본문 바로가기
KERD
논문KCI 등재

Expanding the therapeutic landscape: ezetimibe as non-statin therapy for dyslipidemia

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류내과학

초록

Dyslipidemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), and statins are the primary therapeutic options for reducing low-density lipoprotein cholesterol (LDL-C) levels. However, it can be challenging to achieve optimal LDL-C goals with statin monotherapy. Ezetimibe, a cholesterol absorption inhibitor, offers a potential non-statin therapy to optimize LDL-C management. Key clinical trials, such as IMPROVE-IT and RACING, have demonstrated that the addition of ezetimibe to statin therapy leads to further decreases in LDL-C or significant decreases in major adverse cardiovascular events (MACEs), particularly in patients with high ASCVD risk. Subsequent meta-analyses and clinical trials have further supported the beneficial effect of ezetimibe, suggesting additive decreases in LDL-C and MACEs, as well as pleiotropic effects. This review provides a comprehensive analysis of the clinical implications of ezetimibe for managing dyslipidemia; it also evaluates the available evidence that supports the role of ezetimibe as an adjunct non-statin therapy for long-term use. However, the long-term pleiotropic effects of ezetimibe remain controversial because of limited clinical data. Therefore, additional research is needed to clarify its potential benefits beyond LDL-C reduction. Nonetheless, an understanding of the role of ezetimibe in dyslipidemia management will help clinicians to develop effective treatment strategies.

Abstract

Dyslipidemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), and statins are the primary therapeutic options for reducing low-density lipoprotein cholesterol (LDL-C) levels. However, it can be challenging to achieve optimal LDL-C goals with statin monotherapy. Ezetimibe, a cholesterol absorption inhibitor, offers a potential non-statin therapy to optimize LDL-C management. Key clinical trials, such as IMPROVE-IT and RACING, have demonstrated that the addition of ezetimibe to statin therapy leads to further decreases in LDL-C or significant decreases in major adverse cardiovascular events (MACEs), particularly in patients with high ASCVD risk. Subsequent meta-analyses and clinical trials have further supported the beneficial effect of ezetimibe, suggesting additive decreases in LDL-C and MACEs, as well as pleiotropic effects. This review provides a comprehensive analysis of the clinical implications of ezetimibe for managing dyslipidemia; it also evaluates the available evidence that supports the role of ezetimibe as an adjunct non-statin therapy for long-term use. However, the long-term pleiotropic effects of ezetimibe remain controversial because of limited clinical data. Therefore, additional research is needed to clarify its potential benefits beyond LDL-C reduction. Nonetheless, an understanding of the role of ezetimibe in dyslipidemia management will help clinicians to develop effective treatment strategies.

참고문헌 (92)

  1. Tsao CW, "Heart disease and stroke statistics-2022 update : a report from the American Heart Association", Circulation, 145, pp.e153~e639 (2022)
  2. Hyeok-Hee Lee, "Korea Heart Disease Fact Sheet 2020: Analysis of Nationwide Data", Korean Circulation Journal, 51(6), pp.495~503 (2021), 대한심장학회[DOI]
  3. Pirillo A, "Global epidemiology of dyslipidaemias", Nat Rev Cardiol, 18, pp.689~700 (2021)
  4. 조소미, "Dyslipidemia Fact Sheets in Korea 2020: an Analysis of Nationwide Population-based Data", 지질·동맥경화학회지, 10(2), pp.202~209 (2021), 한국지질동맥경화학회[DOI]
  5. Grundy SM, "2018 AHA", ACC, AAPA, pp.ABC, ACPM[DOI]
  6. Writing Committee, "2022 ACC expert consensus decision pathway for integrating atherosclerotic cardiovascular disease and multimorbidity treatment : a framework for pragmatic, patient-centered care : a report of the American College of Cardiology Solution Set Oversight Committee", J Am Coll Cardiol, 81, pp.292~317 (2023)
  7. Pearson GJ, "2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults", Can J Cardiol, 37, pp.1129~1150 (2021)
  8. Visseren FLJ, "2021 ESC Guidelines on cardiovascular disease prevention in clinical practice", Eur Heart J, 42, pp.3227~3337 (2021)
  9. Borén J, "Low-density lipoproteins cause atherosclerotic cardiovascular disease : pathophysiological, genetic, and therapeutic insights : a consensus statement from the European Atherosclerosis Society Consensus Panel", Eur Heart J, 41, pp.2313~2330 (2020)
  10. Kunutsor SK, "Further proof of a paradoxical relationship between high-density lipoprotein levels and adverse cardiovascular outcomes : are there implications for cardiovascular disease prevention?", Eur J Prev Cardiol, 30, pp.290~292 (2023)
  11. 이은정, "2018 Guidelines for the Management of Dyslipidemia in Korea", 지질·동맥경화학회지, 8(2), pp.78~131 (2019), 한국지질동맥경화학회[DOI]
  12. 이상학, "Dyslipidemia and Rate of Under-Target Low-Density Lipoprotein-Cholesterol in Patients with Coronary Artery Disease in Korea", 지질·동맥경화학회지, 8(2), pp.242~251 (2019), 한국지질동맥경화학회[DOI]
  13. 양여리, "High-Density Lipoprotein Cholesterol and the Risk of Myocardial Infarction, Stroke, and Cause-Specific Mortality: a Nationwide Cohort Study in Korea", 지질·동맥경화학회지, 10(1), pp.74~87 (2021), 한국지질동맥경화학회[DOI]
  14. 홍승표, "The Comparison of the Associations of Lipoprotein(a) and the Atherogenic Index of Plasma With Coronary Artery Calcification in Patients Without High LDL-C: A Comparative Analysis", 지질·동맥경화학회지, 12(2), pp.152~163 (2023), 한국지질동맥경화학회[DOI]
  15. 김경안, "New Therapeutic Approaches to the Treatment of Dyslipidemia 2: LDL-C and Lp(a)", 지질·동맥경화학회지, 12(1), pp.37~46 (2023), 한국지질동맥경화학회[DOI]
  16. Kim Kihyun, "Comparison of the Effects of Highintensity Statin Therapy with Moderate-Intensity Statin and Ezetimibe Combination Therapy on Major Adverse Cardiovascular Events in Patients with Acute Myocardial Infarction: a Nationwide Cohort Study", 지질·동맥경화학회지, 10(3), pp.291~302 (2021), 한국지질동맥경화학회[DOI]
  17. Grundy SM, "2018 American Heart Association", American College of Cardiology, JAMA Cardiol, pp.2019, 4[DOI]
  18. Mach F, "2019 ESC", EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk, 2020, pp.41, 111~188
  19. Handelsman Y, "Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the management of dyslipidemia and prevention of cardiovascular disease algorithm-2020 executive summary", Endocr Pract, 26, pp.1196~1224 (2020)
  20. Newman CB, "Lipid management in patients with endocrine disorders : an endocrine society clinical practice guideline", J Clin Endocrinol Metab, 105, pp.dgaa674~ (2020)
  21. Sweeney ME, "Ezetimibe : an update on the mechanism of action, pharmacokinetics and recent clinical trials", Expert Opin Drug Metab Toxicol, 3, pp.441~450 (2007)
  22. Zhang DW, "Binding of proprotein convertase subtilisin", kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation, 2007, pp.282, 18602~18612
  23. Cannon CP, "Ezetimibe added to statin therapy after acute coronary syndromes", N Engl J Med, 372, pp.2387~2397 (2015)
  24. Sabatine MS, "Evolocumab and clinical outcomes in patients with cardiovascular disease", N Engl J Med, 376, pp.1713~1722 (2017)
  25. Schwartz GG, "Alirocumab and cardiovascular outcomes after acute coronary syndrome", N Engl J Med, 379, pp.2097~2107 (2018)
  26. Schwartz GG, "Transiently achieved very low LDL-cholesterol levels by statin and alirocumab after acute coronary syndrome are associated with cardiovascular risk reduction:the ODYSSEY OUTCOMES trial", Eur Heart J, 44, pp.1408~1417 (2023)
  27. Pandor A, "Ezetimibe monotherapy for cholesterol lowering in 2, 722 people : systematic review and meta-analysis of randomized controlled trials", J Intern Med, 265, pp.568~580 (2009)
  28. Bytyçi I, "Prevalence of statin intolerance : a meta-analysis", Eur Heart J, 43, pp.3213~3223 (2022)
  29. Ara R, "Cost effectiveness of ezetimibe in patients with cardiovascular disease and statin intolerance or contraindications : a Markov model", Am J Cardiovasc Drugs, 8, pp.419~427 (2008)
  30. Nissen SE, "Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3randomized clinical trial", JAMA, 315, pp.1580~1590 (2016)
  31. Ouchi Y, "Ezetimibe lipid-lowering trial on prevention of atherosclerotic cardiovascular disease in 75or older(EWTOPIA 75) : a randomized, controlled trial", Circulation, 140, pp.992~1003 (2019)
  32. Maxfield FR, "Role of cholesterol and lipid organization in disease", Nature, 438, pp.612~621 (2005)
  33. Duan Y, "Regulation of cholesterol homeostasis in health and diseases : from mechanisms to targeted therapeutics", Signal Transduct Target Ther, 7, pp.265~ (2022)
  34. Lee J, "Effect of ezetimibe added to high-intensity statin therapy on low-density lipoprotein cholesterol levels : a meta-analysis", Cardiol Res, 12, pp.98~108 (2021)
  35. Gudzune KA, "Effectiveness of combination therapy with statin and another lipid-modifying agent compared with intensified statin monotherapy : a systematic review", Ann Intern Med, 160, pp.468~476 (2014)
  36. Toth PP, "Network meta-analysis of randomized trials evaluating the comparative efficacy of lipid-lowering therapies added to maximally tolerated statins for the reduction of low-density lipoprotein cholesterol", J Am Heart Assoc, 11, pp.e025551~ (2022)
  37. Baigent C, "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, 377, pp.2181~2192 (2011)
  38. Kouvelos GN, "Effects of rosuvastatin with or without ezetimibe on clinical outcomes in patients undergoing elective vascular surgery : results of a pilot study", J Cardiovasc Pharmacol Ther, 18, pp.5~12 (2013)
  39. Wang X, "Effects of combination of ezetimibe and rosuvastatin on coronary artery plaque in patients with coronary heart disease", Heart Lung Circ, 25, pp.459~465 (2016)
  40. Hagiwara N, "Low-density lipoprotein cholesterol targeting with pitavastatin + ezetimibe for patients with acute coronary syndrome and dyslipidaemia : the HIJ-PROPER study, a prospective, open-label, randomized trial", Eur Heart J, 38, pp.2264~2276 (2017)
  41. Liu Z, "Therapeutic effects of atorvastatin and ezetimibe compared with double-dose atorvastatin in very elderly patients with acute coronary syndrome", Oncotarget, 8, pp.41582~41589 (2017)
  42. Hibi K, "Effects of ezetimibe-statin combination therapy on coronary atherosclerosis in acute coronary syndrome", Circ J, 82, pp.757~766 (2018)
  43. Ogiso M, "Effect of aggressive lipid-lowering therapy in single-vessel vs. multivessel coronary artery disease patients with acute coronary syndrome -Heart Institute of Japan-Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome(HIJ-PROPER)Substudy", Circ Rep, 2, pp.128~134 (2020)
  44. Kim BK, "Longterm efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial", Lancet, 400, pp.380~390 (2022)
  45. Zhan S, "Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events", Cochrane Database Syst Rev, 11, pp.CD012502~ (2018)
  46. Bernardi S, "The complex interplay between lipids, immune system and interleukins in cardio-metabolic diseases", Int J Mol Sci, 19, pp.4058~ (2018)
  47. Kastelein JJ, "Simvastatin with or without ezetimibe in familial hypercholesterolemia", N Engl J Med, 358, pp.1431~1443 (2008)
  48. Howard BV, "Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes : the SANDS randomized trial", JAMA, 299, pp.1678~1689 (2008)
  49. Meaney A, "The VYtorin on Carotid intima-media thickness and overall arterial rigidity(VYCTOR)study", J Clin Pharmacol, 49, pp.838~847 (2009)
  50. Tsujita K, "Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial", J Am Coll Cardiol, 66, pp.495~507 (2015)
  51. Hougaard M, "Influence of ezetimibe in addition to high-dose atorvastatin therapy on plaque composition in patients with ST-segment elevation myocardial infarction assessed by serial : Intravascular ultrasound with iMap : the OCTIVUS trial", Cardiovasc Revasc Med, 18, pp.110~117 (2017)
  52. Newby AC, "Dual role of matrix metalloproteinases(matrixins)in intimal thickening and atherosclerotic plaque rupture", Physiol Rev, 85, pp.1~31 (2005)
  53. Tan H, "Effects of combined lipid-lowering therapy on low-density lipoprotein cholesterol variability and cardiovascular adverse events in patients with acute coronary syndrome", Adv Ther, 38, pp.3389~3398 (2021)
  54. Wolf D, "Immunity and Inflammation in Atherosclerosis", Circ Res, 124, pp.315~327 (2019)
  55. Ridker PM, "A test in context : high-sensitivity C-reactive protein", J Am Coll Cardiol, 67, pp.712~723 (2016)
  56. Luo P, "Effects of atorvastatin in combination with ezetimibe on carotid atherosclerosis in elderly patients with hypercholesterolemia", Genet Mol Res, 13, pp.2377~2384 (2014)
  57. Ren Y, "Comparison of the effect of rosuvastatin versus rosuvastatin", ezetimibe on markers of inflammation in patients with acute myocardial infarction, 2017, pp.14, 4942~4950
  58. Wang J, "Efficacy of ezetimibe combined with atorvastatin in the treatment of carotid artery plaque in patients with type 2 diabetes mellitus complicated with coronary heart disease", Int Angiol, 36, pp.467~473 (2017)
  59. Yang W, "Reduction of C-reactive protein, low-density lipoprotein cholesterol, and its relationship with cardiovascular events of different lipid-lowering therapies: A systematic review and meta-analysis of randomized controlled trials", Medicine(Baltimore), 101, pp.e30563~ (2022)
  60. Cho Y, "Effect of ezetimibe on glucose metabolism and inflammatory markers in adipose tissue", Biomedicines, 8, pp.512~ (2020)
  61. Sun C, "Ezetimibe improves rosuvastatin effects on inflammation and vascular endothelial function in acute coronary syndrome patients undergoing PCI", J Interv Cardiol, 2021, pp.2995602~ (2021)
  62. Krysiak R, "The effect of simvastatin-ezetimibe combination therapy on adipose tissue hormones and systemic inflammation in patients with isolated hypercholesterolemia", Cardiovasc Ther, 32, pp.40~46 (2014)
  63. Mostafa Arabi S, "The effect of combination therapy with statins and ezetimibe on proinflammatory cytokines : a systematic review and meta-analysis of randomized controlled trials", Int Immunopharmacol, 113(Pt B), pp.109477~ (2022)
  64. Hussein O, "Ezetimibe’s effect on platelet aggregation and LDL tendency to peroxidation in hypercholesterolaemia as monotherapy or in addition to simvastatin", Br J Clin Pharmacol, 65, pp.637~645 (2008)
  65. Pesaro AE, "Pleiotropic effects of ezetimibe", simvastatin vs. high dose simvastatin, 2012, pp.158, 400~404
  66. Moutzouri E, "Comparison of the effect of simvastatin versus simvastatin", ezetimibe versus rosuvastatin on markers of inflammation and oxidative stress in subjects with hypercholesterolemia, 2013, pp.231, 8~14
  67. Sakuma M, "Add-on ezetimibe treatment to low-dose statins vs medium-intensity statin monotherapy in coronary artery disease patients with poorly controlled dyslipidemia", Hypertens Res, 42, pp.1923~1931 (2019)
  68. Takase S, "Ezetimibe in combination with statins ameliorates endothelial dysfunction in coronary arteries after stenting : the CuVIC trial(effect of cholesterol absorption inhibitor usage on target vessel dysfunction after coronary stenting), a multicenter randomized controlled trial", Arterioscler Thromb Vasc Biol, 37, pp.350~358 (2017)
  69. Ridker PM, "Cardiovascular benefits and diabetes risks of statin therapy in primary prevention : an analysis from the JUPITER trial", Lancet, 380, pp.565~571 (2012)
  70. Cederberg H, "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, 58, pp.1109~1117 (2015)
  71. Agarwala A, "The association of statin therapy with incident diabetes : evidence, mechanisms, and recommendations", Curr Cardiol Rep, 20, pp.50~ (2018)
  72. Betteridge DJ, "The diabetogenic action of statins-mechanisms and clinical implications", Nat Rev Endocrinol, 12, pp.99~110 (2016)
  73. Her AY, "Effects of atorvastatin 20 mg, rosuvastatin 10 mg, and atorvastatin", ezetimibe 5 mg, J Cardiovasc Pharmacol Ther, pp.2010, 15[DOI]
  74. Adachi H, "Ezetimibe ameliorates atherogenic lipids profiles, insulin resistance and hepatocyte growth factor in obese patients with hypercholesterolemia", Lipids Health Dis, 14, pp.1~ (2015)
  75. Ohbu-Murayama K, "Ezetimibe combined with standard diet and exercise therapy improves insulin resistance and atherosclerotic markers in patients with metabolic syndrome", J Diabetes Investig, 6, pp.325~333 (2015)
  76. Takeshita Y, "The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism : a randomised controlled trial", Diabetologia, 57, pp.878~890 (2014)
  77. Zhong Y, "Effect of ezetimibe on insulin secretion in db", db diabetic mice, 2012, pp.2012, 420854~
  78. Zeng KY, "Non-invasive evaluation of liver steatosis with imaging modalities : new techniques and applications", World J Gastroenterol, 29, pp.2534~2550 (2023)
  79. Kim SH, "Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition", Autophagy, 13, pp.1767~1781 (2017)
  80. Park H, "Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease", J Gastroenterol, 46, pp.101~107 (2011)
  81. Simon TG, "The nonalcoholic fatty liver disease(NAFLD)fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe", Int J Cardiol, 270, pp.245~252 (2018)
  82. 이효영, "Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis", The Korean Journal of Internal Medicine, 34(2), pp.296~304 (2019), 대한내과학회[DOI]
  83. Cho Y, "Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease : an open-label randomized controlled trial(ESSENTIAL study)", BMC Med, 20, pp.93~ (2022)
  84. Stroes ES, "Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management", Eur Heart J, 36, pp.1012~1022 (2015)
  85. Cha JJ, "Effect of rosuvastatin 20 mg versus rosuvastatin 5 mg plus ezetimibe on statin side-effects in elderly patients with atherosclerotic cardiovascular disease : Rationale and design of a randomized, controlled SaveSAMS trial", Am Heart J, 261, pp.45~50 (2023)
  86. Davidson MH, "Striated muscle safety of ezetimibe", simvastatin(Vytorin), 2006, pp.97, 223~228
  87. Lee YJ, "Moderate-intensity statin with ezetimibe vs. high-intensity statin in patients with diabetes and atherosclerotic cardiovascular disease in the RACING trial", Eur Heart J, 44, pp.972~983 (2023)
  88. Dujovne CA, "Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia", Am J Cardiol, 90, pp.1092~1097 (2002)
  89. Phillips PS, "Ezetimibe and statin-associated myopathy", Ann Intern Med, 141, pp.649~ (2004)
  90. Fux R, "Ezetimibe and statin-associated myopathy", Ann Intern Med, 140, pp.671~672 (2004)
  91. Nutescu EA, "Ezetimibe : a selective cholesterol absorption inhibitor", Pharmacotherapy, 23, pp.1463~1474 (2003)
  92. Newman CB, "Safety of statins and nonstatins for treatment of dyslipidemia", Endocrinol Metab Clin North Am, 51, pp.655~679 (2022)

관련 논문AI추천

Pharmacological Strategies beyond Statins: Ezetimibe and PCSK9 Inhibitors나진오, 최자연한국지질동맥경화학회 · 지질·동맥경화학회지2019 · 제8권 제2호Efficacy and Safety of Moderate-Intensity Statin and Ezetimibe Combination Therapy Versus High-Intensity Statin Monotherapy in Patients With Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled TrialsMaryam Sarwar Khan, M Chadi Alraies, Moeed Abdul, Umar Muhammad, Yasmin Farah, Zaidi Farwa한국지질동맥경화학회 · 지질·동맥경화학회지2025 · 제14권 제2호Moderate-Intensity Rosuvastatin/Ezetimibe Combination versus Quadruple-Dose Rosuvastatin Monotherapy: A Meta-Analysis and Systemic Review강유라, 박정미, 이상학연세대학교의과대학 · Yonsei Medical Journal2024 · 제65권 제1호Lipid-Lowering Efficacy of Combination Therapy With Moderate-Intensity Statin and Ezetimibe Versus High-Intensity Statin Monotherapy: A Randomized, Open-Label, Non-Inferiority Trial From Korea연태진, 윤창환, 이준희, 임상욱, Cheol-Ho Kim, Dong Woon Jeon, Hyejung Choi, In-Ho Chae, Sang-Woo Jeong, Seong-Wook Cho, Si-Hyuck Kang, Woo-Hyuk Song한국지질동맥경화학회 · 지질·동맥경화학회지2023 · 제12권 제3호New Therapeutic Approaches to the Treatment of Dyslipidemia 2: LDL-C and Lp(a)김경안, 박훈준한국지질동맥경화학회 · 지질·동맥경화학회지2023 · 제12권 제1호What Do We Get from Recent Statin and CETP Inhibitors Trials?김병진한국지질동맥경화학회 · 지질·동맥경화학회지2018 · 제7권 제1호

이 간행물의 다른 논문 (19건)