Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes
Introduction
Patients with type 2 diabetes have a high risk of developing cardiovascular disease which is also the most frequent cause of death in these patients [1]. Because hyperglycemia is the most typical abnormality observed in type 2 diabetes, normalization of the blood glucose level was assumed to be an efficient therapy for preventing all of the complications of type 2 diabetes. Certainly, the UK Prospective Diabetes Study (UKPDS) 35 identified a positive association between the mean HbA1C value and ischemic heart disease. However, the relationship between diabetic macroangiopathy and HbA1C was weaker than that observed for microangiopathy [2]. In addition, UKPDS 33 showed that intensive treatment leading to a decrease of HbA1C by ∼1% significantly reduces the risk of microangiopathy, but fails to reduce the risk of macroangiopathy [3]. Such results have led to investigators targeting more effective therapies for prevention of the progression of atherosclerosis in type 2 diabetes.
Several epidemiological studies have suggested that an increased dietary intake of fish or fish oil is inversely correlated with the onset of cardiovascular disease [4], [5], [6]. The principle components of fish oil are polyunsaturated n-3 fatty acids (n-3 PUFA), such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). An increased intake of n-3 PUFA results in a corresponding increase of these fatty acids in cellular and circulating lipids [4] due to the replacement of lipids derived from n-6 PUFA such as linoleic acid and arachidonic acid. These changes alter the biochemical properties of cell membranes and modify intercellular signaling. Eicosanoids such as prostaglandins, leukotrienes, and thromboxanes are mainly produced from arachidonic acid and EPA in cell membrane by oxygenases and mediate several intercellular signaling processes. The level of thromboxane A2, a well-known proaggregatory eicosanoid, is markedly reduced through the replacement of arachidonic acids by EPA. Thus, the beneficial effects of an increased intake of n-3 PUFA were originally thought to be due to their anit-thrombotic effect, but recent studies and evidences indicated that n-3 PUFA might have an anti-inflammatory effect [7], [8], an anti-atherosclerotic effect [9], an anti-arrhythmic effect [10], [11], [12], a blood pressure (BP) lowering effect [13], and a triglyceride loweing effect [4] and may also prevent endothelial dysfunction [14]. However, there are only limited data showing the effect of n-3 PUFA on the progression of atherosclerosis in type 2 diabetes.
The carotid intima-media thickness (IMT) is a well established marker of the progression of atherosclerosis and it is widely recognized as a surrogate cardiovascular endpoint [15], [16]. Also, the brachial-ankle pulse wave velocity (baPWV) is considered to be useful predictors of cardiovascular disease in patients with type 2 diabetes [17], [18].
The present study was an open randomized prospective trial that investigated the preventive effect of purified EPA on atherosclerosis in subjects with type 2 diabetes.
Section snippets
Subjects
A total 81 subjects with type 2 diabetes were recruited from among the outpatients of Juntendo University Hospital. Patients who visited the hospital from September 2001 to April 2002 were asked to participate in the study. At screening visit, patients with advanced diabetic complications, severe renal or hepatic disease, overt cardiovascular disease, symptomatic peripheral artery disease (PAD) and malignancy were excluded. The diagnosis of type 2 diabetes was based on the current WHO criteria.
Baseline characteristics
During the follow-up period, 21 patients dropped out of the study (Control group; 1 carcinoma, 1 asthma attack, 9 lost to follow-up, EPA group; 1 carcinoma, 5 poor compliance, 4 lost to follow-up) and 60 patients completed this study. None of the patients developed coronary heart disease, cerebral infarction, or symptomatic arteriosclerosis obliterans during the follow-up period. The baseline clinical characteristics of the patients who completed the study are shown in Table 1. All the clinical
Discussion
Previous studies have demonstrated that an increased dietary intake of fish or daily supplementation of n-3 PUFA can decrease cardiovascular death in patients with a history of myocardial infarction [10], [11], reduce restenosis after percutaneous transluminal coronary angioplasty [22], [23], and keep graft patency after coronary artery bypass surgery [24]. Nevertheless, there have been no clinical studies showing that the administration of n-3 PUFA is effective for primary prevention of
Acknowledgement
We thank Noriko Iijima for the excellent technical assistance.
References (33)
- et al.
Diabetes as an atherogenic factor
Prog Cardiovasc Dis
(1984) - et al.
Marine n-3 polyunsaturated fatty acids and coronary heart disease. Part II. Clinical trials and recommendations
Thromb Res
(2005) - et al.
Marine n-3 polyunsaturated fatty acids and coronary heart disease. Part I. Background, epidemiology, animal data, effects on risk factors and safety
Thromb Res
(2005) - et al.
Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial
Lancet
(2003) - et al.
Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART)
Lancet
(1989) - et al.
Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells
Biochem Biophys Res Commun
(1997) - et al.
Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency
Am J Cardiol
(1996) - et al.
Fish intake is associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease
Am J Clin Nutr
(2004) - et al.
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study
BMJ
(2000) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group
Lancet
(1998)
Omega 3 fatty acids and cardiovascular disease–fishing for a natural treatment
BMJ
Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function
N Engl J Med
The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells
N Engl J Med
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
Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils
Circulation
Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials
J Hypertens
Cited by (122)
Omega-3 Fatty Acids
2023, Clinical Lipidology: A Companion to Braunwald's Heart DiseaseA biological rationale for the disparate effects of omega-3 fatty acids on cardiovascular disease outcomes
2022, Prostaglandins Leukotrienes and Essential Fatty AcidsOmega-3 and omega-6 fatty acids have distinct effects on endothelial fatty acid content and nitric oxide bioavailability
2021, Prostaglandins Leukotrienes and Essential Fatty AcidsEffects of dietary eicosapentaenoic acid and docosahexaenoic acid supplementation on metabolic syndrome: A systematic review and meta-analysis of data from 33 randomized controlled trials
2021, Clinical NutritionCitation Excerpt :Finally, 33 studies were eligible for the present study, including 30 studies using parallel design and 3 studies using cross-over design. Studies were carried out in Asia [22,24,30–33,37,39,40,44], Europe [10,17,20,21,26,28,32,34,36,38], Oceania [11,43,45–47], and North America [18,19,23,25,27,29,35,41]. Among the 33 trials, 22 trials included participants specifically with at least one chronic disease, such as hyperlipidemia, type 2 diabetes, impaired glucose metabolism, hypertriglyceridemia, hypertension or metabolic syndrome [10,11,18,19,22–24,26,27,29–33,37,39,40,42–45,47], and 10 trials included healthy subjects [17,20,21,25,28,34–36,38,41,46].
Clinical effectiveness of fish oil on arterial stiffness: A systematic review and meta-analysis of randomized controlled trials
2021, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :Concerning the type of fish oil supplementation, 4 trials administered DHA or EPA alone [16,28–30], and the other 10 as a combination of DHA and EPA. In addition to healthy participants [26–28,31], some studies recruited individuals with different health status including hypertension [25,32], overweight and obese [13,29], dyslipidemia and coronary artery disease [30], metabolic syndrome [15], type 2 diabetes [16], and psoriatic arthritis [33]. Of the included 14 studies, one study could be considered as a high-quality study with a totally ‘low risk of bias’ for all domains [14], and three had low-quality for they had a ‘high risk of bias’ for the blinding of outcome assessment domain [16,29,30].
Serum long-chain n-3 polyunsaturated fatty acids and aortic calcification in middle-aged men: The population-based cross-sectional ERA-JUMP study
2019, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :To date, no RCT has assessed the effect of pure DHA or compared the effect of pure DHA with EPA on cardiovascular outcomes or atherosclerosis. RCTs of pure EPA conducted among diabetics [8], patients with stable angina [9], and CHD [7] reported an inverse association of EPA with atherosclerosis. The REDUCE-IT trial of pure EPA (at a dose of 4.0 g per day) showed a significant 25% relative risk reduction in CVD outcome among 8000 statin-treated patients with CHD or diabetes [5].