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)



      Japan EPA Lipid Intervention Study (JELIS) was a large-scale clinical trial examining the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemic patients. Herein, we focused on risk factors other than low-density lipoprotein cholesterol (LDL-C) to investigate the effects of EPA on CAD among JELIS primary prevention cases.


      Hypercholesterolemic patients on statin therapy but without evidence of CAD (n = 14,981) were randomly assigned to an EPA group (n = 7503) or a control group (n = 7478). The relationships between incident CAD, the number of CAD risk factors (hypercholesterolemia; obesity; high triglyceride (TG) or low high-density lipoprotein cholesterol (HDL-C); diabetes; and hypertension) and EPA treatment were investigated.


      For the control and EPA groups combined, a higher number of risk factors was directly associated with an increased incidence of CAD. Incidence was lower for the EPA group than for the control group regardless of the numbers of risk factors. Compared to patients with normal serum TG and HDL-C levels, those with abnormal levels (TG ≥150 mg/dL; HDL-C <40 mg/dL) had significantly higher CAD hazard ratio (HR: 1.71; 95% CI: 1.11–2.64; P = 0.014). In this higher risk group, EPA treatment suppressed the risk of CAD by 53% (HR: 0.47; 95% CI: 0.23–0.98; P = 0.043).


      Multiple risk factors besides cholesterol are associated with markedly increased incidence of CAD. High TG with low HDL-C represents a particularly potent risk factor. EPA was effective in reducing the incidence of CAD events for patients with this dyslipidemic pattern, suggesting that EPA may be especially beneficial in patients who with abnormal TG and HDL-C levels (NCT00231738).


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        • Dyerberg J.
        • Bang H.O.
        • Stoffersen E.
        • Moncada S.
        • Vane J.R.
        Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis?.
        Lancet. 1978; 2: 117-119
        • Burr M.L.
        • Fehily A.M.
        • Gilbert J.F.
        • et al.
        Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
        Lancet. 1989; 2: 757-761
        • Daviglus M.L.
        • Stamler J.
        • Orencia A.J.
        • et al.
        Fish consumption and the 30-year risk of fatal myocardial infarction.
        N Engl J Med. 1997; 336: 1046-1053
        • Hu F.B.
        • Bronner L.
        • Willett W.C.
        • et al.
        Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.
        JAMA. 2002; 287: 1815-1821
        • Iso H.
        • Kobayashi M.
        • Ishihara J.
        • et al.
        Intake of fish and n-3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
        Circulation. 2006; 113: 195-202
        • Morris M.C.
        • Manson J.E.
        • Rosner B.
        • et al.
        Fish consumption and cardiovascular disease in the physicians’ health study: a prospective study.
        Am J Epidemiol. 1995; 142: 166-175
      1. 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;354:447–55.

        • 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: 1090-1098
        • Alberti K.G.
        • Zimmet P.
        • Shaw J.
        The metabolic syndrome—a new worldwide definition.
        Lancet. 2005; 366: 1059-1062
        • Arai H.
        • Yamamoto A.
        • Matsuzawa Y.
        • et al.
        Prevalence of metabolic syndrome in the general Japanese population in 2000.
        J Atheroscler Thromb. 2006; 13: 202-208
        • DeFronzo R.A.
        • Ferrannini E.
        Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.
        Diab Care. 1991; 14: 173-194
        • Kaplan N.M.
        The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension.
        Arch Intern Med. 1989; 149: 1514-1520
        • Nakamura T.
        • Tokunaga K.
        • Shimomura I.
        • et al.
        Contribution of visceral fat accumulation to the development of coronary artery disease in non-obese men.
        Atherosclerosis. 1994; 107: 239-246
        • Reaven G.M.
        Banting lecture 1988. Role of insulin resistance in human disease.
        Diabetes. 1988; 37: 1595-1607
        • Lakka H.M.
        • Laaksonen D.E.
        • Lakka T.A.
        • et al.
        The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men.
        JAMA. 2002; 288: 2709-2716
        • Ohnishi H.
        • Saitoh S.
        • Takagi S.
        • et al.
        Incidence of insulin resistance in obese subjects in a rural Japanese population: the Tanno and Sobetsu Study.
        Diab Obes Metab. 2005; 7: 83-87
        • Yokoyama M.
        • Origasa H.
        Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS).
        Am Heart J. 2003; 146: 613-620
      2. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349–57.

        • Shepherd J.
        • et al.
        Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
        N Engl J Med. 1995; 333: 1301-1307
        • Satoh N.
        • Shimatsu A.
        • Kotani K.
        • et al.
        Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and C-reactive protein in metabolic syndrome.
        Diab Care. 2007; 30: 144-146
        • Harris W.S.
        • Park Y.
        • Isley W.L.
        Cardiovascular disease and long-chain omega-3 fatty acids.
        Curr Opin Lipidol. 2003; 14: 9-14
        • Din J.N.
        • Newby D.E.
        • Flapan A.D.
        Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment.
        BMJ. 2004; 328: 30-35
        • Tamura Y.
        • Hirai A.
        • Terano T.
        • et al.
        Clinical and epidemiological studies of eicosapentaenoic acid (EPA) in Japan.
        Prog Lipid Res. 1986; 25: 461-466
        • Kawano H.
        • Yano T.
        • Mizuguchi K.
        • Mochizuki H.
        • Saito Y.
        Changes in aspects such as the collagenous fiber density and foam cell size of atherosclerotic lesions composed of foam cells smooth muscle cells and fibrous components in rabbits caused by all-cis-5,8,11,14,17-icosapentaenoic acid.
        J Atheroscler Thromb. 2002; 9: 170-177
        • Thies F.
        • Garry J.M.
        • Yaqoob P.
        • et al.
        Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial.
        Lancet. 2003; 361: 477-485
        • Carmena R.
        • Duriez P.
        • Fruchart J.C.
        Atherogenic lipoprotein particles in atherosclerosis.
        Circulation. 2004; 109: III2-7
        • Ridker P.M.
        High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention.
        Am J Cardiol. 2003; 92: 17K-22K
        • Itoh M.
        • Suganami T.
        • Satoh N.
        • et al.
        Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects.
        Arterioscler Thromb Vasc Biol. 2007; 27: 1918-1925
        • Okamoto Y.
        • Kihara S.
        • Ouchi N.
        • et al.
        Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice.
        Circulation. 2002; 106: 2767-2770
        • Fruebis J.
        • Tsao T.S.
        • Javorschi S.
        • et al.
        Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.
        Proc Natl Acad Sci USA. 2001; 98: 2005-2010

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