Elsevier

Metabolism

Volume 65, Issue 11, November 2016, Pages 1636-1645
Metabolism

Clinical Science
Effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular disease risk factors: a randomized clinical trial

https://doi.org/10.1016/j.metabol.2016.07.010Get rights and content

Abstract

Background

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the primary omega-3 fatty acids in fish oil, have been shown to reduce cardiovascular disease (CVD) risk.

Objective

This study aimed to examine the independent effects of EPA and DHA on lipid and apolipoprotein levels, as well as on inflammatory biomarkers of CVD risk, using doses often used in the general population.

Design

A blinded, randomized 6-week trial was performed in 121 healthy, normolipidemic subjects who received olive oil placebo 6 g/d, EPA 600 mg/d, EPA 1800 mg/d, or DHA 600 mg/d. The EPA was derived from genetically modified yeast.

Results

The subjects tolerated the supplements well with no safety issues; and the expected treatment-specific increases in plasma EPA and DHA levels were observed. Compared to placebo, the DHA group had significant decreases in postprandial triglyceride (TG) concentrations (− 20%, − 52.2 mg/dL, P = 0.03), significant increases in fasting and postprandial low-density lipoprotein cholesterol (LDL-C) (+ 18.4%, 17.1 mg/dL, P = 0.001), with no significant changes in inflammatory biomarkers. No significant effects were observed in the EPA 600 mg/d group. The high-dose EPA group had significant decreases in lipoprotein-associated phospholipase A2 concentrations (Lp-PLA2) (− 14.1%, − 21.4 ng/mL, P = 0.003).

Conclusions

The beneficial effects of EPA 1800 mg/d on CVD risk reduction may relate in part to the lowering of Lp-PLA2 without adversely affecting LDL-C. In contrast, DHA decreased postprandial TG, but raised LDL-C. Our observations indicate that these dietary fatty acids have divergent effects on cardiovascular risk markers.

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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    1

    Present address: The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

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