`
`
`
`Atherosclerosis 200 (2008) 135-140
`
`www.elsevier.com/locate/atherosclerosis
`
`ATHEROSCLEROSIS
`
`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)
`
`
`
`
`
`
`d, Matsuzaki Origasa Yokoyama b, Hideki Yasushi Saito a,*, Mitsuhiro c, Masunori
`
`
`
`Yuji Matsuzawa e, Yuichi
`
`
`
`Ishikawa f, Shinichi Oikawag, Jun Sasaki h,
`1,
`
`
`Hitoshi Hishida i, Hiroshige Itakura j, Torn Kita k, Akira Kitabatake
`
`
`
`, Kunio Shira to P,
`
`
`
`Shimada N oriaki N aka yam, Toshiie Sakata n, Kazuyuki
`
`for the JELIS Investigators, Japan
`
`
`
`
`" Chiba University Graduate School ofMedicine, Chiba, Japan
`
`
`b Hyo go Prefectural Awaji Ho.1pital, Hyo go, Japan
`
`
`c University of Toyama, Toyama, Japan
`
`
`
`
`
`d Yamaguchi University Graduate School ofMedicine, Yamaguchi, Japan
`
`
`
`e Sumitomo Ho,1pital, Osaka, Japan
`
`
`
`
`f Kobe University Graduate School of Health Sciences, Kobe, Japan
`
`
`
`g Nippon Medical School, Tokyo, Japan
`h International University ofHealth and Welfare Graduate School, Fukuoka, Japan
`
`
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`
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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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`
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`k Kyoto University Graduate School of Medicine, Kyoto, Japan
`
`
`
`1 Kano General Ho.1pital, Osaka, Japan
`
`m Nakaya Clinic, Tokyo, Japan
`
`
`
`"Nakamura Gakuen University, Fukuoka, Japan
`
`
`
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`0 Jichi Medical University, Tochigi, Japan
`
`
`P Saito Ho.1pital, Miyagi, Japan
`
`O
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`
`
`Received 4 October 2007; received in revised form 3 June 2008; accepted 7 June 2008
`
`
`
`
`
`
`
`Available online 19 June 2008
`
`Abstract
`
`Background:
`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
`
`
`
`
`
`
`
`
`Methods:
`
`
`
`
`
`(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
`
`
`
`
`
`
`
`
`Results:
`
`
`
`
`
`
`
`
`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 c:: 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).
`
`* Corresponding author. Tel.: +8143 290 2002: fax: +8143 290 2011.
`
`
`
`yasushi@faculty.chiba-u.jp (Y. Saito).
`
`E-mail address:
`
`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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`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
`
`
`
`
`
`
`
`
`Conclusions:
`
`
`
`
`
`
`
`
`
`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).
`
`
`
`© 2008 Elsevier Ireland Ltd. All rights reserved.
`
`
`
`Keywords: JELIS; Eicosapentaenoic acid; Primmy prevention; Coronmy mte1y disease; Risk factors; HDL-C; Triglycerides
`
`
`
`
`
`
`
`
`
`1.Introduction
`
`2.3. Primary endpoint
`
`75 years) were followed for up to 5 years (mean: 4.6 years)
`
`
`
`
`
`
`using the prospective, randomized, open-label, blinded end
`
`
`point evaluation (PROBE) method. A total of 18,645 patients
`Eicosapentaenoic acid (EPA) is one of the n-3 polyun
`
`
`
`
`
`were registered and randomly assigned to either the EPA with
`
`
`saturated fatty acids (PUFA) found large quantities in fish
`
`
`oil. Ever since Dyerberg and Bang reported that EPA levels
`
`
`
`
`statin (EPA group) or to statin alone (control group). Eighty
`
`
`
`percent (n = 14,981) of the patients had no history of CAD
`
`were high in the blood and diets of Greenland Inuit ( who have
`
`
`and are the subject of this report.
`
`
`
`low prevalence of atherosclerotic diseases [ l] ), the preventive
`
`
`effects of n-3 PUFA, including EPA, has been examined in
`
`
`
`many epidemiological and clinical studies [2-6]. Most stud
`2.2. Procedures
`
`
`ies have found that intake of fish and fish oil are related to
`
`risk for total mortality, sudden death and coronary
`reduced
`Dietary guidance was provided for all patients before the
`
`
`
`
`
`
`
`
`artery disease (CAD). Furthermore, randomized controlled
`
`
`
`start of and during the study. All patients received 10 mg
`
`
`
`
`intervention trials have suggested the suppressive effects of
`
`
`of pravastatin or 5 mg of simvastatin administered once a
`
`fish and fish oil consumption on CAD [7].
`
`
`
`day. In the EPA group, two 3 00-mg capsules containing EPA
`
`
`Using a highly purified (�98%) EPA, not a mixture of
`
`
`
`
`ethylester (EPA-E) with > 98% purity were administered 3
`
`
`
`
`several fatty acids, i.e., fish oil, we conducted a random
`
`times/day, for a total daily dose of 1800 mg.
`
`
`
`ized controlled trial, the Japan EPA Lipid Intervention Study
`
`
`
`
`(JELIS; ClinicalTrials.gov number, NCT00231738) [8], and
`
`
`
`reported that pure EPA suppressed CAD even in Japanese
`
`
`
`
`hypercholesterolemic patients who routinely consume a large
`The primary endpoint was major coronary events (MCE),
`
`
`
`amount of EPA and DHA from fish [ 5]. In the JELIS, EPA
`infarc
`
`
`comprising: sudden cardiac death; fatal myocardial
`
`
`
`
`had no significant effect on total cholesterol (TC) or low
`
`
`
`
`
`tion; nonfatal myocardial infarction; unstable angina pectoris
`
`
`
`
`
`
`density lipoprotein cholesterol (LDL-C) levels indicating that
`
`including hospitalization for documented
`
`ischemic episodes;
`
`
`EPA can lower CAD risk by mechanisms other than LDL-C
`
`
`
`
`and angioplasty/stenting or coronary artery bypass grafting.
`lowering.
`
`
`
`MCE was reported by primary physicians and was examined
`
`Besides LDL-C, other risk factors for CAD include
`
`
`
`
`by the case report committee without knowledge of groups'
`
`
`
`
`obesity, dislipidemia, impaired glucose metabolism and
`assignment.
`
`
`
`hypertension. When present together in the same patients,
`
`
`
`
`these risk markers constitute a syndrome called the vis
`2.4. Risk.factors
`
`
`
`ceral fat syndrome, syndrome X, insulin-resistant syndrome
`
`
`
`and the metabolic syndrome [9-14]. Compared to patients
`The following five risk factors were of primary interest
`
`
`
`with only one of these risk factors,
`
`incidence of CAD in
`
`
`for this report and were defined as indicated at the time of
`
`
`
`patients with multiple factors is higher [15,16]. In addition,
`registration:
`
`
`we assumed that EPA would suppress CAD even in patients
`
`at high risk. The present study focused on CAD risk associ
`A.Hypercholesterolemia: untreated serum TC �250 mg/dL
`
`
`risk factors in
`
`(all subjects in JELIS had serum TC �250 mg/dL).
`
`
`ated with increasing numbers of non-LDL-C
`
`B.Obesity: body mass index (BMI) �25 kg/m2.
`
`
`
`hypercholesterolemic patients and the effects of EPA on the
`risk for CAD in these patients.
`
`
`C.Dyslipidemia: serum triglyceride (TG) � 150 mg/dL
`
`
`
`and/or high-density lipoprotein cholesterol (HDL-C)
`<40mg/dL.
`D.Diabetes: physician-diagnosis or fasting plasma glucose
`
`
`
`
`�126 mg/dL and/or hemoglobin A1c � 6.5%.
`
`
`
`E. Hypertension: physician-diagnosis or systolic blood
`
`
`pressure �140mmHg and/or diastolic blood pressure
`�90mmHg.
`The study design of the JELIS, including inclusion
`
`Furthermore, all subjects were divided into the following
`
`
`
`
`
`
`
`and exclusion criteria, has been reported in detail [ 17].
`
`based on the following serum TG and HDL-C
`four subgroups:
`
`
`
`Briefly, hypercholesterolemic patients with serum TC levels
`
`
`�250mg/dL (men: 40-75 years; women: postmenopausal-
`
`levels at the time of registration:
`
`
`
`2.Materials and methods
`
`
`
`2.1. Study design and patients
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`137
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`5.0
`
`
`2: Control group m EPA group
`
`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).
`
`2.5. Statistical analysis
`
`2
`
`3
`
`4
`
`All analyses were intention-to-treat with the level of sig
`
`
`
`
`
`two-sample A Wilcoxon nificance set at P < 0.05 (two-sided).
`0,0
`
`
`
`test was used to compare continuous variables. A chi-square
`
`
`test was used to compare class variables. Kaplan-Meier meth
`
`
`
`
`ods, the log-rank test, and the Cox proportional hazard model
`
`
`
`were used for survival analysis. The Cox proportional haz
`
`
`ard model was adjusted for age, gender, smoking, diabetes
`
`
`and hypertension. However, we chose age, gender and smok
`Fig. l. Multiple risk factors and the incidence ofMCE. Number of risk fac
`
`
`
`
`
`ing as adjusted factors to analyze the relationships between
`
`
`
`tors at the time of registration was counted: Risk A, hypercholesterolemia
`(all patients); Risk B, body mass index (BMI) 2:25; Risk C, triglyceride
`
`
`
`multiple risk factors and the incidence of MCE. We com
`
`
`
`
`2:150mg/dL or HDL-cholesterol <40mg/dL; Risk D, diabetes; Risk E,
`
`
`puted the power to detect the difference in CAD incidence
`
`
`
`hypertension. The Cox proportional hazard model was adjusted for age,
`
`between EPA and control groups for patients
`with high TG
`
`
`
`
`group. gender, smoking. * P < 0.05 vs. risk number l in the control
`
`and low HDL-C. With a total of 957 patients in the high
`
`
`
`TG/low HDL-C group, we could detect a difference in MCE
`
`incidence of 1 % vs. 0.5% with a power of 57%. The analy
`
`
`
`sis plan for this sub-study was pre-specified according to the
`
`
`
`study hypothesis before the analysis was initiated. All analy
`
`
`
`ses were conducted using SAS software ( version 8.12; SAS
`
`Institute, Cary, NC).
`
`••••••••••
`•••?=?=:=:@mif\llmiiWI
`•
`
`5
`
`Total number ofrisk factors
`
`Number of
`
`patients
`
`1309 132.6 2424 246S 2324 2239 1205 1228 216 242
`
`3.Results
`
`Subject characteristics have been previously reported
`
`
`
`
`
`
`[8]. The number of patients with hypertension and/or dia
`
`
`
`
`betes differed slightly from that originally published because
`
`
`the original designations were based only on physician
`
`
`
`
`diagnosed diabetes or hypertension only. As a result, number
`
`
`
`
`of patients with diabetes was 1238 in control group, and 1258
`
`
`in EPA group. In the same way, number of patients with
`
`
`hypertension was 4004 in control group, and 4015 in EPA
`group.
`Risk for MCE increased in both the EPA and the control
`
`
`
`
`
`groups with increasing numbers of risk factors. The incidence
`
`
`
`of MCE was lower, but not statistically significant, for the
`
`EPA group than for the control group with each number of
`
`risk factors (Fig. 1 ).
`Compared to the low TG/high HDL-C reference group,
`
`
`
`
`HR for MCE was increased only in the high TG/low HDL
`
`C group (HR: 1.71; 95% CI: 1.11-2.64; Fig. 2).
`P=0.014;
`
`
`Other risk factors were compared to the high TG/low HDL-C
`Fig. 2. Incidence ofMCE and triglyceride and HDL-cholesterol levels at the
`
`
`
`
`
`
`group, those in the low TG/high HDL-C group had no sig
`
`
`
`
`
`time of registration for the combined EPA and control group. Hazard ratio
`
`
`
`nificant differences in TC or LDL-C but the proportions of
`
`
`
`and hypertension. and P value adjusted for age, gender, smoking, diabetes,
`
`
`
`male patients, smokers and drinkers; BMI; the prevalence
`
`
`
`HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; HR, hazard
`
`
`
`of diabetes and high diastolic blood pressure. Furthermore,
`
`ratio; CI, confidence interval.
`
`�40 mg/dL <150 mg/dL
`
`TG and HDL-C
`Events (%) p HR 96%CI
`(m ldl)
`
`86 I 6614 1,3 1.00
`TG<160, HOL-C;?40
`
`
`
`TG?.160, HOL-C;:40 9716096 1.6 0.923 1 .. 02 0.76 -1.37
`
`TG<=160 , HDL•C<40 4 / 196 2.0 0.663 1.26 0.46 -3.46
`
`
`
`TG:i:160, HDL-C<40 32 / 957 3.3 0.014 1.71 1.11 -2.64
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`Table l
`
`
`
`
`
`Patient background factors at time of registration and triglyceride and HDL-cholesterol levels
`
`
`
`
`
`
`
`Age (years)
`Male(%)
`Smoker(%)"
`
`Drinker (% )"
`BM! (kg/m2)
`
`Clinical history
`
`
`Diabetesb (%)
`
`Hypertensionc (%)
`
`Blood pressure
`
`Systolic (mmHg)
`
`Diastolic (mmHg)
`
`Lipid profile
`
`Total cholesterol (mg/dL)
`
`LDL-cholesterol (mg/dL)
`
`HDL-cholesterol (mg/dL)
`
`Triglyceride (mg/dL)d
`
`Fatty acid composition
`EPA (mo!%)
`
`TG < 150, HDL:,. 40 (n=6614)
`
`TG:,. 150, HDL<40 (mg/dL) (n=957)
`p
`
`61 ± 8
`1226(19)
`697 (11)
`1170(18)
`23±3
`
`885 (13)
`3297(50)
`
`134± 18
`79± 11
`
`58±9
`486(51)
`312(33)
`336 (35)
`25±3
`
`206(22)
`508 (53)
`
`135 ± 18
`80± 11
`
`274±23
`186± 28
`67± 18
`107(85-128)
`
`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
`
`3.1 ± 1.6
`
`2.5 ± 1.5
`
`<0.0001
`
`
`
`
`
`Data represent number of patients (%) or mean (standard deviation), unless otherwise indicated.
`
`
`
`
`
`
`a Self-reported information.
`b Physician-diagnosed diabetes or fasting plasma glucose ::> 126 mg/dL or hemoglobin
`
`
`
`
`A1c ::>6.5%.
`
`
`
`
`
`
`c Physician-diagnosed hypertension or systolic blood pressure ::> 140 mrnHg or diastolic blood pressure ::>90 mrnHg.
`
`
`
`
`
`
`d Median (interquartile range). LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride.
`
`in the high TG/low HDL-C group, EPA as a proportion of period (Table 2), and the high EPA concentrations remained
`
`
`
`
`
`
`
`
`total plasma fatty acids at registration was lower than that
`
`
`throughout the observation period.
`
`
`
`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
`
`
`
`
`HDL-C, but in did reduce TG (P=0.012; Table 2). In addi
`
`tion, the mean plasma EPA levels in the high TO/low HDL-C
`
`have been shown to lower both LDL-C levels and risk
`group for the control
`
`
`for CAD [18,19]. Besides LDL-C, other risk factors such
`
`group were 2. 3 mol % at registration and
`
`
`2.5 mol % during the observation period, whereas for the EPA
`
`
`
`
`as obesity, dislipidemia, impaired glucose metabolism and
`
`
`
`
`hypertension also increase risk for CAD [9-14]. T his study
`
`
`
`group, mean plasma EPA levels markedly increased from
`
`
`2.6 mol % at registration to 4.5 mol % during the observation
`
`
`
`examined the effects of EPA in the primary prevention sub-
`
`Table 2
`
`Risk factors in the high TG/low HDL-C group at follow-up
`
`TG ::> 150 mg/dL and HDL-C <40 mg/dL
`
`p
`
`
`
`Control group (n=475)
`
`EPA group (n = 482)
`
`Baseline Observation Change from Baseline Observation Change from
`
`period baseline (%)
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`a Median (interquartile range). LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride.
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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
`
`
`
`
`C in the high TG/low HDL-C group during the follow-up
`
`
`period, indicating that the lower MCE rates were the result
`
`
`of other effects of EPA than lowering LDL-C. EPA has many
`
`
`
`
`
`beneficial effects [21,22], including antiplatelet activity [23]
`
`
`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
`
`
`
`
`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
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`IPR2022-00215
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`Ex. 1027, p. 5 of 6
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`140
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`Y Saito et al. I Atherosclerosis 200 (2008) 135-140
`
`
`
`References
`
`[16] Ohnishi H, Saitoh S, Takagi S, et al. Incidence of insulin resistance in
`
`
`
`
`
`
`
`
`obese subjects in a rural Japanese population: the Tanna and Sobetsu
`
`Study. Diab Obes Metab 2005;7:83-7.
`[ l ] Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapen
`
`
`
`[17]Yokoyama M, Origasa H. Effects of eicosapentaenoic acid on car
`
`
`
`
`
`
`
`taenoic acid and prevention of thrombosis and atherosclerosis? Lancet
`
`
`
`diovascular· events in Japanese patients with hypercholesterolemia:
`1978;2:1l7-9.
`
`
`
`
`rationale, design, and baseline char·acteristics of the Japan EPA Lipid
`[2] Burr ML, F ehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and
`
`
`
`
`
`Intervention Study (JELIS). Am Heart J 2003;146:613-20.
`
`
`
`fibre intakes on death and myocardial reinfarction: diet and reinfarction
`
`
`
`[18]Prevention of car·diovascular· events and death with pravastatin in
`
`trial (DART). Lancet 1989;2:757-61.
`
`
`
`
`patients with coronar-y heart disease and a broad range of initial choles
`[3]Daviglus ML, Stamler J, Orencia AJ, et al. Fish consumption and
`
`
`
`
`
`
`
`
`terol levels. The Long-Term Intervention with Pravastatin in Ischaemic
`
`
`
`the 30-year risk of fatal myocardial infarction. N Engl J Med
`(LIPID) Study Group. N Engl J Med 1998;339:
`1349-57.
`Disease
`
`1997;336: 1046-53.
`
`
`
`
`[19] Shepherd J, et al. Prevention of coronar-y heart disease with pravastatin
`[ 4]Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake
`
`
`
`
`in men with hypercholesterolemia. N Engl J Med 1995;333:1301-7.
`
`
`
`and risk of coronar-y heart disease in women. JAMA 2002;287: 1815-21.
`
`
`
`[20] Satoh N, Shimatsu A, Kotani K, et al. Purified eicosapentaenoic acid
`
`
`[5]Iso H, Kobayashi M, Ishihara J, et al. Intake of fish and n-3 fatty
`
`
`
`
`reduces small dense LDL, remnant lipoprotein particles, and C-reactive
`
`
`
`acids and risk of coronar-y heart disease among Japanese: the Japan
`
`
`
`
`protein in metabolic syndrome. Diab Car·e 2007;30: 144-6.
`
`Public Health Center-Based (JPHC) Study Cohort I. Circulation
`
`
`
`[21] Harris WS, Par·k Y, Isley WL. Car·diovascular· disease and long-chain
`2006;113: 195-202.
`
`
`
`omega-3 fatty acids. Curr Opin Lipidol 2003; 14:9-14.
`[6] Morris MC, Manson JE, Rosner B, et al. Fish consumption and car·dio
`
`[22] Din JN, Newby DE, Flapan AD. Omega 3 fatty acids and car·diovascular·
`
`
`
`
`
`
`vascular disease in the physicians' health study: a prospective study.
`
`
`
`disease-fishing for a natural treatment. BMJ 2004;328:30-5.
`
`
`AmJEpidemiol 1995;142:166-75.
`
`[23]Tamura Y, Hirai A, Terano T, et al. Clinical and epidemiological
`
`
`
`
`[7]Dietar-y supplementation with n-3 polyunsaturated fatty acids and vita
`
`
`studies of eicosapentaenoic acid (EPA) in Japan. Prog Lipid Res
`
`
`min E after myocar·dial infarction: results of the GISSI-Prevenzione
`1986;25:461-6.
`
`
`
`
`trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto
`[24] Kawano H, Yano T, Mizuguchi K, Mochizuki H, Saito Y. Changes
`
`
`
`miocar·dico. Lancet 1999;354:447-55.
`
`
`
`in aspects such as the collagenous fiber density and foam cell size
`
`
`
`[8]Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicos
`
`
`
`of atherosclerotic lesions composed of foam cells smooth muscle
`
`
`
`apentaenoic acid on major coronar-y events in hypercholesterolaemic
`
`
`cells and fibrous components in rabbits caused by all-cis-5,8,11,14,17-
`
`
`
`
`
`patients (JELIS): a randomised open-label, blinded endpoint analysis.
`
`
`icosapentaenoic acid. J Atheroscler Thromb 2002;9:170-7.
`Lancet 2007;369:1090-8.
`
`
`[25]Thies F, Gar1-y JM, Yaqoob P, et al. Association of n-3 polynnsatu
`
`
`
`[9] Alberti KG, Zimmet P, Shaw J. The metabolic syndrome-a new world
`
`
`
`rated fatty acids with stability of atherosclerotic plaques: a randomised
`
`
`wide definition. Lancet 2005;366:1059--62.
`
`
`controlled trial. Lancet 2003;361:477-85.
`[10] Arai H, Yamamoto A, Matsuzawa Y, et al. Prevalence of metabolic
`
`
`[26] Carmena R, Duriez P, Fmchart JC. Atherogenic lipoprotein particles in
`
`
`
`
`
`
`
`
`
`syndrome in the general Japanese population in 2000. J Atheroscler
`
`atherosclerosis. Circulation 2004;109:III2-7.
`Thromb 2006;13:202-8.
`
`
`
`[27] Ridker PM. High-sensitivity C-reactive protein and car·diovascular·
`[11]DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syn
`
`
`
`
`
`
`
`
`for screening and primary prevention. Am J Cardiol
`risk: rationale
`
`
`for NIDDM, obesity, hypertension, dyslipidemia,
`drome responsible
`
`2003;92: l 7K-22K.
`
`
`
`and atherosclerotic cardiovascular· disease. Diab Car·e 1991; 14: 173-94.
`[28] Itoh M, Suganami T, Satoh N, et al. Increased adiponectin secre
`
`
`
`
`
`[12] Kaplan NM. The deadly quar·tet. Upper-body obesity, glucose intol
`
`
`
`tion by highly purified eicosapentaenoic acid in rodent models of
`
`
`
`erance, hypertriglyceridemia, and hypertension. Arch Intern Med
`
`
`
`
`obesity and human obese subjects. Arterioscler Thromb Vase Biol
`
`1989;149: 1514-20.
`
`2007;27: 1918-25.
`[13]Nakamura T, Tokunaga K, Shimomura I, et al. Contribution of visceral
`
`
`
`
`[29] Okamoto Y, Kihar·a S, Ouchi N, et al. Adiponectin reduces atheroscle
`
`
`
`
`
`
`
`
`fat accumulation to the development of coronar-y arte1-y disease in non
`
`
`
`rosis in apolipoprotein E-deficient mice. Circulation 2002; l 06:
`
`
`obese men. Atherosclerosis 1994;107:239-46.
`2767-70.
`[14] Reaven GM. Banting lecture 1988. Role of insulin resistance in human
`
`
`
`
`[30]Fmebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product
`
`
`
`
`disease. Diabetes 1988;37:1595-607.
`
`
`
`
`of 30-kDa adipocyte complement-related protein increases fatty acid
`
`
`[15]Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome
`
`
`
`
`oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci
`
`
`
`
`and total and cardiovascular· disease mortality in middle-aged men.
`USA 2001 ;98:2005-10.
`JAMA 2002;288:2709-16.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1027, p. 6 of 6
`
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