EPA versus EPA/DHA: What Have Clinical Trials Taught Us?

eicosapentanoic acid, fish consumption, heart disease, Heart Health, omega 3's, triglycerides

Our new review paper out this week entitled “A Fishy Topic: VITAL, REDUCE-IT, STRENGTH and Beyond; Putting Omega-3 Fatty Acids into Practice in 2021” was designed to reduce the confusion surrounding the use of the marine derived omega 3 fatty acids, EPA (eiscosapentanoic acid) and DHA (docosahexanoic acid).  Coincidentally, this paper compliments last week’s publication in the Lancet journal, EClinical Medicine entitled, “Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis” led by my colleagues,  Drs. Safi Khan and Deepak Bhatt and showing that EPA but not the combination of EPA+DHA was associated with reduced risk of cardiovascular events such as heart attacks, strokes and heart related death (see Figure).

As both EPA and DHA are extracted from oily fish including salmon, sardines, anchovies and herring and both lower triglycerides to a similar degree, why have clinical trials using EPA compared to EPA+DHA shown contrasting results?   Elegant work from Dr. Preston Mason and his co-workers have provided important insights at the cellular level demonstrating that EPA possesses cardioprotective anti-inflammatory, anti-oxidant, endothelial normalizing and membrane stabilizing properties that become suppressed in the presence of DHA.  Thus while DHA plays a pivotal role in brain growth and development, clinical trials to date have not borne out similar benefits with respect to cardioprotection.

I’ve been intrigued with EPA for more that a quarter century after we first observed dramatic differences in the way EPA was processed into cellular lipids when compared to prototypic saturated and monounsaturated fatty acids.   As differences between EPA, DHA and other fatty acids continue to emerge, listed below are a series of highlights related to the intake of these fats whether as a supplement or in medicinal form.

  1. Dietary supplements such as “fish oil” capsules are NOT regulated by the FDA and should not be viewed in the same context as OTC products (such as Advil) that are regulated.
  2. Fish oil capsules, a dietary supplement not regulated by the FDA, has been shown to contain a number of impurities such as saturated fat and oxidized lipids that impair its effectiveness.
  3. EPA but not DHA exhibits heart protective antioxidant, anti-inflammatory and membrane/plaque stabilizing properties that help to reduce the risk of cardiovascular disease.
  4. In the MESA study, higher blood levels of OM3 (inclusive of EPA) were associated with reduced risk of hospitalization for bleeding events.
  5. In the REDUCE-IT USA study, 4 grams of Icosapent ethyl, the prescription form of highly purified EPA, was associated with a 30% reduction of death from all causes.
  6. In the REDUCE-IT trial, total primary events (cardiovascular death, heart attack stroke, stent placement, bypass surgery or hospitalization for unstable angina) were reduced by 30%.

Dr. Michael Miller is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore,MD.  He is a Scientific Advisor for Amarin, Corp. and Steering Committee Member of the REDUCE-IT trial.  Dr. Miller is also the author of several books; including his most recent,  “Heal Your Heart…

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