

    PubMed  Google Scholar 

  77. Meador BM, Huey KA. Statin-associated myopathy and its exacerbation with exercise. Muscle Nerve. 2010;42(4):469–79.

    PubMed  CAS  Google Scholar 

  78. Bouitbir J, Charles AL, Rasseneur L, et al. Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress. J Appl Physiol. 2011;111(5):1477–83.

    PubMed  CAS  Google Scholar 

  79. Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Arch Intern Med. 2012;172(15):1180–2.

    PubMed  Google Scholar 

  80. Mohaupt MG, Karas RH, Babiychuk EB, et al. Association between statin-associated myopathy and skeletal muscle damage. CMAJ. 2009;181(1–2):E11–8.

    PubMed  Google Scholar 

  81. Jacobson TA. Toward “pain-free” statin prescribing: clinical algorithm for diagnosis and management of myalgia. Mayo Clin Proc. 2008;83(6):687–700.

    PubMed  Google Scholar 

  82. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. J Am Med Assoc. 2003;289(13):1681–90.

    CAS  Google Scholar 

  83. MRC/BHF Heart Protection Study Collaborative Group, Armitage J, Bowman L, Collins R, et al. Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomized placebo-controlled trial in 20,536 high-risk people. BMC Clin Pharmacol. 2009;9:6.

    PubMed  Google Scholar 

  84. Hedenmalm K, Alvan G, Ohagen P, Dahl ML. Muscle toxicity with statins. Pharmacoepidemiol Drug Saf. 2010;19(3):223–31.

    PubMed  CAS  Google Scholar 

  85. Backes JM, Howard PA, Ruisinger JF, Moriarty PM. Does simvastatin cause more myotoxicity compared with other statins? Ann Pharmacother. 2009;43(12):2012–20.

    PubMed  CAS  Google Scholar 

  86. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376(9753):1658–69.

    PubMed  Google Scholar 

  87. FDA drug safety communication: Important safety label changes to cholesterol-lowering statin drugs. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258338.htm. Accessed 22 March 2012.

  88. SEARCH Collaborative Group, Link E, Parish S, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359(8):789–99.

    PubMed  CAS  Google Scholar 

  89. Voora D, Shah SH, Spasojevic I, et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol. 2009;54(17):1609–16.

    PubMed  CAS  Google Scholar 

  90. Ghatak A, Faheem O, Thompson PD. The genetics of statin-induced myopathy. Atherosclerosis. 2010;210(2):337–43.

    PubMed  CAS  Google Scholar 

  91. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8A):52C–60C.

    PubMed  CAS  Google Scholar 

  92. Corsini A, Ceska R. Drug–drug interactions with statins: will pitavastatin overcome the statins’ achilles’ heel? Curr Med Res Opin. 2011;27(8):1551–62.

    PubMed  CAS  Google Scholar 

  93. Zipes DP, Zvaifler NJ, Glassock RJ, et al. Rosuvastatin: an independent analysis of risks and benefits. MedGenMed. 2006;8(2):73.

    PubMed  Google Scholar 

  94. Davidson MH. Rosuvastatin safety: lessons from the FDA review and post-approval surveillance. Expert Opin Drug Saf. 2004;3(6):547–57.

    PubMed  CAS  Google Scholar 

  95. Marie I, Delafenetre H, Massy N, Network of the French Pharmacovigilance Centers, et al. Tendinous disorders attributed to statins: a study on ninety-six spontaneous reports in the period 1990–2005 and review of the literature. Arthritis Rheum. 2008;59(3):367–72.

    PubMed  CAS  Google Scholar 

  96. Pullatt RC, Gadarla MR, Karas RH, Alsheikh-Ali AA, Thompson PD. Tendon rupture associated with simvastatin/ezetimibe therapy. Am J Cardiol. 2007;100(1):152–3.

    PubMed  CAS  Google Scholar 

  97. Movahed MR, Samsamsharaiat SA. Reproducible tendinitis-like symptoms related to statin therapy. J Clin Rheumatol. 2006;12(6):320–1.

    PubMed  Google Scholar 

  98. Okamoto H, Koizumi K, Kamitsuji S, et al. Beneficial action of statins in patients with rheumatoid arthritis in a large observational cohort. J Rheumatol. 2007;34(5):964–8.

    PubMed  CAS  Google Scholar 

  99. de Denus S, Spinler SA, Miller K, Peterson AM. Statins and liver toxicity: a meta-analysis. Pharmacotherapy. 2004;24(5):584–91.

    PubMed  Google Scholar 

  100. Tolman KG. The liver and lovastatin. Am J Cardiol. 2002;89(12):1374–80.

    PubMed  CAS  Google Scholar 

  101. Russo MW, Galanko JA, Shrestha R, et al. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl. 2004;10(8):1018–23.

    PubMed  Google Scholar 

  102. Pfeffer MA, Keech A, Sacks FM, et al. Safety and tolerability of pravastatin in long-term clinical trials: prospective pravastatin pooling (PPP) project. Circulation. 2002;105(20):2341–6.

    PubMed  CAS  Google Scholar 

  103. Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology. 2004;126(5):1287–92.

    PubMed  CAS  Google Scholar 

  104. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis. 2004;174(1):193–6.

    PubMed  CAS  Google Scholar 

  105. Erichsen R, Froslev T, Lash TL, et al. Long-term statin use and the risk of gallstone disease: a population-based case-control study. Am J Epidemiol. 2011;173(2):162–70.

    PubMed  Google Scholar 

  106. Sampson UK, Linton MF, Fazio S. Are statins diabetogenic? Curr Opin Cardiol. 2011;26(4):342–7.

    PubMed  Google Scholar 

  107. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103(3):357–62.

    PubMed  CAS  Google Scholar 

  108. Rajpathak SN, Kumbhani DJ, Crandall J, et al. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32(10):1924–9.

    PubMed  CAS  Google Scholar 

  109. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305(24):2556–64.

    Google Scholar 

  110. Nakata M, Nagasaka S, Kusaka I, et al. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia. 2006;49(8):1881–92.

    PubMed  CAS  Google Scholar 

  111. Lalli CA, Pauli JR, Prada PO, et al. Statin modulates insulin signaling and insulin resistance in liver and muscle of rats fed a high-fat diet. Metabolism. 2008;57(1):57–65.

    PubMed  CAS  Google Scholar 

  112. Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565–71.

    PubMed  CAS  Google Scholar 

  113. Hildebrand RD, Hepperlen TW. Lovastatin and hypospermia. Ann Intern Med. 1990;112(7):549–50.

    PubMed  CAS  Google Scholar 

  114. Evans MA, Golomb BA. Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy. 2009;29(7):800–11.

    PubMed  CAS  Google Scholar 

  115. Parker BA, Polk DM, Rabdiya V, et al. Changes in memory function and neuronal activation associated with atorvastatin therapy. Pharmacotherapy. 2010;30(6):236e–240e.

    Google Scholar 

  116. Rosenson RS, Goranson NL. Lovastatin-associated sleep and mood disturbances. Am J Med. 1993;95(5):548–9.

    PubMed  CAS  Google Scholar 

  117. Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med. 2000;108(7):538–46.

    PubMed  CAS  Google Scholar 

  118. Berner JE. Statins can produce ataxia in bipolar disorder: two case reports. J Clin Psychiatry. 2010;71(3):359.

    PubMed  Google Scholar 

  119. Cartwright MS, Jeffery DR, Nuss GR, Donofrio PD. Statin-associated exacerbation of myasthenia gravis. Neurology. 2004;63(11):2188.

    PubMed  Google Scholar 

  120. Engel WK. Reversible ocular myasthenia gravis or mitochondrial myopathy from statins? Lancet. 2003;361(9351):85–6.

    PubMed  CAS  Google Scholar 

  121. Tsivgoulis G, Spengos K, Karandreas N, Panas M, Kladi A, Manta P. Presymptomatic neuromuscular disorders disclosed following statin treatment. Arch Intern Med. 2006;166(14):1519–24.

    PubMed  CAS  Google Scholar 

  122. Rajabally YA, Varakantam V, Abbott RJ. Disorder resembling Guillain-Barre syndrome on initiation of statin therapy. Muscle Nerve. 2004;30(5):663–6.

    PubMed  Google Scholar 

  123. Golomb BA, Kwon EK, Koperski S, Evans MA. Amyotrophic lateral sclerosis-like conditions in possible association with cholesterol-lowering drugs: An analysis of patient reports to the University of California, San Diego (UCSD) Statin Effects Study. Drug Saf. 2009;32(8):649–61.

    PubMed  CAS  Google Scholar 

  124. Corrao G, Zambon A, Bertu L, Botteri E, Leoni O, Contiero P. Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases. J Epidemiol Community Health. 2004;58(12):1047–51.

    PubMed  Google Scholar 

  125. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002;58(9):1333–7.

    PubMed  CAS  Google Scholar 

  126. Hackam DG, Woodward M, Newby LK, et al. Statins and intracerebral hemorrhage: collaborative systematic review and meta-analysis. Circulation. 201;124(20):2233–42.

  127. McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke. 2012;43(8):2149–56.

    PubMed  CAS  Google Scholar 

  128. Machan CM, Hrynchak PK, Irving EL. Age-related cataract is associated with type 2 diabetes and statin use. Optom Vis Sci. 2012;89(8):1165–71.

    PubMed  Google Scholar 

  129. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343–56.

    PubMed  Google Scholar 

  130. Alsheikh-Ali AA, Trikalinos TA, Kent DM, et al. Statins, low-density lipoprotein cholesterol, and risk of cancer. J Am Coll Cardiol. 2008;52(14):1141–7.

    PubMed  CAS  Google Scholar 

  131. Bertagnolli MM, Hsu M, Hawk ET, Adenoma Prevention with Celecoxib (APC) Study Investigators, et al. Statin use and colorectal adenoma risk: results from the adenoma prevention with celecoxib trial. Cancer Prev Res (Phila). 2010;3(5):588–96.

    CAS  Google Scholar 

  132. Jacobs EJ, Newton CC, Thun MJ, et al. Long-term use of cholesterol-lowering drugs and cancer incidence in a large United States cohort. Cancer Res. 2011;71(5):1763–71.

    PubMed  CAS  Google Scholar 

  133. Bulbulia R, Bowman L, Heart Protection Study Collaborative Group, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011;378(9808):2013–20.

    PubMed  CAS  Google Scholar 

  134. Verhulst A, D’Haese PC, De Broe ME. Inhibitors of HMG-CoA reductase reduce receptor-mediated endocytosis in human kidney proximal tubular cells. J Am Soc Nephrol. 2004;15(9):2249–57.

    PubMed  CAS  Google Scholar 

  135. Agarwal R. Effects of statins on renal function. Am J Cardiol. 2006;97(5):748–55.

    PubMed  CAS  Google Scholar 

  136. Vidt DG, Ridker PM, Monyak JT, et al. Longitudinal assessment of estimated glomerular filtration rate in apparently healthy adults: a post hoc analysis from the JUPITER study (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). Clin Ther. 2011;33(6):717–25.

    PubMed  CAS  Google Scholar 

  137. Fassett RG, Robertson IK, Ball MJ, et al. Effect of atorvastatin on kidney function in chronic kidney disease: a randomised double-blind placebo-controlled trial. Atherosclerosis. 2010;213(1):218–24.

    PubMed  CAS  Google Scholar 

  138. Waters DD. Safety of high-dose atorvastatin therapy. Am J Cardiol. 2005;96(5A):69F–75F.

    PubMed  CAS  Google Scholar 

  139. de Zeeuw D. Prospective evaluation of proteinuria and renal function in diabetic patients with progressive renal disease. XLVII European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress.

  140. Savarese G, Musella F, Volpe M, et al. Effects of atorvastatin and rosuvastatin on renal function: a meta-analysis. Int J Cardiol. 2012;S0167–5273(12):621–3.

    Google Scholar 

  141. Wu Y, Wang Y, An C, et al. Effects of rosuvastatin and atorvastatin on renal function: meta-analysis. Circ J. 2012;76(5):1259–66.

    PubMed  CAS  Google Scholar 

  142. Furberg CD, Pitt B. Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med. 2001;2(5):205–7.

    PubMed  Google Scholar 

  143. Jacobson TA. Combination lipid-lowering therapy with statins: safety issues in the postcerivastatin era. Expert Opin Drug Saf. 2003;2(3):269–86.

    PubMed  CAS  Google Scholar 

  144. Davidson MH. Controversy surrounding the safety of cerivastatin. Expert Opin Drug Saf. 2002;1(3):207–12.

    PubMed  CAS  Google Scholar 

  145. Hsia J, MacFadyen JG, Monyak J, et al. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). J Am Coll Cardiol. 2011;57(16):1666–75.

    PubMed  CAS  Google Scholar 

  146. de Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med. 2010;170(12):1032–6.

    PubMed  Google Scholar 

  147. Saku K, Zhang B, Noda K, PATROL Trial Investigators. Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial. Circ J. 2011;75(6):1493–505.

    PubMed  CAS  Google Scholar 

  148. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the bezafibrate infarction prevention (BIP) study. Circulation. 2000;102(1):21–27.

    Google Scholar 

  149. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet. 2005;366(9500):1849–61.

    PubMed  CAS  Google Scholar 

  150. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001;357(9260): 905–10.

    Google Scholar 

  151. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99(6A):3C–18C.

    PubMed  CAS  Google Scholar 

  152. Holoshitz N, Alsheikh-Ali AA, Karas RH. Relative safety of gemfibrozil and fenofibrate in the absence of concomitant cerivastatin use. Am J Cardiol. 2008;101(1):95–7.

    PubMed  CAS  Google Scholar 

  153. Gaist D, Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Lipid-lowering drugs and risk of myopathy: a population-based follow-up study. Epidemiology. 2001;12(5):565–9.

    PubMed  CAS  Google Scholar 

  154. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. J Am Med Assoc. 2004;292(21):2585–90.

    CAS  Google Scholar 

  155. Clouatre Y, Leblanc M, Ouimet D, Pichette V. Fenofibrate-induced rhabdomyolysis in two dialysis patients with hypothyroidism. Nephrol Dial Transplant. 1999;14(4):1047–8.

    PubMed  CAS  Google Scholar 

  156. Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf. 2004;13(7):417–26.

    PubMed  CAS  Google Scholar 

  157. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol. 2004;94(7):935–8.

    PubMed  CAS  Google Scholar 

  158. Enger C, Gately R, Ming EE, et al. Pharmacoepidemiology safety study of fibrate and statin concomitant therapy. Am J Cardiol. 2010;106(11):1594–601.

    PubMed  CAS  Google Scholar 

  159. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol. 2005;95(1):120–2.

    PubMed  CAS  Google Scholar 

  160. Yacsar HY, Ertugrul O, Deniz C. Erythema multiforme associated with gemfibrozil monotherapy. Am J Med Sci. 2010;339(1):86–8.

    PubMed  Google Scholar 

  161. 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(20):1237–45.

    PubMed  CAS  Google Scholar 

  162. Palmer RH. Effects of fibric acid derivatives on biliary lipid composition. Am J Med. 1987;83(5B):37–43.

    PubMed  CAS  Google Scholar 

  163. Raedsch R, Plachky J, Wolf N, et al. Biliary lipids, lithogenic index and biliary drug concentrations during etofibrate and bezafibrate treatment. Eur J Drug Metab Pharmacokinet. 1995;20(2):113–8.

    PubMed  CAS  Google Scholar 

  164. Roglans N, Vazquez-Carrera M, Alegret M, et al. Fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients. Eur J Clin Pharmacol. 2004;59(12):855–61.

    PubMed  CAS  Google Scholar 

  165. Caroli-Bosc FX, Le Gall P, Pugliese P, et al. Role of fibrates and HMG-CoA reductase inhibitors in gallstone formation: Epidemiological study in an unselected population. Dig Dis Sci. 2001;46(3):540–4.

    PubMed  CAS  Google Scholar 

  166. Preiss D, Tikkanen MJ, Welsh P, et al. Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. JAMA. 2012;308(8):804–11.

    PubMed  CAS  Google Scholar 

  167. Roberts WC. Safety of fenofibrate—US and worldwide experience. Cardiology. 1989;76(3):169–79.

    PubMed  CAS  Google Scholar 

  168. Squizzato A, Galli M, Romualdi E, et al. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J. 2010;31(10):1248–56.

    PubMed  CAS  Google Scholar 

  169. de Lorgeril M, Salen P, Paillard F, et al. Lipid-lowering drugs and homocysteine. Lancet. 1999;353(9148):209–10.

    PubMed  Google Scholar 

  170. Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet. 1999;354(9174):219–20.

    PubMed  CAS  Google Scholar 

  171. Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet. 2001;358(9275):39–40.

    PubMed  CAS  Google Scholar 

  172. Landray MJ, Townend JN, Martin S, et al. Lipid-lowering drugs and homocysteine. Lancet. 1999;353(9168):1974–5.

    PubMed  CAS  Google Scholar 

  173. Bissonnette R, Treacy E, Rozen R, et al. Fenofibrate raises plasma homocysteine levels in the fasted and fed states. Atherosclerosis. 2001;155(2):455–62.

    PubMed  CAS  Google Scholar 

  174. Genest J, Frohlich J, Steiner G. Effect of fenofibrate-mediated increase in plasma homocysteine on the progression of coronary artery disease in type 2 diabetes mellitus. Am J Cardiol. 2004;93(7):848–53.

    PubMed  CAS  Google Scholar 

  175. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007;99(6A):22C–31C.

    PubMed  CAS  Google Scholar 

  176. Jacobson TA. A “hot” topic in dyslipidemia management—“how to beat a flush”: optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention. Mayo Clin Proc. 2010;85(4):365–79.

    PubMed  CAS  Google Scholar 

  177. Kamal-Bahl S, Watson DJ, Ambegaonkar BM. Patients’ experiences of niacin-induced flushing in clinical practice: a structured telephone interview. Clin Ther. 2009;31(1):130–40.

    PubMed  Google Scholar 

  178. Kamal-Bahl SJ, Burke TA, Watson DJ, et al. Dosage, titration, and gaps in treatment with extended release niacin in clinical practice. Curr Med Res Opin. 2008;24(6):1817–21.

    PubMed  CAS  Google Scholar 

  179. Kamal-Bahl SJ, Burke T, Watson D, et al. Discontinuation of lipid modifying drugs among commercially insured United States patients in recent clinical practice. Am J Cardiol. 2007;99(4):530–4.

    PubMed  Google Scholar 

  180. Dunbar RL, Gelfand JM. Seeing red: flushing out instigators of niacin-associated skin toxicity. J Clin Invest. 2010;120(8):2651–5.

    PubMed  CAS  Google Scholar 

  181. Goldberg RB, Jacobson TA. Effects of niacin on glucose control in patients with dyslipidemia. Mayo Clin Proc. 2008;83(4):470–8.

    PubMed  CAS  Google Scholar 

  182. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. J Am Med Assoc. 1990;264(6):723–6.

    CAS  Google Scholar 

  183. Wi J, Kim JY, Park S, et al. Optimal pharmacologic approach to patients with hypertriglyceridemia and low high-density lipoprotein-cholesterol: Randomized comparison of fenofibrate 160 mg and niacin 1500 mg. Atherosclerosis. 2010;213(1):235–40.

    PubMed  CAS  Google Scholar 

  184. Fazio S, Guyton JR, Lin J, et al. Long-term efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in hyperlipidaemic patients with diabetes or metabolic syndrome. Diabetes Obes Metab. 2010;12(11):983–93.

    PubMed  CAS  Google Scholar 

  185. Pozzilli P, Browne PD, Kolb H. Meta-analysis of nicotinamide treatment in patients with recent-onset IDDM. The nicotinamide trialists. Diabetes Care. 1996;19(12):1357–63.

    PubMed  CAS  Google Scholar 

  186. Zhao XQ, Morse JS, Dowdy AA, et al. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (the HDL atherosclerosis treatment study). Am J Cardiol. 2004;93(3):307–12.

    PubMed  CAS  Google Scholar 

  187. Guyton JR, Fazio S, Adewale AJ, et al. Effect of extended-release niacin on new-onset diabetes among hyperlipidemic patients treated with ezetimibe/simvastatin in a randomized controlled trial. Diabetes Care. 2012;35(4):857–60.

    PubMed  CAS  Google Scholar 

  188. McKenney JM, Proctor JD, Harris S, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. J Am Med Assoc. 1994;271(9):672–7.

    CAS  Google Scholar 

  189. Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother. 2002;36(2):288–95.

    PubMed  CAS  Google Scholar 

  190. Alsheikh-Ali AA, Karas RH. The safety of niacin in the US Food and Drug Administration adverse event reporting database. Am J Cardiol. 2008;101(8A):9B–13B.

    PubMed  CAS  Google Scholar 

  191. Guyton JR. Extended-release niacin for modifying the lipoprotein profile. Expert Opin Pharmacother. 2004;5(6):1385–98.

    PubMed  CAS  Google Scholar 

  192. Shah S, Ceska R, Gil-Extremera B, et al. Efficacy and safety of extended-release niacin/laropiprant plus statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract. 2010;64(6):727–38.

    PubMed  CAS  Google Scholar 

  193. Maccubbin D, Bays HE, Olsson AG, et al. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract. 2008;62(12):1959–70.

    PubMed  CAS  Google Scholar 

  194. Altmann SW, Davis HR Jr, Zhu LJ, et al. Niemann-pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science. 2004;303(5661):1201–4.

    PubMed  CAS  Google Scholar 

  195. Davis HR Jr, Zhu LJ, Hoos LM, et al. Niemann-pick C1 like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. J Biol Chem. 2004;279(32):33586–92.

    PubMed  CAS  Google Scholar 

  196. Sudhop T, Lutjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106(15):1943–8.

    PubMed  CAS  Google Scholar 

  197. Ezzet F, Krishna G, Wexler DB, et al. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther. 2001;23(6):871–85.

    PubMed  CAS  Google Scholar 

  198. Pandor A, Ara RM, Tumur I, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: Systematic review and meta-analysis of randomized controlled trials. J Intern Med. 2009;265(5):568–80.

    PubMed  CAS  Google Scholar 

  199. Hou R, Goldberg AC. Lowering low-density lipoprotein cholesterol: Statins, ezetimibe, bile acid sequestrants, and combinations: comparative efficacy and safety. Endocrinol Metab Clin N Am. 2009;38(1):79–97.

    CAS  Google Scholar 

  200. Zieve F, Wenger NK, Ben-Yehuda O, et al. Safety and efficacy of ezetimibe added to atorvastatin versus up titration of atorvastatin to 40 mg in patients > or = 65 years of age (from the ZETia in the ELDerly [ZETELD] study). Am J Cardiol. 2010;105(5):656–63.

    PubMed  CAS  Google Scholar 

  201. Florentin M, Liberopoulos EN, Elisaf MS. Ezetimibe-associated adverse effects: What the clinician needs to know. Int J Clin Pract. 2008;62(1):88–96.

    PubMed  CAS  Google Scholar 

  202. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358(14):1431–43.

    PubMed  CAS  Google Scholar 

  203. Stein E, Stender S, Mata P, et al. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J. 2004;148(3):447–55.

    PubMed  CAS  Google Scholar 

  204. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose-comparison study of the combination of ezetimibe and simvastatin (vytorin) versus atorvastatin in patients with hypercholesterolemia: the vytorin versus atorvastatin (VYVA) study. Am Heart J. 2005;149(3):464–73.

    PubMed  CAS  Google Scholar 

  205. Goldberg AC, Sapre A, Liu J, Ezetimibe Study Group, et al. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2004;79(5):620–9.

    PubMed  CAS  Google Scholar 

  206. Slim H, Thompson PD. Ezetimibe-related myopathy: a systematic review. J Clin Lipidol. 2008;2(5):328–34.

    PubMed  Google Scholar 

  207. Kashani A, Sallam T, Bheemreddy S, et al. Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials. Am J Cardiol. 2008;101(11):1606–13.

    PubMed  CAS  Google Scholar 

  208. Mikhailidis DP, Sibbring GC, Ballantyne CM, et al. Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin. 2007;23(8):2009–26.

    PubMed  CAS  Google Scholar 

  209. Bays HE, Ose L, Fraser N, et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther. 2004;26(11):1758–73.

    PubMed  CAS  Google Scholar 

  210. Gagne C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90(10):1084–91.

    PubMed  CAS  Google Scholar 

  211. Stolk MF, Becx MC, Kuypers KC, et al. Severe hepatic side effects of ezetimibe. Clin Gastroenterol Hepatol. 2006;4(7):908–11.

    PubMed  Google Scholar 

  212. Tuteja S, Pyrsopoulos NT, Wolowich WR, et al. Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation. Pharmacotherapy. 2008;28(9):1188–93.

    PubMed  Google Scholar 

  213. Mikhailidis DP, Wierzbicki AS, Daskalopoulou SS, et al. The use of ezetimibe in achieving low density lipoprotein lowering goals in clinical practice: position statement of a United Kingdom consensus panel. Curr Med Res Opin. 2005;21(6):959–69.

    PubMed  CAS  Google Scholar 

  214. Landray M, Baigent C, Leaper C, et al. The Second United Kingdom Heart and Renal Protection (UK-HARP-II) study: a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD. Am J Kidney Dis. 2006;47(3):385–95.

    PubMed  CAS  Google Scholar 

  215. Bergman AJ, Burke J, Larson P, et al. Interaction of single-dose ezetimibe and steady-state cyclosporine in renal transplant patients. J Clin Pharmacol. 2006;46(3):328–36.

    PubMed  CAS  Google Scholar 

  216. Oswald S, Nassif A, Modess C, et al. Pharmacokinetic and pharmacodynamic interactions between the immunosuppressant sirolimus and the lipid-lowering drug ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2010;87(6):663–7.

    PubMed  CAS  Google Scholar 

  217. Oswald S, Nassif A, Modess C, et al. Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011;89(4):524–8.

    PubMed  CAS  Google Scholar 

  218. McKenney JM, Farnier M, Lo KW, et al. Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia. J Am Coll Cardiol. 2006;47(8):1584–7.

    PubMed  CAS  Google Scholar 

  219. Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467–94.

    PubMed  CAS  Google Scholar 

  220. Bergman AJ, Burke J, Larson P, et al. Effects of ezetimibe on cyclosporine pharmacokinetics in healthy subjects. J Clin Pharmacol. 2006;46(3):321–7.

    PubMed  CAS  Google Scholar 

  221. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008;359(13):1357–66.

    PubMed  CAS  Google Scholar 

  222. Einarsson K, Ericsson S, Ewerth S, et al. Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism. Eur J Clin Pharmacol. 1991;40(Suppl 1):S53–8.

    PubMed  Google Scholar 

  223. Grundy SM, Ahrens EH Jr, Salen G. Interruption of the enterohepatic circulation of bile acids in man: Comparative effects of cholestyramine and ileal exclusion on cholesterol metabolism. J Lab Clin Med. 1971;78(1):94–121.

    PubMed  CAS  Google Scholar 

  224. Shepherd J, Packard CJ, Bicker S, Lawrie TD, Morgan HG. Cholestyramine promotes receptor-mediated low-density-lipoprotein catabolism. N Engl J Med. 1980;302(22):1219–22.

    PubMed  CAS  Google Scholar 

  225. Bays HE, Goldberg RB. The ‘forgotten’ bile acid sequestrants: is now a good time to remember? Am J Ther. 2007;14(6):567–80.

    PubMed  Google Scholar 

  226. Davidson MH, Dillon MA, Gordon B, et al. Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med. 1999;159(16):1893–900.

    PubMed  CAS  Google Scholar 

  227. Davidson MH, Donovan JM, Misir S, Jones MR. A 50-week extension study on the safety and efficacy of colesevelam in adults with primary hypercholesterolemia. Am J Cardiovasc Drugs. 2010;10(5):305–14.

    PubMed  CAS  Google Scholar 

  228. Handelsman Y, Goldberg RB, Garvey WT, et al. Colesevelam hydrochloride to treat hypercholesterolemia and improve glycemia in prediabetes: a randomized, prospective study. Endocr Pract. 2010;16(4):617–28.

    PubMed  Google Scholar 

  229. Heel RC, Brogden RN, Pakes GE, et al. Colestipol: a review of its pharmacological properties and therapeutic efficacy in patients with hypercholesterolaemia. Drugs. 1980;19(3):161–80.

    PubMed  CAS  Google Scholar 

  230. Lloyd-Still JD. Cholestyramine therapy and intestinal obstruction in infants. Pediatrics. 1977;59(4):626–7.

    PubMed  CAS  Google Scholar 

  231. Merten DF, Grossman H. Intestinal obstruction associated with cholestyramine therapy. AJR Am J Roentgenol. 1980;134(4):827–8.

    PubMed  CAS  Google Scholar 

  232. Jacobson TA, Armani A, McKenney JM, et al. Safety considerations with gastrointestinally active lipid-lowering drugs. Am J Cardiol. 2007;99(6A):47C–55C.

    PubMed  CAS  Google Scholar 

  233. Colesevelam hydrochloride. Welchol Product Information Web site. http://www.welchol.com/hcp/about_welchol/safety_profile.html#isi. Accessed 18 Feb 2012.

  234. Crouse JR 3rd. Hypertriglyceridemia: a contraindication to the use of bile acid binding resins. Am J Med. 1987;83(2):243–8.

    PubMed  Google Scholar 

  235. Denke MA, Grundy SM. Hypertriglyceridemia: a relative contraindication to the use of bile acid-binding resins? Hepatology. 1988;8(4):974–5.

    PubMed  CAS  Google Scholar 

  236. Nigro ND, Bhadrachari N, Chomchai C. A rat model for studying colonic cancer: effect of cholestyramine on induced tumors. Dis Colon Rectum. 1973;16(6):438–43.

    PubMed  CAS  Google Scholar 

  237. Colestid [colestipol] prescribing information. http://www.pdr.net. Accessed 15 Feb 2011.

  238. Questran [cholestyramine] prescribing information. http://www.pdr.net. Accessed 15 Feb 2011.

  239. West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut. 1975;16(2):93–8.

    PubMed  CAS  Google Scholar 

  240. Donovan JM, Stypinski D, Stiles MR, et al. Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent. Cardiovasc Drugs Ther. 2000;14(6):681–90.

    PubMed  CAS  Google Scholar 

  241. Brown KS, Armstrong IC, Wang A, et al. Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. J Clin Pharmacol. 2010;50(5):554–65.

    PubMed  CAS  Google Scholar 

  242. Bays HE, Dujovne CA. Drug interactions of lipid-altering drugs. Drug Saf. 1998;19(5):355–71.

    PubMed  CAS  Google Scholar 

  243. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002.

    Google Scholar 

  244. Barter PJ, Brewer HB Jr, Chapman MJ, et al. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(2):160–7.

    PubMed  CAS  Google Scholar 

  245. Zhong S, Sharp DS, Grove JS, et al. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest. 1996;97(12):2917–23.

    PubMed  CAS  Google Scholar 

  246. McKenney JM, Davidson MH, Shear CL, et al. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin. J Am Coll Cardiol. 2006;48(9):1782–90.

    PubMed  CAS  Google Scholar 

  247. Clerc RG, Stauffer A, Weibel F, et al. Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens. 2010;28(8):1676–86.

    PubMed  CAS  Google Scholar 

  248. Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol. 2008;154(7):1465–73.

    PubMed  CAS  Google Scholar 

  249. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363(25):2406–15.

    PubMed  CAS  Google Scholar 

  250. Davidson MH. Update on CETP inhibition. J Clin Lipidol. 2010;4(5):394–8.

    PubMed  Google Scholar 

  251. Derks M, Abt M, Phelan M, et al. Coadministration of dalcetrapib with pravastatin, rosuvastatin, or simvastatin: no clinically relevant drug-drug interactions. J Clin Pharmacol. 2010;50(10):1188–201.

    PubMed  CAS  Google Scholar 

  252. Stein EA, Roth EM, Rhyne JM, et al. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J. 2010;31(4):480–8.

    PubMed  CAS  Google Scholar 

  253. Bell JD, Barnard ML, Parkes HG, et al. Effects of ω-3 fatty acids on the NMR profile of plasma lipoproteins. J Lipid Res. 1996;37(8):1664–74.

    PubMed  CAS  Google Scholar 

  254. Calabresi L, Donati D, Pazzucconi F, et al. Omacor in familial combined hyperlipidemia: effects on lipids and low density lipoprotein subclasses. Atherosclerosis. 2000;148(2):387–96.

    PubMed  CAS  Google Scholar 

  255. McKenney JM, Sica D. Prescription omega-3 fatty acids for the treatment of hypertriglyceridemia. Am J Health Syst Pharm. 2007;64(6):595–605.

    PubMed  CAS  Google Scholar 

  256. Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of omacor in severe hypertriglyceridemia. J Cardiovasc Risk. 1997;4(5–6):385–91.

    PubMed  CAS  Google Scholar 

  257. Glauber H, Wallace P, Griver K, et al. Adverse metabolic effect of omega-3 fatty acids in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1988;108(5):663–8.

    PubMed  CAS  Google Scholar 

  258. Annuzzi G, Rivellese A, Capaldo B, et al. A controlled study on the effects of ω-3 fatty acids on lipid and glucose metabolism in non-insulin-dependent diabetic patients. Atherosclerosis. 1991;87(1):65–73.

    PubMed  CAS  Google Scholar 

  259. Kaushik M, Mozaffarian D, Spiegelman D, et al. Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. Am J Clin Nutr. 2009;90(3):613–20.

    PubMed  CAS  Google Scholar 

  260. Wu JH, Micha R, Imamura F, et al. Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis. Br J Nutr. 2012;107(Suppl 2):S214–27.

    PubMed  CAS  Google Scholar 

  261. Pedersen HS, Mulvad G, Seidelin KN, et al. ω-3 fatty acids as a risk factor for haemorrhagic stroke. Lancet. 1999;353(9155):812–3.

    PubMed  CAS  Google Scholar 

  262. Gajos G, Zalewski J, Rostoff P, et al. Reduced thrombin formation and altered fibrin clot properties induced by polyunsaturated omega-3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (OMEGA-PCI clot). Arterioscler Thromb Vasc Biol. 2011;31(7):1696–702.

    PubMed  CAS  Google Scholar 

  263. Wu D, Meydani SN. ω-3 polyunsaturated fatty acids and immune function. Proc Nutr Soc. 1998;57(4):503–9.

    PubMed  CAS  Google Scholar 

  264. Bhangle S, Kolasinski SL. Fish oil in rheumatic diseases. Rheum Dis Clin N Am. 2011;37(1):77–84.

    Google Scholar 

  265. Gruppo Italiano per lo Studio della Sopravvivenza Nell’infarto Miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354(9177):447–55.

    Google Scholar 

  266. Roth EM, Bays HE, Forker AD, et al. Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects. J Cardiovasc Pharmacol. 2009;54(3):196–203.

    PubMed  CAS  Google Scholar 

  267. Davidson MH, Stein EA, Bays HE, et al. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2007;29(7):1354–67.

    PubMed  CAS  Google Scholar 

  268. Nambi V, Ballantyne CM. Combination therapy with statins and omega-3 fatty acids. Am J Cardiol. 2006;98(4A):34i–8i.

    PubMed  CAS  Google Scholar 

  269. Kroes R, Schaefer EJ, Squire RA, et al. A review of the safety of DHA45-oil. Food Chem Toxicol. 2003;41(11):1433–46.

    PubMed  CAS  Google Scholar 

  270. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99(6A):35C–43C.

    PubMed  CAS  Google Scholar 

  271. Wang C, Harris WS, Chung M, et al. ω-3 fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006;84(1):5–17.

    PubMed  CAS  Google Scholar 

  272. Wei MY, Jacobson TA. Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. Curr Atheroscler Rep. 2011;13(6):474–83.

    PubMed  CAS  Google Scholar 

  273. Anderson BM, Ma DW. Are all ω-3 polyunsaturated fatty acids created equal? Lipids Health Dis. 2009;8:33.

    PubMed  Google Scholar 

  274. Mozaffarian D, Wu JH. (ω-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr. 2012;142(3):614S–25S.

    PubMed  CAS  Google Scholar 

  275. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, plAcebo-controlled, randomized, double-blINd, 12-week study with an open-label extension [MARINE] trial). Am J Cardiol. 2011;108(5):682–90.

    PubMed  CAS  Google Scholar 

  276. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110(7):984–92.

    Google Scholar 

  277. Smuts CM, Huang M, Mundy D, et al. A randomized trial of docosahexaenoic acid supplementation during the third trimester of pregnancy. Obstet Gynecol. 2003;101(3):469–79.

    PubMed  CAS  Google Scholar 

  278. Ramakrishnan U, Stein AD, Parra-Cabrera S, et al. Effects of docosahexaenoic acid supplementation during pregnancy on gestational age and size at birth: randomized, double-blind, placebo-controlled trial in Mexico. Food Nutr Bull. 2010;31(2 Suppl):S108–16.

    PubMed  Google Scholar 

  279. Krauss-Etschmann S, Shadid R, Campoy C, et al. Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid: a European randomized multicenter trial. Am J Clin Nutr. 2007;85(5):1392–400.

    PubMed  CAS  Google Scholar 

  280. Prasad V, Cifu A, Ioannidis JP. Reversals of established medical practices: evidence to abandon ship. J Am Med Assoc. 2012;307(1):37–8.

    CAS  Google Scholar 

  281. Mills EJ, O’Regan C, Eyawo O, Wu P, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. Eur Heart J. 2011;32(11):1409–15.

    PubMed  CAS  Google Scholar 

  282. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012; 380(9841): 581–90.

    Google Scholar 

  283. Dale KM, Coleman CI, Shah SA, et al. Impact of gender on statin efficacy. Curr Med Res Opin. 2007;23(3):565–74.

    PubMed  CAS  Google Scholar 

  284. Gutierrez J, Ramirez G, Rundek T, et al. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis-statin therapy to prevent recurrent CV events. Arch Intern Med. 2012;172(12):909–19.

    PubMed  CAS  Google Scholar 

  285. Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol. 2012;59(6):572–82.

    PubMed  CAS  Google Scholar 

  286. Palmer SC, Craig JC, Navaneethan SD, et al. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;157(4):263–75.

    PubMed  Google Scholar 

  287. Prasad V, Vandross A. Cardiovascular primary prevention: How high should we set the bar? Arch Intern Med. 2012;172(8):656–9; (discussion 659).

    Google Scholar 

  288. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. J Am Med Assoc. 2012;307(12):1302–9.

    CAS  Google Scholar 

  289. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294(3):326–33.

    PubMed  CAS  Google Scholar 

  290. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4(3):337–45.

    PubMed  Google Scholar 

  291. Sniderman A, McQueen M, Contois J, Williams K, Furberg CD. Why is non-high-density lipoprotein cholesterol a better marker of the risk of vascular disease than low-density lipoprotein cholesterol? J Clin Lipidol. 2010;4(3):152–5.

    PubMed  Google Scholar 

  292. Baruch L, Chiong VJ, Agarwal S, Gupta B. Discordance of Non-HDL and directly measured LDL cholesterol: which lipid measure is preferred when calculated LDL is inaccurate? Cholesterol. 2013;2013:502948

  293. Rana JS, Boekholdt SM. Should we change our lipid management strategies to focus on non-high-density lipoprotein cholesterol? Curr Opin Cardiol. 2010;25(6):622–6.

    PubMed  Google Scholar 

  294. Hayward RA, Krumholz HM. Three reasons to abandon low-density lipoprotein targets: An open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes. 2012;5(1):2–5.

    PubMed  Google Scholar 

  295. Hayward RA, Hofer TP, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006;145(7):520–30.

    PubMed  Google Scholar 

  296. Trial of clofibrate in the treatment of ischaemic heart disease. Five-year study by a group of physicians of the Newcastle upon Tyne region. Br Med J. 1971;4(5790):767–75.

    Google Scholar 

  297. Ischaemic heart disease. A secondary prevention trial using clofibrate. Report by a research committee of the Scottish Society of Physicians. Br Med J. 1971;4(5790):775–84.

    Google Scholar 

  298. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-density lipoprotein cholesterol Intervention Trial study group. N Engl J Med. 1999;341(6):410–8.

    PubMed  CAS  Google Scholar 

  299. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74.

    PubMed  Google Scholar 

  300. Abourbih S, Filion KB, Joseph L, et al. Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review. Am J Med. 2009;122(10):962e1–8.

    Google Scholar 

  301. Goldenberg I, Benderly M, Goldbourt U, BIP Study Group. Secondary prevention with bezafibrate therapy for the treatment of dyslipidemia: an extended follow-up of the BIP trial. J Am Coll Cardiol. 2008;51(4):459–65.

    PubMed  CAS  Google Scholar 

  302. Studer M, Briel M, Leimenstoll B, et al. Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med. 2005;165(7):725–30.

    PubMed  CAS  Google Scholar 

  303. Preiss D, Tikkanen MJ, Welsh P, et al. Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. J Am Med Assoc. 2012;308(8):804–11.

    CAS  Google Scholar 

  304. McPherson R. Comparative effects of simvastatin and cholestyramine on plasma lipoproteins and CETP in humans. Can J Clin Pharmacol. 1999;6(2):85–90.

    PubMed  CAS  Google Scholar 

  305. Ballantyne CM, Miller E, Chitra R. Efficacy and safety of rosuvastatin alone and in combination with cholestyramine in patients with severe hypercholesterolemia: a randomized, open-label, multicenter trial. Clin Ther. 2004;26(11):1855–64.

    PubMed  CAS  Google Scholar 

  306. Simons LA. Comparison of atorvastatin alone versus simvastatin +/− cholestyramine in the management of severe primary hypercholesterolaemia (the Six Cities Study). Aust N Z J Med. 1998;28(3):327–33.

    PubMed  CAS  Google Scholar 

  307. Garg A, Grundy SM. Cholestyramine therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. A short-term, double-blind, crossover trial. Ann Intern Med. 1994;121(6):416–22.

    PubMed  CAS  Google Scholar 

  308. Bays HE, Goldberg RB, Truitt KE, et al. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med. 2008;168(18):1975–83.

    PubMed  CAS  Google Scholar 

  309. Fonseca VA, Rosenstock J, Wang AC, et al. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care. 2008;31(8):1479–84.

    PubMed  CAS  Google Scholar 

  310. Goldberg RB, Fonseca VA, Truitt KE, et al. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med. 2008;168(14):1531–40.

    PubMed  CAS  Google Scholar 

  311. Rigby SP, Handelsman Y, Lai YL, et al. Effects of colesevelam, rosiglitazone, or sitagliptin on glycemic control and lipid profile in patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy. Endocr Pract. 2010;16:53–63.

    PubMed  Google Scholar 

  312. 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(10):1092–7.

    PubMed  CAS  Google Scholar 

  313. Gagne C, Gaudet D, Bruckert E, Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105:2469–75.

    PubMed  CAS  Google Scholar 

  314. Treatment of HDL to reduce the incidence of vascular events HPS2-THRIVE—full text view—ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT00461630. Accessed Aug 20 2012.

  315. IMPROVE-IT: Examining outcomes in subjects with acute coronary syndrome: vytorin (Ezetimibe/Simvastatin) vs simvastatin (P04103 AM5)—full text view—ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT00202878?term-IMPROVE+IT&rank=1. Accessed August 20 2012.

  316. Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. N Engl J Med. 1997;336(15):1046–53.

    PubMed  CAS  Google Scholar 

  317. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312(19):1205–9.

    PubMed  CAS  Google Scholar 

  318. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain ω-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. J Am Med Assoc. 1995;274(17):1363–7.

    CAS  Google Scholar 

  319. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2(8666):757–61.

    PubMed  CAS  Google Scholar 

  320. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–8.

    PubMed  CAS  Google Scholar 

  321. Kromhout D, Giltay EJ, Geleijnse JM, Alpha Omega Trial Group. ω-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363(21):2015–26.

    PubMed  CAS  Google Scholar 

  322. Rauch B, Schiele R, Schneider S, et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation. 2010;122(21):2152–9.

    PubMed  CAS  Google Scholar 

  323. Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ. 2010;341:c6273.

    PubMed  Google Scholar 

  324. Calder PC, Yaqoob P. Marine omega-3 fatty acids and coronary heart disease. Curr Opin Cardiol. 2012;27(4):412–9.

    PubMed  Google Scholar 

  325. 2006 > pfizer stops all torcetrapib clinical trials in interest of patient safety. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108792.htm. Accessed 20 August 2012.

  326. Luscher TF, Taddei S, Kaski JC, et al. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Eur Heart J. 2012;33(7):857–65.

    PubMed  Google Scholar 

  327. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011;378(9802):1547–59.

    Google Scholar 

  328. Roche—roche provides update on phase III study of dalcetrapib. http://www.roche.com/media/media_releases/med-cor-2012-05-07.htm. Accessed 20 August 2012.

  329. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306(19):2099–109.

    PubMed  CAS  Google Scholar 

  330. REVEAL: Randomized EValuation of the effects of anacetrapib through lipid-modification—full text view—ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT01252953?term=reveal&rank=1. Accessed 20 August 2012.

  331. Angerer P, Kothny W, Störk S, von Schacky C. Effect of dietary supplementation with omega-3 fatty acids on progression of atherosclerosis in carotid arteries. Cardiovasc Res. 2002;54(1):183–90.

    PubMed  CAS  Google Scholar 

  332. Shepherd J, Blauw GJ, Murphy MB, PROSPER study group, PROspective Study of Pravastatin in the Elderly at Risk, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623–30.

    PubMed  CAS  Google Scholar 

  333. Colhoun HM, Betteridge DJ, Durrington PN, CARDS investigators, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685–96.

    PubMed  CAS  Google Scholar 

  334. Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110(18):2809–16.

    PubMed  CAS  Google Scholar 

  335. Anderssen SA, Hjelstuen AK, Hjermann I, et al. Fluvastatin and lifestyle modification for reduction of carotid intima-media thickness and left ventricular mass progression in drug-treated hypertensives. Atherosclerosis. 2005;178(2):387–97.

    PubMed  CAS  Google Scholar 

  336. Knopp RH, d’Emden M, Smilde JG, et al. 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(7):1478–85.

    PubMed  CAS  Google Scholar 

  337. Nakamura H, Arakawa K, Itakura H, MEGA Study Group, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006;368(9542):1155–63.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank John Mitchell for his help in the preparation of the manuscript

Disclosure

Syed Mohiuddin and Marc Rendell have participated in clinical research protocols in the past involving some of the agents mentioned in this paper.

Author information

Authors and Affiliations

  1. Division of Cardiology, Creighton University School of Medicine, Omaha, USA

    Venkata M. Alla, Andrew DeNazareth & Syed Mohiuddin

  2. Department of Internal Medicine, Baylor College of Medicine, Houston, USA

    Vrinda Agrawal

  3. Department of Internal Medicine, Omaha Veterans Affairs Hospital, Omaha, USA

    Sudha Ravilla

  4. Department of Endocrinology, Creighton Diabetes Center, Creighton University School of Medicine, 601 North 30th Street, Omaha, NE, 68131, USA

    Marc Rendell

Authors
  1. Venkata M. Alla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vrinda Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew DeNazareth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Syed Mohiuddin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sudha Ravilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marc Rendell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marc Rendell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alla, V.M., Agrawal, V., DeNazareth, A. et al. A Reappraisal of the Risks and Benefits of Treating to Target with Cholesterol Lowering Drugs. Drugs 73, 1025–1054 (2013). https://doi.org/10.1007/s40265-013-0072-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-013-0072-9

Keywords

Search

Navigation