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Molecular & Cellular Toxicology

, Volume 15, Issue 1, pp 9–17 | Cite as

Statin-induced liver and muscle toxicities

  • Wang-Soo LeeEmail author
  • Jaetaek KimEmail author
Review Paper
  • 24 Downloads

Abstract

Purpose of review

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are a class of lipid-lowering medications by inhibiting the enzyme HMG-CoA reductase. Statins are important drugs for the prevention of cardiovascular disease. The prominent value of statins is well established during the past three decades. The efficacy and safety of statins have been evaluated in many large randomized controlled trials.

Recent findings

Currently, emerging concerns with statin-induced liver toxicity (SILT) and muscle toxicity (SIMT) have been introduced. However, exact mechanisms of SILT and SIMT have not been well understood. Moreover, there is an increasing concern currently about their safety associated with genetic polymorphisms. Thus, this article reviews the mechanisms of statin-drug interactions and their adverse effects with a particular focus on SILT and SIMT. It is recommended that the specific pharmacology for the different statins should be understood to maximize their benefit and minimize statin-induced toxicity. Significant toxicity may be induced by statin-drug interactions, and understanding how certain drugs interact with statins will help physicians in safely prescribing these agents.

Keywords

Hydroxymethylglutaryl-CoA reductase inhibitors Muscular diseases Chemical and drug induced liver injury 

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References

  1. 1.
    Wooten, J. M. A brief drug class review: Considerations for statin use, toxicity, and drug interactions. South Med J 111, 39–44 (2018).CrossRefGoogle Scholar
  2. 2.
    Endo, A., Kuroda, M. & Tanzawa, K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 72, 323–326 (1976).CrossRefGoogle Scholar
  3. 3.
    Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172 (2015).CrossRefGoogle Scholar
  4. 4.
    Endo, A. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci 8, 484–493 (2010).CrossRefGoogle Scholar
  5. 5.
    Collins, R. et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 388, 2532–2561 (2016).CrossRefGoogle Scholar
  6. 6.
    Wang, C. Y., Liu, P. Y. & Liao, J. K. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med 14, 37–44 (2008).CrossRefGoogle Scholar
  7. 7.
    Bays, H., Cohen, D. E., Chalasani, N., Harrison, S. A. & The National Lipid Association’s Statin Safety Task Force. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol 8, S47–S57 (2014).Google Scholar
  8. 8.
    Patel, A. M. et al. Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study. Ann Intern Med 158, 869–876 (2013).CrossRefGoogle Scholar
  9. 9.
    Stancu, C. & Sima, A. Statins: mechanism of action and effects. J Cell Mol Med 5, 378–387 (2001).CrossRefGoogle Scholar
  10. 10.
    Miller, P. E. & Martin, S. S. Approach to statin use in 2016: an update. Curr Atheroscler Rep 18, 20 (2016).CrossRefGoogle Scholar
  11. 11.
    Causevic-Ramosevac, A. & Semiz, S. Drug interactions with statins. Acta Pharm 63, 277–293 (2013).CrossRefGoogle Scholar
  12. 12.
    Wiggins, B. S. et al. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation 134, e468–e495 (2016).CrossRefGoogle Scholar
  13. 13.
    Gavronski, M. et al. Potential drug interactions with statins: Estonian register-based study. Open Med (Wars) 10, 254–260 (2015).Google Scholar
  14. 14.
    Bellosta, S. & Corsini, A. Statin drug interactions and related adverse reactions. Expert Opin Drug Saf 11, 933–946 (2012).CrossRefGoogle Scholar
  15. 15.
    Kalliokoski, A. & Niemi, M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 158, 693–705 (2009).CrossRefGoogle Scholar
  16. 16.
    Karahalil, B. et al. Hepatotoxicity associated with statins. Arh Hig Rada Toksikol 68, 254–260 (2017).CrossRefGoogle Scholar
  17. 17.
    Cueto, R. et al. Statins: hepatic disease and hepatotoxicity risk. Open Gastroenterol J 2, 18–23 (2008).CrossRefGoogle Scholar
  18. 18.
    Abdoli, N., Azarmi, Y. & Eghbal, M. A. Protective effects of N-acetylcysteine against the statins cytotoxicity in freshly isolated rat hepatocytes. Adv Pharm Bull 4, 249–254 (2014).Google Scholar
  19. 19.
    Tolosa, L., Carmona, A., Castell, J. V., Gómez-Lechón, M. J. & Donato, M. T. High-content screening of druginduced mitochondrial impairment in hepatic cells: effects of statins. Arch Toxicol 89, 1847–1860 (2015).CrossRefGoogle Scholar
  20. 20.
    Chalasani, N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepat 41, 690–695 (2005).CrossRefGoogle Scholar
  21. 21.
    de Denus, S., Spinler, S. A., Miller, K. & Peterson, A. M. Statins and liver toxicity: a meta-analysis. Pharmacotherapy 24, 584–591 (2004).CrossRefGoogle Scholar
  22. 22.
    Kirchheiner, J. et al. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterollowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther 74, 186–194 (2003).CrossRefGoogle Scholar
  23. 23.
    Flockhart, D. A. & Rae, J. M. Cytochrome P450 3A pharmacogenetics: the road that needs traveled. Pharmacogenom J 3, 3–5 (2003).CrossRefGoogle Scholar
  24. 24.
    Chalasani, N. & Björnsson, E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 138, 2246–2259 (2010).CrossRefGoogle Scholar
  25. 25.
    Zhong, G. et al. Meta-analysis of studies using statins as a reducer for primary liver cancer risk. Sci Rep 6, 26256 (2016).CrossRefGoogle Scholar
  26. 26.
    Kim, H., Kim, N., Lee, D. H. & Kim, H. S. Analysis of national pharmacovigilance data associated with statin use in Korea. Basic Clin Pharmacol Toxicol 121, 409–413 (2017).CrossRefGoogle Scholar
  27. 27.
    Russo, M. W. et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepat 60, 679–686 (2014).CrossRefGoogle Scholar
  28. 28.
    Perdices, E. V. et al. Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry. Rev Esp Enferm Dig 106, 246–254 (2014).Google Scholar
  29. 29.
    Thapar, M., Russo, M. W. & Bonkovsky, H. L. Statins and liver injury. Gastroenterol Hepatol (N Y) 9, 605–606 (2013).Google Scholar
  30. 30.
    Committee for the Korean Guidelines for the Management of Dyslipidemia. 2015 Korean Guidelines for the Management of Dyslipidemia: Executive Summary (English Translation). Korean Circ J 46, 275–306 (2016).Google Scholar
  31. 31.
    Hong, J. Y., Kim, H. S. & Choi, I. Y. Pilot algorithm designed to help early detection of HMG-CoA reductase inhibitor-induced hepatotoxicity. Healthc Inform Res 23, 199–207 (2017).CrossRefGoogle Scholar
  32. 32.
    Jose, J. Statins and its hepatic effects: Newer data, implications, and changing recommendations. J Pharm Bioallied Sci 8, 23–28 (2016).CrossRefGoogle Scholar
  33. 33.
    Reuben, A., Koch, D. G., Lee, W. M. & Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 52, 2065–2076 (2010).CrossRefGoogle Scholar
  34. 34.
    Russo, M. W., Scobey, M. & Bonkovsky, H. L. Druginduced liver injury associated with statins. Semin Liver Dis 29, 412–422 (2009).CrossRefGoogle Scholar
  35. 35.
    Selva-O’Callaghan, A. et al. Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. Expert Rev Clin Immunol 14, 215–224 (2018).CrossRefGoogle Scholar
  36. 36.
    Ramachandran, R. & Wierzbicki, A. S. Statins, muscle disease and mitochondria. J Clin Med 6, 75 (2017).CrossRefGoogle Scholar
  37. 37.
    Stroes, E. S. et al. European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel statement on assessment, aetiology and management. Eur Heart J 36, 1012–1022 (2015).Google Scholar
  38. 38.
    Sakamoto, K. & Kimura, J. Mechanism of statin-induced rhabdomyolysis. J Pharmacol Sci 123, 289–294 (2013).CrossRefGoogle Scholar
  39. 39.
    Backes, J. M., Ruisinger, J. F., Gibson, C. A. & Moriarty, P. M. Statin-associated muscle symptoms-managing the highly intolerant. J Clin Lipidol 11, 24–33 (2017).CrossRefGoogle Scholar
  40. 40.
    SEARCH Collaborative Group et al. SLCO1B1 variants and statin-induced myopathy genome wide study. N Engl J Med 359, 789–799 (2008).Google Scholar
  41. 41.
    Canestaro, W. J., Austin, M. A. & Thummel, K. E. Genetic factors affecting statin concentrations and subsequent myopathy: A HuGENet systematic review. Genet Med 16, 810–819 (2014).CrossRefGoogle Scholar
  42. 42.
    Mangravite, L. M. et al. A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature 502, 377–380 (2013).CrossRefGoogle Scholar
  43. 43.
    Du Souich, P., Roederer, G. & Dufour, R. Myotoxicity of statins: Mechanism of action. Pharmacol Ther 175, 1–16 (2017).CrossRefGoogle Scholar
  44. 44.
    Apostolopoulou, M., Corsini, A. & Roden, M. The role of mitochondria in statin-induced myopathy. Eur J Clin Investig 45, 745–754 (2015).CrossRefGoogle Scholar
  45. 45.
    Sirvent, P., Mercier, J. & Lacampagne, A. New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol 8, 333–338 (2008).CrossRefGoogle Scholar
  46. 46.
    Hou, T., Li, Y., Chen, W., Heffner, R. R. & Vladutiu, G. D. Histopathologic and biochemical evidence for mitochondrial disease among 279 patients with severe statin myopathy. J Neuromuscul Dis 4, 77–87 (2017).CrossRefGoogle Scholar
  47. 47.
    Kaufmann, P. et al. Toxicity of statins on rat skeletal muscle mitochondria. Cell Mol Life Sci 63, 2415–2425 (2006).CrossRefGoogle Scholar
  48. 48.
    Sirvent, P. et al. Simvastatin induces impairment in skeletal muscle while heart is protected. Biochem Biophys Res Commun 338, 1426–1434 (2005).CrossRefGoogle Scholar
  49. 49.
    Nakahara, K., Yada, T., Kuriyama, M. & Osame, M. Cytosolic Ca2+ increase and cell damage in L6 rat myoblasts by HMG-CoA reductase inhibitors. Biochem Biophys Res Commun 202, 1579–1585 (1994).CrossRefGoogle Scholar
  50. 50.
    Inoue, R. et al. Ca2+-releasing effect of cerivastatin on the sarcoplasmic reticulum of mouse and rat skeletal muscle fibers. J Pharmacol Sci 93, 279–288 (2003).CrossRefGoogle Scholar
  51. 51.
    Subramanian, R., Fang, X. & Prueksaritanont, T. Structural characterization of in vivo rat glutathione adducts and a hydroxylated metabolite of simvastatin hydroxy acid. Drug Metab Dispos 30, 225–230 (2002).CrossRefGoogle Scholar
  52. 52.
    Schirris, T. J. et al. Statin-induced myopathy is associated with mitochondrial complex III inhibition. Cell Metab 22, 399–407 (2015).CrossRefGoogle Scholar
  53. 53.
    Paiva, H. et al. High-dose statins and skeletal muscle metabolism in humans: A randomized, controlled trial. Clin Pharmacol Ther 78, 60–68 (2005).CrossRefGoogle Scholar
  54. 54.
    Stringer, H. A., Sohi, G. K., Maguire, J. A. & Cote, H. C. Decreased skeletal muscle mitochondrial DNA in patients with statin-induced myopathy. J Neurol Sci 325, 142–147 (2013).CrossRefGoogle Scholar
  55. 55.
    Mullen, P. J. et al. Susceptibility to simvastatin-induced toxicity is partly determined by mitochondrial respiration and phosphorylation state of Akt. Biochim Biophys Acta 1813, 2079–2087 (2011).CrossRefGoogle Scholar
  56. 56.
    Bonifacio, A. et al. Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo. Arch Toxicol 90, 203–215 (2016).CrossRefGoogle Scholar
  57. 57.
    Bouitbir, J. et al. Opposite effects of statins on mitochondria of cardiac and skeletal muscles: A ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1. Eur Heart J 33, 1397–1407 (2012).CrossRefGoogle Scholar
  58. 58.
    Mallinson, J. E. et al. Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents. J Physiol 590, 6389–6402 (2012).CrossRefGoogle Scholar
  59. 59.
    Goodman, C. A. et al. Statin-induced increases in atrophy gene expression occur independently of changes in PGC1alpha protein and mitochondrial content. PLoS ONE 10, e0128398 (2015).CrossRefGoogle Scholar
  60. 60.
    Hafizi Abu Bakar, M. et al. Mitochondrial dysfunction as a central event for mechanisms underlying insulin resistance: The roles of long chain fatty acids. Diabetes Metab Res Rev 31, 453–475 (2015).CrossRefGoogle Scholar
  61. 61.
    Wierzbicki, A. S., Poston, R. & Ferro, A. The lipid and non-lipid effects of statins. Pharmacol Ther 99, 95–112 (2003).CrossRefGoogle Scholar
  62. 62.
    Banach, M. et al. Effects of coenzyme Q10 on statin-induced myopathy: A meta-analysis of randomized controlled trials. Mayo Clin Proc 90, 24–34 (2015).CrossRefGoogle Scholar
  63. 63.
    Mammen, A. L. et al. Increased frequency of DRB1* 11:01 in anti hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Res (Hoboken) 64, 1233–1237 (2012).CrossRefGoogle Scholar
  64. 64.
    Patel, J., Superko, H. R., Martin, S. S., Blumenthal, R. S. & Christopher-Stine, L. Genetic and immunologic susceptibility to statin-related myopathy. Atherosclerosis 240, 260–271 (2015).CrossRefGoogle Scholar
  65. 65.
    Tiniakou, E. et al. More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Rheumatology (Oxford) 56, 787–794 (2017).Google Scholar
  66. 66.
    Wang, T. H. & Lin, T. F. Monascus rice products. Adv Food Nutr Res 53, 123–159 (2007).CrossRefGoogle Scholar
  67. 67.
    Zhao, Z. J., Pan, Y. Z., Liu, Q. J. & Li, X. H. Exposure assessment of lovastatin in Pu-erh tea. Int J Food Microbiol 164, 26–31 (2013).CrossRefGoogle Scholar
  68. 68.
    Mancini, G. B. et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 29, 1553–1568 (2013).CrossRefGoogle Scholar
  69. 69.
    Mancini, G. B. et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Consensus Working Group update. Can J Cardiol 32, S35–65 (2016).CrossRefGoogle Scholar
  70. 70.
    Rosenson, R. S. et al. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol 8, S58–71 (2014).CrossRefGoogle Scholar
  71. 71.
    Taylor, F. et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 1, CD004816 (2013).Google Scholar
  72. 72.
    Bruckert, E., Hayem, G., Dejager, S., Yau, C. & Bégaud, B. Mild to moderate muscular symptoms with highdosage statin therapy in hyperlipidemic patients -the PRIMO study. Cardiovasc Drugs Ther 19, 403–414 (2005).CrossRefGoogle Scholar
  73. 73.
    El-Salem, K. et al. Prevalence and risk factors of muscle complications secondary to statins. Muscle Nerve 44, 877–881 (2011).CrossRefGoogle Scholar
  74. 74.
    Parker, B. A. et al. Effect of statins on skeletal muscle function. Circulation 127, 96–103 (2013).CrossRefGoogle Scholar
  75. 75.
    Christopher-Stine, L. et al. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 62, 2757–2766 (2010).CrossRefGoogle Scholar
  76. 76.
    Nazir, S., Lohani, S., Tachamo, N., Poudel, D. & Donato, A. Statin-associated autoimmune myopathy: a systematic review of 100 cases. J Clin Rheumatol 23, 149–154 (2017).CrossRefGoogle Scholar
  77. 77.
    Selva-O’Callaghan, A., Alvarado-Cardenas, M., Marin, A. & Pinal-Fernandez, I. Statins and myositis: the role of anti-HMGCR antibodies. Expert Rev Clin Immunol 11, 1277–1279 (2015).CrossRefGoogle Scholar
  78. 78.
    Floyd, J. S., Brody, J. A., Tiniakou, E., Psaty, B. M. & Mammen, A. Absence of anti-HMG-CoA reductase autoantibodies in severe self-limited statin-related myopathy. Muscle Nerve 54, 142–144 (2016).CrossRefGoogle Scholar
  79. 79.
    Law, M. & Rudnicka, A. R. Statin safety: a systematic review. Am J Cardiol 97, 52C–60C (2006).CrossRefGoogle Scholar
  80. 80.
    Bosch, X., Poch, E. & Grau, J. M. Rhabdomyolysis and acute kidney injury. N Engl J Med 361, 62–72 (2009).CrossRefGoogle Scholar

Copyright information

© The Korean Society of Toxicogenomics and Toxicoproteomics and Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Division of Cardiology, Department of Internal Medicine, College of MedicineChung-Ang UniversitySeoulRepublic of Korea
  2. 2.Division of Endocrinology and Metabolism, Department of Internal Medicine, College of MedicineChung-Ang UniversitySeoulRepublic of Korea

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