Нежелательные эффекты терапии статинами: реальные доказательства


Цитировать

Полный текст

Аннотация

Цель. Осветить современные представления о переносимости и безопасности терапии статинами. Материалы и методы. Рассмотрены данные 73 научных источников, опубликованных в российской и зарубежной печати в 1996-2018 гг. Результаты. Общепризнанно, что статины - препараты 1-й линии терапии для лечения гиперхолестеринемии и комбинированной гиперлипидемии. К настоящему времени накоплено достаточно доказательств, подтверждающих, что снижение уровня холестерина липопротеидов низкой плотности предотвращает появление атеросклеротических заболеваний, уменьшает риск сердечно-сосудистой и общей смертности. Основные проблемы современной терапии статинами связаны с назначением их в неадекватных дозах для профилактики атеросклеротических заболеваний, низкой приверженностью и непереносимостью. Проблема непереносимости статинов стала актуальной в последние годы. Предложены критерии ее определения, рядом экспертов предлагается заменить понятие «непереносимость статинов» термином «статин-ассоциированные побочные эффекты». Наиболее часто обсуждаемыми нежелательными эффектами статинов являются мышечные симптомы (миалгии/миопатии), гепатотоксичность (печеночная гиперферментемия), развитие новых случаев сахарного диабета и деменции, когнитивные нарушения. Механизмы развития этих нежелательных эффектов до сих пор неясны. Выделяют определенные факторы и состояния, способные спровоцировать появление тех или иных нежелательных эффектов, а также абсолютные противопоказания к терапии статинами. Возникновение нежелательных эффектов на терапии статинами зависит от дозы статина, возраста пациента, пола, коморбидности и сопутствующей терапии. Многие нежелательные эффекты статинов носят класс-эффект. В то же время каждый из статинов имеет особенности структуры и метаболизма, взаимодействия с другими лекарственными препаратами, разные фармакокинетические характеристики. Питавастатин - статин последнего поколения с отличительными фармакологическими особенностями, нейтральным диабетогенным эффектом и т.д. Развитие нежелательных эффектов на статинах часто преувеличено, а польза от их приема в предупреждении атеросклеротических заболеваний превышает возможные риски. Истинное появление некоторых нежелательных эффектов на терапии статинами требует дополнительных доказательств. Заключение. В целом статины имеют хороший профиль переносимости и разрешены к назначению большинству пациентов, нуждающихся в гиполипидемической терапии.

Об авторах

Марина Геннадьевна Бубнова

ФГБУ НМИЦ ПМ

Email: mbubnova@gnicpm.ru
д-р мед. наук, проф., рук. отд. реабилитации и вторичной профилактики сочетанной патологии с лаб. профилактики атеросклероза и тромбоза 10, 3, Petroverigskii ln., Moscow, 101990, Russian Federation

Список литературы

  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

© ООО "Эко-Вектор", 2019

Creative Commons License
Эта статья доступна по лицензии Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Данный сайт использует cookie-файлы

Продолжая использовать наш сайт, вы даете согласие на обработку файлов cookie, которые обеспечивают правильную работу сайта.

О куки-файлах