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Comparison of Efficacy and Safety of Statin–Ezetimibe Combination Therapy with Statin Monotherapy in Patients with Diabetes: A Meta-Analysis of Randomized Controlled Studies

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Abstract

Introduction

Dyslipidemia in diabetes mellitus is characterized by hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). Additionally, the potentially increased risk of morbidity and mortality following atherosclerotic cardiovascular diseases should be considered in the treatment of dyslipidemia in patients with diabetes.

Methods

We performed a meta-analysis of the published data to compare the effects of HMG-CoA reductase inhibitor (statin)–ezetimibe combination therapy and statin monotherapy on lipid and glucose parameters in patients with diabetes. We also compared safety based on the adverse events reported for the two groups.

Results

In total, 17 articles were included in this meta-analysis. In the efficacy assessment, the combination treatment afforded a significantly greater reduction in LDL-C than did statin monotherapy (standard difference in means 0.691; 95% confidence interval 0.534–0.847). A significantly greater improvement effect was observed in the levels of HDL-C, total cholesterol, triglyceride, and apolipoprotein B, but not apolipoprotein A1, with combination therapy than with statin monotherapy. Additionally, combination therapy reduced fasting blood glucose levels more significantly than did statin monotherapy. In terms of safety, there were no significant differences in treatment-related adverse events between the two treatments.

Conclusions

Statin–ezetimibe combination therapy enhances levels of LDL-C and other lipids without increasing the risk of adverse events compared with statin monotherapy. The present meta-analysis presents valid evidence for appropriate drug regimens to treat dyslipidemia in patients with diabetes.

Registration

PROSPERO Identifier Number CRD42021244578

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References

  1. Sherling DH, Perumareddi P, Hennekens CH. Metabolic syndrome. J Cardiovasc Pharmacol Ther. 2017;22:365–7.

    Article  CAS  Google Scholar 

  2. Taskinen MR. Diabetic dyslipidemia: from basic research to clinical practice. Diabetologia. 2003;46:733–9.

    Article  Google Scholar 

  3. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation. 2004;110:227–39.

    Article  Google Scholar 

  4. Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285:2486–97. https://doi.org/10.1001/jama.285.19.2486

  5. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–96.

    Article  CAS  Google Scholar 

  6. Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117–25.

  7. Giugliano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalán R, Špinar J, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2018;137:1571–82. https://doi.org/10.1161/CIRCULATIONAHA.117.030950.

    Article  CAS  PubMed  Google Scholar 

  8. Darkes MJ, Poole RM, Goa KL. Ezetimibe. Am J Cardiovasc Drugs. 2003;3:67–76 (discussion 77–8).

    Article  CAS  Google Scholar 

  9. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.

    Article  CAS  Google Scholar 

  10. Nubaumer B, Glechner A, Kaminski-Hartenthaler A, Mahlknecht P, Gartlehner G. Ezetimibe-statin combination therapy. Dtsch Arztebl Int. 2016;113:445–53.

    Google Scholar 

  11. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.

    Article  CAS  Google Scholar 

  12. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–29.

    Article  Google Scholar 

  13. Mantel N, Henszel W. Statistical aspects of the analysis of data from retrospective sties of diseases. J Natl Cancer Inst. 1959;22:719–48.

    CAS  PubMed  Google Scholar 

  14. DerSimonian R, Larid N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  Google Scholar 

  15. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometircs. 1994;50:1088–101.

    Article  CAS  Google Scholar 

  16. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  Google Scholar 

  17. Simons L, Tonkon M, Masana L, Maccubbin D, Shah A, Lee M, Gumbiner B. Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with diabetes mellitus or metabolic syndrome. Curr Med Res Opin. 2004;20:1437–45. https://doi.org/10.1185/030079904x2321.

    Article  CAS  PubMed  Google Scholar 

  18. Gaudiani LM, Lewin A, Meneghini L, Perevozskaya I, Plotkin D, Mitchel Y, Shah S. Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients. Diabetes Obes Metab. 2005;7:88–97. https://doi.org/10.1111/j.1463-1326.2004.00420.x.

    Article  CAS  PubMed  Google Scholar 

  19. Denke M, Pearson T, McBride P, Gazzara RA, Brady WE, Tershakovec AM. Ezetimibe added to ongoing statin therapy improves LDL-C goal attainment and lipid profile in patients with diabetes or metabolic syndrome. Diabetes Vasc Dis Res. 2006;3:93–102. https://doi.org/10.3132/dvdr.2006.020.

    Article  Google Scholar 

  20. Goldberg RB, Guyton JR, Mazzone T, Weinstock RS, Polis A, Edwards P, et al. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clin Proc. 2006;81:1579–88.

    Article  CAS  Google Scholar 

  21. Constance C, Westphal S, Chung N, Lund M, Sisk CM, Johnson-Levonas AO, et al. Efficacy of ezetimibe/simvastatin 10/20 and 10/40 mg compared with atorvastatin 20 mg in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2007;9:575–84.

    Article  CAS  Google Scholar 

  22. Settergren M, Böhm F, Rydén L, Pernow J. Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycemia and coronary artery disease. Eur Heart J. 2008;29:1753–60. https://doi.org/10.1093/eurheartj/ehn166.

    Article  CAS  PubMed  Google Scholar 

  23. Polis AB, Abate N, Catapano AL, Ballantyne CM, Davidson MH, Smugar SS, Tershakovec AM. Affiliations expand Low-density lipoprotein cholesterol reduction and goal achievement with ezetimibe/simvastatin versus atorvastatin or rosuvastatin in patients with diabetes, metabolic syndrome, or neither disease, stratified by national cholesterol education program risk category. Metab Syndr Relat Disord. 2009;7:601–10. https://doi.org/10.1089/met.2009.0009.

    Article  CAS  PubMed  Google Scholar 

  24. Bardini G, Giorda CB, Pontiroli E, Le Grazie C, Rotella CM. Ezetimibe + simvastatin versus doubling the dose of simvastatin in high cardiovascular risk diabetics: a multicenter, randomized trial (the LEAD study). Cardiovasc Diabetol. 2010;9:20. https://doi.org/10.1186/1475-2840-9-20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ruggenenti P, Cattaneo D, Rota S, Iliev I, Parvanova A, Diadei O, et al. Effects of combined ezetimibe and simvastatin therapy as compared with simvastatin alone in patients with type 2 diabetes: a prospective randomized double-blind clinical trial. Diabetes Care. 2010;33:1954–6. https://doi.org/10.2337/dc10-0320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kawagoe Y, Hattori Y, Nakano A, Aoki C, Tanaka S, Ohta S, et al. Comparative study between high-dose fluvastatin and low-dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients. Endocr J. 2011;58:171–5.

    Article  CAS  Google Scholar 

  27. Uemura Y, Watarai M, Ishii H, Koyasu M, Takemoto K, Yoshikawa D, et al. Atorvastatin 10mg plus ezetimibe 10mg compared with atorvastatin 20mg: Impact on the lipid profile in japanese patients with abnormal glucose tolerance and coronary artery disease. J Cardiol. 2012;59:50–6.

    Article  Google Scholar 

  28. Vaverkova H, Farnier M, Averna M, Missault L, Viigimaa M, Dong Q, et al. Lipid-altering efficacy of ezetimibe/simvastatin 10/20 mg compared to rosuvastatin 10 mg in high-risk patients with and without type 2 diabetes mellitus inadequately controlled despite prior statin monotherapy. Cardiovasc Ther. 2012;30:61–74. https://doi.org/10.1111/j.1755-5922.2010.00181.x.

    Article  CAS  PubMed  Google Scholar 

  29. Rosen JB, Jimenez JG, Pirags V, Vides H, Massaad R, Hanson ME, et al. Consistency of effect of ezetimibe/simvastatin compared with intensified lipid-lowering treatment strategies in obese and non-obese diabetic subjects. Lipids Health Dis. 2013;12:103. https://doi.org/10.1186/1476-511X-12-103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Torimoto K, Okada Y, Mori H, Hajime M, Tanaka K, Kurozumi A, et al. Efficacy of combination of ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes. Lipids Health Dis. 2013;12:137. https://doi.org/10.1186/1476-511X-12-137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Villegas-Rivera G, Román-Pintos LM, Cardona-Muñoz EG, Arias-Carvajal O, Rodríguez-Carrizalez AD, Troyo-Sanromán R, et al. 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: 756294. https://doi.org/10.1155/2015/756294.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sakamoto K, Kawamura M, Watanabe T, Ashidate K, Kohro T, Tanaka A, et al. Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects. Lipids Health Dis. 2017;16:122–4. https://doi.org/10.1186/s12944-017-0508-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. El-Tamalawy MM, Ibrahim OM, Hassan TM, El-Barbari AA. Effect of combination therapy of ezetimibe and atorvastatin on remnant lipoprotein versus double atorvastatin dose in egyptian diabetic patients. J Clin Pharmacol. 2018;58:34–41. https://doi.org/10.1002/jcph.976.

    Article  CAS  PubMed  Google Scholar 

  34. Menotti A, Keys A, Blackburn H, Kromhout D, Karvonen M, Nissinen A, et al. Comparison of multivariate predictive power of major risk factors for coronary heart diseases in different countries: results from eight nations of the Seven Countries Study, 25-year follow-up. J Cardiovasc risk. 1996;3:69–75.

    Article  CAS  Google Scholar 

  35. Gotto AM Jr. Low high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report. Circulation. 2001;103:2213–8.

    Article  CAS  Google Scholar 

  36. Miao XY, Liu HZ, Jin MM, Sun BR, Tian H, Li J, et al. A comparative meta-analysis of the efficacy of statin-ezetimibe co-therapy versus statin monotherapy in reducing cardiovascular and cerebrovascular adverse events in patients with type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci. 2019;23:2302–10. https://doi.org/10.26355/eurrev_201903_17279.

    Article  PubMed  Google Scholar 

  37. Leiter LA, Betteridge DJ, Farnier M, Guyton JR, Lin J, Shah A, et al. Lipid-altering efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in patients with and without diabetes: an analysis of pooled data from 27 clinical trials. Diabetes Obes Metab. 2011;13:615–28. https://doi.org/10.1111/j.1463-1326.2011.01383.x].

    Article  CAS  PubMed  Google Scholar 

  38. Lally SE, Owens D, Tomkin GH. Sitosterol and cholesterol in chylomicrons of type 2 diabetic and non-diabetic subjects: the relationship with ATP binding cassette proteins G5 and G8 and niemann-pick C1-like 1 mRNA. Diabetologia. 2007;50:217–9. https://doi.org/10.1007/s00125-006-0504-0.

    Article  CAS  PubMed  Google Scholar 

  39. Lally S, Owens D, Tomkin GH. Genes that affect cholesterol synthesis, cholesterol absorption, and chylomicron assembly: the relationship between the liver and intestine in control and streptozotosin diabetic rats. Metabolism. 2007;56:430–8.

    Article  CAS  Google Scholar 

  40. Tomkin GH. The intestine as a regulator of cholesterol homeostasis in diabetes. Atheroscler Suppl. 2008;9:27–32. https://doi.org/10.1016/j.atherosclerosissup.2008.05.012.

    Article  CAS  PubMed  Google Scholar 

  41. Kenichi T, Seigo S, Hitoshi S, Hideki S, Takuro Y, Kenshi Y, 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. https://doi.org/10.1016/j.jacc.2015.05.065.

    Article  Google Scholar 

  42. Koichiro F, Kenshi Y, Suguru N, Hideki S, Takuro Y, Koichi N, et al. Effects of statin plus ezetimibe on coronary plaques in acute coronary syndrome patients with diabetes mellitus: sub-analysis of PRECISE-IVUS trial. J Atheroscler Thromb. 2021;28:181–93. https://doi.org/10.5551/jat.54726.

    Article  CAS  Google Scholar 

  43. Wu H, Shang H, Wu J. Effect of ezetimibe on glycemic control: a systematic review and meta-analysis of randomized controlled trials. Endocrine. 2018;60:229–39. https://doi.org/10.1007/s12020-018-1541-4.

    Article  CAS  PubMed  Google Scholar 

  44. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Cren AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010;375:735–42. https://doi.org/10.1016/S0140-6736(09)61965-6.

    Article  CAS  PubMed  Google Scholar 

  45. Erqou S, Lee CC, Adler AI. Statins and glycemic control in individuals with diabetes: a systematic review and meta-analysis. Diabetologia. 2014;57:2444–52. https://doi.org/10.1007/s00125-014-3374-x.

    Article  CAS  PubMed  Google Scholar 

  46. Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in non-diabetics: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2010;87:98–107. https://doi.org/10.1016/j.diabres.2009.10.008.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea

    Kwang-Hee Shin

  2. College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea

    Hye Duck Choi

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  1. Kwang-Hee Shin
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Correspondence to Hye Duck Choi.

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This research was supported by a 2020 Yeungnam University Research Grant.

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Shin KH and Choi HD have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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Shin KH and Choi HD conducted the search, collected the data, performed the analysis, and wrote the manuscript.

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Shin, KH., Choi, H.D. Comparison of Efficacy and Safety of Statin–Ezetimibe Combination Therapy with Statin Monotherapy in Patients with Diabetes: A Meta-Analysis of Randomized Controlled Studies. Am J Cardiovasc Drugs 22, 395–406 (2022). https://doi.org/10.1007/s40256-021-00516-3

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