Elsevier

Atherosclerosis

Volume 206, Issue 2, October 2009, Pages 535-539
Atherosclerosis

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)

https://doi.org/10.1016/j.atherosclerosis.2009.03.029Get rights and content

Abstract

Background

JELIS was a large-scale clinical trial that investigated the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD). In this paper, the data of patients registered in JELIS were analysed to compare the incidence of CAD between patients with impaired glucose metabolism (IGM) and normoglycemic (NG) patients. The effect of EPA on the incidence of CAD in patients with IGM was also assessed.

Methods

The 18,645 hypercholesterolemic patients registered in JELIS were divided into two groups. One group consisted of patients with IGM (n = 4565), which included the patients who had diabetes mellitus and patients who had a fasting plasma glucose of 110 mg/dL or higher, either at the time of registration or after 6 months. The other group consisted of NG patients (n = 14,080). CAD incidence of the two groups over the average 4.6-year follow-up period was compared, and the effect of EPA was assessed.

Results

Compared to NG patients, IGM patients had a significantly higher CAD hazard ratio (1.71 in the non-EPA group and 1.63 in the EPA group). The treatment with EPA resulted in a 22% decrease in the CAD incidence (P = 0.048) in IGM patients and an 18% decrease (P = 0.062) in NG patients.

Conclusions

It was found that the CAD risk in IGM patients is higher than in NG patients, and that highly purified EPA is very effective in decreasing the incidence of CAD among Japanese IGM patients, even though the intake of fish is high.

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.

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