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Cited by 33Fatty Acid Research and HealthLipoproteins and Cardiovascular HealthAquaculture Nutrition and Growth

Differentiating EPA from EPA/DHA in cardiovascular risk reduction

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Toth, Peter P., Chapman, M. John, Parhofer, Klaus G., Nelson, John R.·2022·American Heart Journal Plus: Cardiology Research and Practice
DOI 10.1016/j.ahjo.2022.100148PMC PMC10978325
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Abstract

None of the clinical trials of omega-3 fatty acids using combinations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were able to show any effect on cardiovascular outcomes, despite reductions in triglyceride levels. In contrast, the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT), which employed high-dose (4 g) purified EPA, demonstrated a 25% reduction in atherosclerotic cardiovascular disease–related events compared with placebo (hazard ratio 0.75; 95% confidence interval 0.68–0.83; P < 0.001). Moreover, REDUCE-IT is the first clinical trial using a lipid-lowering agent as adjuvant therapy to a statin to show a significant reduction in cardiovascular mortality. Significant reductions in stroke, need for revascularization, and myocardial infarction were also observed. The pharmacology of EPA is distinct from that of DHA, with a differential effect on membrane structure, lipoprotein oxidation, and the production of downstream metabolites that promote the resolution of inflammation. Attained plasma levels of EPA may be an important determinant of efficacy, with a substudy of REDUCE-IT suggesting that the threshold for clinical benefit of EPA is approximately 100 μg/mL, a level achieved in only a minority of patients in other studies. No similar clinical trials of DHA monotherapy have been conducted, so no such threshold has been established. The results of the REDUCE-IT and the Japan EPA Lipid Intervention Study (JELIS) together affirm the efficacy of EPA therapy for cardiovascular disease risk reduction in certain patient populations.

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  • No RCT has ever demonstrated significant reduction in cardiovascular events with EPA/DHA as adjunct to a high-intensity statin therapy, unlike purified EPA.

    “Despite an extensive literature investigating EPA/DHA for cardiovascular risk reduction, unlike purified EPA no RCT has ever demonstrated significant reduction in cardiovascular events with EPA/DHA as adjunct to a high-intensity statin therapy.1”

    From Effects of Eicosapentaenoic Acid vs Eicosapentaenoic/Docosahexaenoic Acids on Cardiovascular Mortality (2025) · cites this paper as [1]

    The Conclusions (page not provided) state that only EPA-alone formulations have demonstrated reductions in major cardiovascular events when added to contemporary medical therapy, including statins. The STRENGTH and REDUCE-IT sections likewise contrast a null EPA/DHA trial with a beneficial purified-EPA trial in statin-treated patients. The paper does not specify high-intensity statin therapy, so that qualifier is not supported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • There is an apparent need to differentiate the role of DHA and EPA in conferring lipid and vascular impacts.

    “There is an apparent need to differentiate the role of DHA and EPA in conferring lipid and vascular impacts. 11 , 146 , 147 , 148”

    From Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials (2023) · cites this paper as [147]

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References 73 · Cited by 33

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Authors
Toth, P. P., Chapman, M. J., Parhofer, K. G., & Nelson, J. R.
Affiliations
  • Johns Hopkins University (US)
  • Pitié-Salpêtrière Hospital (FR)
  • Ludwig-Maximilians-Universität München (DE)
Corresponding author
Toth, Peter P.
ORCID
Venue
American Heart Journal Plus: Cardiology Research and Practice
Publisher
Elsevier BV
Published
2022-05
Volume
17
Pages
100148
ISSN
2666-6022 (ISSN-L)
DOI
10.1016/j.ahjo.2022.100148
PMC
PMC10978325
OpenAlex
W4281978879
Cited by
33
References
73
Citations by year
2026: 5 · 2025: 18 · 2024: 7 · 2023: 3
FWCI
0.94
Type
journal article
Language
en
Open access
Licence
Locations
  • American Heart Journal Plus Cardiology Research and Practice (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • CSL Limited
  • Merck
  • Amarin Pharma Inc
  • Pfizer
  • Kowa Company
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Agricultural and Biological Sciences › Aquatic Science › Aquaculture Nutrition and Growth
Keywords
eicosapentaenoic acid, docosahexaenoic acid, omega-3 fatty acids, REDUCE-IT trial, cardiovascular risk reduction, atherosclerotic cardiovascular disease, triglycerides, lipoprotein oxidation, inflammation resolution, cardiovascular mortality

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