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Comparative Safety and Efficacy of Low/Moderate-Intensity Statin plus Ezetimibe Combination Therapy vs. High-Intensity Statin Monotherapy in Patients with Atherosclerotic Cardiovascular Disease: An Updated Meta-Analysis

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Abstract

Aim

Statin therapy is considered the gold standard for treating hypercholesterolemia. This updated meta-analysis aims to compare the efficacy and safety of a low/moderate-intensity statin in combination with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD).

Methods

A systematic search of two databases (PubMed and Cochrane CENTRAL) was conducted from inception to January 2023 and a total of 21 randomized clinical trials (RCTs) were identified and included in the analysis. Data were pooled using Hedges’s g and a Mantel–Haenszel random-effects model to derive standard mean differences (SMDs) and 95% confidence intervals (Cis). The primary outcome studied was the effect of these treatments on lipid parameters and safety events.

Results

The results revealed that combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels (SMD= − 0.41; CI − 0.63 to − 0.19; P = 0.0002). There was no significant change in the levels of high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), high-sensitivity C-reactive protein (hs-CRP), Apo A1, or Apo B. The safety of these treatments was assessed by the following markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine phosphokinase (CK), and a significant difference was only observed in CK (SMD: − 0.81; CI − 1.52 to − 0.10; P = 0.02).

Conclusion

This meta-analysis demonstrated that the use of low/moderate-intensity statin combination therapy significantly reduced LDL-C levels compared with high-intensity statin monotherapy, making it preferable for patients with related risks. However, further trials are encouraged to evaluate potential adverse effects associated with combined therapy.

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References

  1. Banach M, Burchardt P, Chlebus K, Dobrowolski P, Dudek D, Dyrbuś K, Gąsior M, Jankowski P, Jóźwiak J, Kłosiewicz-Latoszek L, Kowalska I, Małecki M, Prejbisz A, Rakowski M, Rysz J, Solnica B, Sitkiewicz D, Sygitowicz G, Sypniewska G, Tomasik T, Windak A, Zozulińska-Ziółkiewicz D, Cybulska B. PoLA/CFPiP/PCS/PSLD/PSD/PSH guidelines on diagnosis and therapy of lipid disorders in Poland 2021. Arch Med Sci. 2021;17:1447–1547. Available at: https://www.archivesofmedicalscience.com/PoLA-CFPiP-PCS-PSLD-PSD-PSH-guidelines-on-diagnosis-and-therapy-of-lipid-disorders,141941,0,2.html. Accessed 8 July 2023.

  2. Khan SU, Michos ED. Cardiovascular mortality after intensive LDL-Cholesterol lowering: does baseline LDL-Cholesterol really matter? Am J Prev Cardiol. 2020;1: 100013.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet. 2005;366(9493):1267-78. Available at: http://www.thelancet.com/article/S0140673605673941/fulltext. Accessed 8 July 2023.

  4. Tan H, Liu L, Zheng Q, Zhang D, Liu Q, Cui D, Gao L, Wang Z, Wang WL, Liu J. Effects of combined lipid-lowering therapy on low-density lipoprotein cholesterol variability and cardiovascular adverse events in patients with acute coronary syndrome. Adv Ther. 2021;38:3389–98.

    Article  CAS  PubMed  Google Scholar 

  5. Oh PC, Jang AY, Ha K, Kim M, Moon J, Suh SY, Lee K, Han SH, Kang WC. Effect of atorvastatin (10 mg) and ezetimibe (10 mg) combination compared to atorvastatin (40 mg) alone on coronary atherosclerosis. Am J Cardiol. 2021;154:22–8.

    Article  CAS  PubMed  Google Scholar 

  6. Oh M, Kim H, Shin EW, Sung C, Kim DH, Moon DH, Kim N, Eo JS, Kim JW, Lee CW. Comparison of high-dose rosuvastatin versus low-dose rosuvastatin plus ezetimibe on carotid atherosclerotic plaque inflammation in patients with acute coronary syndrome. J Cardiovasc Transl Res. 2020;13:900–7.

    Article  PubMed  Google Scholar 

  7. Ah YM, Jeong M, Choi HD. Comparative safety and efficacy of low- or moderate-intensity statin plus ezetimibe combination therapy and high-intensity statin monotherapy: a meta-analysis of randomized controlled studies. PLoS One. 2022;17.

  8. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372.

  9. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane handbook for systematic reviews of interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.

  10. Zhu Y, Hu H, Yang J, Yao Q, Xu H, Yu Y, Liu T, Lin S. The efficacy and safety of statin in combination with ezetimibe compared with double-dose statin in patients with high cardiovascular risk: a meta-analysis. Biomol Biomed. 2020;20:169–182. Available at: https://www.bjbms.org/ojs/index.php/bjbms/article/view/4437. Accessed 8 July 2023.

  11. Shaya FT, Sing K, Milam R, Husain F, del Aguila MA, Patel MY. Lipid-lowering efficacy of ezetimibe in patients with atherosclerotic cardiovascular disease: a systematic review and meta-analyses. Am J Cardiovasc Drugs. 2020;20:239–48. https://doi.org/10.1007/s40256-019-00379-9.

    Article  PubMed  Google Scholar 

  12. Kim BK, Hong SJ, Lee YJ, Hong SJ, Yun KH, Hong BK, Heo JH, Rha SW, Cho YH, Lee SJ, Ahn CM, Kim JS, Ko YG, Choi D, Jang Y, Hong MK. Long-term 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. 2022;400:380–90.

    Article  CAS  PubMed  Google Scholar 

  13. Liu C, Liu Q, Xiao X. Effectiveness and safety of combinational therapy compared with intensified statin monotherapy in patients with coronary heart disease. Exp Ther Med. 2018;15:4683–8.

    PubMed  PubMed Central  Google Scholar 

  14. Wu NQ, Guo YL, Zhu CG, Gao Y, Zhao X, Sun D, Sun J, Xu RX, Liu G, Dong Q, Li JJ. Comparison of statin plus ezetimibe with double-dose statin on lipid profiles and inflammation markers. Lipids Health Dis. 2018;17.

  15. Ran D, Nie HJ, Gao YL, Deng SB, Du JL, Liu YJ, Jing XD, She Q. A randomized, controlled comparison of different intensive lipid-lowering therapies in Chinese patients with non-ST-elevation acute coronary syndrome (NSTE-ACS): ezetimibe and rosuvastatin versus high-dose rosuvastatin. Int J Cardiol. 2017;235:49–55.

    Article  PubMed  Google Scholar 

  16. Yang YJ, Lee SH, Kim BS, Cho YK, Cho HJ, Cho KI, Kim SY, Ryu JK, Cho JM, Park JI, Park JS, Park CG, Chun WJ, Kim MA, Jin DK, Lee N, Kim BJ, Koh KK, Suh J, Lee SH, Lee BK, Oh SJ, Jin HY, Ahn Y, Lee SG, Bae JH, Park WJ, Lee SC, Lee HC, Lee J, Park C, Lee B, Jang Y. Combination therapy of rosuvastatin and ezetimibe in patients with high cardiovascular risk. Clin Ther. 2017;39:107–17.

    Article  CAS  PubMed  Google Scholar 

  17. Japaridze L, Sadunishvili M, Megreladze I. Combination therapy effectiveness of ezetimibe and atorvastatin in patients with acute coronary syndrome. Georg Med News. 2016:15–22.

  18. Pytel E, Bukowska B, Koter-Michalak M, Olszewska-Banaszczyk M, Gorzelak-Pabiś P, Broncel M. Effect of intensive lipid-lowering therapies on cholinesterase activity in patients with coronary artery disease. Pharmacol Rep. 2017;69:150–5.

    Article  CAS  PubMed  Google Scholar 

  19. Pytel E, Jackowska P, Chwatko G, Olszewska-Banaszczyk M, Koter-Michalak M, Kubalczyk P, Broncel M. Intensive statin therapy, used alone or in combination with ezetimibe, improves homocysteine level and lipid peroxidation to a similar degree in patients with coronary artery diseases. Pharmacol Rep. 2016;68:344–8.

    Article  CAS  PubMed  Google Scholar 

  20. Villegas-Rivera G, Román-Pintos LM, Cardona-Muñoz EG, Arias-Carvajal O, Rodríguez-Carrizalez AD, Troyo-Sanromán R, Pacheco-Moisés FP, Moreno-Ulloa A, Miranda-Díaz AG. Effects of ezetimibe/simvastatin and rosuvastatin on oxidative stress in diabetic neuropathy: a randomized, double-blind, placebo-controlled clinical trial. Oxid Med Cell Longev. 2015;2015.

  21. Deharo P, Pankert M, Quilici J, Grosdidier C, Verdier V, Bonnet G, Morange P, Alessi MC, Bonnet JL, Cuisset T. Safety and effectiveness of the association ezetimibe-statin (E-S) versus high dose rosuvastatin after acute coronary syndrome: the SAFE-ES study. Ann Cardiol Angeiol (Paris). 2014;63:222–7.

    Article  CAS  PubMed  Google Scholar 

  22. Moreira FT, Ramos SC, Monteiro AM, Helfenstein T, Gidlund M, Damasceno NRT, FigueiredoNeto AM, Izar MC, Fonseca FAH. Effects of two lipid lowering therapies on immune responses in hyperlipidemic subjects. Life Sci. 2014;98:83–7.

    Article  CAS  PubMed  Google Scholar 

  23. Westerink J, Deanfield JE, Imholz BP, Spiering W, Basart DC, Coll B, Kastelein JJP, Visseren FLJ. High-dose statin monotherapy versus low-dose statin/ezetimibe combination on fasting and postprandial lipids and endothelial function in obese patients with the metabolic syndrome: the PANACEA study. Atherosclerosis. 2013;227:118–24.

    Article  CAS  PubMed  Google Scholar 

  24. Araujo DB, Bertolami MC, Ferreira WP, Abdalla DSP, Faludi AA, Nakamura Y, Bricharello LP. Pleiotropic effects with equivalent low-density lipoprotein cholesterol reduction: comparative study between simvastatin and simvastatin/ezetimibe coadministration. J Cardiovasc Pharmacol. 2010;55:1–5.

    Article  CAS  PubMed  Google Scholar 

  25. Hajer GR, Dallinga-Thie GM, Vark-Van Der Zee LCV, Olijhoek JK, Visseren FLJ. Lipid-lowering therapy does not affect the postprandial drop in high density lipoprotein-cholesterol (HDL-c) plasma levels in obese men with metabolic syndrome: a randomized double blind crossover trial. Clin Endocrinol (Oxf). 2008;69:870–7.

    Article  CAS  PubMed  Google Scholar 

  26. Ostad MA, Eggeling S, Tschentscher P, Schwedhelm E, Böger R, Wenzel P, Meinertz T, Munzel T, Warnholtz A. Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: results of the CEZAR study. Atherosclerosis. 2009;205:227–32.

    Article  CAS  PubMed  Google Scholar 

  27. Olijhoek JK, Hajer GR, Van Der GY, Dallinga-Thie GM, Visseren FLJ. The effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin alone on post-fat load endothelial function in patients with metabolic syndrome: a randomized double-blind crossover trial. J Cardiovasc Pharmacol. 2008;52:145–50.

    Article  CAS  PubMed  Google Scholar 

  28. Settergren M, Böhm F, Rydén L, Pernow J. Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease. Eur Heart J. 2008;29:1753–60.

    Article  CAS  PubMed  Google Scholar 

  29. Piorkowski M, Fischer S, Stellbaum C, Jaster M, Martus P, Morguet AJ, Schultheiss HP, Rauch U. Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets? J Am Coll Cardiol. 2007;49:1035–42.

    Article  CAS  PubMed  Google Scholar 

  30. Mahdy Ali K, Wonnerth A, Huber K, Wojta J. Cardiovascular disease risk reduction by raising HDL cholesterol–current therapies and future opportunities. Br J Pharmacol. 2012;167(6):1177–94. https://doi.org/10.1111/j.1476-5381.2012.02081.x.

    Article  CAS  PubMed  Google Scholar 

  31. Carrero JJ, Andersson Franko M, Obergfell A, Gabrielsen A, Jernberg T. hsCRP level and the risk of death or recurrent cardiovascular events in patients with myocardial infarction: a healthcare-based study. J Am Heart Assoc. 2019;8(11): e012638. https://doi.org/10.1161/JAHA.119.012638. (Epub 2019 May 29).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Choi S. The potential role of biomarkers associated with ASCVD risk: risk-enhancing biomarkers. J Lipid Atheroscler. 2019;8(2):173–82. https://doi.org/10.12997/jla.2019.8.2.173. (Epub 2019 Sep 4).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Beckett RD, Schepers SM, Gordon SK. Risk of new-onset diabetes associated with statin use. SAGE Open Med. 2015;30(3):2050312115605518. https://doi.org/10.1177/2050312115605518.

    Article  Google Scholar 

  34. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013;127(1):96–103. https://doi.org/10.1161/CIRCULATIONAHA.112.136101. (Epub 2012 Nov 26).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge Research Council of Pakistan (RCOP) for their support along all aspects of conducting this study.

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Authors and Affiliations

  1. Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan

    Ishaque Hameed, Syeda Ayesha Shah, Ashnah Aijaz, Hasan Mushahid, Syed Husain Farhan, Adam Bilal Khan, Reeha Amjad, Fawad Alvi, Mustafa Murtaza & Zaid Zuberi

  2. Department of Medicine, Ziauddin University, Karachi, Pakistan

    Muhammad Dada

  3. Department of Internal Medicine, Albany Medical Center, Albany, USA

    Mohammad Hamza

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Correspondence to Hasan Mushahid.

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Conflicts of interest

Ishaque Hameed, Syeda Ayesha Shah, Ashnah Aijaz, Hasan Mushahid, Syed Husain Farhan, Muhammad Dada, Adam Bilal Khan, Reeha Amjad, Fawad Alvi, Mustafa Murtaza, Zaid Zuberi, and Mohammad Hamza declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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Data availability statement

All data generated or analyzed during this study are included in this published article (and its supplementary information files)

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Author contributions

Ishaque Hameed: Resources, writing—review and editing, project administration. Syeda Ayesha Shah: Conceptualization, investigation, writing—original draft. Ashnah Aijaz: Formal analysis, writing—original draft. Hasan Mushahid: Investigation, writing—original draft, writing—review and editing. Syed Husain Farhan: Formal analysis, writing—original draft. Muhammad Dada: Methodology, writing—reviewing and editing. Adam Khan: Methodology, writing—original draft. Reeha Amjad: Formal analysis, writing—original draft, writing—review and editing. Fawad Alvi: Writing—original draft, writing—review and editing. Mustafa Murtaza: Methodology, writing—original draft. Zaid Zuberi: Methodology, writing—original draft. Mohammad Hamza: Writing—review and editing, project administration.

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Hameed, I., Shah, S.A., Aijaz, A. et al. Comparative Safety and Efficacy of Low/Moderate-Intensity Statin plus Ezetimibe Combination Therapy vs. High-Intensity Statin Monotherapy in Patients with Atherosclerotic Cardiovascular Disease: An Updated Meta-Analysis. Am J Cardiovasc Drugs (2024). https://doi.org/10.1007/s40256-024-00642-8

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