Drug Safety

, Volume 33, Issue 3, pp 171–187 | Cite as

Risk Factors and Drug Interactions Predisposing to Statin-Induced Myopathy

Implications for Risk Assessment, Prevention and Treatment
  • Yiannis S. Chatzizisis
  • Konstantinos C. Koskinas
  • Gesthimani Misirli
  • Chris Vaklavas
  • Apostolos Hatzitolios
  • George D. Giannoglou
Review Article

Abstract

HMG-CoA reductase inhibitors (‘statins’) represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of statins, the patient population suitable for long-term statin treatment is expected to further expand. An overall positive safety and tolerability profile of statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical.

The purpose of this review is to summarize the factors that increase the risk of statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant inter-individual variability in the myopathic risk are presented. Physicochemical properties of statins have been implicated in the differential risk of currently marketed statins. Pharmacokinetic interactions with concomitant medications that interfere with statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of statins with other classes of lipid-lowering agents; current data on the relative safety of available combinations are summarized. Finally, we provide an update of current guidelines for the prevention and management of statin myopathy.

The identification of patients with an increased proclivity to statin-induced myopathy could allow more cost-effective approaches of monitoring and screening, facilitate targeted prevention of potential complications, and further improve the already overwhelmingly positive benefit-risk ratio of statins.

References

  1. 1.
    Chatzizisis YS, Jonas M, Beigel R, et al. Attenuation of inflammation and expansive remodeling by valsartan alone or in combination with simvastatin in high-risk coronary atherosclerotic plaques. Atherosclerosis 2009; 203: 387–94PubMedCrossRefGoogle Scholar
  2. 2.
    Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001; 292(5519): 1160–4PubMedCrossRefGoogle Scholar
  3. 3.
    Grundy SM, Cleeman JI, Merz CN, et al., for the Coordinating Committee of the National Cholesterol Education Program and Endorsed by the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227–39PubMedCrossRefGoogle Scholar
  4. 4.
    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: 1495–504PubMedCrossRefGoogle Scholar
  5. 5.
    Schwarz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACLE study: a randomized controlled trial. JAMA 2001; 285: 1711–8CrossRefGoogle Scholar
  6. 6.
    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): 7–22CrossRefGoogle Scholar
  7. 7.
    Shepherd J, Blauw GJ, Murphy MB, et al., PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. PROspective Study of Pravastatin in the Elderly at Risk. Lancet 2002; 360: 1623–30PubMedCrossRefGoogle Scholar
  8. 8.
    Sever PS, Dahlof B, Poulter NR, et al., ASCOT investigators. 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: 1149–58PubMedCrossRefGoogle Scholar
  9. 9.
    Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf 2002; 25(9): 649–63PubMedCrossRefGoogle Scholar
  10. 10.
    Bolego C, Baetta R, Bellosta S, et al. Safety considerations for statins. Curr Opin Lipidol 2002; 13(6): 637–44PubMedCrossRefGoogle Scholar
  11. 11.
    Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al., and Writing Committee Members. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002; 106: 1024–8PubMedCrossRefGoogle Scholar
  12. 12.
    Bays H. Statin safety: an overview and assessment of the data: 2005. Am J Cardiol 2006; 97 Suppl. 8A: 6–26CCrossRefGoogle Scholar
  13. 13.
    Armitage J. The safety of statins in clinical practice. Lancet 2007; 370: 1781–90PubMedCrossRefGoogle Scholar
  14. 14.
    Pedersen TR, Faergeman O, Kastelein JP, 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: 2437–45PubMedCrossRefGoogle Scholar
  15. 15.
    Law M, Rudnicka AR. Statin safety: evidence from the published literature. Am J Cardiol 2006; 97 Suppl. 8A: 52–60CCrossRefGoogle Scholar
  16. 16.
    Davidson MH, Clark JA, Glass LM, et al. Statin safety: an appraisal from the Adverse Event Reporting System (AERS). Am J Cardiol 2006; 97 Suppl. 8A: 32–43CCrossRefGoogle Scholar
  17. 17.
    Ridker PM, Danielson E, Fonseca FA, et al., JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359(21): 2195–207PubMedCrossRefGoogle Scholar
  18. 18.
    de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs. a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292: 1307–16PubMedCrossRefGoogle Scholar
  19. 19.
    LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352: 1425–35PubMedCrossRefGoogle Scholar
  20. 20.
    The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–59CrossRefGoogle Scholar
  21. 21.
    Thompson PD, Clarkson PM, Rosenson RS. An assessment of statin safety by muscle experts. Am J Cardiol 2006; 97 Suppl.: 69–76CCrossRefGoogle Scholar
  22. 22.
    US Food and Drug Administration. Office of Drug Safety annual report 2001 [online]. Available from URL: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm169925.htm. [Accessed 2009 Aug 5]
  23. 23.
    Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002; 346(7): 539–40PubMedCrossRefGoogle Scholar
  24. 24.
    Kashani A, Phillips CO, Foody JA, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation 2006; 114: 2788–97PubMedCrossRefGoogle Scholar
  25. 25.
    Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients: the PRIMO study. Cardiovasc Drugs Ther 2005; 19: 403–14PubMedCrossRefGoogle Scholar
  26. 26.
    Silva MA, Swanson AC, Gandhi PG, et al. Statin-related adverse events: a meta-analysis. Clin Ther 2006; 28: 26–33PubMedCrossRefGoogle Scholar
  27. 27.
    Wlodarczyk J, Sullivan D, Smith M. Comparison of benefits and risks of rosuvastatin versus atorvastatin from a meta-analysis of head-to-head randomized controlled trials. Am J Cardiol 2008; 102(12): 1654–62PubMedCrossRefGoogle Scholar
  28. 28.
    Vaklavas C, Chatzizisis YS, Ziakas A, et al. Molecular basis of statin-associated myopathy. Atherosclerosis 2009 Jan; 202(1): 18–28PubMedCrossRefGoogle Scholar
  29. 29.
    Morita I, Sato I, Ma L, et al. Enhancement of membrane fluidity in cholesterol-poor endothelial cells pre-treated with simvastatin. Endothelium 1997; 5(2): 107–13PubMedCrossRefGoogle Scholar
  30. 30.
    Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 2007; 49: 2231–7PubMedCrossRefGoogle Scholar
  31. 31.
    Laaksonen R, Jokelainen K, Sahi T, et al. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther 1995; 57: 62–6PubMedCrossRefGoogle Scholar
  32. 32.
    Chatzizisis YS, Vaklavas C, Giannoglou GD. Coenzyme Q10 depletion: etiopathogenic or predisposing factor in statin associated myopathy [letter]? Am J Cardiol 2008 Apr 1; 101(7): 1071PubMedCrossRefGoogle Scholar
  33. 33.
    Sakamoto K, Mikami H, Kimura J. Involvement of organic anion transporting polypeptides in the toxicity of hydrophilic pravastatin and lipophilic fluvastatin in rat skeletal myofibres. Br J Pharmacol 2008; 154: 1482–90PubMedCrossRefGoogle Scholar
  34. 34.
    Dorajoo R, Pereira BP, Yu Z, et al. Role of multi-drug resistance-associated protein-1 transporter in statin induced myopathy. Life Sci 2008; 82: 823–30PubMedCrossRefGoogle Scholar
  35. 35.
    Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 1998; 19(1): 26–37PubMedCrossRefGoogle Scholar
  36. 36.
    Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 2006; 112: 71–105PubMedCrossRefGoogle Scholar
  37. 37.
    Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation 2004; 109 Suppl. III: III50–7PubMedGoogle Scholar
  38. 38.
    Haria M, McTavish D. Pravastatin: a reappraisal of its pharmacological properties and clinical effectiveness in the management of coronary heart disease. Drugs 1997; 53(2): 299–336PubMedCrossRefGoogle Scholar
  39. 39.
    White CM. A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol 2002; 42: 963–70PubMedGoogle Scholar
  40. 40.
    Schech S, Graham D, Staffa J, et al. Risk factors for statinassociated rhabdomyolysis. Pharmacoepidemiol Drug Saf 2007; 16(3): 352–8PubMedCrossRefGoogle Scholar
  41. 41.
    Lee E, Ryan S, Birmingham B, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 2005; 78(4): 330–41PubMedCrossRefGoogle Scholar
  42. 42.
    Tan C-E, Ma S, Wai D, et al. Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians? Diabetes Care 2004; 27: 1182–6PubMedCrossRefGoogle Scholar
  43. 43.
    Matsuzawa Y, Kita T, Mabuchi H, et al., for the J-LIT Study Group. Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51 321 Japanese hypercholesterolemic patients: implication of the J-LIT study, a large scale nationwide cohort study. Circ J 2003; 67: 287–94PubMedCrossRefGoogle Scholar
  44. 44.
    Morales D, Chung N, Zhu J-R, et al. Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies. Curr Med Res Opin 2004; 20: 1235–43PubMedCrossRefGoogle Scholar
  45. 45.
    Tan CE, Loh LM, Tai ES. Do Singapore patients require lower doses of statins? The SGH Lipid Clinic experience. Singapore Med J 2003; 44: 635–8PubMedGoogle Scholar
  46. 46.
    Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol 2004; 44: 1083–105PubMedCrossRefGoogle Scholar
  47. 47.
    Wang A, Yu BN, Luo CH, et al. Ile 118Val genetic polymorphism of CYP3A4 and its effects on lipid-lowering efficacy of simvastatin in Chinese hyperlipidemic patients. Eur J Clin Pharmacol 2005; 60: 843–8PubMedCrossRefGoogle Scholar
  48. 48.
    Liao JK. Safety and efficacy of statins in Asians. Am J Cardiol 2007; 99(3): 410–4PubMedCrossRefGoogle Scholar
  49. 49.
    Food and Drug Administration Center for Drug Evaluation and Research. FDA Public Health Advisory on Crestor (rosuvastatin) [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm051756.htm [Accessed 2009 Aug 1]
  50. 50.
    Saito M, Hirata-Koizumi M, Urano T, et al. A literature search on pharmacokinetic drug interactions of statins and analysis of how such interactions are reflected in package inserts in Japan. J Clin Pharm Ther 2005; 30: 21–37PubMedCrossRefGoogle Scholar
  51. 51.
    Vermes A, Vermes I. Genetic polymorphisms in cytochrome P450 enzymes: effect on efficacy and tolerability of HMG-CoA reductase inhibitors. Am J Cardiovasc Drugs 2004; 4: 247–55PubMedCrossRefGoogle Scholar
  52. 52.
    Mulder AB, van Lijf HJ, Bon MA, et al. Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin. Clin Pharmacol Ther 2001; 70: 546–51PubMedCrossRefGoogle Scholar
  53. 53.
    Morimoto K, Ueda S, Seki N, et al. OATPC(OATP01B1)*15 is associated with statin-induced myopathy in hypercholesterolemic patients. Clin Pharmacol Ther 2005; 77: P21CrossRefGoogle Scholar
  54. 54.
    Oh J, Ban MR, Miskie BA, et al. Genetic determinants of statin intolerance. Lipids Health Dis 2007; 6: 7PubMedCrossRefGoogle Scholar
  55. 55.
    The SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy: a genomewide study. N Engl J Med 2008; 359(8): 789–99CrossRefGoogle Scholar
  56. 56.
    Leung NM, Ooi TC, McQueen MJ. Use of statins and fibrates in hyperlipidemic patients with neuromuscular disorders. Arch Intern Med 2000; 132: 418–9Google Scholar
  57. 57.
    Franc S, Bruckert E, Giral P, et al. Rhabdomyolysis in patients with preexisting myopathy, treated with antilipemic agents. Presse Med 1997; 26: 1855–8PubMedGoogle Scholar
  58. 58.
    Oh SJ, Dhall R, Young A, et al. Statins may aggravate myasthenia gravis. Muscle Nerve 2008; 38: 1101–7PubMedCrossRefGoogle Scholar
  59. 59.
    Vladutiu R, Isackson P, Peltier W, et al. Genetic risk factors and metabolic abnormalities associated with lipid lowering therapies. Muscle Nerve 2006; 34(2): 153–62PubMedCrossRefGoogle Scholar
  60. 60.
    Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001; 59: 260–9PubMedCrossRefGoogle Scholar
  61. 61.
    Nichols GA, Koro CE. Does statin therapy initiation increase the risk for myopathy? An observational study of 32 225 diabetic and nondiabetic patients. Clin Ther 2007; 29(8): 1761–70PubMedCrossRefGoogle Scholar
  62. 62.
    Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med 2007; 18: 90–100PubMedCrossRefGoogle Scholar
  63. 63.
    Bar SL, Holmes DT, Frohlich J. Asymptomatic hypothyroidism and statin induced myopathy. Can Fam Physician 2007; 53(3): 428–31PubMedGoogle Scholar
  64. 64.
    Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008; 337: a2286PubMedCrossRefGoogle Scholar
  65. 65.
    Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol 2007; 49: 1753–62PubMedCrossRefGoogle Scholar
  66. 66.
    Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA 2003; 289(13): 1681–90PubMedCrossRefGoogle Scholar
  67. 67.
    Ronaldson KJ, O’Shea JM, Boyd IW. Risk factors for rhabdomyolysis with simvastatin and atorvastatin. Drug Saf 2006; 29(11): 1061–7PubMedCrossRefGoogle Scholar
  68. 68.
    Wong WM, Wai-Hung Shek T, Chan KH. Rhabdomyolysis triggered by cytomegalovirus infection in a heart transplant patient on concomitant cyclosporine and atorvastatin therapy. Gastroenterol Hepatol 2004; 19(8): 952–3CrossRefGoogle Scholar
  69. 69.
    Finsterer J, Zuntner G. Rhabdomyolysis from simvastatin triggered by infection and muscle exertion. South Med J 2005; 98(8): 827–9PubMedCrossRefGoogle Scholar
  70. 70.
    Betrosian A, Thireos E, Kofinas G, et al. Bacterial sepsis-induced rhabdomyolysis. Intensive Care Med 1999; 25: 469–74PubMedCrossRefGoogle Scholar
  71. 71.
    Thompson PD, Zmuda JM, Domalik LJ, et al. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism 1997; 46: 1206–10PubMedCrossRefGoogle Scholar
  72. 72.
    Wilhelmi M, Winterhalter M, Fisher S, et al. Massive postoperative rhabdomyolysis following combined CABG/ abdominal aortic replacement: a possible association with HMG-CoA reductase inhibitors. Cardiovasc Drugs Ther 2002; 16(5): 471–5PubMedCrossRefGoogle Scholar
  73. 73.
    East C, Alivizatos PA, Grundy SM, et al. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. N Engl J Med 1988; 318(1): 47–8PubMedCrossRefGoogle Scholar
  74. 74.
    Schouten O, Kertai MD, Bax JJ, et al. Safety of perioperative statin use in high-risk patients undergoing major vascular surgery. Am J Cardiol 2005; 95(5): 658–60PubMedCrossRefGoogle Scholar
  75. 75.
    Antons KA, Williams CD, Baker SK, et al. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med 2006; 119: 400–9PubMedCrossRefGoogle Scholar
  76. 76.
    Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six-week tolerability of simvastatin 80 and 160mg/day. Am J Cardiol 1997; 257(79): 38–42CrossRefGoogle Scholar
  77. 77.
    Rosenson RS, Bays HE. Results of two clinical trials on the safety and efficacy of pravastatin 80 and 160mg per day. Am J Cardiol 2003; 91: 878–81PubMedCrossRefGoogle Scholar
  78. 78.
    Masters BA, Palmoski MJ, Flint OP, et al. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pravastatin, lovastatin and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol 1995; 131: 163–74PubMedCrossRefGoogle Scholar
  79. 79.
    Ziegler K, Stunkel W. Tissue-selective action of pravastatin due to hepatocellular uptake via sodium-independent bile acid transporter. Biochem Biophys Acta 1992; 1139: 203–9PubMedCrossRefGoogle Scholar
  80. 80.
    Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol 2006; 97 Suppl.: 27–31CCrossRefGoogle Scholar
  81. 81.
    Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med 1995; 333: 664–5PubMedCrossRefGoogle Scholar
  82. 82.
    Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332–4PubMedCrossRefGoogle Scholar
  83. 83.
    Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998; 64: 177–82PubMedCrossRefGoogle Scholar
  84. 84.
    Lee AJ, Maddix DS. Rhabdomyolysis secondary to drug interaction between simvastatin and clarithromycin. Ann Pharmacother 2001; 35: 26–31PubMedCrossRefGoogle Scholar
  85. 85.
    Mousa O, Brater DC, Sunblad KJ, et al. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67: 267–74PubMedCrossRefGoogle Scholar
  86. 86.
    Lewin JJ, Nappi JM, Taylor MH. Rhabdomyolysis with concurrent atorvastatin and diltiazem. Ann Pharmacother 2002; 36: 1546–8PubMedCrossRefGoogle Scholar
  87. 87.
    Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of HMG-CoA reductase inhibitors for treatment of hyperlipidemia in patients with HIV infection. Pharmacotherapy 2000; 20: 1066–71PubMedCrossRefGoogle Scholar
  88. 88.
    Lenhard JM, Croom DK, Weiel JE, et al. HIV protease inhibitors stimulate hepatic triglyceride synthesis. Arterioscler Thromb Vasc Biol 2000; 20: 2625–9PubMedCrossRefGoogle Scholar
  89. 89.
    Chuk SK, Penzak SR. Risk-benefit of HMG-CoA reductase inhibitors in the treatment of HIV protease inhibitor-related hyperlipidaemia. Expert Opin Drug Saf 2002; 1(1): 5–11CrossRefGoogle Scholar
  90. 90.
    Gazi IF, Liberopoulos EN, Athyros VG, et al. Statins and solid organ transplantation. Curr Pharm Des 2006; 12(36): 4771–83PubMedCrossRefGoogle Scholar
  91. 91.
    Pichard L, Domergue J, Fourtanier G, et al. Metabolism of the new immumosuppresor cyclosporin G by human liver cytochrome P450. Biochem Pharmacol 1996; 51(5): 591–8PubMedCrossRefGoogle Scholar
  92. 92.
    Norman DJ, Illingworth DR, Munson J, et al. Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin. N Engl J Med 1988; 318: 46–7PubMedCrossRefGoogle Scholar
  93. 93.
    Park JW, Siekmeier R, Merz M, et al. Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A. Int J Clin Pharmacol Therapeut 2002; 40: 439–50Google Scholar
  94. 94.
    Corsini A, Bellosta S, Baetta R, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999; 84: 413–28PubMedCrossRefGoogle Scholar
  95. 95.
    Moguorosi A, Bradley B, Showealter A, et al. Rhabdomyolysis and acute renal failure due to combination therapy with simvastatin and warfarin. J Intern Med 1999; 246: 599–602CrossRefGoogle Scholar
  96. 96.
    Kantola T, Backman JT, Niemi M, et al. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 2000; 56: 225–9PubMedCrossRefGoogle Scholar
  97. 97.
    Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Phermacother 2001; 35: 908–17CrossRefGoogle Scholar
  98. 98.
    Murdock DK, Murdock AK, Murdock RW, et al. Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J 1999; 138: 151–5PubMedCrossRefGoogle Scholar
  99. 99.
    Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate+statin versus gemfibrozil+any statin. Am J Cardiol 2005; 95: 120–2PubMedCrossRefGoogle Scholar
  100. 100.
    Franssen R, Vergeer M, Stroes ES, et al. Combination statin-fibrate therapy: safety aspects. Diabetes Obes Metab 2009 Feb; 11(2): 89–94PubMedCrossRefGoogle Scholar
  101. 101.
    Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004; 292: 2585–90PubMedCrossRefGoogle Scholar
  102. 102.
    Prueksaritanont T, Subramanian R, Fang X, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos 2002; 30: 505–12PubMedCrossRefGoogle Scholar
  103. 103.
    Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfi brozil and statins. J Pharmacol Exp Ther 2002; 301: 1042–51PubMedCrossRefGoogle Scholar
  104. 104.
    Schoonjans K, Steals B, Auwerx J. Role of peroxisome proliferator activated receptor in mediating effects of fibrates and fatty acids on gene expression. J Lipid Res 1996; 37: 907–25PubMedGoogle Scholar
  105. 105.
    Kyrklund C, Backman JT, Neuvonen M, et al. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther 2003; 73: 538–44PubMedCrossRefGoogle Scholar
  106. 106.
    Reaven P, Witztum JL. Lovastatin, nicotinic acid, and rhabdomyolysis. Ann Intern Med 1988; 109: 597–8PubMedCrossRefGoogle Scholar
  107. 107.
    Bays H. Safety of niacin and simvastatin combination therapy. Am J Cardiol 2008; 101 Suppl.: 3–8BCrossRefGoogle Scholar
  108. 108.
    Fux R, Morike K, Gundel UF, et al. Ezetimibe and statin-associated myopathy. Ann Intern Med 2004; 140: 671–2PubMedCrossRefGoogle Scholar
  109. 109.
    Simard C, Poirier P. Ezetimibe-associated myopathy in monotherapy and in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Can J Cardiol 2006; 22(2): 141–4PubMedCrossRefGoogle Scholar
  110. 110.
    Pearson TA, Denke MA, McBride PE, et al. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe addon to statin for effectiveness (EASE) trial. Mayo Clin Proc 2005 May; 80(5): 587–95PubMedCrossRefGoogle Scholar
  111. 111.
    Davidson MH, Maccubbin D, Stepanavage M, et al. Striated muscle safety of ezetimibe/simvastatin (Vytorin). Am J Cardiol 2006 Jan 15; 97(2): 223–8PubMedCrossRefGoogle Scholar
  112. 112.
    Conard SE, Bays HE, Leiter LA, et al. Efficacy and safety of ezetimibe added on to atorvastatin (20 mg) versus uptitration of atorvastatin (to 40mg) in hypercholesterolemic patients at moderately high risk for coronary heart disease. Am J Cardiol 2008 Dec 1; 102(11): 1489–94PubMedCrossRefGoogle Scholar
  113. 113.
    Leiter LA, Bays H, Conard S, et al. Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with uptitration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol 2008; 102: 1495–501PubMedCrossRefGoogle Scholar
  114. 114.
    Davidson MH, Armani A, McKenney JM, et al. Safety considerations with fibrate therapy. Am J Cardiol 2007; 99 Suppl.: 3–18CCrossRefGoogle Scholar
  115. 115.
    Spence JD, Munoz CE, Hendricks L, et al. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol 1995; 76 Suppl.: 80–3ACrossRefGoogle Scholar
  116. 116.
    McKenney JM, Davidson MH, Jacobson TA, et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006; 97 Suppl.: 89–94CCrossRefGoogle Scholar
  117. 117.
    Chatzizisis YS, Misirli G, Hatzitolios AI, et al. The syndrome of rhabdomyolysis: complications and treatment. Eur J Intern Med 2008; 19(8): 568–74PubMedCrossRefGoogle Scholar
  118. 118.
    Stein EA, Ballantyne CM, Windler E, et al. Efficacy and tolerability of fluvastatin XL 80mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins. Am J Cardiol 2008; 101: 490–6PubMedCrossRefGoogle Scholar
  119. 119.
    Glueck CJ, Aregawi D, Agloria M, et al. Rosuvastatin 5 and 10mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies. Clin Ther 2006; 28: 933–42PubMedCrossRefGoogle Scholar
  120. 120.
    Matalka MS, Ravnan MC, Deedwania PC. Is alternate daily dose of atorvastatin effective in treating patients with hyperlipidemia? The Alternate Day Versus Daily Dosing of Atorvastatin Study (ADDAS). Am Heart J 2002; 144: 674–7PubMedGoogle Scholar
  121. 121.
    Juszczyk MA, Seip RL, Thompson PD. Decreasing LDL cholesterol and medication cost with every-other-day statin therapy. Prev Cardiol 2005; 8: 197–9PubMedCrossRefGoogle Scholar
  122. 122.
    Athyros VG, Tziomalos K, Kakafika AI, et al. Effectiveness of ezetimibe alone or in combination with twice a week atorvastatin (10mg) for statin intolerant high-risk patients. Am J Cardiol 2008; 101(4): 483–5PubMedCrossRefGoogle Scholar
  123. 123.
    Backes JM, Venero CV, Gibson CA, et al. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. Ann Pharmacother 2008; 42: 341–6PubMedCrossRefGoogle Scholar
  124. 124.
    Backes JM, Moriarty PM, Ruisinger JF, et al. Effects of once weekly rosuvastatin among patients with a prior statin intolerance. Am J Cardiol 2007; 100: 554–5PubMedCrossRefGoogle Scholar
  125. 125.
    Mackie BD, Satija S, Nell C, et al. Monday, Wednesday, and Friday dosing of rosuvastatin in patients previously intolerant to statin therapy [letter]. Am J Cardiol 2007; 99: 291PubMedCrossRefGoogle Scholar
  126. 126.
    Gadarla M, Kearns A, Thompson PD. Efficacy of rosuvastatin (5mg and 10mg) twice a week in patients intolerant to daily statins. Am J Cardiol 2008; 10(12): 1747–8CrossRefGoogle Scholar
  127. 127.
    Gazi IF, Daskalopoulou SS, Nair DR, et al. Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin. Curr Med Res Opin 2007; 23: 2183–92PubMedCrossRefGoogle Scholar
  128. 128.
    Rivers SM, Kane MP, Busch RS, et al. Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance. Endocr Pract 2007; 13: 11–6PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Yiannis S. Chatzizisis
    • 1
    • 2
  • Konstantinos C. Koskinas
    • 2
  • Gesthimani Misirli
    • 1
  • Chris Vaklavas
    • 3
  • Apostolos Hatzitolios
    • 4
  • George D. Giannoglou
    • 1
  1. 1.1st Cardiology DepartmentAHEPA University Hospital, Aristotle University Medical SchoolThessalonikiGreece
  2. 2.Cardiovascular DivisionBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Department of Internal MedicineUniversity of Texas Medical School at HoustonHoustonUSA
  4. 4.1st Propedeutic Department of Internal MedicineAHEPA University Hospital, Aristotle University Medical SchoolThessalonikiGreece

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