CardioNerds Tommy Das (Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic) and Rick Ferraro (Director of CardioNerds Journal Club and cardiology fellow at the Johns Hopkins Hospital) join Dr. Erin Michos (Associate Professor of Cardiology at the Johns Hopkins Hospital and Editor-In-Chief of the American Journal of Preventative Cardiology) for a discussion about the effect of DHA and EPA on triglycerides and why DHA/EPA combinations may have exhibited limited benefits in trials. This episode is part of the CardioNerds Lipids Series which is a comprehensive series lead by co-chairs Dr. Rick Ferraro and Dr. Tommy Das and is developed in collaboration with the American Society For Preventive Cardiology (ASPC).

Relevant disclosures: None

Pearls • Notes • References • Guest Profiles • Production Team

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1. The best intervention for heart disease is prevention! The InterHeart trial showed that 9 modifiable risk factors (dyslipidemia, smoking, hypertension, diabetes, abdominal obesity, dietary patterns, physical activity, consumption of alcohol, and psychosocial factors) predict 90% of acute myocardial infarction. So many acute events can be prevented1.
2. Atherosclerotic vascular disease events increase across a range of triglyceride levels, even from 50-200mg/dL. So even in a relatively normal range, lower triglycerides seem to be better. Over ¼ of US adults have triglycerides over 150.
3. While 8% of US adults take fish oil supplements, multiple meta-analyses have failed to show any benefit to the use of dietary omega-3 supplementation2. Dietary supplements these are not meant for medical use and are not studied or regulated as such!

1. What are DHA and EPA?

• DHA, or docosahexaenoic acid, and EPA, or eicosapentaenoic acid, are n-3 polyunsaturated fatty acids, also known as omega-3 fatty acids. These compounds have been of considerable interest for over two decades given observed association of high dietary omega-3 fatty acid intake with reduced cardiovascular events3. As both are important omega-3 fatty acids, trials on the benefits of DHA and EPA have often focused on the two compounds in combination.

2. What was the GISSI-Prevenzione Trial and why was it Important?

• GISSI-Prevenzione trial (Lancet 1999), was one of the earliest trials to study DHA and EPA4. In this trial, the authors evaluated the effect of omega-3 supplementation as a combination pill of DHA and EPA on cardiovascular events and death in patients with recent myocardial infarction (the last three months). Over a 3.5-year follow-up period, participants treated with DHA/EPA combination experienced a significant reduction in death, nonfatal MI, and stroke.
• As this was an early trial, patients were largely not on statins, as these were not supported at the time of study initiation (Only 5% were on cholesterol-lowering medications at baseline, and only 45% were on cholesterol-lowering therapy at study completion). The benefits seen in this trial may not extend to modern practice with patients on contemporary background therapy.
• The trial participants were also not representative of our modern patients for a variety of other reasons. 85% of participants in the trial were men. 42.2% of patients in EPA/DHA arm were current smokers, and 35.4% were prior smokers. Only 14.2% of patients had diabetes and 14.7% with BMI >30.
• Notably, the decrease in triglycerides in this trial was only 3%, implying that triglyceride lowering did not entirely explain the benefit in cardiovascular events seen.

3. What about the data after the GISSI-Prevensione Trial?

• After this positive trial for DHA/EPA in combination, subsequent trial data in support of DHA/EPA has been less robust.
• The Alpha Omega trial in 2010, ORIGIN in 2012, ASCEND in 2018, and VITAL in 2019 were all trials of DHA/EPA combinations versus placebo, and all exhibited no significant differences in cardiovascular events with DHA/EPA use5–8.
• The recent STRENGTH trial, published in 2020, also showed no reduction in cardiovascular events when taking DHA/EPA in combination (and as discussed in CardioNerds episode 136!)9. This remained the case upon sub-analysis of patients from the STRENGTH trial with the highest levels of serum EPA, who again exhibited no cardiovascular benefit.

4. Why then don’t DHA and EPA seem to work in combination?

• In short, we do not know.
• It seems that the beneficial effects of EPA – which as monotherapy has shown benefit across numerous trials (namely JELIS and REDUCE-IT) – are somehow offset by the combination with DHA, via a mitigation of anti-inflammatory processes or otherwise – this remains theoretical10,11.
• The EVAPORATE trial of purified EPA showed lower total plaque in participants taking EPA, suggesting a possible mechanism of effect12.

5. What About Dietary Omega-3 Supplements?

• 8% of US adults take fish oil supplements.
• Multiple meta-analyses have failed to show any benefit to the use of dietary omega-3 supplementation2.
• Note that the term “over the counter” is not correct when referring to these supplements! Over the counter refers to medications that are FDA regulated, just not prescription. Omega-3 supplements have minimal FDA oversight, which is perhaps another reason to avoid them.

1.     Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. The Lancet. 2004;364(9438):937-952. doi:10.1016/S0140-6736(04)17018-9

2.     Abbasi J. Another Nail in the Coffin for Fish Oil Supplements. JAMA. 2018;319(18):1851-1852. doi:10.1001/jama.2018.2498

3.     Bang HO, Dyerberg J, Hjørne N. The Composition of Food Consumed by Greenland Eskimos. Acta Medica Scandinavica. 1976;200(1-6):69-73. doi:10.1111/j.0954-6820.1976.tb08198.x

4.     GISSI-Prevenzione, Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. The Lancet. 1999;354(9177):447-455. doi:10.1016/S0140-6736(99)07072-5

5.     Kromhout D, Giltay EJ, Geleijnse JM. n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction. N Engl J Med. 2010;363(21):2015-2026. doi:10.1056/NEJMoa1003603

6.     The ORIGIN Trial Investigators. n–3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia. N Engl J Med. 2012;367(4):309-318. doi:10.1056/NEJMoa1203859

7.     The ASCEND Study Collaborative Group. Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med. 2018;379(16):1540-1550. doi:10.1056/NEJMoa1804989

8.     Manson JE, Cook NR, Lee IM, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2018;380(1):33-44. doi:10.1056/NEJMoa1809944

9.     Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020;324(22):2268-2280. doi:10.1001/jama.2020.22258

10.   Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792

11.   Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. The Lancet. 2007;369(9567):1090-1098. doi:10.1016/S0140-6736(07)60527-3

12.   Budoff MJ, Bhatt DL, Kinninger A, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. European Heart Journal. 2020;41(40):3925-3932. doi:10.1093/eurheartj/ehaa652

Dr. Erin Donnelly Michos is an Associate Professor of Medicine at Johns Hopkins School of Medicine, with joint appointment in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. She is the Director of Women’s Cardiovascular Health and the Associate Director of Preventive Cardiology with the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease. Dr. Michos completed medical school at Northwestern University in Chicago, IL, and then completed both her Internal Medicine residency and Cardiology fellowship at the Johns Hopkins Hospital in Baltimore, MD.  She also completed her MHS in Cardiovascular Epidemiology at the Johns Hopkins Bloomberg School of Public Health. She has authored or co-authored over 300 manuscripts in peer reviewed journals and is an internationally known leader in preventive cardiology and women’s health.