Spotlight on Icosapent Ethyl for Cardiovascular Risk Reduction: Evidence to Date

References

• McLennan PL. Myocardial membrane fatty acids and the antiarrhythmic actions of dietary fish oil in animal models. Lipids. 2001;36(Suppl):S111–S114. doi:10.1007/s11745-001-0692-x
   PubMed Web of Science ®Google Scholar
• Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation. 2003;107(21):2646–2652. doi:10.1161/01.CIR.0000069566.78305.33
   PubMed Web of Science ®Google Scholar
• Kim W, Khan NA, McMurray DN, Prior IA, Wang N, Chapkin RS. Regulatory activity of polyunsaturated fatty acids in T-cell signaling. Prog Lipid Res. 2010;49(3):250–261. doi:10.1016/j.plipres.2010.01.002
   PubMed Web of Science ®Google Scholar
• Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58(20):2047–2067. doi:10.1016/j.jacc.2011.06.063
   PubMed Web of Science ®Google Scholar
• Musunuru K, Kathiresan S. Surprises from genetic analyses of lipid risk factors for atherosclerosis. Circ Res. 2016;118(4):579–585. doi:10.1161/CIRCRESAHA.115.306398
   PubMed Web of Science ®Google Scholar
• Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45(11):1345–1352. doi:10.1038/ng.2795
   PubMed Web of Science ®Google Scholar
• Sarwar N, Sandhu MS, Ricketts SL, et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010;375(9726):1634–1639.
   PubMed Web of Science ®Google Scholar
• Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–1574.
   PubMed Web of Science ®Google Scholar
• Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849–1861.
   PubMed Web of Science ®Google Scholar
• Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J Clin Lipidol. 2012;6(1):5–18. doi:10.1016/j.jacl.2011.10.018
   PubMed Web of Science ®Google Scholar
• Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, plAcebo-controlled, randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108(5):682–690. doi:10.1016/j.amjcard.2011.04.015
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110(7):984–992. doi:10.1016/j.amjcard.2012.05.031
   PubMed Web of Science ®Google Scholar
• Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs. 2013;13(1):37–46. doi:10.1007/s40256-012-0002-3
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Bays HE, Braeckman RA, et al. Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies. J Clin Lipidol. 2016;10(3):635–645.e631. doi:10.1016/j.jacl.2016.02.008
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Braeckman RA, Bays HE, et al. Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (The ANCHOR study). J Clin Lipidol. 2015;9(3):377–383. doi:10.1016/j.jacl.2014.11.009
   PubMed Web of Science ®Google Scholar
• Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371(1):22–31.
   PubMed Web of Science ®Google Scholar
• Brinton EA, Ballantyne CM, Bays HE, Kastelein JJ, Braeckman RA, Soni PN. Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study. Cardiovasc Diabetol. 2013;12:100. doi:10.1186/1475-2840-12-100
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Manku MS, Bays HE, et al. Icosapent ethyl effects on fatty acid profiles in statin-treated patients with high triglycerides: the randomized, Placebo-controlled ANCHOR study. Cardiol Ther. 2019;8(1):79–90. doi:10.1007/s40119-019-0131-8
   PubMed Web of Science ®Google Scholar
• Miller M, Ballantyne CM, Bays HE, et al. Effects of icosapent ethyl (eicosapentaenoic acid ethyl ester) on atherogenic lipid/ lipoprotein,apolipoprotein, and inflammatory parameters in patients with elevated high-sensitivity C-reactive protein (from the ANCHOR study). Am J Cardiol. 2019;124(5):696–701. doi:10.1016/j.amjcard.2019.05.057
   PubMed Web of Science ®Google Scholar
• Mita T, Watada H, Ogihara T, et al. Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes. Atherosclerosis. 2007;191(1):162–167. doi:10.1016/j.atherosclerosis.2006.03.005
   PubMed Web of Science ®Google Scholar
• Nishio R, Shinke T, Otake H, et al. Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma. Atherosclerosis. 2014;234(1):114–119. doi:10.1016/j.atherosclerosis.2014.02.025
   PubMed Web of Science ®Google Scholar
• Shearer GC, Savinova OV, Harris WS. Fish oil – how does it reduce plasma triglycerides? Biochim Biophys Acta. 2012;1821(5):843–851. doi:10.1016/j.bbalip.2011.10.011
   PubMed Web of Science ®Google Scholar
• Clarke SD, Jump D. Polyunsaturated fatty acids regulate lipogenic and peroxisomal gene expression by independent mechanisms. Prostaglandins Leukot Essent Fatty Acids. 1997;57(1):65–69. doi:10.1016/S0952-3278(97)90494-4
   PubMed Web of Science ®Google Scholar
• Lang CA, Davis RA. Fish oil fatty acids impair VLDL assembly and/or secretion by cultured rat hepatocytes. J Lipid Res. 1990;31(11):2079–2086.
   PubMed Web of Science ®Google Scholar
• Park Y, Jones PG, Harris WS. Triacylglycerol-rich lipoprotein margination: a potential surrogate for whole-body lipoprotein lipase activity and effects of eicosapentaenoic and docosahexaenoic acids. Am J Clin Nutr. 2004;80(1):45–50. doi:10.1093/ajcn/80.1.45
   PubMed Web of Science ®Google Scholar
• Khan S, Minihane AM, Talmud PJ, et al. Dietary long-chain n-3 PUFAs increase LPL gene expression in adipose tissue of subjects with an atherogenic lipoprotein phenotype. J Lipid Res. 2002;43(6):979–985.
   PubMed Web of Science ®Google Scholar
• Berge RK, Madsen L, Vaagenes H, Tronstad KJ, Göttlicher M, Rustan AC. In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipidaemic derivatives decrease hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation. Biochem J. 1999;343(Pt 1):191–197. doi:10.1042/bj3430191
   PubMedGoogle Scholar
• Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010;68(5):280–289. doi:10.1111/nure.2010.68.issue-5
   PubMed Web of Science ®Google Scholar
• Fredman G, Hellmann J, Proto JD, et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun. 2016;7:12859. doi:10.1038/ncomms12859
   PubMed Web of Science ®Google Scholar
• Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92–101. doi:10.1038/nature13479
   PubMed Web of Science ®Google Scholar
• Mason RP, Jacob RF, Shrivastava S, Sherratt SCR, Chattopadhyay A. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta. 2016;1858(12):3131–3140. doi:10.1016/j.bbamem.2016.10.002
   PubMed Web of Science ®Google Scholar
• Cawood AL, Ding R, Napper FL, et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010;212(1):252–259. doi:10.1016/j.atherosclerosis.2010.05.022
   PubMed Web of Science ®Google Scholar
• Yokoyama M, Origasa H, Matsuzaki M, 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):1090–1098. doi:10.1016/S0140-6736(07)60527-3
   PubMed Web of Science ®Google Scholar
• Nosaka K, Miyoshi T, Iwamoto M, et al. Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study. Int J Cardiol. 2017;228:173–179. doi:10.1016/j.ijcard.2016.11.105
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22. doi:10.1056/NEJMoa1812792
   PubMed Web of Science ®Google Scholar
• Bays HE, Ballantyne CM, Doyle RT, Juliano RA, Philip S. Icosapent ethyl: eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies. Prostaglandins Other Lipid Mediat. 2016;125:57–64. doi:10.1016/j.prostaglandins.2016.07.007
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Steg PG, Miller M, et al. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol. 2019;73(22):2791–2802. doi:10.1016/j.jacc.2019.02.032
   PubMed Web of Science ®Google Scholar
• Baum SJ. ANCHOR trial conclusions regarding the effects of pure eicosapentaenoic acid on low-density lipoprotein cholesterol. Am J Cardiol. 2013;111(3):454–455. doi:10.1016/j.amjcard.2012.11.035
   PubMed Web of Science ®Google Scholar
• Patrone V, Minuti A, Lizier M, et al. Differential effects of coconut versus soy oil on gut microbiota composition and predicted metabolic function in adult mice. BMC Genomics. 2018;19(1):808. doi:10.1186/s12864-018-5202-z
   PubMedGoogle Scholar
• Costantini L, Molinari R, Farinon B, Merendino N. Impact of omega-3 fatty acids on the gut microbiota. Int J Mol Sci. 2017;18(12):2645. doi:10.3390/ijms18122645
   PubMed Web of Science ®Google Scholar
• Jia X, Kohli P, Virani SS. Omega-3 fatty acid and cardiovascular outcomes: insights from recent clinical trials. Curr Atheroscler Rep. 2019;21(1):1. doi:10.1007/s11883-019-0763-0
   PubMed Web of Science ®Google Scholar
• Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA lipid intervention study (JELIS). Atherosclerosis. 2008;200(1):135–140. doi:10.1016/j.atherosclerosis.2008.06.003
   PubMed Web of Science ®Google Scholar
• 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):447–455. doi:10.1016/S0140-6736(99)07072-5
   PubMed Web of Science ®Google Scholar
• Tavazzi L, Maggioni AP, Marchioli 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):1223–1230. doi:10.1016/S0140-6736(08)61239-8
   PubMed Web of Science ®Google Scholar
• Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309–318.
   PubMed Web of Science ®Google Scholar
• Kromhout D, Giltay EJ, Geleijnse JM, Group AOT. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363(21):2015–2026. doi:10.1056/NEJMoa1003603
   PubMed Web of Science ®Google Scholar
• Rauch B, Schiele R, Schneider S, 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):2152–2159. doi:10.1161/CIRCULATIONAHA.110.948562
   PubMed Web of Science ®Google Scholar
• Roncaglioni MC, Tombesi M, Avanzini F, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19):1800–1808.
   PubMed Web of Science ®Google Scholar
• Bowman L, Mafham M, Wallendszus K, et al. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med. 2018;379(16):1540–1550.
   PubMed Web of Science ®Google Scholar
• Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018;380(1):23-32.
   Web of Science ®Google Scholar
• Association AD. 10. Cardiovascular disease and risk management. Diabetes Care. 2019;42(Suppl 1):S103–S123. doi:10.2337/dc19-S010
   PubMedGoogle Scholar
• Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019;290:140–205.
   Google Scholar
• Orringer CE, Jacobson TA, Maki KC. National lipid association scientific statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk. J Clin Lipidol. 2019;13(6):860–872. doi:10.1016/j.jacl.2019.10.014
   PubMed Web of Science ®Google Scholar
• Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines. Circulation. 2019;139(25):e1082–e1143. doi:10.1161/CIR.0000000000000625
   PubMed Web of Science ®Google Scholar
• Jia X, Akeroyd JM, Nasir K, et al. Eligibility and cost for icosapent ethyl based on the REDUCE-IT trial. Circulation. 2019;139(10):1341–1343. doi:10.1161/CIRCULATIONAHA.118.038691
   PubMed Web of Science ®Google Scholar
• Khera R, Valero-Elizondo J, Saxena A, Virani SS, Krumholz HM, Nasir K. National population and cost implications of treatment with icosapentyl ethyl in the united states: an assessment based on the REDUCE-IT trial. bioRxiv. 2018.
   Google Scholar
• Kodera S, Morita H, Kiyosue A, Ando J, Komuro I. Cost-effectiveness of statin plus eicosapentaenoic acid combination therapy for cardiovascular disease prevention in japanese patients with hypercholesterolemia- an analysis based on the Japan eicosapentaenoic acid lipid intervention study (JELIS). Circ J. 2018;82(4):1076–1082. doi:10.1253/circj.CJ-17-0995
   PubMed Web of Science ®Google Scholar
• Institute for Clinical and Economic Review. Additive Therapies for Cardiovascular Disease: Effectiveness and Value; 2019. Available from: https://icer-review.org/wp-content/uploads/2019/02/ICER_CVD_Draft_Evidence_Report_072419.pdf. Accessed December 2, 2019.
   Google Scholar
• Ganda OP, Bhatt DL, Mason RP, Miller M, Boden WE. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol. 2018;72(3):330–343. doi:10.1016/j.jacc.2018.04.061
   PubMed Web of Science ®Google Scholar
• UMIN-CTR Clinical Trial. Randomized trial for evaluation in secondary prevention efficacy of combination therapy — statin and eicosapentaenoic acid UMIN000012069; 2018. Available from: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014051. Accessed November 22, 2019.
   Google Scholar
• Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018;41(10):1281–1288. doi:10.1002/clc.23055
   PubMed Web of Science ®Google Scholar
• Laake K, Myhre P, Nordby LM, et al. Effects of ω3 supplementation in elderly patients with acute myocardial infarction: design of a prospective randomized placebo controlled study. BMC Geriatr. 2014;14:74. doi:10.1186/1471-2318-14-74
   PubMed Web of Science ®Google Scholar