Omega-3 Fatty Acid Supplements Not Beneficial for Reducing Cardiovascular Events, Trials Show

Omega-3 fatty acids — a family of polyunsaturated fatty acids — are essential components of cell membranes,[1] of which three types are most important: alpha-linolenic acid (ALA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

ALA comes from plants, such as chia seeds and flaxseeds, soybeans and walnuts. EPA and DHA largely come from seafoods (especially fatty fish). For adults, the daily recommended amount of ALA ranges from 1.1 to 1.6 grams, but no specific recommended amounts have been established for EPA and DHA.

Because less than 15% of ALA can be converted to EPA and then to DHA in the liver, consuming EPA and DHA, optimally from dietary sources, is encouraged. All three omega-3 fatty acids also are available in widely used dietary supplements.

Although numerous studies have examined whether consuming omega-3 fatty acids, especially EPA and DHA, has cardiovascular (heart and blood vessel) protective benefits, most of these studies used observational designs.

Accordingly, the Food and Drug Administration (FDA) permitted the makers of conventional foods and dietary supplements that contain EPA and DHA to claim that these products may reduce the risk of hypertension and coronary artery heart disease, even though the agency acknowledges that the evidence for this claim is “inconclusive and highly inconsistent.”[2]

Two recent well-designed, randomized, double-blind, controlled trials showed no benefit for combined oral EPA and DHA supplements for reducing the risk of cardiovascular events compared with a corn-oil placebo. The first, the STRENGTH trial, was funded by AstraZeneca and was conducted by Cleveland Clinic and international researchers.[3] Its findings were published in the Dec. 8, 2020, issue of the Journal of the American Medical Association. The second, the OMEMI trial, was a foundation-funded trial conducted by Norwegian researchers.[4] Its findings were published in the Feb. 9, 2021, issue of Circulation.

The STRENGTH trial[5]

The researchers of this trial enrolled nearly 13,100 adults (mean age was 63 years) who had, or were at high risk of, cardiovascular disease; had high triglyceride blood levels and low high-density lipoprotein cholesterol levels; and had already been taking statins (cholesterol-lowering medications) for at least four weeks. They randomly assigned one-half of these subjects to receive a high daily dose (4 grams) of a combined EPA and DHA supplement and the other half to receive a corn-oil placebo.

In their interim analysis of the trial data, the researchers found a 19% decline in triglyceride levels in the EPA-DHA–group subjects and only a 1% decline in the placebo-group subjects. However, the trial’s endpoint — a serious cardiovascular event (coronary revascularization [bypass surgery or angioplasty], heart attack, hospitalization for unstable angina, nonfatal stroke or cardiovascular death) — occurred in 12% of subjects in both the EPA-DHA and placebo groups after a median of approximately three-and-a-half years of follow-up.

The researchers also found that new-onset atrial fibrillation (a common abnormal heart rhythm) occurred in 2% of the EPA-DHA–group subjects and only 1% of the placebo-group subjects. Furthermore, gastrointestinal adverse events (abdominal discomfort, diarrhea, indigestion and nausea) were reported in 25% of the EPA-DHA–group subjects and only 15% of the placebo-group subjects.

Therefore, the researchers concluded that the trial, if continued, was unlikely to show that the EPA and DHA supplement would be better than the placebo and halted the trial early.

The OMEMI trial[6]

The researchers of this trial recruited more than 1,000 older adults (mean age was 75 years) who had suffered a heart attack two to eight weeks before enrollment.

Approximately 97% and 41% of these subjects took daily statins and cod-liver oil (600 milligrams of EPA and DHA), respectively, before and after enrollment.

The researchers randomly assigned one-half of these subjects to receive 1.8 grams of a combined EPA and DHA supplement and the other half to receive a corn-oil placebo every day.

After two years of follow-up, the trial’s primary endpoint — hospitalization for heart failure, nonfatal heart attack, stroke, unscheduled revascularization or death — occurred in the same proportion (approximately 20%) of subjects in both groups.

Moreover, new-onset atrial fibrillation occurred in 7% of the EPA-DHA–group subjects and just 4% of the placebo-group subjects.

Prior evidence

The negative results of the STRENGTH and OMEMI trials contradict those of the REDUCE-IT trial.[7] This nearly 8,180-subject trial supported the FDA approval of an EPA-only prescription drug (VASCEPA) as an add-on to maximally tolerated statin therapy to reduce the risk of cardiovascular events in adults with elevated triglycerides and established cardiovascular disease as well as certain high-risk diabetic patients.[8]

The REDUCE-IT trial showed that Vascepa-treated subjects had a 25% reduction in cardiovascular events compared with those who received a mineral-oil placebo.

It is hard to compare the results of the REDUCE-IT trial with those of the STRENGTH and OMEMI trials because the former used a single omega-3 fatty acid and a different placebo oil than the latter trials. Particularly, there is concern that use of mineral oil in the placebo group of the REDUCE-IT trial may have increased the risk of cardiovascular events in this group. This, in turn, may have contributed to the higher rates of cardiovascular events in this group compared with those in the Vascepa-treated group.[9]

Hopefully, additional trials will further clarify these questions.

What You Can Do

What You Can Do To reduce your risk of cardiovascular disease, consume a healthy diet that is high in vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish.[10] Also, minimize your intake of trans fats (hydrogenated vegetable oils), processed and red meat, refined carbohydrates and sweetened beverages.

The best and safest way to benefit from omega-3 fatty acids is from food, especially fatty fish that is low in mercury — including herring, mackerel, salmon, sardines and trout.[11]

Until there is compelling evidence that EPA and DHA fatty acids from dietary supplements have cardiovascular protective effects, it is best not to take them. Also, it is important to exercise and try to decrease stress and avoid smoking.

If you have elevated triglyceride levels in the blood that have not been controlled by dietary changes or statin therapy, talk to your doctor about whether you should take FDA-approved omega-3 fatty acid prescription medications — LOVAZA[12],[13] (which contain EPA and DHA) or VASCEPA (which contains EPA only).[14]
 

References

[1] National Institutes of Health, Office of Dietary Supplements. Omega-3 fatty acids. Fact sheet for health professionals. March 26, 2021. https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/. Accessed April 9, 2021.

[2] Food and Drug Administration. FDA announces new qualified health claims for EPA and DHA omega-3 consumption and the risk of hypertension and coronary heart disease. June 19, 2019. https://www.fda.gov/food/cfsan-constituent-updates/fda-announces-new-qualified-health-claims-epa-and-dha-omega-3-consumption-and-risk-hypertension-and. Accessed April 8, 2021.

[3] 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.

[4] Kalstad AA, Myhre PL, Laake K, et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: A randomized, controlled trial. Circulation. 2021;143(6):528-539.

[5] 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.

[6] Kalstad AA, Myhre PL, Laake K, et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: A randomized, controlled trial. Circulation. 2021;143(6):528-539.

[7] 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.

[8] Amarin Pharma, Inc. Label: icosapent ethyl (VASCEPA). December 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202057s035lbl.pdf. Accessed April 14, 2021.

[9] Curfman G. Do omega-3 fatty acids benefit health? JAMA. 2020;324(22):2280-2281.

[10] Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596-e646.

[11] National Institutes of Health, Office of Dietary Supplements. Omega-3 fatty acids. Fact sheet for health professionals. March 26, 2021. https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/. Accessed April 14, 2021.

[12] LOVAZA: Limited use drug for lowering triglycerides. Worst Pills, Best Pills News. April 2009. https://www.worstpills.org/newsletters/view/634. Accessed April 8, 2021.

[13] GlaxoSmithKline. Label: omega-3-acid ethyl esters capsules (LOVAZA). September 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021654s044lbl.pdf. Accessed April 14, 2021.

[14] Amarin Pharma, Inc. Label: icosapent ethyl (VASCEPA). December 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202057s035lbl.pdf. Accessed April 14, 2021.