Efficacy of Ezetimibe/Simvastatin (10/10 mg) Versus High Dose Statin in Dyslipidemia Patients: A Meta-Analysis of Randomized Controlled Trials
Abstract
Background: The monotherapies of statin and ezetimibe had not successfully achieved their objectives in the management of lipid levels of dyslipidemia patients. We aimed to compare the effects of combined low-dose simvastatin and ezetimibe versus high-dose statin on the lipid-lowering treatment of dyslipidemia patients.
Methods: We searched five databases published before May 2018, namely PubMed, Embase, Cochrane, Web of Science, and Clinicaltrials.gov. Completely published randomized controlled trials (RCTs) comparing the effect of high-dose statin (S) with ezetimibe/simvastatin (10/10 mg; E/S) on the management of dyslipidemia patients were included.
Results: A total of ten RCTs met the inclusion criteria, including 1,624 patients (E/S:691, S:933). Six outcomes underwent pooled analysis, including weighted mean difference (WMD) from baseline in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high sensitivity C-reactive protein (hs-CRP), triglyceride (TG), and non-high-density lipoprotein cholesterol (non-HDL-C). No significant gap was found between high-dose statin and ezetimibe/simvastatin (10/10 mg) in LDL-C (-1.55; 95% confidence interval [CI]:-4.42~1.31, P=0 .29), HDL-C (1.05; 95%CI:-0.21~2.3, P=0 .1), TG (4.03; 95%CI:-4.53~12.58, P=0 .36), and hs-CRP (0.14; 95%CI:-0.50~0.78, P=0.67). However, there was significant difference found between the two lipid-lowering treatments in TC (-0.45; 95%CI:-9.07~ -0.83, P=0.02) and non-HDL-C (-4.97; 95%CI -8.46~-1.49, P=0 .005).
Conclusions: Ezetimibe co-administered with simvastatin (10 mg) and high-dose statin monotherapy may show similar effects in reducing LDL-C, TG, and hs-CRP levels and in increasing HDL-C levels. However, the results suggest that there was greater TC and non-HDL-C lowering through high-dose statin monotherapy as compared with ezetimibe/simvastatin co-administration.
1. Dandapat S, Robinson JG (2016). Guidelines for Management of Hyperlipidemia: Implications for Treatment of Patients with Stroke Secondary to Atherosclerotic Disease. Curr Neurol Neurosci Rep, 16:24.
2. Mozaffarian D, Benjamin EJ, Go AS, et al (2016). Heart isease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation, 133:e38-360.
3. Zhang Y, Bai L, Shi M et al (2017). Features and risk factors of carotid atherosclerosis in a population with high stroke incidence in China. Oncotarget, 8:57477-57488.
4. Pandor A, Ara RM, Tumur I et al (2009). Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med, 265:568-80.
5. Shapiro MD, Fazio S (2016). From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk. Circ Res, 118:732-49.
6. Isles CG, Paterson JR (2000). Identifying patients at risk for coronary heart disease: implications from trials of lipid-lowering drug therapy. QJM, 93:567-74.
7. Eckel RH, Jakicic JM, Ard JD, et al (2014). 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 63:2960-84.
8. Noma K, Higashi Y (2012). How to use ezetimibe as an anti-atherogenic agent via inhibition of rho-Kinase. Circ J, 76:1836-1837.
9. Ye Y, Zhao X, Zhai G, Guo L et al (2012). Effect of high-dose statin versus low-dose statin plus ezetimibe on endothelial function: a meta-analysis of randomized trials. J Cardiovasc Pharmacol Ther, 17:357-65.
10. Catapano AL, Farnier M, Foody JM et al (2014). Combination therapy in dyslipidemia: where are we now? Atherosclerosis, 237:319-35.
11. Barter PJ, Brandrup-Wognsen G, Palmer MK, Nicholls SJ (2010). Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database. J Lipid Res, 51:1546-53.
12. Preiss D, Seshasai SR, Welsh P, et al (2011). Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA, 305:2556-64.
13. Chatzizisis YS, Koskinas KC, Misirli G et al (2010). Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf, 33:171-87.
14. Stone NJ, Robinson JG, Lichtenstein AH, et al (2014). 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 63:2889-934.
15. Yamaoka-Tojo M, Tojo T, Takahira N et al (2011). Ezetimibe and reactive oxygen species. Curr Vasc Pharmacol, 9:109-20.
16. Capps N (2006). Total and low-density lipoprotein cholesterol responses to ezetimibe in clinical practice. Int J Clin Pract, 60:867-9.
17. Nakamura K, Miyoshi T, Yunoki K, Ito H (2016). Postprandial hyperlipidemia as a potential residual risk factor. J Cardiol, 67:335-9.
18. Kastelein JJ, Akdim F, Stroes ES, et al (2008). Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med, 358:1431-43.
19. Rossebo AB, Pedersen TR, Boman K, et al (2008). Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med, 359:1343-56.
20. Baigent C, Landray MJ, Reith C, et al (2011). 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, 377:2181-2192.
21. Cannon CP, Blazing MA, Giugliano RP, et al (2015). Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med, 372:2387-97.
22. Lyseng-Williamson KA (2012). Ezetimibe/simvastatin: a guide to its clinical use in hypercholesterolemia. Am J Cardiovasc Drugs, 12:49-56.
23. Khavandi M, Duarte F, Ginsberg HN, Reyes-Soffer G (2017). Treatment of Dyslipidemias to Prevent Cardiovascular Disease in Patients with Type 2 Diabetes. Curr Cardiol Rep, 19:7.
24. Moher D, Liberati A, Tetzlaff J, Altman DG (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med, 6:e1000097.
25. Sahebkar A, Simental-Mendia LE, Guerrero-Romero F et al (2015). Effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) concentrations: a systematic review and meta-analysis of clinical trials. Diabetes Obes Metab, 17:1042-55.
26. Goldberg AC, Sapre A, Liu J et al (2004). Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: A randomized, double-blind, placebo-controlled trial. Mayo Clin Proc, 79:620-629.
27. Ose L, Johnson-Levonas A, Reyes R et al (2007). A multi-centre, randomised, double-blind 14-week extension study examining the long-term safety and efficacy profile of the ezetimibe/simvastatin combination tablet. Int J Clin Pract, 61:1469-80.
28. Ballantyne CM, Abate N, Yuan Z et al (2005). 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, 149:464-73.
29. Davidson MH, McGarry T, Bettis R, et al (2002). Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol, 40:2125-2134.
30. Araujo DB, Bertolami MC, Ferreira WP et al (2010). Pleiotropic effects with equivalent low-density lipoprotein cholesterol reduction: comparative study between simvastatin and simvastatin/ezetimibe coadministration. J Cardiovasc Pharmacol, 55:1-5.
31. Settergren M, Bohm F, Ryden L, Pernow J (2008). Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease. Eur Heart J, 29:1753-60.
32. Settergren M, Bohm F, Ryden L et al (2009). Lipid lowering versus pleiotropic effects of statins on skin microvascular function in patients with dysglycaemia and coronary artery disease. J Intern Med, 266:492-8.
33. Olijhoek JK, Hajer GR, van der Graaf Y et al (2008). 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, 52:145-150.
34. Garcia MMO, Varela CG, Silva PF, et al (2016). Endothelial effect of statin therapy at a high dose versus low dose associated with ezetimibe. Arq Bras Cardiol, 106:279-288.
35. Rudofsky G, Reismann P, Groener JB, et al (2012). Identical LDL-cholesterol lowering but non-identical effects on NF-kappaB activity: High dose simvastatin vs combination therapy with ezetimibe. Atherosclerosis, 223:190-6.
36. Westerink J, Deanfield J, Imholz B et al (2013). 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, 227:118-24.
37. Bays HE, Ose L, Fraser N et al (2004). A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther, 26:1758-73.
38. Sager PT, Melani L, Lipka L et al (2003). Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol, 92:1414-8.
39. Angelopoulos J, Krassakopoulos N, Nathanson R et al (2009). Co-administration of ezetimibe and a statin in management of dyslipidemias: a meta-analysis of clinical trials. Arch Med Sci, 5:347-363.
40. Kashani A, Sallam T, Bheemreddy S et al (2008). Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials. Am J Cardiol, 101:1606-13.
41. Toth PP, Morrone D, Weintraub WS et al (2012). 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 Pract, 66:800-812.
2. Mozaffarian D, Benjamin EJ, Go AS, et al (2016). Heart isease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation, 133:e38-360.
3. Zhang Y, Bai L, Shi M et al (2017). Features and risk factors of carotid atherosclerosis in a population with high stroke incidence in China. Oncotarget, 8:57477-57488.
4. Pandor A, Ara RM, Tumur I et al (2009). Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med, 265:568-80.
5. Shapiro MD, Fazio S (2016). From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk. Circ Res, 118:732-49.
6. Isles CG, Paterson JR (2000). Identifying patients at risk for coronary heart disease: implications from trials of lipid-lowering drug therapy. QJM, 93:567-74.
7. Eckel RH, Jakicic JM, Ard JD, et al (2014). 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 63:2960-84.
8. Noma K, Higashi Y (2012). How to use ezetimibe as an anti-atherogenic agent via inhibition of rho-Kinase. Circ J, 76:1836-1837.
9. Ye Y, Zhao X, Zhai G, Guo L et al (2012). Effect of high-dose statin versus low-dose statin plus ezetimibe on endothelial function: a meta-analysis of randomized trials. J Cardiovasc Pharmacol Ther, 17:357-65.
10. Catapano AL, Farnier M, Foody JM et al (2014). Combination therapy in dyslipidemia: where are we now? Atherosclerosis, 237:319-35.
11. Barter PJ, Brandrup-Wognsen G, Palmer MK, Nicholls SJ (2010). Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database. J Lipid Res, 51:1546-53.
12. Preiss D, Seshasai SR, Welsh P, et al (2011). Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA, 305:2556-64.
13. Chatzizisis YS, Koskinas KC, Misirli G et al (2010). Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf, 33:171-87.
14. Stone NJ, Robinson JG, Lichtenstein AH, et al (2014). 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 63:2889-934.
15. Yamaoka-Tojo M, Tojo T, Takahira N et al (2011). Ezetimibe and reactive oxygen species. Curr Vasc Pharmacol, 9:109-20.
16. Capps N (2006). Total and low-density lipoprotein cholesterol responses to ezetimibe in clinical practice. Int J Clin Pract, 60:867-9.
17. Nakamura K, Miyoshi T, Yunoki K, Ito H (2016). Postprandial hyperlipidemia as a potential residual risk factor. J Cardiol, 67:335-9.
18. Kastelein JJ, Akdim F, Stroes ES, et al (2008). Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med, 358:1431-43.
19. Rossebo AB, Pedersen TR, Boman K, et al (2008). Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med, 359:1343-56.
20. Baigent C, Landray MJ, Reith C, et al (2011). 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, 377:2181-2192.
21. Cannon CP, Blazing MA, Giugliano RP, et al (2015). Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med, 372:2387-97.
22. Lyseng-Williamson KA (2012). Ezetimibe/simvastatin: a guide to its clinical use in hypercholesterolemia. Am J Cardiovasc Drugs, 12:49-56.
23. Khavandi M, Duarte F, Ginsberg HN, Reyes-Soffer G (2017). Treatment of Dyslipidemias to Prevent Cardiovascular Disease in Patients with Type 2 Diabetes. Curr Cardiol Rep, 19:7.
24. Moher D, Liberati A, Tetzlaff J, Altman DG (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med, 6:e1000097.
25. Sahebkar A, Simental-Mendia LE, Guerrero-Romero F et al (2015). Effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) concentrations: a systematic review and meta-analysis of clinical trials. Diabetes Obes Metab, 17:1042-55.
26. Goldberg AC, Sapre A, Liu J et al (2004). Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: A randomized, double-blind, placebo-controlled trial. Mayo Clin Proc, 79:620-629.
27. Ose L, Johnson-Levonas A, Reyes R et al (2007). A multi-centre, randomised, double-blind 14-week extension study examining the long-term safety and efficacy profile of the ezetimibe/simvastatin combination tablet. Int J Clin Pract, 61:1469-80.
28. Ballantyne CM, Abate N, Yuan Z et al (2005). 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, 149:464-73.
29. Davidson MH, McGarry T, Bettis R, et al (2002). Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol, 40:2125-2134.
30. Araujo DB, Bertolami MC, Ferreira WP et al (2010). Pleiotropic effects with equivalent low-density lipoprotein cholesterol reduction: comparative study between simvastatin and simvastatin/ezetimibe coadministration. J Cardiovasc Pharmacol, 55:1-5.
31. Settergren M, Bohm F, Ryden L, Pernow J (2008). Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease. Eur Heart J, 29:1753-60.
32. Settergren M, Bohm F, Ryden L et al (2009). Lipid lowering versus pleiotropic effects of statins on skin microvascular function in patients with dysglycaemia and coronary artery disease. J Intern Med, 266:492-8.
33. Olijhoek JK, Hajer GR, van der Graaf Y et al (2008). 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, 52:145-150.
34. Garcia MMO, Varela CG, Silva PF, et al (2016). Endothelial effect of statin therapy at a high dose versus low dose associated with ezetimibe. Arq Bras Cardiol, 106:279-288.
35. Rudofsky G, Reismann P, Groener JB, et al (2012). Identical LDL-cholesterol lowering but non-identical effects on NF-kappaB activity: High dose simvastatin vs combination therapy with ezetimibe. Atherosclerosis, 223:190-6.
36. Westerink J, Deanfield J, Imholz B et al (2013). 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, 227:118-24.
37. Bays HE, Ose L, Fraser N et al (2004). A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther, 26:1758-73.
38. Sager PT, Melani L, Lipka L et al (2003). Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol, 92:1414-8.
39. Angelopoulos J, Krassakopoulos N, Nathanson R et al (2009). Co-administration of ezetimibe and a statin in management of dyslipidemias: a meta-analysis of clinical trials. Arch Med Sci, 5:347-363.
40. Kashani A, Sallam T, Bheemreddy S et al (2008). Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials. Am J Cardiol, 101:1606-13.
41. Toth PP, Morrone D, Weintraub WS et al (2012). 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 Pract, 66:800-812.
| Files | ||
| Issue | Vol 48 No 8 (2019) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v48i8.2979 | |
| Keywords | ||
| Ezetimibe Statin Cholesterol Inflammation Meta-analysis | ||
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How to Cite
1.
YANG G, HAN D, MA J, ZHANG X. Efficacy of Ezetimibe/Simvastatin (10/10 mg) Versus High Dose Statin in Dyslipidemia Patients: A Meta-Analysis of Randomized Controlled Trials. Iran J Public Health. 2019;48(8):1405-1417.
