Fixed combinations of lipid-lowering drugs: issue status and prospects
Yu.V. Kotovskaya, E.A. Yeruslanova
Russian Clinical and Research Center of Gerontology, the branch of the Pirogov Russian National Research Medical University, Moscow
A decrease in low-density lipoprotein cholesterol (LDL cholesterol) level using HMG-CoA reductase inhibitors (statins) is the cornerstone of primary and secondary prevention of adverse cardiovascular outcomes. The European Society of Cardiology 2019 updated guidelines on the dyslipidemia treatment include LDL cholesterol low target levels for patients of the medium, high and very high risk. New treatment targets increase the combination therapy role, whereas, the addition of ezetimibe to the HMG-CoA reductase inhibitor (statin) is the first step. This approach is well studied, effective and safe. This combination has a synergistic effect and improves carbohydrate metabolism. The review provides an analysis of the main characteristics, clinical efficacy and safety of fixed combinations in modern lipid-lowering agents. Also, it shows the prospects of combination therapy using ezetimibe. Considered studies allowed to establish that the fixed combination application of statin and ezetimibe leads to an increase in patients adherence to long-term lipid-lowering therapy, and, consequently, a prognosis improvement in patients.
Keywords: HMG-CoA reductase inhibitors, ezetimibe, rosuvastatin, atorvastatin, simvastatin, fixed combinations of lipid-lowering agents, Rosulip Plus.
For citation: Kotovskaya: Yu.V., Yeruslanova E.A. Fixed combinations of lipid-lowering drugs: issue status and prospects. RMJ. Medical Review. 2019;10(I):45–48.
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28. Sattar N., Preiss D., Murray H.M. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742.
29. Barkas F., Elisaf M., Liberopoulos E. et al. Statin therapy with or without ezetimibe and the progression to diabetes. J Clin Lipidol. 2016;10(2):306–313.
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31. Ai C., Zhang S., He Q., Shi J. Comparing the combination therapy of ezetimibe and atorvastatin with atorvastatin monotherapy for regulating blood lipids: a systematic review and metaanalyse. Lipids Health Dis. 2018 Oct 17;17(1):239. DOI: 10.1186/s12944-018-0880-8.
32. Tsujita K., Sugiyama S., Sumida H. 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.
33. Leiter L.A., Bays H., Conard S. et al. Efficacy and safety of ezetimibe added on to atorvastatin(40 mg) compared with uptitration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol. 2008;102:1495–1501.
34. Ridker P.M., Danielson E., Fonseca F.A. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–2207.
35. Yusuf S., Bosch J., Dagenais G. et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016;374:2021–2031. DOI: 10.1056/NEJMoa1600176.
36. Ballantyne C.M., Weiss R., Moccetti T. et al. Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol. 2007;99(5):673–680.
37. Kim K.J., Kim S.H., Yoon Y.W. et al. Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe). Cardiovasc Ther. 2016;34(5):371–382.
38. Hong S.J., Jeong H.S., Ahn J.C. et al. A phase III, multicenter, randomized, double-blind, active comparator clinical trial to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus rosuvastatin monotherapy in patients with hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin and Ezetimibe for Hypercholesterolemia) randomized controlled trial. Clin Ther. 2018;40(2):226–241.e224.
39. Bays H.E., Davidson M.H., Massaad R. et al. Am J Cardiol. Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study). 2011 Aug 15;108(4):523–30. DOI: 10.1016/j.amjcard.2011.03.079. Epub 2011 May 17.
40. Penson P., McGowan M., Banach M. Evaluating bempedoic acid for the treatment of hyperlipidaemia. Expert Opin Investig Drugs. 2017;26(2):251–259.
41. Burke A.C., Huff M.W. ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia. Curr Opin Lipidol. 2017;28(2):193–200.
42. Bilen O., Ballantyne C.M. Bempedoic acid (ETC-1002): an investigational inhibitor of ATP citrate lyase. Curr Atheroscler Rep. 2016;18(10):61.
43. Thompson P.D., MacDougall D.E., Newton R.S. et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016;10(3):556–567.
44. Nash S. Evaluation of the efficacy and safety of bempedoic acid (ETC-1002) in patients with hyperlipidemia and statin intolerant (CLEAR Serenity). NCT02988115. https://clinicaltrials.gov.
2. Grundy S.M., Cleeman J.I., Merz C.N. et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation. 2004;110(2):227–239.
3. Wood D., De Backer G., Faergeman O et al. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Athero sclerosis. 1998;140(2):199–270.
4. Euroaspire II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries: principal results from EUROASPIRE II Euro Heart Survey Programme. Eur Heart J. 2001;22(7):554–572.
5. Jones P., Kafonek S., Laurora I., Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol. 1998;81(5):582–587.
6. Baigent C., Keech A., Kearney P.M. et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–1278.
7. Baigent C., Blackwell L., Emberson J. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: ametaanalysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–1681.
8. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7–22.
9. Mach F., Baigent С., Catapano A.L. et al., ESC Scientific Document Group, 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS), European Heart Journal, ehz455. https://doi.org/10.1093/eurheartj/ehz455.
10. Schleyer T., Hui S., Wang J. et al. Quantifying Unmet Need in Statin-Treated Hyperlipidemia Patients and the Potential Benefit of Further LDL-C Reduction Through an EHR-Based Retrospective Cohort Study. Journal of Managed Care and Specialty Pharmacy. 2019;25(5):544. DOI: 10.18553/jmcp.2019.25.5.544.
11. Cannon C.P., Braunwald E., McCabe C.H. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–1504.
12. De Lemos J.A., Blazing M.A., Wiviott S.D. et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292(11):1307–1316.
13. LaRosa J.C., Grundy S.M., Waters D.D. et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425–1435.
14. Cannon C.P., Steinberg B.A., Murphy S.A. et al. Metaanalysis of cardiovascular outcomes trials comparing inten- sive versus moderate statin therapy. J Am Coll Cardiol. 2006;48(3):438–445.
15. Pearson T.A., Laurora I., Chu H., Kafonek S. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med. 2000;160(4):459–467.
16. Bell D.S. Combine and conquer: advantages and disadvantages of fixed-dose combination therapy. Diabetes Obes Metab. 2013;15(4):291–300.
17. 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;344:1383–1389.
18. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005 Feb;19(1):117–125. Review.
19. The ESC Handbook on Cardiovascular Pharmacotherapy. Edited by J.C. Kaski, K.P. Kjeldsen. Oxford University Press. First edition published in 2019.
20. Sudhop T., Lutjohann D., Kodal A. et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106(15):1943–1948.
21. Betters J.L., Yu L. NPC1L1 and cholesterol transport. FEBS Lett. 2010;584(13):2740–2747.
22. Ballantyne C.M., Houri J., Notarbartolo A. et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107(19):2409–2415.
23. Davidson M.H., McGarry T., Bettis R. et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002;40(12):2125–2134.
24. Bays H.E., Davidson M.H., Massaad R. et al. Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE study). Am J Cardiol. 2011;108(4):523–530.
25. Marphy S.A., Cannon C.P., Blazing M.A. et al. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. J Am Coll Cardiol. 2016;67:353–361.
26. Stanifer J.W., Charytan D.M., White J. et al. Benefit of Ezetimibe Added to Simvastatin in Reduced Kidney Function. J Am Soc Nephrol. 2017 May 15:pii: AS. N.2016090957. DOI: 10.1681/ASN.2016090957. [Epub ahead of print]
27. Kei A.A., Filippatos T.D., Elisaf M.S. The safety of ezetimibe and simvastatin combination for the treatment of hypercholesterolemia. Expert Opin Drug Saf. 2016;15(4):559–569.
28. Sattar N., Preiss D., Murray H.M. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742.
29. Barkas F., Elisaf M., Liberopoulos E. et al. Statin therapy with or without ezetimibe and the progression to diabetes. J Clin Lipidol. 2016;10(2):306–313.
30. Adams S.P., Tsang M., Wright J.M. Lipid-lowering efficacy of atorvastatin. Cochrane Database Syst Rev. 2015;(3):CD008226.
31. Ai C., Zhang S., He Q., Shi J. Comparing the combination therapy of ezetimibe and atorvastatin with atorvastatin monotherapy for regulating blood lipids: a systematic review and metaanalyse. Lipids Health Dis. 2018 Oct 17;17(1):239. DOI: 10.1186/s12944-018-0880-8.
32. Tsujita K., Sugiyama S., Sumida H. 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.
33. Leiter L.A., Bays H., Conard S. et al. Efficacy and safety of ezetimibe added on to atorvastatin(40 mg) compared with uptitration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol. 2008;102:1495–1501.
34. Ridker P.M., Danielson E., Fonseca F.A. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–2207.
35. Yusuf S., Bosch J., Dagenais G. et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016;374:2021–2031. DOI: 10.1056/NEJMoa1600176.
36. Ballantyne C.M., Weiss R., Moccetti T. et al. Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol. 2007;99(5):673–680.
37. Kim K.J., Kim S.H., Yoon Y.W. et al. Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe). Cardiovasc Ther. 2016;34(5):371–382.
38. Hong S.J., Jeong H.S., Ahn J.C. et al. A phase III, multicenter, randomized, double-blind, active comparator clinical trial to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus rosuvastatin monotherapy in patients with hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin and Ezetimibe for Hypercholesterolemia) randomized controlled trial. Clin Ther. 2018;40(2):226–241.e224.
39. Bays H.E., Davidson M.H., Massaad R. et al. Am J Cardiol. Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study). 2011 Aug 15;108(4):523–30. DOI: 10.1016/j.amjcard.2011.03.079. Epub 2011 May 17.
40. Penson P., McGowan M., Banach M. Evaluating bempedoic acid for the treatment of hyperlipidaemia. Expert Opin Investig Drugs. 2017;26(2):251–259.
41. Burke A.C., Huff M.W. ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia. Curr Opin Lipidol. 2017;28(2):193–200.
42. Bilen O., Ballantyne C.M. Bempedoic acid (ETC-1002): an investigational inhibitor of ATP citrate lyase. Curr Atheroscler Rep. 2016;18(10):61.
43. Thompson P.D., MacDougall D.E., Newton R.S. et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016;10(3):556–567.
44. Nash S. Evaluation of the efficacy and safety of bempedoic acid (ETC-1002) in patients with hyperlipidemia and statin intolerant (CLEAR Serenity). NCT02988115. https://clinicaltrials.gov.
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