EFFECTIVENESS OF EZETIMIBE IN ROUTINE CLINICAL PRACTICE
Main Article Content
Abstract
Atherosclerosis is the primary cause of mortality in our field. Secondary prevention trials show that lowering c-LDL is associated with reduced coronary risk. Hence, sometimes, despite the high dosages of statins, the objective which has been recommended by various panels of experts, only achieves results in a modest 10-20% of patients, as is usual in patients with cardiovascular disease (CVD), with elevated risk of sustaining it, or in diabetic patients, for whom most associations suggest an c-LDL <70 mg/dl.
Ezitimibe is the first selective inhibitor of dietary cholesterol and billiary absorption in the intestinal wall, through the absorption of the NPCL1 transporter protein. Monotherapy has achieved an average reduction of 20% in total cholesterol readings (TC), 22% in c-LDL and 10% in TG, with a minimal increase (3%) of c-HDL. Ezetimibe, in monotherapy and in combined therapy, has shown that as well as reducing levels of inflammatory markers, reactive C-protein and ferritin, have improved endothelial functions.
Patients are increasingly in need of lipid-lowering drug treatments, and more intensive ones, in order to achieve their c-LDL objectives. Since the normal statin dosages reduce the concentrations of c-LDL by 30-40%, in some cases monotherapy using statin is insufficient in order to achieve optimum effects, preferably in high-risk patients. Double therapy, statin-ezetimibe, reduces c-LDL levels with greater efficacy than a single statin and is a more effective strategy for achieving objectives.
Article Details
How to Cite
SARMIENTO, Enrique Gonzalez et al.
EFFECTIVENESS OF EZETIMIBE IN ROUTINE CLINICAL PRACTICE.
Medical Research Archives, [S.l.], v. 6, n. 11, nov. 2018.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1839>. Date accessed: 19 apr. 2024.
doi: https://doi.org/10.18103/mra.v6i11.1839.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease.Am J Cardiol. 1995; 76:69-77
2. Neaton JD, Blackburn H, Jacobs D, Kuller L, Lee DJ, Sherwin R, Shih J, Stamler J, Wentworth D. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Tria Research Group. Arch Intern Med. 1992; 152:1490-500
3. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corrà U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Løchen ML, Löllgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I1, Verschuren WMM, Binno S; ESC Scientific Document Group.The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). European Heart Journal, 2016;37:2315–2381
4. Lobos Bejarano JM, Galve E, Royo-Bordonada MÁ, Alegría Ezquerra E, Armario P, Brotons Cuixart C, Camafort Babkowski M, Cordero Fort A, Maiques Galán A, Mantilla Morató T, Pérez Pérez A, Pedro-Botet J, Villar Álvarez F, González-Juanatey JR; Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention; Spanish Society of Cardiology. Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology Position Statement on Dyslipidemia Management. Differences Between the European and American Guidelines. Rev Esp Cardiol. 2014; 67:913–919
5. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360:7-22
6. Pfeffer MA, Sacks FM, Moyé LA, Brown L, Rouleau JL, Hartley LH, Rouleau J, Grimm R, Sestier F, Wickemeyer W, et al.Cholesterol and Recurrent Events: a secondary prevention trial for normolipidemic patients. CARE Investigators. Am J Cardiol. 1995; 76:98-106
7. LIPID Study Group (Long-term Intervention with Pravastatin in Ischaemic Disease). Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up. Lancet. 2002; 359:1379-87
8. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9
9. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA. 1997; 278:313-21
10. La Rosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a metaanalysis of randomized controlled trials. JAMA. 1999; 282:2340-6
11. Cholesterol Treatment Trialists’ (CTT) Collaboration1, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. 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
12. Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999; 341:498-511
13. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries; principal results from EUROASPIRE II Euro Heart Survey Programme. Eur Heart J. 2001; 22:554-72
14. Van Ganse E1, Laforest L, Alemao E, Davies G, Gutkin S, Yin D. Lipid-modifying therapy and attainment of cholesterol goals in Europe: The Return on Expenditure Achieved for Lipid Therapy (REALITY) study. Curr Med Res Opin. 2005;21:1389-99
15. González-Juanatey JR, Millán J, Alegría E, Guijarro C, Lozano JV, Vitale GC. Vitale Prevalence and characteristics of lipid abnormalities in patients treated with statins in primary and secondary prevention in Spain. DYSIS-Spain Study. Rev Esp Cardiol. 2011; 64:286-94
16. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103:357-62
17. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al.Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195-207
18. Sattar N. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials Lancet. 2010; 375:735–42.
19. Aleesa A Carter, Tara Gomes, Ximena Camacho, David N Juurlink, Baiju R Shah, Muhammad M Mamdani. Risk of incident diabetes among patients treated withstatins: population-based study. BMJ. 2013; 346:1-11
20. Barkas Fotios, Elisaf Moses, Liberopoulos Evangelos, Klouras Eleftherios, Liamis George, Rizos Evangelos C. Statin therapy with or without ezetimibe and the progression to diabetes. J Clin Lipidol. 2016; 10:306-13
21. Filippatos TD, Mikhailidis DP. Lipid-lowering drugs acting at the level of the gastrointestinal tract. Curr Pharm Des. 2009; 15:490-516
22. Scheffer PG, Bakker SJ, Heine RJ, Teerlink T. Measurement of LDL particle size in whole plasma and serum by high performance gel-filtration chromatography using a fluorescent lipid probe. Clin Chem. 1998; 44:2148-51
23. Knopp RH, Gitter H, Truitt T, Bays H, Manion CV, Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP; Ezetimibe Study Group. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003; 24:729-41.
24. Jurado J. Effectiveness of ezetimibe in clinical practice. Am J Cardiol.2004;93:641
25. Pascual Izuel JM, Rodilla Sala E, Sánchez Juan C. Clinical efficacy of ezetimibe and combined use with statins. Rev Clin Esp. 2005; 205:496-8
26. Knopp RH, Gitter H, Truitt T, Bays H, Manion CV, Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP; Ezetimibe Study Group. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003; 24:729-41.
27. Pesaro AE, Serrano CV Jr, Fernandes JL, Cavalcanti AB, Campos AH, Martins HS, Maranhão RC, de Lemos JA, Souza HP, Nicolau JC.Pleiotropic effects of ezetimibe/ simvastatin vs. high dose simvastatin. Int J Cardiol 2012; 158:400-4
28. González Sarmiento E, Zurro Hernández J, Fernández Galante I. Effectiveness of ezetimibe in routine clinical practice. Effect on lipid profile and other laboratory parameters. Endocrinol Nutr. 2008; 55:165-9
29. Sager PT, Melani L, Lipka L, Strony J, Yang B, Suresh R, et al. Ezetimibe Study Group. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol. 2003; 92:1414-8
30. European Association for Cardiovascular Prevention & Rehabilitation1, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011; 32:1769-818
31. Stein E. Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J Suppl 2001;3:E11-E16
32. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J. 2005; 149:464-73.
33. Leiter LA, Bays H, Conard S, Bird S, Rubino J, Hanson ME, Tomassini JE, Tershakovec AM. Efficacy and Safety of Ezetimibe Added on to Atorvastatin (40 mg) Compared with Uptitration of Atorvastatin (to 80 mg) in Hypercholesterolemic Patients at High Risk of Coronary Heart Disease. Ez PATH Trial. Am J Cardiol 2008; 102:1495-501
34. Harold E. Bays Safety and Efficacy of Ezetimibe Added on to Rosuvastatin 5 or 10 mg Versus Up-Titration of Rosuvastatin in Patients with Hypercholesterolemia (the ACTE Study), Am J Cardiol 2011;108:523-30
35. Roeters van Lennep HW, Liem AH, Dunselman PH, Dallinga-Thie GM, Zwinderman AH, Jukema JW. The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study. Curr Med Res Opin. 2008; 24:685-94
36. Dai YY, Zhang HS, Zhang XG, Guan QG, Gao Y, Li YZ, Zhang YL, Jia DL, Sun YX, Qi GX, Tian W. Statin-ezetimibe versus statin lipid-lowering therapy in patients with acute coronary syndromes undergoing percutaneous coronary intervention. J Thorac Dis. 2017; 9:1345-1352
37. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E; ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008; 358:1431-43.
38. Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008; 359:1343-56.
39. Villines TC, Stanek EJ, Devine PJ, Turco M, Miller M, Weissman NJ, Griffen L, Taylor AJ. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration J Am Coll Cardiol. 2010; 55:2721-6.
40. Hibi K, Sonoda S, Kawasaki M, Otsuji Y, Murohara T, Ishii H, Sato K, Koshida R, Ozaki Y, Sata M, Morino Y, Miyamoto T, Amano T, Morita S, Kozuma K, Kimura K, Fujiwara H. Effects of Ezetimibe-Statin Combination Therapy on Coronary Atherosclerosis in Acute Coronary Syndrome. Circ J 2018; 82:757-766
41. Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K, et al. 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 2015;66: 495-507
42. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al., SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): A randomized placebo-controlled trial. Lancet. 2011; 377:2181-92
43. Kato ET, Cannon CP, Blazing MA, Bohula E, Guneri S, White JA, Murphy SA, Park JG, Braunwald E, Giugliano RP. Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). J Am Heart Assoc. 2017:18;6.
44. Filippatos TD, Florentin M, Georgoula M, Elisaf MS. Pharmacological management of diabetic dyslipidemia. Expert Rev Clin Pharmacol. 2017; 10:187-200.
45. Hibi K, Sonoda S, Kawasaki M, Otsuji Y, Murohara T, Ishii H, Sato K, Koshida R, Ozaki Y, Sata M, Morino Y, Miyamoto T, Amano T, Morita S, Kozuma K, Kimura K, Fujiwara H; Effects of Ezetimibe-Statin Combination Therapy on Coronary Atherosclerosis in Acute Coronary Syndrome. Circ J. 2018:82:757-766
46. Russell M, Silverman A, Fleg JL, Lee ET, Mete M, Weir M, Wilson C, Yeh F, Howard BV, Howard WM. Achieving lipid targets in adults with type 2 diabetes: the Stop Atherosclerosis in Native Diabetics Study. J Clin Lipidol.2010 ;4:435-43
47. Fei Y, Guyatt GH, Alexander PE, El Dib R, Siemieniuk RAC, Vandvik PO, Nunnally ME, Gomaa H, Morgan RL, Agarwal A, Zhang Y, Bhatnagar N, Spencer FA. Addition of Ezetimibe to statins for patients at high cardiovascular risk: Systematic review of patient-important outcomes. J Eval Clin Pract. 2018; 24:222-231
48. Ferrières J, Dallongeville J, Rossignol M, Bénichou J, Caro JJ, Getsios D, Hernandez L, Abenhaim L, Grimaldi-Bensouda L. Model-observational bridging study on the effectiveness of ezetimibe on cardiovascular morbidity and mortality in France: A population-based study. J Clin Lipidol. 2016; 10:1379-1388
49. Lin Wu FL, Wang J, Ho W, Chou CH, Wu YJ, Choo DW, Wang YW, Chen PY, Chien KL, Lin ZF. Effectiveness of a combination of ezetimibe and statins in patients with acute coronary syndrome and multiple comorbidities: a 6-year population-based cohort study. Int J Cardiol. 2017; 233:43-51
2. Neaton JD, Blackburn H, Jacobs D, Kuller L, Lee DJ, Sherwin R, Shih J, Stamler J, Wentworth D. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Tria Research Group. Arch Intern Med. 1992; 152:1490-500
3. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corrà U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Løchen ML, Löllgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I1, Verschuren WMM, Binno S; ESC Scientific Document Group.The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). European Heart Journal, 2016;37:2315–2381
4. Lobos Bejarano JM, Galve E, Royo-Bordonada MÁ, Alegría Ezquerra E, Armario P, Brotons Cuixart C, Camafort Babkowski M, Cordero Fort A, Maiques Galán A, Mantilla Morató T, Pérez Pérez A, Pedro-Botet J, Villar Álvarez F, González-Juanatey JR; Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention; Spanish Society of Cardiology. Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology Position Statement on Dyslipidemia Management. Differences Between the European and American Guidelines. Rev Esp Cardiol. 2014; 67:913–919
5. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360:7-22
6. Pfeffer MA, Sacks FM, Moyé LA, Brown L, Rouleau JL, Hartley LH, Rouleau J, Grimm R, Sestier F, Wickemeyer W, et al.Cholesterol and Recurrent Events: a secondary prevention trial for normolipidemic patients. CARE Investigators. Am J Cardiol. 1995; 76:98-106
7. LIPID Study Group (Long-term Intervention with Pravastatin in Ischaemic Disease). Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up. Lancet. 2002; 359:1379-87
8. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9
9. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA. 1997; 278:313-21
10. La Rosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a metaanalysis of randomized controlled trials. JAMA. 1999; 282:2340-6
11. Cholesterol Treatment Trialists’ (CTT) Collaboration1, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. 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
12. Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999; 341:498-511
13. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries; principal results from EUROASPIRE II Euro Heart Survey Programme. Eur Heart J. 2001; 22:554-72
14. Van Ganse E1, Laforest L, Alemao E, Davies G, Gutkin S, Yin D. Lipid-modifying therapy and attainment of cholesterol goals in Europe: The Return on Expenditure Achieved for Lipid Therapy (REALITY) study. Curr Med Res Opin. 2005;21:1389-99
15. González-Juanatey JR, Millán J, Alegría E, Guijarro C, Lozano JV, Vitale GC. Vitale Prevalence and characteristics of lipid abnormalities in patients treated with statins in primary and secondary prevention in Spain. DYSIS-Spain Study. Rev Esp Cardiol. 2011; 64:286-94
16. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103:357-62
17. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al.Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195-207
18. Sattar N. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials Lancet. 2010; 375:735–42.
19. Aleesa A Carter, Tara Gomes, Ximena Camacho, David N Juurlink, Baiju R Shah, Muhammad M Mamdani. Risk of incident diabetes among patients treated withstatins: population-based study. BMJ. 2013; 346:1-11
20. Barkas Fotios, Elisaf Moses, Liberopoulos Evangelos, Klouras Eleftherios, Liamis George, Rizos Evangelos C. Statin therapy with or without ezetimibe and the progression to diabetes. J Clin Lipidol. 2016; 10:306-13
21. Filippatos TD, Mikhailidis DP. Lipid-lowering drugs acting at the level of the gastrointestinal tract. Curr Pharm Des. 2009; 15:490-516
22. Scheffer PG, Bakker SJ, Heine RJ, Teerlink T. Measurement of LDL particle size in whole plasma and serum by high performance gel-filtration chromatography using a fluorescent lipid probe. Clin Chem. 1998; 44:2148-51
23. Knopp RH, Gitter H, Truitt T, Bays H, Manion CV, Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP; Ezetimibe Study Group. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003; 24:729-41.
24. Jurado J. Effectiveness of ezetimibe in clinical practice. Am J Cardiol.2004;93:641
25. Pascual Izuel JM, Rodilla Sala E, Sánchez Juan C. Clinical efficacy of ezetimibe and combined use with statins. Rev Clin Esp. 2005; 205:496-8
26. Knopp RH, Gitter H, Truitt T, Bays H, Manion CV, Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP; Ezetimibe Study Group. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003; 24:729-41.
27. Pesaro AE, Serrano CV Jr, Fernandes JL, Cavalcanti AB, Campos AH, Martins HS, Maranhão RC, de Lemos JA, Souza HP, Nicolau JC.Pleiotropic effects of ezetimibe/ simvastatin vs. high dose simvastatin. Int J Cardiol 2012; 158:400-4
28. González Sarmiento E, Zurro Hernández J, Fernández Galante I. Effectiveness of ezetimibe in routine clinical practice. Effect on lipid profile and other laboratory parameters. Endocrinol Nutr. 2008; 55:165-9
29. Sager PT, Melani L, Lipka L, Strony J, Yang B, Suresh R, et al. Ezetimibe Study Group. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol. 2003; 92:1414-8
30. European Association for Cardiovascular Prevention & Rehabilitation1, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011; 32:1769-818
31. Stein E. Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J Suppl 2001;3:E11-E16
32. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J. 2005; 149:464-73.
33. Leiter LA, Bays H, Conard S, Bird S, Rubino J, Hanson ME, Tomassini JE, Tershakovec AM. Efficacy and Safety of Ezetimibe Added on to Atorvastatin (40 mg) Compared with Uptitration of Atorvastatin (to 80 mg) in Hypercholesterolemic Patients at High Risk of Coronary Heart Disease. Ez PATH Trial. Am J Cardiol 2008; 102:1495-501
34. Harold E. Bays Safety and Efficacy of Ezetimibe Added on to Rosuvastatin 5 or 10 mg Versus Up-Titration of Rosuvastatin in Patients with Hypercholesterolemia (the ACTE Study), Am J Cardiol 2011;108:523-30
35. Roeters van Lennep HW, Liem AH, Dunselman PH, Dallinga-Thie GM, Zwinderman AH, Jukema JW. The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study. Curr Med Res Opin. 2008; 24:685-94
36. Dai YY, Zhang HS, Zhang XG, Guan QG, Gao Y, Li YZ, Zhang YL, Jia DL, Sun YX, Qi GX, Tian W. Statin-ezetimibe versus statin lipid-lowering therapy in patients with acute coronary syndromes undergoing percutaneous coronary intervention. J Thorac Dis. 2017; 9:1345-1352
37. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E; ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008; 358:1431-43.
38. Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008; 359:1343-56.
39. Villines TC, Stanek EJ, Devine PJ, Turco M, Miller M, Weissman NJ, Griffen L, Taylor AJ. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration J Am Coll Cardiol. 2010; 55:2721-6.
40. Hibi K, Sonoda S, Kawasaki M, Otsuji Y, Murohara T, Ishii H, Sato K, Koshida R, Ozaki Y, Sata M, Morino Y, Miyamoto T, Amano T, Morita S, Kozuma K, Kimura K, Fujiwara H. Effects of Ezetimibe-Statin Combination Therapy on Coronary Atherosclerosis in Acute Coronary Syndrome. Circ J 2018; 82:757-766
41. Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K, et al. 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 2015;66: 495-507
42. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al., SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): A randomized placebo-controlled trial. Lancet. 2011; 377:2181-92
43. Kato ET, Cannon CP, Blazing MA, Bohula E, Guneri S, White JA, Murphy SA, Park JG, Braunwald E, Giugliano RP. Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). J Am Heart Assoc. 2017:18;6.
44. Filippatos TD, Florentin M, Georgoula M, Elisaf MS. Pharmacological management of diabetic dyslipidemia. Expert Rev Clin Pharmacol. 2017; 10:187-200.
45. Hibi K, Sonoda S, Kawasaki M, Otsuji Y, Murohara T, Ishii H, Sato K, Koshida R, Ozaki Y, Sata M, Morino Y, Miyamoto T, Amano T, Morita S, Kozuma K, Kimura K, Fujiwara H; Effects of Ezetimibe-Statin Combination Therapy on Coronary Atherosclerosis in Acute Coronary Syndrome. Circ J. 2018:82:757-766
46. Russell M, Silverman A, Fleg JL, Lee ET, Mete M, Weir M, Wilson C, Yeh F, Howard BV, Howard WM. Achieving lipid targets in adults with type 2 diabetes: the Stop Atherosclerosis in Native Diabetics Study. J Clin Lipidol.2010 ;4:435-43
47. Fei Y, Guyatt GH, Alexander PE, El Dib R, Siemieniuk RAC, Vandvik PO, Nunnally ME, Gomaa H, Morgan RL, Agarwal A, Zhang Y, Bhatnagar N, Spencer FA. Addition of Ezetimibe to statins for patients at high cardiovascular risk: Systematic review of patient-important outcomes. J Eval Clin Pract. 2018; 24:222-231
48. Ferrières J, Dallongeville J, Rossignol M, Bénichou J, Caro JJ, Getsios D, Hernandez L, Abenhaim L, Grimaldi-Bensouda L. Model-observational bridging study on the effectiveness of ezetimibe on cardiovascular morbidity and mortality in France: A population-based study. J Clin Lipidol. 2016; 10:1379-1388
49. Lin Wu FL, Wang J, Ho W, Chou CH, Wu YJ, Choo DW, Wang YW, Chen PY, Chien KL, Lin ZF. Effectiveness of a combination of ezetimibe and statins in patients with acute coronary syndrome and multiple comorbidities: a 6-year population-based cohort study. Int J Cardiol. 2017; 233:43-51