Adverse effects of statin therapy: real evidence

Abstract


Aim. To provide a current view on the tolerability and safety of statin therapy. Materials and methods. The data of 73 scientific sources from Russian and foreign literature published within 1996-2018 are considered. Results. It is generally accepted that statins are first-line therapeutic agents for hypercholesterolemia and combined hyperlipidemia. Today there in growing evidence that lowering of low-density lipoprotein cholesterol levels prevents atherosclerotic diseases and reduces a risk of cardiovascular and overall mortality. Main issues of current statin therapy include a use of inadequate dosage for atherosclerotic diseases prevention, low treatment compliance and drug intolerance. In recent years the issue of statin intolerance has become of great importance. Criteria were proposed for determining an inability to tolerate statins, some experts suggest replacing definition of “statin intolerance” with the term “statin-associated side-effects”. Most discussed adverse effects due to statins include muscle-related symptoms (myalgia/myopathy), hepatotoxicity (hepatic hyperenzymemia) new-onset diabetes, dementia and cognitive impairment. Mechanisms of development of these adverse effects are still unclear. Certain factors and conditions capable of triggering some adverse effects as well as absolute contraindications to statin therapy were established. Some factors and conditions capable of triggering some adverse effects as well as absolute contraindications to statin therapy were identified. Occurrence of statin-associated side-effects depends on statin dose, a patient's age, gender, comorbidity and concomitant therapy. Many adverse effects of statins are drug class effect. At the same time each of statins has specific features of its structure, metabolism, drug interactions and pharmacokinetics. Pitavastatin belongs to the last generation of statins and it has distinct pharmacological features and neutral diabetogenic effects, etc. Risk of adverse effects due to statins is often exaggerated while benefit from the use of statins for preventing atherosclerotic diseases outweighs potential risks. Real occurrence of some adverse effects due to statin therapy requires additional evidence. Conclusion. Overall, statins have a good tolerability profile and are approved for use in the vast majority of patients who required lipid-lowering therapy.

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About the authors

Marina G. Bubnova

National Medical Research Center for Preventive Medicine of the Ministry of Health of the Russian Federation

Email: mbubnova@gnicpm.ru
10, 3, Petroverigskii ln., Moscow, 101990, Russian Federation
D. Sci. (Med.), Head of the Department of Rehabilitation and Secondary Prevention of Combined Pathology with a Laboratory Prevention of Atherosclerosis and Thrombosis

References

  1. Ference B.A, Ginsberg H.N, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017; 38: 2459-72. doi: 10.1093/eurheartj/ ehx144
  2. Baigent C, Blackwell L, Emberson J et al. Cholesterol Treatment Trialists’ (CTT) Collaboration, 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: 1670-81. doi: 10.1016/S0140-6736(10)61350-5
  3. Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem 2007; 40: 575-84. doi: 10.1016/j.clinbiochem
  4. Catapano A.L, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2016; 37: 2999-3058. doi: 10.1093/eurheartj/ ehw272.
  5. Sirtori C.R. The pharmacology of statins. Pharmacol Res 2014; 88: 3-11.
  6. Catapano A.L. Pitavastatin: a different pharmacological profile. Clin Lipidol 2012; 7 (3): 3-9.
  7. Banach M, Stulc T, Dent R et al. Statin non-adherence and residual cardiovascular risk: there is need for substantial improvement. Int J Cardiol 2016; 225: 184-96.
  8. Бубнова М.Г., Аронов Д.М., Деев А.Д. Терапия статинами в реальной клинической практике у пожилых пациентов с гиперлипидемией и коронарной болезнью сердца. Российская программа ЭФФОРТ. Атеросклероз и дислипидемии. 2018; 1: 5-16.
  9. Ward N.C, Watts G.F, Eckel R.H. Statin Toxicity Mechanistic Insights and Clinical Implications. Сirc Res 2019; 124: 328-50. doi: 10.1161/CIRCRESAHA.118.312782
  10. Toth P.P, Patti A.M, Giglio R.V et al. Management of Statin Intolerance in 2018: Still More Questions Than Answers. Am J Cardiovasc Drugs https://doi.org/10.1007/s40256-017-0259-7
  11. Tobert J.A, Newman C.B. Statin tolerability: in defence of placebocontrolled trials. Eur J Prev Cardiol 2016; 23: 891-6. doi: 10.1177/2047487315602861
  12. Banach M, Rizzo M, Toth P.P et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci 2015; 11: 1-23. doi: 10.5114/aoms.2015.49807
  13. Tobert J.A, Newman C.B. The nocebo effect in the context of statin intolerance. J Clin Lipidol 2016; 10: 739-47.
  14. Gupta A, Thompson D, Whitehouse A et al. ASCOT Investigators. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet 2017; 389: 2473-81. doi: 10.1016/S0140-6736(17)31075-9
  15. Nissen S.E. Statin denial: an internet-driven cult with deadly consequences. Ann Intern Med 2017; 167: 281-2.
  16. Khan S, Holbrook A, Shah B.R. Does Googling lead to statin intolerance? Int J of Cardiol 2018; 25: 25-7. doi: 10.1016/j.ijcard.2018.02.085
  17. Penson P.E, Mancini G.B.J, Toth P.P et al. Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group & International Lipid Expert Panel (ILEP). Introducing the ‘Drucebo’ effect in statin therapy: a systematic review of studies comparing reported rates of statin-associated muscle symptoms, under blinded and open-label conditions. J Cachexia Sarcopenia Muscle 2018; 9: 1023-33. doi: 10.1002/jcsm.12344
  18. Guyton J.R, Bays H.E, Grundy S.M, Jacobson T.A. The national lipid association statin intolerance panel. An assessment by thestatin intolerance panel: 2014 update. J Clin Lipidol 2014; 8 (Suppl. 3): S72-81.
  19. Grundy S.M, Stone N.J, Bailey A.L et al. 2018 AHA/ACC/AACVPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA Guideline on the Management of Blood Cholesterol: а report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018. doi: 10.1161/CIR.0000000000000625
  20. Cohen J.D, Brinton E.A, Ito M.K, Jacobson T.A. Understanding statin use in America and gaps in patient education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol 2012; 6: 208-15.
  21. Chodick G, Shalev V, Gerber Y et al. Longterm persistence with statin treatment in a not-for-profit health maintenance organization: a population-based retrospective cohort study in Israel. Clin Ther 2008; 30: 2167-79.
  22. Law M, Rudnicka A.R. Statin safety: a systematic review. Am J Cardiol 2006; 97: 52C-60C.
  23. Rosenson R.S, Baker S.K, Jacobson T.A et al. The National Lipid Association’s Muscle Safety Expert P. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol 2014; 8: S58-S71.
  24. Stroes E.S, Thompson P.D, Corsini A et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, A etiology and Management. Eur Heart J 2015; 36: 1012-22.
  25. Newman C.B, Preiss D, Tobert J.А et al. Statin Safety and Associated Adverse Events A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2018; 38: e00-e00. doi: 10.1161/ATV.0000000000000073
  26. Rosenson R.S, Miller K, Bayliss M et al. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): revision for clinical use, content validation, and interrater reliability. Cardiovasc Drugs Ther 2017; 31: 179-86.
  27. Muntean D.M, Thompson P.D, Catapano A.L et al. Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms? Drug Discov Today 2017; 22: 85-96. doi: 10.1016/j.drudis.2016.09.001
  28. Elam M.B, Majumdar G, Mozhui K et al. Patients experiencing statin induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge. PLoS One 2017; 12: e0181308. doi: 10.1371/journal.pone.0181308
  29. Brunham L.R, Baker S, Mammen A et al. Role of genetics in the prediction of statin-associatedmuscle symptoms and optimization of statin use and adherence. Cardiovasc Res 2018; 114: 1073-81. doi: 10.1093/cvr/cvy119
  30. De Pinieux G, Chariot P, Ammi-Sand M et al. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol 1996; 42: 333-7.
  31. Calvano J, Achanzar W, Murphy B et al. Evaluation of micro-RNAs-208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats. Toxicol Appl Pharmacol 2016; 312: 53-60.
  32. Davidson M.H, Robinson J.G. Safety of aggressive lipid management. J Am Coll Cardiol 2007; 49: 1753-62.
  33. 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 2014; 8: S47-S57.
  34. Mach F, Ray K.K, Wiklund O et al. European Atherosclerosis Society Consensus Panel. Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J 2018; 39: 2526-39. doi: 10.1093/eurheartj/ehy182
  35. Catapano A.L, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2016; 37: 2999-3058.
  36. Pastori D, Polimeni L, Baratta F et al. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 2015; 47: 4-11.
  37. Kim R.G, Loomba R, Prokop L.J, Singh S. Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017; 15: 1521-30.
  38. Sattar N, Preiss D, Murray H.M et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet 2010; 375: 735-42.
  39. Preiss D, Seshasai S.R, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a metaanalysis. JAMA 2011; 305: 2556-64.
  40. Waters D.D, Ho J.E, DeMicco D.A et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol 2011; 57: 1535-45.
  41. Cederberg H, Stanca´kova A, Yaluri N et al. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia 2015; 58: 1109-17.
  42. Nielsen S.F, Nordestgaard B.G. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol 2014; 2: 894-900.
  43. Betteridge D.J, Carmena R. The diabetogenic action of statins-mechanisms and clinical implications. Nat Rev Endocrinol 2016; 12: 90-110.
  44. Swerdlow D.I, Preiss D, Kuchenbaecker K.B et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015; 385: 351-61.
  45. Vallejo-Vaz A.J, Kondapally Seshasai S.R, Kurogi K et al. Effect of pitavastatin on glucose, HbA1c and incident diabetes: a meta-analysis of randomized controlled clinical trials in individuals without diabetes. Atherosclerosis 2015; 241: 409-18. doi: 10.1016/j.atherosclerosis. 2015.06.001
  46. Simons M, Keller P, Dichgans J, Schulz J.B. Cholesterol and Alzheimer’s disease: is there a link? Neurology 2001; 57: 1089-93.
  47. U.S. Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. 2012 https://www.fda.gov/drugs/ drugsafety/ucm293101.htm (14 September 2017).
  48. Richardson K, Schoen M, French B et al. Statins and cognitive function: a systematic review. Ann Intern Med 2013; 159: 688-97.
  49. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo controlled trial. Lancet 2002; 360: 7-22.
  50. Trompet S, van Vliet P, de Craen A.J. et al. Pravastatin and cognitive function in the elderly. Results of the PROSPER study. J Neurol 2010; 257: 85-90.
  51. Ott B.R, Daiello L.A, Dahabreh I.J et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med 2015; 30: 348-58.
  52. Song Y, Nie H, Xu Y et al. Association of statin use with risk of dementia: a meta-analysis of prospective cohort studies. Ger Gerontol Int 2013; 13: 817-24.
  53. Wolozin B, Kellman W, Ruosseau P et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000; 57: 1439-43.
  54. Giugliano R.P, Wiviott S.D, Blazing M.A et al. Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol a prespecified analysis of the IMPROVE-IT trial. JAMA Cardiol 2017; 2: 547-55.
  55. Giugliano R.P, Pedersen T.R, Park J.G et al. FOURIER Investigators. Clinical efficacy and safety of achieving very low LDLcholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017; 390: 1962-71.
  56. Giugliano R.P, Mach F, Zavitz K et al. EBBINGHAUS Investigators. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017; 377: 633-43.
  57. Kastelein J.J, Braamskamp M. Pitavastatin: an overview of the LIVES study. Clin Lipidol 2012; 7 (3 Suppl. 1): 25-31.
  58. Teramoto T. Pitavastatin: clinical effects from the LIVES Study. Atheroscler Suppl. 2011; 12: 285-8.
  59. Kurihara Y, Douzono T, Kawakita K, Nagasaka Y. A large-scale, long-term, prospective postmarketing surveillance of pitavastatin (LIVALO Tablet) - LIVALO Effectiveness and Safety (LIVES) Study. Jpn Pharmacol Ther 2008; 36: 709-31.
  60. Taguchi I, Iimuro S, Iwata H et al. High dose versus low-dose pitavastatin in Japanese patients with stable coronary artery disease (REAL-CAD): a randomized superiority trial. Circulation 2018; 137: 1997-2009. doi: 10.1161/circulationaha.117.032615
  61. Takano H, Mizuma H, Kuwabara Y et al. Оn behalf of the PEARL Study Investigators Effects of Pitavastatin in Japanese Patients With Chronic Heart Failure. The Pitavastatin Heart Failure Study (PEARL Study). Circ J 2013; 77: 917-25.
  62. Hiro T, Kimura T, Morimoto T et al. for the JAPAN-ACS Investigators. 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: 293-302.
  63. Hyogo H, Ikegami T, Tokushige K et al. Efficacy of pitavastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: an open-label, pilot study. Hepatol Res 2011; 41: 1057-65.
  64. Vallejo-Vaz A.J, Kondapally Seshasai S.R, Kurogi K et al. Effect of pitavastatin on glucose, HbA1c and incident diabetes: a meta-analysis of randomized controlled clinical trials in individuals without diabetes. Atherosclerosis 2015; 241: 409-18. doi: 10.1016/j.atherosclerosis. 2015.06.001
  65. Teramoto T, Shimano H, Yokote K, Urashima M. New evidence on pitavastatin: efficacy and safety in clinical studies. Exp Opin Pharmacother 2010; 11: 817-28.
  66. J-PREDICT Study Group: Japan Prevention Trial of Diabetes by Pitavastatin in Patients with Impaired Glucose Tolerance (J-PREDICT) http://clinicaltrials.gov/ct2/show/NCT00301392.
  67. Chapman M.J, Orsoni A, Robillard P et al. Effect of high-dose pitavastatin on glucose homeostasis in patients at elevated risk of new-onset diabetes: insights from the CAPITAIN and PREVAIL-US studies. Curr Med Res Opin 2014; 1-10.
  68. Huang C, Huang Y, Hsu B. Pitavastatin improves glycated hemoglobin in patients with poorly controlled type 2 diabetes. Diabetes Invest 2016; 7: 769-76.
  69. Wang Y, Fu X, Gu X, et al. Effects of intensive pitavastatin therapy on glucose control in patients with non-ST elevation acute coronary syndrome. Am J Cardiovasc Dis 2017; 7(4): 89-96.
  70. Drew B.G, Rye K.A, Duffy S.J et al. The emerging role of HDL in glucose metabolism. Nat Rev Endocrinol 2012; 8: 237-45.
  71. Wu X, Yu Z, Su W et al. Low levels of ApoA1 improve risk prediction of type 2 diabetes mellitus. J Clinic Lipidol 2017. http://creativecommons.org/licenses/by-nc-nd/4.0/
  72. Li S, Shin H.J, Ding E.L, van Dam R.M. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2009; 302: 179-88.
  73. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy [published correction appears in Lancet. 2017; 389: 602]. Lancet 2016; 388: 2532-61. doi: 10.1016/S0140-6736(16)31357-5

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