Skip to main content
SpringerLink
Log in

Add-on Ezetimibe Reduces Small Dense Low-Density Lipoprotein Cholesterol Levels Without Affecting Absorption of Eicosapentaenoic Acid in Patients with Coronary Artery Disease: A Pilot Study

  • Short Communication
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Background

Residual risk of cardiovascular disease from increased small dense low-density lipoprotein (sdLDL)-cholesterol levels and low n-3 polyunsaturated fatty acid (PUFA) levels is a considerable therapeutic issue. The purpose of this study was to evaluate the effect of ezetimibe as an add-on to statins and supplemental eicosapentaenoic acid (EPA) on sdLDL cholesterol and absorption of EPA in patients with coronary artery disease.

Methods

The study population consisted of ten male patients who were concurrently receiving statins and EPA 1,800 mg/day. Serum lipids and PUFAs, including EPA and arachidonic acid, were measured in blood samples collected before ezetimibe (baseline), 4 weeks after starting 10-mg/day ezetimibe, and 4 weeks after discontinuing ezetimibe.

Results

Ezetimibe significantly decreased sdLDL-cholesterol levels after 4 weeks of treatment (baseline 35 ± 13 mg/dl; treatment 27 ± 9 mg/dl), but the levels returned to baseline after discontinuation of ezetimibe (37 ± 13 mg/dl). The concentration of EPA did not significantly change during the study.

Conclusion

Ezetimibe shows great promise as an add-on therapy to statins to reduce sdLDL-cholesterol-related residual risk of cardiovascular disease without affecting absorption of supplemental EPA in patients with coronary artery disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. 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(8934):1383–9.

    Google Scholar 

  2. LIPID Study Group. 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(9315):1379–87.

    Article  Google Scholar 

  3. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335(14):1001–9.

    Article  PubMed  CAS  Google Scholar 

  4. Alagona P Jr. Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy. Am J Manag Care. 2009;15(3 Suppl):S65–73.

    PubMed  Google Scholar 

  5. Nakamura T, Obata JE, Hirano M, Kitta Y, Fujioka D, Saito Y, et al. Predictive value of remnant lipoprotein for cardiovascular events in patients with coronary artery disease after achievement of LDL-cholesterol goals. Atherosclerosis. 2011;218(1):163–7.

    Article  PubMed  CAS  Google Scholar 

  6. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation. 1990;82(2):495–506.

    Article  PubMed  CAS  Google Scholar 

  7. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, 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.

    Article  PubMed  Google Scholar 

  8. Yunoki K, Nakamura K, Miyoshi T, Enko K, Kubo M, Murakami M, et al. Impact of hypertriglyceridemia on endothelial dysfunction during statin +/− ezetimibe therapy in patients with coronary heart disease. Am J Cardiol. 2011;108(3):333–9.

    Article  PubMed  CAS  Google Scholar 

  9. Nakamura T, Hirano M, Kitta Y, Fujioka D, Saito Y, Kawabata K, et al. A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy. J Cardiol. 2012;60(1):12–7.

    Article  PubMed  Google Scholar 

  10. Uemura Y, Watarai M, Ishii H, Koyasu M, Takemoto K, Yoshikawa D, 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.

    Article  PubMed  Google Scholar 

  11. Tsunoda T, Nozue T, Yamada M, Mizuguchi I, Sasaki M, Michishita I. Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. Diabetes Res Clin Pract. 2013;100(1):46–52.

    Article  PubMed  CAS  Google Scholar 

  12. Winkler K, Jacob S, Muller-Schewe T, Hoffmann MM, Konrad T. Ezetimibe alone and in combination lowers the concentration of small, dense low-density lipoproteins in type 2 diabetes mellitus. Atherosclerosis. 2012;220(1):189–93.

    Article  PubMed  CAS  Google Scholar 

  13. Nordoy A, Hansen JB, Brox J, Svensson B. Effects of atorvastatin and omega-3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis. 2001;11(1):7–16.

    PubMed  CAS  Google Scholar 

  14. Satoh N, Shimatsu A, Kotani K, Sakane N, Yamada K, Suganami T, et al. Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and C-reactive protein in metabolic syndrome. Diabetes Care. 2007;30(1):144–6.

    Article  PubMed  CAS  Google Scholar 

  15. Labonte ED, Camarota LM, Rojas JC, Jandacek RJ, Gilham DE, Davies JP, et al. Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1−/− mice. Am J Physiol Gastrointest Liver Physiol. 2008;295(4):G776–83.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, et al. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan—2012 version. J Atheroscler Thromb. 2013;20(6):517–23.

    Article  PubMed  Google Scholar 

  17. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.

    PubMed  CAS  Google Scholar 

  18. Schectman G, Patsches M, Sasse EA. Variability in cholesterol measurements: comparison of calculated and direct LDL cholesterol determinations. Clin Chem. 1996;42(5):732–7.

    PubMed  CAS  Google Scholar 

  19. Ito Y, Fujimura M, Ohta M, Hirano T. Development of a homogeneous assay for measurement of small dense LDL cholesterol. Clin Chem. 2011;57(1):57–65.

    Article  PubMed  CAS  Google Scholar 

  20. Berneis K, Rizzo M, Berthold HK, Spinas GA, Krone W, Gouni-Berthold I. Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial. Eur Heart J. 2010;31(13):1633–9.

    Article  PubMed  CAS  Google Scholar 

  21. Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, et al. Niemann–Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science. 2004;303(5661):1201–4.

    Article  PubMed  CAS  Google Scholar 

  22. Kurisu S, Ishibashi K, Kato Y, Mitsuba N, Dohi Y, Nishioka K, et al. Effects of lipid-lowering therapy with strong statin on serum polyunsaturated fatty acid levels in patients with coronary artery disease. Heart Vessels. 2013;28(1):34–8.

    Article  PubMed  Google Scholar 

  23. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999;354(9177):447–55.

  24. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1223–30.

    Article  PubMed  Google Scholar 

  25. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–8.

    Article  PubMed  CAS  Google Scholar 

  26. Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, et al. n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309–18.

    Article  PubMed  CAS  Google Scholar 

  27. Kromhout D, Giltay EJ, Geleijnse JM. n-3 Fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363(21):2015–26.

    Article  PubMed  CAS  Google Scholar 

  28. Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation. 2010;122(21):2152–9.

    Article  PubMed  CAS  Google Scholar 

  29. Harris WS, Von Schacky C. The Omega-3 Index: a new risk factor for death from coronary heart disease? Prev Med. 2004;39(1):212–20.

    Article  PubMed  CAS  Google Scholar 

  30. Eckel RH, Jakicic JM, Ard JD, Hubbard VS, de Jesus JM, Lee IM, et al. 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. Circulation. 2013.

  31. Albert CM, Hennekens CH, O’Donnell CJ, Ajani UA, Carey VJ, Willett WC, et al. Fish consumption and risk of sudden cardiac death. JAMA. 1998;279(1):23–8.

    Article  PubMed  CAS  Google Scholar 

  32. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312(19):1205–9.

    Article  PubMed  CAS  Google Scholar 

  33. Lemaitre RN, King IB, Mozaffarian D, Kuller LH, Tracy RP, Siscovick DS. n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am J Clin Nutr. 2003;77(2):319–25.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a Japan Health Promotion Foundation research grant 2013 to TM.

Conflict of interest

None of the authors have any potential conflict of interest that might be relevant to the content of this study.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Motoki Kubo, Tomonari Kimura, Yoko Noda, Kunihisa Kohno, Kazufumi Nakamura & Hiroshi Ito

  2. Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Toru Miyoshi & Hiroshi Morita

Authors
  1. Motoki Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toru Miyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomonari Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoko Noda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kunihisa Kohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazufumi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroshi Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroshi Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toru Miyoshi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kubo, M., Miyoshi, T., Kimura, T. et al. Add-on Ezetimibe Reduces Small Dense Low-Density Lipoprotein Cholesterol Levels Without Affecting Absorption of Eicosapentaenoic Acid in Patients with Coronary Artery Disease: A Pilot Study. Am J Cardiovasc Drugs 14, 387–392 (2014). https://doi.org/10.1007/s40256-014-0082-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-014-0082-3

Keywords

Search

Navigation