Suppressive effect of EPA on the incidence of coronary events in hypercholesterolemia with impaired glucose metabolism: Sub-analysis of the Japan EPA Lipid Intervention Study (JELIS)☆
Introduction
Dyslipidemia is a major factor that is related to coronary artery disease (CAD) risk in diabetic patients [1]. Intervention studies of lipid management using HMG-CoA reductase inhibitors (statins) found that, on subgroup analysis of diabetic patients with dyslipidemia, a decrease in LDL-C led to a reduction in their CAD risk [2], [3], [4], [5], [6], [7], [8]. The American Diabetes Association guidelines recommend that diabetic patients should have their lipid levels managed so that they reach target levels.
Recently, there have been several reports indicating that the intake of fish, fish oil and n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduced the incidence of CAD [9], [10], [11].
The results of a 16-year follow-up survey involving more than 80,000 people showed that the CAD risk was lower in those who ate fish regularly and in those who consumed high quantities of n-3 fatty acids [10]. Cohort studies in Japan have also indicated that a high n-3 PUFA intake reduces the CAD risk [12]. However, no similar study has been done in patients with abnormal glucose metabolism (diabetic patients and those with abnormal serum glucose levels), who have been shown to have a CAD risk that is higher than non-diabetic patients.
A large-scale intervention clinical trial (Japan EPA Lipid Intervention Study: JELIS) that included hypercholesterolemic patients was done in Japan to study the effects of EPA, which was purified to >98%, as approved by the Ministry of Health, Labour and Welfare of Japan for use as a lipid-lowering agent. After an average of 4.6 years of follow-up of the 18,645 cases, including patients with a history of CAD, it was found that the incidence of CAD was reduced by 19% with EPA treatment [13]. Diabetic patients constituted 16% of the JELIS patients. The unadjusted hazard ratio for CAD by EPA treatment with or without diabetes were already indicated in the previous paper [13], and EPA treatment reduced the incidence of CAD in both absent and present diabetes groups, but it was not statistically significant in diabetic patients. Thus, in the present paper, the effects of EPA on the incidence of CAD in patients with impaired glucose metabolism, including diabetic patients and patients with hyperglycemia, were studied.
Section snippets
Study design and patients
The JELIS trial design has been previously described in detail [14]. A Prospective Randomized Open-label Blinded-endpoint Evaluation (PROBE) method follow-up survey of hypercholesterolemic patients with a serum total cholesterol (TC) of 250 mg/dL or higher (males aged 40–75 years, and postmenopausal females aged up to 75 years) was conducted for a maximum of 5 years (average, 4.6 years). Using the central registration system, the cases registered in JELIS (18,645 cases) were divided randomly
Patient background
Age, ratio of males, smoking habit, drinking habit, BMI, CAD history, and hypertension were all significantly higher in IGM patients than in NG patients. It was also noted that high-density lipoprotein cholesterol (HDL-C) levels were lower, but triglyceride (TG), FPG, HbA1C, and systolic blood pressure levels were significantly higher in IGM patients than in NG patients. No differences were found in TC and EPA levels at baseline between the IGM and NG patients (Table 1).
Effects of EPA on blood parameters and blood pressure
The effects of EPA on
Discussion
In the present sub-analysis, we found that IGM patients were at an increased risk for CAD compared to NG patients, and that this risk in IGM patients was reduced by EPA treatment. Recent epidemiological research has shown that patients with diabetes mellitus or individuals with a higher level of blood glucose have a high incidence of atherosclerotic diseases. The present study, which analysed the 4565 IGM patients included among the 18,645 cases enrolled in JELIS, also found an increased CAD
Acknowledgments
This study was supported by grants from Mochida Pharmaceutical Co. Ltd., Tokyo, Japan. We thank all trial participants and the large numbers of doctors, nurses, and hospital staff who made long-term commitments to the study.
References (28)
- et al.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long-term treatment with lovastatin
The American Journal of Cardiology
(2001) - et al.
Risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes mellitus on low-dose simvastatin therapy: implication from Japan Lipid Intervention Trial (J-LIT)
Atherosclerosis
(2007) - et al.
Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis
Lancet
(2007) - et al.
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)
American Heart Journal
(2003) - et al.
Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes
Atherosclerosis
(2007) - et al.
Effect of orally administered eicosapentaenoic acid (EPA) on the formation of leukotriene B4 and leukotriene B5 by rat leukocytes
Biochemical Pharmacology
(1984) - et al.
The effects of the oral administration of fish oil concentrate on the release and the metabolism of [14C]arachidonic acid and [14C]eicosapentaenoic acid by human platelets
Thrombosis Research
(1982) - et al.
Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial
Lancet
(2003) - et al.
Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression
Hepatology (Baltimore, MD)
(2003) - et al.
A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids
The Journal of Biological Chemistry
(1999)
Fish oil fatty acids and human platelets: dose-dependent decrease in dienoic and increase in trienoic thromboxane generation
Biochemical Pharmacology
Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23)
British Medical Journal
Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S)
Diabetes Care
Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial
The Care Investigators, Circulation
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ClinicalTrials.gov number, NCT00231738.