Ezetimibe in optimal lipid-lowering therapy: concerted stances and controversial issues
V.S. Gurevich1,2
1St. Petersburg State University
2North-Western State Medical University named after I.I. Mechnikov, Saint Petersburg
Nowadays, the incidence and mortality by clinical atherosclerosis complications remain high. Therefore, the search for new approaches to the pharmacological correction of atherogenic dyslipidemia is relevant. Currently, lipid-lowering therapy is based on a number of drugs with different mechanisms of action and comparable efficacy and safety characteristics. The article is devoted to assessing the efficacy and safety of an intestinal cholesterol absorption inhibitor — ezetimibe, which is currently widely used in combined lipid-lowering therapy. Clinical study results on the ezetimibe use in combination with statins in patients with various cardiovascular risk categories are analyzed. The article also discusses the ezetimibe benefits in combination with minimal and medium statin doses to achieve target levels of lipid parameters and to reduce the side effects risk of first-line drugs as well as the data on the ezetimibe effectiveness in cardiovascular patients with concomitant type 2 diabetes mellitus and chronic kidney disease. The necessary background about ezetimibe in current Russian and foreign guidelines on the correction of lipid metabolism disorders for prevention and treatment of clinical atherosclerosis complications is presented.
Keywords: ezetimibe, combined lipid-lowering therapy, target lipid levels, cardiovascular risk categories.
For citation: Gurevich V.S. Ezetimibe in optimal lipid-lowering therapy: concerted stances and controversial issues. RMJ. Medical Review. 2019;6:11–16.
References
1. Муромцева Г.А., Концевая А.В., Константинов В.В. и др. Распространенность факторов риска неинфекционных заболеваний в российской популяции в 2012–2013 гг. Результаты исследования ЭССЕ-РФ. Кардиоваскулярная терапия и профилактика. 2014;13(6):4–11 [Muromtseva G.A., Kontsevaya A.V., Konstantinov V.V. et al. The prevalence of risk factors for noncommunicable diseases in the Russian population in 2012–2013. The results of the ESSE-RF study. Cardiovascular therapy and prevention. 2014;13(6):4–11 (in Russ.)].
2. Ахмеджанов Н.М., Небиеридзе Д.В., Сафарян А.С. и др. Анализ исследования АРГО: часть I. Рациональная фармакотерапия в кардиологии. 2015;11(3):252–259 [Akhmedzhanov N.М., Nebieridze D.V., Safaryan A.S. et al. Analysis of the ARGO study: part I. Rational pharmacotherapy in cardiology. 2015;11(3):252–259 (in Russ.)].
3. Уразгильдеева С.А., Нижегородцев М.Ю., Садовников П.С. и др. Возрастные и гендерные особенности липидного спектра крови городских жителей (по результатам кросс-секционного исследования). Рациональная фармакотерапия в кардиологии. 2017;13(5):637–644 [Urazgildeeva S.A., Nizhegorodtsev M.Yu., Sadovnikov P.S. et al. Age and gender features of the blood lipid spectrum in urban residents (according to the results of a cross-sectional study). Rational pharmacotherapy in cardiology. 2017;13(5):637–644 (in Russ.)].
4. Catapano A., Graham I., deBacker G.D. et al. 2016 ESC/EAS Guidelines for the Management of Dyslipideamias. The Task Force for the management of Dyslipideamias. Eur Heart J.2016; 37(39): 2999–3058.
5. Ежов М.В., Сергиенко И.В., Аронов Д.М. и др. Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации, VI пересмотр. Атеросклероз и дислипидемии. 2017;3:3–22 [Yezhov, M.V., Sergienko, I.V., Aronov, D.M. and others. Diagnosis and correction of lipid metabolism disorders for the prevention and treatment of atherosclerosis. Russian recommendations, VI revision. Atherosclerosis and dyslipidemia. 2017;3:3–22 (in Russ.)].
6. Оганов Р.Г., Кухарчук В.В., Арутюнов Г.П. и др. Сохраняющиеся нарушения показателей липидного спектра у пациентов с дислипидемией, получающих статины, в реальной клинической практике в Российской Федерации (российская часть исследования DYSIS). Кардиоваскулярная терапия и профилактика. 2012;11(4)1–10 [Oganov R.G., Kukharchuk V.V., Arutyunov G.P. et al. Continued impairment of lipid profile in patients with dyslipidemia receiving statins in actual clinical practice in the Russian Federation (the Russian part of the DYSIS study). Cardiovascular therapy and prevention, 2012;11(4):1–10 (in Russ.)].
7. Kotseva K., De Backer G., De Bacquer D. et al. Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: Results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry. Eur J Prev Cardiol. 2019;26(8):824–835. DOI: 10.1177/2047487318825350.
8. Ference B., Ginsberg H., Kausik 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(32):2459–2472. DOI: 10.1093/eurheartj/ehx144.
9. Egom E.E., Hafeez H. Biochemistry of Statins. Adv Clin Chem. 2016;73:127–168.
10. Ge L., Wang J., Qi W. et al. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metab. 2008;7:508–519.
11. Cannon C.P., Giugliano R.P., Blazing M.A. et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes:Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatinversus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J. 2008;156:826–832.
12. Mach F., Ray K.K., Wiklund O. et al. 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(27):2526–2539.
13. Sattar N., Preiss D., Murrey H. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–742.
14. Liang X., He Q., Zhao Q. Effect of Stains on LDL Reduction and Liver Safety: A Systematic Review and Meta-Analysis. Biomed Res Int. 2018;2018:7092414. DOI: 10.1155/2018/7092414. eCollection 2018.
15. Nissen S. Statin intolerance. An elusive but morbid disorder. JACC 2017;69(11):1396–1398.
16. Ежов М., Бажан С.С., Ершова А.И. и др. Клинические рекомендации по семейной гиперхолестеринемии. Атеросклероз и дислипидемии. 2019;1:1–43 [Yezhov M., Bazhan S.S., Ershova A.I. et al. Clinical guidelines on familial hypercholesterolemia. Atherosclerosis and dyslipidemia. 2019;1:1–43 (in Russ.)].
17. Ballantyne C.M., Houri J., Notarbartolo A. et al. Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107(19): 2409–2415.
18. Ballantyne C.M., Weiss R., Mossetti T. et al. Efficacy and Safety of Rosuvastatin 40 mg Alone or in Combination with Ezetimibe in Patients at High Risk of Cardiovascular Disease (Results from the Explorer Study). Am J Cardiol. 2007;99:673–680.
19. Baigent C., Landray M.J., Reith C. et al The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–2192.
20. Tsujita K., Sugiyama S., Sugida H. et.al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention. JACC. 2015; 66(5):495–507.
21. Toth P.P., Morrone D., Weintraub W.S. et al. Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6–24 weeks. Int J Clin Praсt. 2012;66(8):800–813.
22. Liu Z., Hao H., Yin C. et al. Therapeutic effects of atorvastatin and ezetimibe compared with double-dose atorvastatin in very elderly patients with acute coronary syndrome. Oncotarget. 2017; 8(25):41582–41589.
23. Sager P.T., Melani L., Lipka L. et al. Effect of coadministration of ezetimib and simvastatin on high-density sensitivity C-reactive protein. Am J Cardiol. 2003;1414–1418.
24. Tsunoda T., Nozue T., Yamada M. et al. Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. Diabetes Res Clin Pract. 2013;100(1):46–52.
25. Yagi S., Akaike M., Aihara K. et al. Ezetimibe ameliorates metabolic disorders and microalbuminuria in patients with hypercholesterolemia. J. Atheroscler. Thromb. 2010;17(2):173–180.
26. Толкачева В.В., Малая И.П., Багманова Н.Х. и др. Изучение биоэквивалентности препаратов эзетимиба у здоровых добровольцев после однократного приема натощак. Consilium Medicum. 2019;21(1):87–91 [Tolkacheva V.V., Malaya I.P., Bagmanova N.Kh. et al. Study of the bioequivalence of ezetimibe preparations in healthy volunteers after a single fasting dose. Consilium Medicum. 2019;21(1):87–91 (in Russ.)].
27. Сусеков А.В., Кобалава Ж.Д., Гуревич В.С. и др. Возможности клинического применения препарата эзетимиба Отрио (АО «АКРИХИН», Россия) у пациентов высокого и очень высокого сердечно-сосудистого риска, не достигших целевых значений показателей липидного обмена. Заключение Совета экспертов. Кардиология. 2019;59(5S):47–57 [Susekov A.V., Kobalava J.D., Gurevich V.S. et al. Possibilities of clinical use of the drug ezetimiba Otrio (AKRIKHIN JSC, Russia) in patients of high and very high cardiovascular risk who have not reached the target values of lipid metabolism. Conclusion of the Council of Experts. Cardiology. 2019;59(5S):47–57 (in Russ.)].
2. Ахмеджанов Н.М., Небиеридзе Д.В., Сафарян А.С. и др. Анализ исследования АРГО: часть I. Рациональная фармакотерапия в кардиологии. 2015;11(3):252–259 [Akhmedzhanov N.М., Nebieridze D.V., Safaryan A.S. et al. Analysis of the ARGO study: part I. Rational pharmacotherapy in cardiology. 2015;11(3):252–259 (in Russ.)].
3. Уразгильдеева С.А., Нижегородцев М.Ю., Садовников П.С. и др. Возрастные и гендерные особенности липидного спектра крови городских жителей (по результатам кросс-секционного исследования). Рациональная фармакотерапия в кардиологии. 2017;13(5):637–644 [Urazgildeeva S.A., Nizhegorodtsev M.Yu., Sadovnikov P.S. et al. Age and gender features of the blood lipid spectrum in urban residents (according to the results of a cross-sectional study). Rational pharmacotherapy in cardiology. 2017;13(5):637–644 (in Russ.)].
4. Catapano A., Graham I., deBacker G.D. et al. 2016 ESC/EAS Guidelines for the Management of Dyslipideamias. The Task Force for the management of Dyslipideamias. Eur Heart J.2016; 37(39): 2999–3058.
5. Ежов М.В., Сергиенко И.В., Аронов Д.М. и др. Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации, VI пересмотр. Атеросклероз и дислипидемии. 2017;3:3–22 [Yezhov, M.V., Sergienko, I.V., Aronov, D.M. and others. Diagnosis and correction of lipid metabolism disorders for the prevention and treatment of atherosclerosis. Russian recommendations, VI revision. Atherosclerosis and dyslipidemia. 2017;3:3–22 (in Russ.)].
6. Оганов Р.Г., Кухарчук В.В., Арутюнов Г.П. и др. Сохраняющиеся нарушения показателей липидного спектра у пациентов с дислипидемией, получающих статины, в реальной клинической практике в Российской Федерации (российская часть исследования DYSIS). Кардиоваскулярная терапия и профилактика. 2012;11(4)1–10 [Oganov R.G., Kukharchuk V.V., Arutyunov G.P. et al. Continued impairment of lipid profile in patients with dyslipidemia receiving statins in actual clinical practice in the Russian Federation (the Russian part of the DYSIS study). Cardiovascular therapy and prevention, 2012;11(4):1–10 (in Russ.)].
7. Kotseva K., De Backer G., De Bacquer D. et al. Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: Results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry. Eur J Prev Cardiol. 2019;26(8):824–835. DOI: 10.1177/2047487318825350.
8. Ference B., Ginsberg H., Kausik 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(32):2459–2472. DOI: 10.1093/eurheartj/ehx144.
9. Egom E.E., Hafeez H. Biochemistry of Statins. Adv Clin Chem. 2016;73:127–168.
10. Ge L., Wang J., Qi W. et al. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metab. 2008;7:508–519.
11. Cannon C.P., Giugliano R.P., Blazing M.A. et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes:Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatinversus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J. 2008;156:826–832.
12. Mach F., Ray K.K., Wiklund O. et al. 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(27):2526–2539.
13. Sattar N., Preiss D., Murrey H. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–742.
14. Liang X., He Q., Zhao Q. Effect of Stains on LDL Reduction and Liver Safety: A Systematic Review and Meta-Analysis. Biomed Res Int. 2018;2018:7092414. DOI: 10.1155/2018/7092414. eCollection 2018.
15. Nissen S. Statin intolerance. An elusive but morbid disorder. JACC 2017;69(11):1396–1398.
16. Ежов М., Бажан С.С., Ершова А.И. и др. Клинические рекомендации по семейной гиперхолестеринемии. Атеросклероз и дислипидемии. 2019;1:1–43 [Yezhov M., Bazhan S.S., Ershova A.I. et al. Clinical guidelines on familial hypercholesterolemia. Atherosclerosis and dyslipidemia. 2019;1:1–43 (in Russ.)].
17. Ballantyne C.M., Houri J., Notarbartolo A. et al. Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107(19): 2409–2415.
18. Ballantyne C.M., Weiss R., Mossetti T. et al. Efficacy and Safety of Rosuvastatin 40 mg Alone or in Combination with Ezetimibe in Patients at High Risk of Cardiovascular Disease (Results from the Explorer Study). Am J Cardiol. 2007;99:673–680.
19. Baigent C., Landray M.J., Reith C. et al The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–2192.
20. Tsujita K., Sugiyama S., Sugida H. et.al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention. JACC. 2015; 66(5):495–507.
21. Toth P.P., Morrone D., Weintraub W.S. et al. Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6–24 weeks. Int J Clin Praсt. 2012;66(8):800–813.
22. Liu Z., Hao H., Yin C. et al. Therapeutic effects of atorvastatin and ezetimibe compared with double-dose atorvastatin in very elderly patients with acute coronary syndrome. Oncotarget. 2017; 8(25):41582–41589.
23. Sager P.T., Melani L., Lipka L. et al. Effect of coadministration of ezetimib and simvastatin on high-density sensitivity C-reactive protein. Am J Cardiol. 2003;1414–1418.
24. Tsunoda T., Nozue T., Yamada M. et al. Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. Diabetes Res Clin Pract. 2013;100(1):46–52.
25. Yagi S., Akaike M., Aihara K. et al. Ezetimibe ameliorates metabolic disorders and microalbuminuria in patients with hypercholesterolemia. J. Atheroscler. Thromb. 2010;17(2):173–180.
26. Толкачева В.В., Малая И.П., Багманова Н.Х. и др. Изучение биоэквивалентности препаратов эзетимиба у здоровых добровольцев после однократного приема натощак. Consilium Medicum. 2019;21(1):87–91 [Tolkacheva V.V., Malaya I.P., Bagmanova N.Kh. et al. Study of the bioequivalence of ezetimibe preparations in healthy volunteers after a single fasting dose. Consilium Medicum. 2019;21(1):87–91 (in Russ.)].
27. Сусеков А.В., Кобалава Ж.Д., Гуревич В.С. и др. Возможности клинического применения препарата эзетимиба Отрио (АО «АКРИХИН», Россия) у пациентов высокого и очень высокого сердечно-сосудистого риска, не достигших целевых значений показателей липидного обмена. Заключение Совета экспертов. Кардиология. 2019;59(5S):47–57 [Susekov A.V., Kobalava J.D., Gurevich V.S. et al. Possibilities of clinical use of the drug ezetimiba Otrio (AKRIKHIN JSC, Russia) in patients of high and very high cardiovascular risk who have not reached the target values of lipid metabolism. Conclusion of the Council of Experts. Cardiology. 2019;59(5S):47–57 (in Russ.)].
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