American Journal of Cardiovascular Drugs

, Volume 13, Issue 5, pp 343–351

Effects of Ezetimibe/Simvastatin 10/20 mg vs. Atorvastatin 20 mg on Apolipoprotein B/Apolipoprotein A1 in Korean Patients with Type 2 Diabetes Mellitus: Results of a Randomized Controlled Trial

  • Ju-Hee Lee
  • Hyun-Jae Kang
  • Hyo-Soo Kim
  • Dae-Won Sohn
  • Byung-Hee Oh
  • Young-Bae Park
Original Research Article



Although the efficacy of ezetimibe/simvastatin and atorvastatin on traditional lipid parameters has been studied extensively, the apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio, which has a better predictive value for cardiovascular events, has not previously been used as a primary endpoint in these two treatment groups.


Our objective was to compare the efficacy and safety of ezetimibe/simvastatin 10/20 mg versus atorvastatin 20 mg once daily in Korean patients with type 2 diabetes mellitus.

Study Design

This study was an open-label, randomized, controlled study. Type 2 diabetes patients with high levels of low-density lipoprotein (LDL) cholesterol (>100 mg/dL) were randomized to receive ezetimibe/simvastatin or atorvastatin.

Main Outcome Measure

The primary endpoint was the difference in the percent change of ApoB/ApoA1 at 12 weeks, and secondary endpoints were changes in lipid profiles, glycosylated hemoglobin (HbA1c), homeostatic model assessment (HOMA) index, and C-reactive protein.


In total, 132 patients (66 for each group) were enrolled and randomized. After 12 weeks of treatment, the ApoB/ApoA1 ratio was significantly reduced in both groups; however, the difference of changes between the two groups was not statistically significant (ezetimibe/simvastatin −38.6 ± 18.0 % vs. atorvastatin −34.4 ± 15.5 %; p = 0.059). There were no significant differences in changes to total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, triglycerides, ApoB, and ApoB48 between the two groups. However, the increments of ApoA1 were significantly greater in the ezetimibe/simvastatin group than in the atorvastatin group (2.8 ± 10.0 vs. −1.8 ± 9.8 %; p = 0.002). In the per-protocol analysis, improvement in ApoB/ApoA1 was significantly greater in the ezetimibe/simvastatin group (−42.8 ± 11.8 vs. −36.7 ± 13.2 %; p = 0.019). The changes in HbA1c, HOMA index, and C-reactive protein were comparable between the two groups. The adverse reaction rate was similar between the two groups (24.2 vs. 34.9 %; p = 0.180).


Ezetimibe/simvastatin 10/20 mg is comparable to atorvastatin 20 mg for the management of dyslipidemia, and may have more favorable effects on apolipoprotein profiles than atorvastatin 20 mg in Korean patients with type 2 diabetes mellitus.


  1. 1.
    Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287(19):2570–81.PubMedCrossRefGoogle Scholar
  2. 2.
    Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51(15):1512–24.PubMedCrossRefGoogle Scholar
  3. 3.
    Walldius G, Jungner I, Holme I, et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358(9298):2026–33.PubMedCrossRefGoogle Scholar
  4. 4.
    Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet. 2004;364(9438):937–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Talmud PJ, Hawe E, Miller GJ, et al. Nonfasting apolipoprotein B and triglyceride levels as a useful predictor of coronary heart disease risk in middle-aged UK men. Arterioscler Thromb Vasc Biol. 2002;22(11):1918–23.PubMedCrossRefGoogle Scholar
  6. 6.
    Parish S, Peto R, Palmer A, et al. The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls. Eur Heart J. 2009;30(17):2137–46.PubMedCrossRefGoogle Scholar
  7. 7.
    Sierra-Johnson J, Fisher RM, Romero-Corral A, Somers VK, Lopez-Jimenez F, Ohrvik J, et al. Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population. Eur Heart J. 2009;30(6):710–7.PubMedCrossRefGoogle Scholar
  8. 8.
    van der Steeg WA, Boekholdt SM, Stein EA, et al. Role of the apolipoprotein B–apolipoprotein A-I ratio in cardiovascular risk assessment: a case–control analysis in EPIC-Norfolk. Ann Intern Med. 2007;146(9):640–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Ballantyne CM, Abate N, Yuan Z, et al. 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(3):464–73.PubMedCrossRefGoogle Scholar
  10. 10.
    Goldberg RB, Guyton JR, Mazzone T, et al. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clin Proc. 2006;81(12):1579–88.PubMedCrossRefGoogle Scholar
  11. 11.
    Guyton JR, Goldberg RB, Mazzone T, et al. Lipoprotein and apolipoprotein ratios in the VYTAL trial of ezetimibe/simvastatin compared with atorvastatin in type 2 diabetes. J Clin Lipidol. 2008;2(1):19–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Ballantyne CM, Blazing MA, King TR, et al. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol. 2004;93(12):1487–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Uemura Y, Watarai M, Ishii H, et al. Atorvastatin 10 mg plus ezetimibe 10 mg compared with atorvastatin 20 mg: impact on the lipid profile in Japanese patients with abnormal glucose tolerance and coronary artery disease. J Cardiol. 2012;59(1):50–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Tremblay AJ, Lamarche B, Hogue JC, et al. Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia. J Lipid Res. 2009;50(7):1463–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Crouse JR 3rd, Frohlich J, Ose L, et al. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol. 1999;83(10):1476–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Milionis HJ, Rizos E, Kostapanos M, et al. Treating to target patients with primary hyperlipidaemia: comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study). Curr Med Res Opin. 2006;22(6):1123–31.PubMedCrossRefGoogle Scholar
  17. 17.
    US National Center for Health Statistics. Health, United States, 2010: with special feature on death and dying. Hyattsville: National Center for Health Statistics; 2011.Google Scholar
  18. 18.
    Korean Ministry of Health and Welfare. Korea Health Statistics 2009: Korea National Health and Nutrition Examination Survey (KNHANES IV-3). 2011.Google Scholar
  19. 19.
    Ravid Z, Bendayan M, Delvin E, et al. Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G873–85.PubMedCrossRefGoogle Scholar
  20. 20.
    Gylling H, Miettinen TA. Cholesterol absorption, synthesis, and LDL metabolism in NIDDM. Diabetes Care. 1997;20(1):90–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Lupattelli G, De Vuono S, Mannarino E. Patterns of cholesterol metabolism: pathophysiological and therapeutic implications for dyslipidemias and the metabolic syndrome. Nutr Metab Cardiovasc Dis. 2011;21(9):620–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Okada K, Yagyu H, Kotani K, et al. Lipid-lowering effects of ezetimibe for hypercholesterolemic patients with and without type 2 diabetes mellitus. Endocr J. 2010;57(10):903–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Goldberg RB, Guyton JR, Mazzone T, et al. Relationships between metabolic syndrome and other baseline factors and the efficacy of ezetimibe/simvastatin and atorvastatin in patients with type 2 diabetes and hypercholesterolemia. Diabetes Care. 2010;33(5):1021–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Huptas S, Geiss HC, Otto C, et al. Effect of atorvastatin (10 mg/day) on glucose metabolism in patients with the metabolic syndrome. Am J Cardiol. 2006;98(1):66–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Tanaka A, Yamada N, Saito Y, et al. A double-blind trial on the effects of atorvastatin on glycemic control in Japanese diabetic patients with hypercholesterolemia. Clin Chim Acta. 2001;312(1–2):41–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Takano T, Yamakawa T, Takahashi M, et al. Influences of statins on glucose tolerance in patients with type 2 diabetes mellitus. J Atheroscler Thromb. 2006;13(2):95–100.PubMedCrossRefGoogle Scholar
  27. 27.
    Her AY, Kim JY, Kang SM, et al. Effects of atorvastatin 20 mg, rosuvastatin 10 mg, and atorvastatin/ezetimibe 5 mg/5 mg on lipoproteins and glucose metabolism. J Cardiovasc Pharmacol Ther. 2010;15(2):167–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Moutzouri E, Liberopoulos E, Mikhailidis DP, et al. Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance. Int J Clin Pract. 2011;65(11):1141–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Pearson T, Ballantyne C, Sisk C, et al. Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels. Am J Cardiol. 2007;99(12):1706–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Tamaki N, Ueno H, Morinaga Y, et al. Ezetimibe ameliorates atherosclerotic and inflammatory markers, atherogenic lipid profiles, insulin sensitivity, and liver dysfunction in Japanese patients with hypercholesterolemia. J Atheroscler Thromb. 2012;19(6):532–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Naples M, Baker C, Lino M, et al. Ezetimibe ameliorates intestinal chylomicron overproduction and improves glucose tolerance in a diet-induced hamster model of insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2012;302(9):G1043–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Deushi M, Nomura M, Kawakami A, et al. Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett. 2007;581(29):5664–70.PubMedCrossRefGoogle Scholar
  33. 33.
    Muraoka T, Aoki K, Iwasaki T, et al. Ezetimibe decreases SREBP-1c expression in liver and reverses hepatic insulin resistance in mice fed a high-fat diet. Metabolism. 2011;60(5):617–28.PubMedCrossRefGoogle Scholar
  34. 34.
    Dagli N, Yavuzkir M, Karaca I. The effects of high dose pravastatin and low dose pravastatin and ezetimibe combination therapy on lipid, glucose metabolism and inflammation. Inflammation. 2007;30(6):230–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Araujo DB, Bertolami MC, Ferreira WP, et al. Pleiotropic effects with equivalent low-density lipoprotein cholesterol reduction: comparative study between simvastatin and simvastatin/ezetimibe coadministration. J Cardiovasc Pharmacol. 2010;55(1):1–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Robinson JG, Ballantyne CM, Hsueh W, et al. Achievement of specified low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol apolipoprotein B, and high-sensitivity C-reactive protein levels with ezetimibe/simvastatin or atorvastatin in metabolic syndrome patients with and without atherosclerotic vascular disease (from the VYMET study). J Clin Lipidol. 2011;5(6):474–82.PubMedCrossRefGoogle Scholar
  37. 37.
    Conard S, Bays H, Leiter LA, et al. Ezetimibe added to atorvastatin compared with doubling the atorvastatin dose in patients at high risk for coronary heart disease with diabetes mellitus, metabolic syndrome or neither. Diabetes Obes Metab. 2010;12(3):210–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Ju-Hee Lee
    • 1
  • Hyun-Jae Kang
    • 1
  • Hyo-Soo Kim
    • 1
  • Dae-Won Sohn
    • 1
  • Byung-Hee Oh
    • 1
  • Young-Bae Park
    • 1
  1. 1.Division of Cardiology, Department of Internal MedicineSeoul National University Hospital, College of Medicine, Seoul National UniversitySeoulSouth Korea

Personalised recommendations