Clinical ScienceEffects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular disease risk factors: a randomized clinical trial☆
Introduction
The major omega-3 fatty acids in the diet are α-linolenic acid (ALA, 18:3n-3), as found in plant oils, and eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) as found in fish or fish oil [1]. High doses of fish oil (≥ 6 g/d) have been shown to be very effective in lowering plasma triglyceride (TG) concentrations in hypertriglyceridemic subjects, and for reducing the secretion of very low-density lipoprotein (VLDL) apolipoprotein (apo) B-100 [2], [3]. Results from the Diet and Reinfarction Trial (DART) and the larger Italian GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico) study of post-myocardial infarction patients have shown that standard over-the-counter fish oil (2 g) and pharmacologic grade concentrated fish oil (1 g) can reduce the risk of both recurrence of coronary heart disease (CHD) events or death from CHD [4], [5], [6]. One of the bioactive constituents of fish oil, EPA, has also been shown to reduce cardiovascular disease (CVD) risk. The Japan EPA Lipid Investigation Study (JELIS) demonstrated that EPA 1800 mg/d reduced CVD risk and recurrent stroke in patients with elevated cholesterol levels on statin therapy, especially in those with both hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) [7], [8], [9], [10]. Furthermore, CVD risk was inversely correlated with on trial plasma EPA levels independent of both low-density lipoprotein cholesterol (LDL-C) and HDL-C [11].
While the evidence clearly indicates that omega-3 fatty acids can reduce CVD events, especially in patients with prior CHD, and high dose fish oil (> 6 g/d) and concentrated omega-3 fatty acids (4 g/d) are approved treatments for lowering TG in patients with significant hypertriglyceridemia (> 500 mg/dL), the independent effects of EPA and DHA on specific biochemical markers associated with CVD at lower doses have not been well defined. Of particular interest are the effects of doses ≤ 2 g/d in individuals without significant cardiovascular morbidity or hyperlipidemia. Preventive therapy with over-the-counter 1 g fish oil capsules recommended by healthcare providers usually consists of up to two capsules per day, with each capsule usually containing up to 200 mg of DHA and 300 mg of EPA. The primary aim of this study, therefore, was to examine the individual effects of EPA and DHA on lipid and lipoprotein concentrations and inflammatory biomarkers associated with CVD risk, with doses frequently used in clinical practice for CVD risk reduction in healthy, normolipidemic subjects. We used a novel EPA oil produced by genetically modified yeast. For comparison, we also examined the effects of a higher dose, EPA 1800 mg/d, which has been shown to lower CVD risk in the JELIS trial.
Section snippets
Study Design
This was a randomized, double-blinded, placebo-controlled trial investigating the effects of EPA and DHA on CVD risk-associated biomarkers at a single center in the United States. A novel EPA-enriched oil produced from genetically modified oleaginous yeast at doses of 600 mg and 1800 mg of EPA per day, as well as a comparator oil providing 600 mg of DHA per day, was tested, relative to olive oil placebo. We used a four-armed parallel design with 1:1:1:1 allocation, as shown in Fig. 1. The study
Results
One hundred twenty one patients were enrolled: 30 in the placebo group, 30 in the EPA 600 group, 31 in the EPA 1800 group, and 30 in the DHA 600 group. Three subjects did not meet the eligibility criteria (based on supplement use) after the screening visit and were excluded. There were 11 total drop-outs (4 from the placebo, 3 from EPA 600, 2 from EPA 1800, and 2 from DHA 600 groups), all due to loss of follow-up, with a similar drop-out rate in all study arms (P = 0.61, Fisher's exact test) as
Discussion
The primary objective of this study was to evaluate the effects of a novel EPA-rich oil at a 600 mg/d dose versus DHA at a 600 mg/d dose versus olive oil placebo on CVD risk markers at doses typically used in the general population. A secondary aim was to examine the effects of EPA 1800 mg/d versus EPA 600 mg/d versus olive oil placebo.
A number of investigators have directly compared the effects of DHA versus EPA in human trials [22], [23], [24], [25], [26], [27]. Grimsgaard et al. in 1997 studied
Author Contributions
EJS designed the study in consultation with DuPont Applied Biosciences, the study sponsor. IBA, EJS, SS, RG, JAG, and MLD carried out the human protocol. IBA, SS, RG, BFA, and KVH performed all laboratory assays, except for plasma fatty acid analyses which were done on contract at Nutrasource Diagnostics (Guelph, Canada). IBA, EJS, SLF, and BFA analyzed the data. EJS and IBA wrote the manuscript, and all authors provided critical review. EJS had primary responsibility for the final content. All
Funding
The study was supported by a research grant from DuPont Applied Biosciences, Wilmington, DE, USA to Dr. Ernst J. Schaefer and the Cardiovascular Research Clinic, where all patients were seen. Additional support was provided by US Department of Agriculture Research Service Contract 53-3K-06 (EJS) and by project grant P50 HL083813-01 from the National Institutes of Health (EJS), which provided support for some of the biochemical assays.
Conflict of Interest
None of the authors has any conflicts of interest.
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2022, Journal of Clinical LipidologyCitation Excerpt :High fish intake has been shown to decrease the production of very low density lipoprotein apolipoprotein B-100, as compared to low fish intake, thereby, accounting for the triglyceride-lowering effect.35 Moreover, when supplementary oral EPA (0.6 and 1.8 g/day) and DHA (0.6 and 1.8 g/day) were compared relative to olive oil 6 g/day (placebo), it was noted that DHA had a greater triglyceride-lowering effect than EPA and raised LDL-C, whereas EPA 1.8 g/day significantly decreased postprandial plasma concentrations of lipoprotein associated phospholipase A2 (LpPLA2), a biomarker of vascular inflammation and atherosclerotic plaque development and instability.36 EPA and DHA have also been shown to have different effects on gene expression in human white blood cells.
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2021, Journal of Clinical LipidologyCitation Excerpt :These mechanistic differences also may explain other important differences in the independent effects of EPA and DHA on markers of CV risk. For example, the fairly consistent observation of a dose-dependent increase specific to DHA on LDL-C and HDL-C juxtaposed against the (albeit modest) net percent decreases in LDL-C and non-HDL-C specific to EPA.29,30 Moreover, these mechanistic differences are likely at play in considering the pleiotropic impact seemingly specific to EPA beyond lipoprotein metabolism, ranging from beneficial effects on endothelial function and oxidative stress to the mitigation of nascent and stabilization of established plaque.28,31
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Clinical trial registration number: NCT00988585.
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Present address: The Children's Hospital of Philadelphia, Philadelphia, PA, USA.