Atherosclerosis
Volume 195, Issue 1 , Pages 7-16 , November 2007

Statin-associated adverse effects beyond muscle and liver toxicity

  • D.N. Kiortsis

      Affiliations

    • Laboratory of Physiology, Medical School, University of Ioannina, Ioannina, Greece
    • ,
  • T.D. Filippatos

      Affiliations

    • Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
    • ,
  • D.P. Mikhailidis

      Affiliations

    • Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free & University College Medical School, London, UK
    • ,
  • M.S. Elisaf

      Affiliations

    • Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
    • Corresponding Author InformationCorresponding author. Tel.: +30 26510 97509; fax: +30 26510 97016.
    • ,
  • E.N. Liberopoulos

      Affiliations

    • Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece

Received 5 August 2006 ,Revised 17 September 2006 ,Accepted 2 October 2006.

References 

  1. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–1009
  2. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389
  3. Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18:220–228
  4. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711–1718
  5. Newman CB, Palmer G, Silbershatz H, Szarek M. Safety of atorvastatin derived from analysis of 44 completed trials in 9416 patients. Am J Cardiol. 2003;92:670–676
  6. Pasternak RC, Smith SC, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Stroke. 2002;33:2337–2341
  7. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol. 1998;81:582–587
  8. Ballantyne CM, Blazing MA, Hunninghake DB, et al. Effect on high-density lipoprotein cholesterol of maximum dose simvastatin and atorvastatin in patients with hypercholesterolemia: results of the Comparative HDL Efficacy and Safety Study (CHESS). Am Heart J. 2003;146:862–869
  9. El-Hajj II, Mourad FH, Shabb NS, Barada KA. Atorvastatin-induced severe gastric ulceration: a case report. World J Gastroenterol. 2005;11:3159–3160
  10. Batey RG, Harvey M. Cholestasis associated with the use of pravastatin sodium. Med J Aust. 2002;176:561
  11. Yoshida EM, Levin A. Lovastatin and cholestasis. CMAJ. 1993;148:374
  12. Rea WE, Durrant DC, Boldy DA. Ulcerative colitis after statin treatment. Postgrad Med J. 2002;78:286–287
  13. Miltiadous G, Anthopoulou A, Elisaf M. Acute pancreatitis possibly associated with combined salicylate and atorvastatin therapy. JOP. 2003;4:20–21
  14. Tysk C, Al-Eryani AY, Shawabkeh AA. Acute pancreatitis induced by fluvastatin therapy. J Clin Gastroenterol. 2002;35:406–408
  15. Pezzilli R, Ceciliato R, Corinaldesi R, Barakat B. Acute pancreatitis due to simvastatin therapy: increased severity after rechallenge. Dig Liver Dis. 2004;36:639–640
  16. Johnson JL, Loomis IB. A case of simvastatin-associated pancreatitis and review of statin-associated pancreatitis. Pharmacotherapy. 2006;26:414–422
  17. Singh S, Nautiyal A, Dolan JG. Recurrent acute pancreatitis possibly induced by atorvastatin and rosuvastatin. Is statin induced pancreatitis a class effect?. JOP. 2004;5:502–504
  18. Lons T, Chousterman M. Simvastatin: a new drug responsible for acute pancreatitis?. Gastroenterol Clin Biol. 1991;15:93–94[in French]
  19. Belaiche G, Ley G, Slama JL. Acute pancreatitis associated with atorvastatin therapy. Gastroenterol Clin Biol. 2000;24:471–472[in French]
  20. Singh S. Drug induced pancreatitis might be a class effect of statin drugs. JOP. 2005;6:380
  21. Anagnostopoulos GK, Tsiakos S, Margantinis G, Kostopoulos P, Arvanitidis D. Acute pancreatitis due to pravastatin therapy. JOP. 2003;4:129–132
  22. Thisted H, Jacobsen J, Munk EM, et al. Statins and the risk of acute pancreatitis: a population-based case–control study. Aliment Pharmacol Ther. 2006;23:185–190
  23. Segal AS. Alopecia associated with atorvastatin. Am J Med. 2002;113:171
  24. Krasovec M, Elsner P, Burg G. Generalized eczematous skin rash possibly due to HMG-CoA reductase inhibitors. Dermatology. 1993;186:248–252
  25. Mehregan DR, Mehregan DA, Pakideh S. Cheilitis due to treatment with simvastatin. Cutis. 1998;62:197–198
  26. Pua VS, Scolyer RA, Barnetson RS. Pravastatin-induced lichenoid drug eruption. Australas J Dermatol. 2006;47:57–59
  27. Adcock BB, Hornsby LB, Jenkins K. Dermographism: an adverse effect of atorvastatin. J Am Board Fam Pract. 2001;14:148–151
  28. Anliker MD, Wuthrich B. Chronic urticaria to atorvastatin. Allergy. 2002;57:366
  29. Pfeiffer CM, Kazenoff S, Rothberg HD. Toxic epidermal necrolysis from atorvastatin. JAMA. 1998;279:1613–1614
  30. Gerson RJ, MacDonald JS, Alberts AW, et al. On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase inhibitors. Exp Eye Res. 1990;50:65–78
  31. Adamska-Dyniewska H, Chojnowska-Jezierska J, Cybulska B, et al. Lovastatin in the treatment of hypercholesterolemia. Pol Arch Med Wewn. 1994;92:54–62[in Polish]
  32. Bousquet E, Amar J, Salvador M, Chamontin B. Cataract and simvastatin: case report. Therapie. 1998;53:505–507[in French]
  33. Schlienger RG, Haefeli WE, Jick H, Meier CR. Risk of cataract in patients treated with statins. Arch Intern Med. 2001;161:2021–2026
  34. Smeeth L, Hubbard R, Fletcher AE. Cataract and the use of statins: a case–control study. QJM. 2003;96:337–343
  35. Klein BE, Klein R, Lee KE, Grady LM. Statin use and incident nuclear cataract. JAMA. 2006;295:2752–2758
  36. Fraunfelder FW. Ocular hemorrhage possibly the result of HMG-CoA reductase inhibitors. J Ocul Pharmacol Ther. 2004;20:179–182
  37. Bucca C, Marsico A, Panaro E, Bigo P, Brussino L. Statins and nasal polyps. Ann Intern Med. 2005;142:310–311
  38. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ. 1990;301:309–314
  39. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22
  40. 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;366:1267–1278
  41. Muldoon MF, Manuck SB, Mendelsohn AB, Kaplan JR, Belle SH. Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials. BMJ. 2001;322:11–15
  42. Keller S, Frishman WH. Neuropsychiatric effects of cardiovascular drug therapy. Cardiol Rev. 2003;11:73–93
  43. Stewart RA, Sharples KJ, North FM, et al. Long-term assessment of psychological well-being in a randomized placebo-controlled trial of cholesterol reduction with pravastatin. The LIPID Study Investigators. Arch Intern Med. 2000;160:3144–3152
  44. Boumendil E, Tubert-Bitter P. Depression-induced absenteeism in relation to antihyperlipidemic treatment: a study using GAZEL cohort data. Epidemiology. 1995;6:322–325
  45. Duits N, Bos FM. Depressive symptoms and cholesterol-lowering drugs. Lancet. 1993;341:114
  46. Rosenson RS, Goranson NL. Lovastatin-associated sleep and mood disturbances. Am J Med. 1993;95:548–549
  47. Ehrenberg BL, Lamon-Fava S, Corbett KE, et al. Comparison of the effects of pravastatin and lovastatin on sleep disturbance in hypercholesterolemic subjects. Sleep. 1999;22:117–121
  48. Gregoor PJ. Atorvastatin may cause nightmares. BMJ. 2006;332:950
  49. Boriani G, Biffi M, Strocchi E, Branzi A. Nightmares and sleep disturbances with simvastatin and metoprolol. Ann Pharmacother. 2001;35:1292
  50. Vgontzas AN, Kales A, Bixler EO, Manfredi RL, Tyson KL. Effects of lovastatin and pravastatin on sleep efficiency and sleep stages. Clin Pharmacol Ther. 1991;50:730–737
  51. Roth T, Richardson GR, Sullivan JP, et al. Comparative effects of pravastatin and lovastatin on nighttime sleep and daytime performance. Clin Cardiol. 1992;15:426–432
  52. Orsi A, Sherman O, Woldeselassie Z. Simvastatin-associated memory loss. Pharmacotherapy. 2001;21:767–769
  53. King DS, Wilburn AJ, Wofford MR, et al. Cognitive impairment associated with atorvastatin and simvastatin. Pharmacotherapy. 2003;23:1663–1667
  54. Bollen EL, Gaw A, Buckley BM. Statin therapy and the prevention of dementia. Arch Neurol. 2001;58:1023–1024
  55. Etminan M, Gill S, Samii A. The role of lipid-lowering drugs in cognitive function: a meta-analysis of observational studies. Pharmacotherapy. 2003;23:726–730
  56. Gurm HS, Hoogwerf B. The Heart Protection Study: high-risk patients benefit from statins, regardless of LDL-C level. Cleve Clin J Med. 2003;70:991–997
  57. Liberopoulos EN, Mikhailidis DP. Could statins be useful in the treatment of patients with migraine?. Headache. 2006;46:672–675
  58. Ramsey CS, Snyder QC. Altitude-induced migraine headache secondary to pravastatin: case report. Aviat Space Environ Med. 1998;69:603–606
  59. Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363:1607–1608
  60. Golomb BA, Criqui MH, White HL, Dimsdale JE. The UCSD Statin Study: a randomized controlled trial assessing the impact of statins on selected noncardiac outcomes. Contr Clin Trials. 2004;25:178–202
  61. Ahmad S. Lovastatin and peripheral neuropathy. Am Heart J. 1995;130:1321
  62. Chong PH, Boskovich A, Stevkovic N, Bartt RE. Statin-associated peripheral neuropathy: review of the literature. Pharmacotherapy. 2004;24:1194–1203
  63. Jeppesen U, Gaist D, Smith T, Sindrup SH. Statins and peripheral neuropathy. Eur J Clin Pharmacol. 1999;54:835–838
  64. Rajabally YA, Varakantam V, Abbott RJ. Disorder resembling Guillain–Barre syndrome on initiation of statin therapy. Muscle Nerve. 2004;30:663–666
  65. Gaist D, Garcia Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy?. Eur J Clin Pharmacol. 2001;56:931–933
  66. Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case–control study. Neurology. 2002;58:1333–1337
  67. Corrao G, Zambon A, Bertu L, et al. Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case–control study using automated databases. J Epidemiol Commun Health. 2004;58:1047–1051
  68. Anderson JL, Muhlestein JB, Bair TL, et al. Do statins increase the risk of idiopathic polyneuropathy?. Am J Cardiol. 2005;95:1097–1099
  69. Phan T, McLeod JG, Pollard JD, et al. Peripheral neuropathy associated with simvastatin. J Neurol Neurosurg Psychiatry. 1995;58:625–628
  70. Rosch PJ. Peripheral neuropathy. Lancet. 2004;364:1663–1664
  71. Jackson G. Erectile dysfunction and cardiovascular disease. Int J Clin Pract. 1999;53:363–368
  72. Rizvi K, Hampson JP, Harvey JN. Do lipid-lowering drugs cause erectile dysfunction? A systematic review. Fam Pract. 2002;19:95–98
  73. Bruckert E, Giral P, Heshmati HM, Turpin G. Men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. J Clin Pharm Ther. 1996;21:89–94
  74. Halkin A, Lossos IS, Mevorach D. HMG-CoA reductase inhibitor-induced impotence. Ann Pharmacother. 1996;30:192
  75. de Graaf L, Brouwers AH, Diemont WL. Is decreased libido associated with the use of HMG-CoA-reductase inhibitors?. Br J Clin Pharmacol. 2004;58:326–328
  76. Jay RH, Sturley RH, Stirling C, et al. Effects of pravastatin and cholestyramine on gonadal and adrenal steroid production in familial hypercholesterolaemia. Br J Clin Pharmacol. 1991;32:417–422
  77. Aerts J, Karmochkine M, Raguin G. Gynecomastia due to pravastatin. Presse Med. 1999;28:787;[in French]
  78. Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation. 2001;103:2248–2253
  79. Szczeklik A, Undas A, Musial J, et al. Antithrombotic actions of statins. Med Sci Monit. 2001;7:1381–1385
  80. Tsiara S, Elisaf M, Mikhailidis DP. Early vascular benefits of statin therapy. Curr Med Res Opin. 2003;19:540–556
  81. Liberopoulos EN, Daskalopoulou SS, Mikhailidis DP. Early statin therapy in patients with acute coronary syndrome. Hellenic J Cardiol. 2005;46:5–8
  82. Groneberg DA, Barkhuizen A, Jeha T. Simvastatin-induced thrombocytopenia. Am J Hematol. 2001;67:277
  83. McCarthy LJ, Porcu P, Fausel CA, Sweeney CJ, Danielson CF. Thrombotic thrombocytopenic purpura and simvastatin. Lancet. 1998;352:1284–1285
  84. Koduri PR. Simvastatin and thrombotic thrombocytopenic purpura. Lancet. 1998;352:2020
  85. Sundram F, Roberts P, Kennedy B, Pavord S. Thrombotic thrombocytopenic purpura associated with statin treatment. Postgrad Med J. 2004;80:551–552
  86. Nikolsky E, Sadeghi HM, Effron MB, et al. Impact of in-hospital acquired thrombocytopenia in patients undergoing primary angioplasty for acute myocardial infarction. Am J Cardiol. 2005;96:474–481
  87. Antons KA, Williams CD, Baker SK, Phillips PS. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med. 2006;119:400–409
  88. Agarwal R. Effects of statins on renal function. Am J Cardiol. 2006;97:748–755
  89. Vidt DG, Cressman MD, Harris S, Pears JS, Hutchinson HG. Rosuvastatin-induced arrest in progression of renal disease. Cardiology. 2004;102:52–60
  90. Kostapanos M, Milionis H, Gazi I, et al. Rosuvastatin increases alpha-1 microglobulin urinary excretion in patients with primary dyslipidemia. J Clin Pharmacology; in press.
  91. Weber MH, Verwiebe R. Alpha 1-microglobulin (protein HC): features of a promising indicator of proximal tubular dysfunction. Eur J Clin Chem Clin Biochem. 1992;30:683–691
  92. 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;15:2249–2257
  93. Sidaway JE, Davidson RG, McTaggart F, et al. Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase reduce receptor-mediated endocytosis in opossum kidney cells. J Am Soc Nephrol. 2004;15:2258–2265
  94. Agarwal R, Curley TM. The role of statins in chronic kidney disease. Am J Med Sci. 2005;330:69–81
  95. Tiwari A. An overview of statin-associated proteinuria. Drug Discov Today. 2006;11:458–464
  96. van Zyl-Smit R, Firth JC, Duffield M, Marais AD. Renal tubular toxicity of HMG-CoA reductase inhibitors. Nephrol Dial Transplant. 2004;19:3176–3179
  97. Tonolo G, Ciccarese M, Brizzi P, et al. Reduction of albumin excretion rate in normotensive microalbuminuric type 2 diabetic patients during long-term simvastatin treatment. Diabetes Care. 1997;20:1891–1895
  98. Tonolo G, Melis MG, Formato M, et al. Additive effects of simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients. Eur J Clin Invest. 2000;30:980–987
  99. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol. 2004;57:728–734
  100. Liberopoulos EN, Mikhailidis DP, Athyros VG, Elisaf MS. The effect of cholesterol-lowering treatment on renal function. Am J Kidney Dis. 2006;47:561
  101. Kakafika A, Liamis G, Elisaf M, Mikhailidis D. Effect of atorvastatin on serum creatinine levels. Curr Med Res Opin. 2001;17:230–231
  102. Elisaf M, Mikhailidis DP. Statins and renal function. Angiology. 2002;53:493–502
  103. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005–2016
  104. Tsouli SG, Liberopoulos EN, Athyros VG, Mikhailidis DP, Elisaf MS. Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander?. Metabolism. 2006;55:1293–1301
  105. Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis. 2004;43:589–599
  106. Kakafika A, Tsimihodimos V, Elisaf M. Effect of atorvastatin on serum uric acid levels. Atherosclerosis. 2001;158:255
  107. Milionis HJ, Kakafika AI, Tsouli SG, et al. Effects of statin treatment on uric acid homeostasis in patients with primary hyperlipidemia. Am Heart J. 2004;148:635–640
  108. Milionis HJ, Liberopoulos EN, Achimastos A, Elisaf MS, Mikhailidis DP. Statins: another class of antihypertensive agents?. J Hum Hypertens. 2006;20:320–335
  109. Hanson J, Bossingham D. Lupus-like syndrome associated with simvastatin. Lancet. 1998;352:1070
  110. Noel B, Panizzon RG. Lupus-like syndrome associated with statin therapy. Dermatology. 2004;208:276–277
  111. Quiceno GA, Cush JJ. Iatrogenic rheumatic syndromes in the elderly. Clin Geriatr Med. 2005;21:577–588vii
  112. Vasconcelos OM, Campbell WW. Dermatomyositis-like syndrome and HMG-CoA reductase inhibitor (statin) intake. Muscle Nerve. 2004;30:803–807
  113. Giordano N, Senesi M, Mattii G, et al. Polymyositis associated with simvastatin. Lancet. 1997;349:1600–1601
  114. Pelli N, Setti M. Atorvastatin as a trigger of autoimmune hepatitis. J Hepatol. 2004;40:716
  115. Wolters LM, Van Buuren HR. Rosuvastatin-associated hepatitis with autoimmune features. Eur J Gastroenterol Hepatol. 2005;17:589–590
  116. Liebhaber MI, Wright RS, Gelberg HJ, Dyer Z, Kupperman JL. Polymyalgia, hypersensitivity pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a report of ten cases. Chest. 1999;115:886–889
  117. Lantuejoul S, Brambilla E, Brambilla C, Devouassoux G. Statin-induced fibrotic nonspecific interstitial pneumonia. Eur Respir J. 2002;19:577–580
  118. McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363:2015–2021
  119. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–1630
  120. Bjerre LM, LeLorier J. Do statins cause cancer? A meta-analysis of large randomized clinical trials. Am J Med. 2001;110:716–723
  121. Poynter JN, Gruber SB, Higgins PD, et al. Statins and the risk of colorectal cancer. N Engl J Med. 2005;352:2184–2192
  122. Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA. 2006;295:74–80

PII: S0021-9150(06)00603-4

doi: 10.1016/j.atherosclerosis.2006.10.001

Atherosclerosis
Volume 195, Issue 1 , Pages 7-16 , November 2007

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