ELSEVIER
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`Atherosclerosis 200 (2008) 135-140
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`www.elsevier.com/locate/atherosclerosis
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`ATHEROSCLEROSIS
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`Effects of EPA on coronary artery disease in hypercholesterolemic
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`patients with multiple risk factors: Sub-analysis of primary prevention
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`cases from the Japan EPA Lipid Intervention Study (JELIS)
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`d, Matsuzaki Origasa Yokoyama b, Hideki Yasushi Saito a,*, Mitsuhiro c, Masunori
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`Yuji Matsuzawa e, Yuichi
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`Ishikawa f, Shinichi Oikawag, Jun Sasaki h,
`1,
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`Hitoshi Hishida i, Hiroshige Itakura j, Torn Kita k, Akira Kitabatake
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`, Kunio Shira to P,
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`Shimada N oriaki N aka yam, Toshiie Sakata n, Kazuyuki
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`for the JELIS Investigators, Japan
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`" Chiba University Graduate School ofMedicine, Chiba, Japan
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`b Hyo go Prefectural Awaji Ho.1pital, Hyo go, Japan
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`c University of Toyama, Toyama, Japan
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`d Yamaguchi University Graduate School ofMedicine, Yamaguchi, Japan
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`e Sumitomo Ho,1pital, Osaka, Japan
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`f Kobe University Graduate School of Health Sciences, Kobe, Japan
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`g Nippon Medical School, Tokyo, Japan
`h International University ofHealth and Welfare Graduate School, Fukuoka, Japan
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`i Fujita Health University School of Medicine, Aichi, Japan
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`.i Ibaraki Christian University, Ibaraki, Japan
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`k Kyoto University Graduate School of Medicine, Kyoto, Japan
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`1 Kano General Ho.1pital, Osaka, Japan
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`m Nakaya Clinic, Tokyo, Japan
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`"Nakamura Gakuen University, Fukuoka, Japan
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`0 Jichi Medical University, Tochigi, Japan
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`P Saito Ho.1pital, Miyagi, Japan
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`O
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`Received 4 October 2007; received in revised form 3 June 2008; accepted 7 June 2008
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`Available online 19 June 2008
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`Abstract
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`Background:
`Japan EPA Lipid Intervention Study (JELIS) was a large-scale clinical trial examining the effects of eicosapentaenoic acid (EPA)
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`on coronary artery disease (CAD) in hypercholesterolemic patients. Herein, we focused on risk factors other than low-density lipoprotein
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`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
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`Methods:
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`(n = 7503) or a control group (n = 7478). The relationships between incident CAD, the number of CAD risk factors (hypercholesterolemia;
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`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
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`Results:
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`CAD. Incidence was lower for the EPA group than for the control group regardless of the numbers of risk factors. Compared to patients with
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`normal serum TG and HDL-C levels, those with abnormal levels (TG c:: 150 mg/dL; HDL-C <40 mg/dL) had significantly higher CAD hazard
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`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%
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`CI: 0.23-0.98; P = 0.043).
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`* Corresponding author. Tel.: +8143 290 2002: fax: +8143 290 2011.
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`yasushi@faculty.chiba-u.jp (Y. Saito).
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`E-mail address:
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`0021-9150/$-see front matter© 2008 Elsevier Ireland Ltd. All rights reserved.
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`doi: l 0.1016/j.atherosclerosis.2008.06.003
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1027, p. 1 of 6
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`136
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`Y Saito et al. I Atherosclerosis 200 (2008) 135-140
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`Multiple risk factors besides cholesterol are associated with markedly increased incidence of CAD. High TG with low HDL-C
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`Conclusions:
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`represents a particularly potent risk factor. EPA was effective in reducing the incidence of CAD events for patients with this dyslipidemic
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`pattern, suggesting that EPA may be especially beneficial in patients who with abnormal TG and HDL-C levels (NCT0023 l 738).
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`© 2008 Elsevier Ireland Ltd. All rights reserved.
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`Keywords: JELIS; Eicosapentaenoic acid; Primmy prevention; Coronmy mte1y disease; Risk factors; HDL-C; Triglycerides
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`1.Introduction
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`2.3. Primary endpoint
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`75 years) were followed for up to 5 years (mean: 4.6 years)
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`using the prospective, randomized, open-label, blinded end­
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`point evaluation (PROBE) method. A total of 18,645 patients
`Eicosapentaenoic acid (EPA) is one of the n-3 polyun­
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`were registered and randomly assigned to either the EPA with
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`saturated fatty acids (PUFA) found large quantities in fish
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`oil. Ever since Dyerberg and Bang reported that EPA levels
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`statin (EPA group) or to statin alone (control group). Eighty
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`percent (n = 14,981) of the patients had no history of CAD
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`were high in the blood and diets of Greenland Inuit ( who have
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`and are the subject of this report.
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`low prevalence of atherosclerotic diseases [ l] ), the preventive
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`effects of n-3 PUFA, including EPA, has been examined in
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`many epidemiological and clinical studies [2-6]. Most stud­
`2.2. Procedures
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`ies have found that intake of fish and fish oil are related to
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`risk for total mortality, sudden death and coronary
`reduced
`Dietary guidance was provided for all patients before the
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`artery disease (CAD). Furthermore, randomized controlled
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`start of and during the study. All patients received 10 mg
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`intervention trials have suggested the suppressive effects of
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`of pravastatin or 5 mg of simvastatin administered once a
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`fish and fish oil consumption on CAD [7].
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`day. In the EPA group, two 3 00-mg capsules containing EPA
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`Using a highly purified (�98%) EPA, not a mixture of
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`ethylester (EPA-E) with > 98% purity were administered 3
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`several fatty acids, i.e., fish oil, we conducted a random­
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`times/day, for a total daily dose of 1800 mg.
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`ized controlled trial, the Japan EPA Lipid Intervention Study
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`(JELIS; ClinicalTrials.gov number, NCT00231738) [8], and
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`reported that pure EPA suppressed CAD even in Japanese
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`hypercholesterolemic patients who routinely consume a large
`The primary endpoint was major coronary events (MCE),
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`amount of EPA and DHA from fish [ 5]. In the JELIS, EPA
`infarc­
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`comprising: sudden cardiac death; fatal myocardial
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`had no significant effect on total cholesterol (TC) or low­
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`tion; nonfatal myocardial infarction; unstable angina pectoris
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`density lipoprotein cholesterol (LDL-C) levels indicating that
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`including hospitalization for documented
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`ischemic episodes;
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`EPA can lower CAD risk by mechanisms other than LDL-C
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`and angioplasty/stenting or coronary artery bypass grafting.
`lowering.
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`MCE was reported by primary physicians and was examined
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`Besides LDL-C, other risk factors for CAD include
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`by the case report committee without knowledge of groups'
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`obesity, dislipidemia, impaired glucose metabolism and
`assignment.
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`hypertension. When present together in the same patients,
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`these risk markers constitute a syndrome called the vis­
`2.4. Risk.factors
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`ceral fat syndrome, syndrome X, insulin-resistant syndrome
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`and the metabolic syndrome [9-14]. Compared to patients
`The following five risk factors were of primary interest
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`with only one of these risk factors,
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`incidence of CAD in
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`for this report and were defined as indicated at the time of
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`patients with multiple factors is higher [15,16]. In addition,
`registration:
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`we assumed that EPA would suppress CAD even in patients
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`at high risk. The present study focused on CAD risk associ­
`A.Hypercholesterolemia: untreated serum TC �250 mg/dL
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`risk factors in
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`(all subjects in JELIS had serum TC �250 mg/dL).
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`ated with increasing numbers of non-LDL-C
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`B.Obesity: body mass index (BMI) �25 kg/m2.
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`hypercholesterolemic patients and the effects of EPA on the
`risk for CAD in these patients.
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`C.Dyslipidemia: serum triglyceride (TG) � 150 mg/dL
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`and/or high-density lipoprotein cholesterol (HDL-C)
`<40mg/dL.
`D.Diabetes: physician-diagnosis or fasting plasma glucose
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`�126 mg/dL and/or hemoglobin A1c � 6.5%.
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`E. Hypertension: physician-diagnosis or systolic blood
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`pressure �140mmHg and/or diastolic blood pressure
`�90mmHg.
`The study design of the JELIS, including inclusion
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`Furthermore, all subjects were divided into the following
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`and exclusion criteria, has been reported in detail [ 17].
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`based on the following serum TG and HDL-C
`four subgroups:
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`Briefly, hypercholesterolemic patients with serum TC levels
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`�250mg/dL (men: 40-75 years; women: postmenopausal-
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`levels at the time of registration:
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`2.Materials and methods
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`2.1. Study design and patients
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`Hikma Pharmaceuticals
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`Y. Saito et al. I Atherosclerosis 200 /2008) 135-140
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`137
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`5.0
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`2: Control group m EPA group
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`1.TG <150mg/dL and HDL-C 2:-_40mg/dL (low TG/high
`HDL-C group).
`2.TG 2:: 150 mg/dL and HDL-C 2:-_40 mg/dL (high TG/high
`HDL-C group).
`3.TG <150 mg/dL and HDL-C <40 mg/dL (low TG/low
`HDL-C group).
`4.TG 2:: 150 mg/dL and HDL-C <40 mg/dL (high TG/low
`HDL-C group).
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`2.5. Statistical analysis
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`2
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`3
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`4
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`All analyses were intention-to-treat with the level of sig­
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`two-sample A Wilcoxon nificance set at P < 0.05 (two-sided).
`0,0
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`test was used to compare continuous variables. A chi-square
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`test was used to compare class variables. Kaplan-Meier meth­
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`ods, the log-rank test, and the Cox proportional hazard model
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`were used for survival analysis. The Cox proportional haz­
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`ard model was adjusted for age, gender, smoking, diabetes
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`and hypertension. However, we chose age, gender and smok­
`Fig. l. Multiple risk factors and the incidence ofMCE. Number of risk fac­
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`ing as adjusted factors to analyze the relationships between
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`tors at the time of registration was counted: Risk A, hypercholesterolemia
`(all patients); Risk B, body mass index (BMI) 2:25; Risk C, triglyceride
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`multiple risk factors and the incidence of MCE. We com­
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`2:150mg/dL or HDL-cholesterol <40mg/dL; Risk D, diabetes; Risk E,
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`puted the power to detect the difference in CAD incidence
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`hypertension. The Cox proportional hazard model was adjusted for age,
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`between EPA and control groups for patients
`with high TG
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`group. gender, smoking. * P < 0.05 vs. risk number l in the control
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`and low HDL-C. With a total of 957 patients in the high
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`TG/low HDL-C group, we could detect a difference in MCE
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`incidence of 1 % vs. 0.5% with a power of 57%. The analy­
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`sis plan for this sub-study was pre-specified according to the
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`study hypothesis before the analysis was initiated. All analy­
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`ses were conducted using SAS software ( version 8.12; SAS
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`Institute, Cary, NC).
`
`••••••••••
`•••?=?=:=:@mif\llmiiWI
`•
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`5
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`Total number ofrisk factors
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`Number of
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`patients
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`1309 132.6 2424 246S 2324 2239 1205 1228 216 242
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`3.Results
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`Subject characteristics have been previously reported
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`[8]. The number of patients with hypertension and/or dia­
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`betes differed slightly from that originally published because
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`the original designations were based only on physician­
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`diagnosed diabetes or hypertension only. As a result, number
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`of patients with diabetes was 1238 in control group, and 1258
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`in EPA group. In the same way, number of patients with
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`hypertension was 4004 in control group, and 4015 in EPA
`group.
`Risk for MCE increased in both the EPA and the control
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`groups with increasing numbers of risk factors. The incidence
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`of MCE was lower, but not statistically significant, for the
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`EPA group than for the control group with each number of
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`risk factors (Fig. 1 ).
`Compared to the low TG/high HDL-C reference group,
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`HR for MCE was increased only in the high TG/low HDL­
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`C group (HR: 1.71; 95% CI: 1.11-2.64; Fig. 2).
`P=0.014;
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`Other risk factors were compared to the high TG/low HDL-C
`Fig. 2. Incidence ofMCE and triglyceride and HDL-cholesterol levels at the
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`group, those in the low TG/high HDL-C group had no sig­
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`time of registration for the combined EPA and control group. Hazard ratio
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`nificant differences in TC or LDL-C but the proportions of
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`and hypertension. and P value adjusted for age, gender, smoking, diabetes,
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`male patients, smokers and drinkers; BMI; the prevalence
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`HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; HR, hazard
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`of diabetes and high diastolic blood pressure. Furthermore,
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`ratio; CI, confidence interval.
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`�40 mg/dL <150 mg/dL
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`TG and HDL-C
`Events (%) p HR 96%CI
`(m ldl)
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`86 I 6614 1,3 1.00
`TG<160, HOL-C;?40
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`TG?.160, HOL-C;:40 9716096 1.6 0.923 1 .. 02 0.76 -1.37
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`TG<=160 , HDL•C<40 4 / 196 2.0 0.663 1.26 0.46 -3.46
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`TG:i:160, HDL-C<40 32 / 957 3.3 0.014 1.71 1.11 -2.64
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`138
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`Y Saito et al. I Atherosclerosis 200 (2008) 135-140
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`Table l
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`Patient background factors at time of registration and triglyceride and HDL-cholesterol levels
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`Age (years)
`Male(%)
`Smoker(%)"
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`Drinker (% )"
`BM! (kg/m2)
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`Clinical history
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`Diabetesb (%)
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`Hypertensionc (%)
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`Blood pressure
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`Systolic (mmHg)
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`Diastolic (mmHg)
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`Lipid profile
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`Total cholesterol (mg/dL)
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`LDL-cholesterol (mg/dL)
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`HDL-cholesterol (mg/dL)
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`Triglyceride (mg/dL)d
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`Fatty acid composition
`EPA (mo!%)
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`TG < 150, HDL:,. 40 (n=6614)
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`TG:,. 150, HDL<40 (mg/dL) (n=957)
`p
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`61 ± 8
`1226(19)
`697 (11)
`1170(18)
`23±3
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`885 (13)
`3297(50)
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`134± 18
`79± 11
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`58±9
`486(51)
`312(33)
`336 (35)
`25±3
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`206(22)
`508 (53)
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`135 ± 18
`80± 11
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`274±23
`186± 28
`67± 18
`107(85-128)
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`277±30
`186 ± 33
`35±4
`272(207-399)
`
`<0.0001
`<0.0001
`<0.0001
`<0.0001
`<0.0001
`
`<0.0001
`0.062
`
`0.071
`0.001
`
`0.779
`0.658
`<0.0001
`<0.0001
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`3.1 ± 1.6
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`2.5 ± 1.5
`
`<0.0001
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`
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`Data represent number of patients (%) or mean (standard deviation), unless otherwise indicated.
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`a Self-reported information.
`b Physician-diagnosed diabetes or fasting plasma glucose ::> 126 mg/dL or hemoglobin
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`
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`A1c ::>6.5%.
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`c Physician-diagnosed hypertension or systolic blood pressure ::> 140 mrnHg or diastolic blood pressure ::>90 mrnHg.
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`d Median (interquartile range). LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride.
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`in the high TG/low HDL-C group, EPA as a proportion of period (Table 2), and the high EPA concentrations remained
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`total plasma fatty acids at registration was lower than that
`
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`throughout the observation period.
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`
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`in the reference group (Table 1). EPA treatment lowered the
`risk for MCE for the high-risk
`high TG/low HDL-C group
`
`by 53% (HR: 0.47; 95% CI: 0.23-0.98; Fig. 3).
`P=0.043;
`4.Discussion
`
`
`For the high-risk group, EPA did not affect TC, LDL-C or
`LDL-C is an important risk factor for CAD, and statins
`
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`
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`HDL-C, but in did reduce TG (P=0.012; Table 2). In addi­
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`tion, the mean plasma EPA levels in the high TO/low HDL-C
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`have been shown to lower both LDL-C levels and risk
`group for the control
`
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`for CAD [18,19]. Besides LDL-C, other risk factors such
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`group were 2. 3 mol % at registration and
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`2.5 mol % during the observation period, whereas for the EPA
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`as obesity, dislipidemia, impaired glucose metabolism and
`
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`
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`hypertension also increase risk for CAD [9-14]. T his study
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`group, mean plasma EPA levels markedly increased from
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`2.6 mol % at registration to 4.5 mol % during the observation
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`
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`examined the effects of EPA in the primary prevention sub-
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`Table 2
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`Risk factors in the high TG/low HDL-C group at follow-up
`
`TG ::> 150 mg/dL and HDL-C <40 mg/dL
`
`p
`
`
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`Control group (n=475)
`
`EPA group (n = 482)
`
`Baseline Observation Change from Baseline Observation Change from
`
`period baseline (%)
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`period baseline (%)
`
`Blood pressure
`
`Systolic (mmHg) 136 ± 18
`
`Diastolic (mmHg) 81 ± 11
`
`134 ± 14
`79±9
`
`0
`-2
`
`134 ± 17
`79± 10
`
`134± 14
`0
`78±9 -1
`
`0.700
`0.159
`
`Lipid profile
`
`Total cholesterol (mg/dL) 277±29 229 ±37
`
`LDL-cholesterol (mg/dL) 185±30 140±35
`
`HDL-cholesterol (mg/dL) 35±4
`42±9
`22
`
`
`218 (166-291) -18 Triglyceride (mg/dL)" 277(215-400)
`
`229±35 -17
`276±32
`-17
`142±35 -20
`-22 187 ± 35
`42±9
`35±4
`22
`269 (201-399) 202(150---271) -23
`
`0.522
`0.129
`0.776
`0.012
`
`Fatty acid composition
`EPA (mo!%)
`2.3 ± 1.3 2.5 ± 1.2 28
`
`2.6 ± 1.6 4.5 ± 1.9 120
`
`<0.0001
`
`Data represent mean (standard deviation), unless othe1wise indicated.
`
`
`
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`
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`
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`a Median (interquartile range). LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride.
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`Y. Saito et al. I Atherosclerosis 200 /2008) 135-140
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`139
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`5.0
`
`HR: 0.47
`95%CI: 0.23-0.98
`P«0.043
`
`
`
`Control group
`
`EPA group
`
`2
`
`3
`
`4
`
`432
`
`443
`EPA 482 455
`
`392
`
`403
`
`Number of patients
`414
`400
`Control 475 444
`427
`413
`
`In the present study, EPA treatment had no effect on LDL­
`
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`
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`C in the high TG/low HDL-C group during the follow-up
`
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`period, indicating that the lower MCE rates were the result
`
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`of other effects of EPA than lowering LDL-C. EPA has many
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`
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`beneficial effects [21,22], including antiplatelet activity [23]
`
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`and plaque-stabilizing properties [24,25], and thus these were
`
`likely responsible, at least in part, for the reductions
`in MCE.
`
`
`
`While risk reduction in all primary prevention subjects of
`
`
`JELIS was 18% [8], risk reduction by 53% was achieved in
`
`high TG/low HDL-C group. This suggests that the factors
`
`
`
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`that EPA appears to influence (plaque destabilization, rup­
`
`
`
`ture, and formation of occlusive thrombus) may be especially
`5 Years
`
`important mechanisms of MCE in patients with this form of
`
`
`
`
`dyslipidemia. EPA administration to the high TG/low HDL­
`
`
`C group slightly lowered TG and did not change in HDL-C.
`
`
`Although the effects of EPA on serum TG and HDL-C were
`Fig. 3. Effects of EPA on the incidence ofMCE for the high TG/low HDL-C
`
`
`
`
`limited, EPA markedly suppressed MCE in the high TG/low
`
`
`
`
`group. Hazard ratio and P value adjusted for age. gender. smoking. diabetes.
`
`HDL-C group, and this suggests that EPA acts on mecha­
`
`
`
`
`and hypertension. HR, hazard ratio; Cl, confidence interval.
`
`
`nisms upstream of high TG/low HDL-C to suppress multiple
`risks.
`Metabolic syndrome has been noted as a new risk fac­
`
`
`group of JELIS as a function of other CAD risk factors
`
`tor for CAD [9, 10]. Metabolic
`
`syndrome is characterized
`
`
`
`
`obesity; dislipidemia; diabetes; and hypertension. In both the
`
`by accumulation of risk factors such as hypertension, dis­
`
`
`control and EPA groups, greater number of risk factors was
`
`
`
`
`
`lipidemia and impaired glucose metabolism on the basis of
`
`
`
`associated with increased incidence of MCE. This indicates
`risk factors other than
`
`visceral fat accumulation.
`that risk for MCE in the JELIS involved
`
`
`In the present study, high TG and
`
`
`
`low HDL-C levels (the components of the metabolic syn­
`
`
`LDL-C. When dividing subjects with a number of risk accu­
`risk factors for MCE.
`of MCE for the
`drome) were shown to be important
`
`
`mulations among the 5 risk factors, incidence
`group for all
`EPA group was lower than that for the control
`
`EPA was most effective in the high TG/low HDL group in
`
`
`
`reducing incidence of MCE. Hence, this particular patient
`
`subjects combined, regardless of the number of risk factors.
`
`
`
`population may benefit the most from EPA treatment. Satoh
`
`
`But these differences were not statistically significant, most
`
`likely due to the low n in each subcategory.
`
`et al. administered 1800 mg/day of EPA-E (the same dose
`
`as the JELIS) for 3 months to type II diabetics with the
`
`
`
`EPA suppresses TG synthesis in the liver and thereby low­
`
`
`
`ers serum TG levels and decreases atherogenic lipoproteins
`
`
`
`metabolic syndrome and reported that levels of sdLDL and
`
`
`
`remnant lipoproteins, which are risk factors for new cardio­
`
`
`such as remnants and small dense LDL (sdLDL) [20]. Conse­
`
`
`
`vascular events [26], decreased, and that levels of plasma
`
`
`quently, we compared MCE rates in the high TG/low HDL-C
`
`group to those in the low TG/high HDL-C reference group
`
`
`
`C-reactive protein (CRP), a marker of inflammation that has
`as a risk factor for cardiovascular events [27],
`been examined
`
`at the time of registration and found them to be increased
`
`
`
`also decreased [20]. In addition, ltoh et al. reported that the
`
`by 71 %. This shows that high TG/low HDL-C patients are at
`
`
`
`increased risk for MCE. Furthermore, within the high TG/low
`
`same regimen increased adiponectin [28], an adipocytokine
`
`
`HDL-C group, EPA administration markedly reduced risk for
`
`
`
`known to improve arteriosclerosis [29] and diabetes [30].
`
`factors
`
`
`MCE by 53%. When comparing patient background
`
`
`
`The present results among JELIS primary prevention cases
`
`
`showed that multiple risk factors increase the risk of MCE.
`
`
`
`at the time of registration between these two groups, no sig­
`
`
`For the high TG/low HDL-C group, risk of MCE was par­
`
`
`nificant differences in TC or LDL-C were seen, but the ratio
`
`
`ticularly high, and EPA was shown to potently suppress
`
`
`
`of male patients, ratio of smokers and drinkers, BMI, inci­
`
`dence of diabetes and diastolic blood pressure for the high
`MCE. In the high TG/low HDL-C group, level of plasma
`
`
`
`EPA at the time of registration was low, but EPA adminis­
`
`TG/low HDL-C group were all significantly higher. Thus,
`
`
`this group had many other features of the metabolic syndrome
`
`
`
`
`tration increased plasma levels, suggesting some correlation
`
`between plasma EPA level and MCE risk.
`
`
`
`besides just high TG and low HDL-C. The present results also
`
`
`suggest that EPA is effective for suppressing onset of MCE
`
`
`
`
`in groups with multiple risk factors. Interestingly, plasma
`EPA level for the high TG/low HDL-C group at the time of
`Acknowledgments
`
`
`registration was significantly lower when compared to the
`This study was supported by grants from Machida Phar­
`
`
`
`
`
`
`low TG/high HDL-C group. These results suggest some pre­
`
`maceutical Co. Ltd., Tokyo, Japan. We thank all trial
`
`
`
`
`
`existing baseline association between multiple risk factors
`
`
`
`
`participants and the large numbers of doctors, nurses, and
`
`and low plasma EPA levels, even in a Japanese population
`
`
`
`hospital staff who made long-term commitments to the study.
`with high fish intake.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1027, p. 5 of 6
`
`

`

`140
`
`
`
`Y Saito et al. I Atherosclerosis 200 (2008) 135-140
`
`
`
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