Are Omega-3 Supplements Heart-Healthy?

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Omega-3 fatty acids, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are renowned for their therapeutic benefits for a broad range of bodily systems. Modern-day research has focused on some key health areas where supplementation can play a role, perhaps none larger than cardiovascular health.

Omega-3 fatty acids support the heart in numerous ways. First, these fatty acids are preferentially incorporated into cell membrane phospholipids, where they both influence signaling across membranes and preserve membrane fluidity. Omega-3s are also able to modulate the function of calcium and sodium membrane channels, and in doing so, promote anti-arrhythmic effects.

Omega-3 fatty acids also support heart health on several anti-inflammatory fronts, which means they may potentially prevent vascular damage that leads to atherosclerosis and endothelial dysfunction.¹ For instance, omega-3s prevent the conversion of the omega-6 fatty acid, arachidonic acid, into pro-inflammatory eicosanoids. By substituting for arachidonic acid in cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, omega-3s therefore decrease inflammation. In addition, omega-3s further promote anti-inflammation, including in vascular walls, by leading to the production of lipid mediators known as resolvins and protectins.
 

The Negative Current
Given these important attributes, it’s easy to see how DHA and EPA became broadly known as useful contributors to heart health. Yet, despite the fact that several published intervention studies and meta-analyses back the positive effects of omega-3 fats on cardiovascular health, controversy remains about their true value. Mainstream publications, including The New York Times² and The Washington Post³, have questioned the science behind omega-3s, basing their questions on recent reviews and meta-analyses showing neutral effects of omega-3s on cardiovascular disease prevention.

A recent report published by the Agency for Healthcare Research and Quality (a division of the U.S. Department of Health and Human Services) evaluated the effects of, and associations between, omega-3 fatty acid intake and cardiovascular disease outcomes, looking at factors such as blood lipids, blood pressure, risk of cardiovascular mortality, and development of cardiovascular events.⁴ The reviewers searched for published studies between 2002 and 2015 and chose 61 randomized controlled trials and 37 longitudinal observational studies to include in the analysis. While the researchers concluded that there was evidence of a benefit of omega-3 fats for raising HDL cholesterol, lowering triglycerides, and lowering the total cholesterol:HDL ratio, they also said there was weak evidence to show that omega-3s help to reduce all-cause mortality, blood pressure, and myocardial infarct. They also noted that higher marine omega-3 intake was associated with a small but significant increase in LDL (bad) cholesterol levels. In addition, in terms of stroke prevention and cardiovascular death, the randomized controlled trials found no protective effect of omega-3s. (Evidence from observational studies, however, did indicate potential benefits of omega-3 intake.)

Additionally, in a recent observational study led by Jinnie Rhee of the Harvard T.H. Chan School of Public Health (Boston, MA), researchers assessed the association between consumption of fish and long-chain omega-3 polyunsaturated fatty acids (PUFA), including α-linolenic acid and marine omega-3 fatty acids, and the incidence of cardiovascular disease in healthy women who were enrolled in the Women’s Health Study.⁵ This analysis included 22 years of follow-up data from 38,392 women without a prior history of cardiovascular disease. Researchers found no association between the intake of fish, α-linolenic acid, or marine fatty acids and the risk of major cardiovascular disease, nor any association with individual cardiovascular events such as myocardial infarction, stroke, and cardiovascular death in this cohort.

Furthermore, a Canadian review looking at the evidence from randomized controlled trials on the primary and secondary prevention of cardiovascular disease was also not wholly supportive of omega-3s. The review included eight intervention studies (enrolling more than 1,000 patients with at least a one-year follow-up), as well as two published meta-analyses of randomized controlled trials.⁶ In the five trials including patients with preexisting cardiovascular disease, the reviewers found that only one trial demonstrated a reduction in the incidence of cardiovascular events; in the three trials looking at primary prevention with omega-3 fatty acids, only one trial demonstrated a minor reduction in major coronary events. Similarly, the two meta-analyses, which looked at secondary prevention in patients who have had a heart attack, concluded that omega-3 fatty acids do not further reduce the incidence of cardiovascular events as an adjunct to standard drug therapy. Based on their review, the authors concluded that there is currently a lack of evidence supporting routine omega-3 supplementation for either primary or secondary prevention of cardiovascular disease.

Evidence in Favor of Omega-3s
Juxtaposing these negative results, however, is a slew of positive research attesting to the benefits of omega-3 supplements for cardiovascular risk reduction.

For example, in a study led by Liana Del Gobbo from Stanford University School of Medicine (Stanford, CA), researchers pooled evidence from 19 cohort studies (17 of which were prospective trials) from 16 countries to assess the benefits of omega-3 fatty acids on coronary heart disease.⁷ The pooled analysis included 45,637 individuals without prevalent coronary heart disease, and the researchers analyzed the correlation of circulating and tissue biomarkers of omega-3 status with the incidence of total coronary heart disease, fatal coronary heart disease, and non-fatal myocardial infarction. They found that each standard deviation increase in the individual levels of EPA, DHA, and DPA (docosapentaenoic acid; another marine-derived omega-3 fatty acid) was associated with an approximately 9% lower risk of fatal coronary heart disease, while the sum of all three led to an 11% lower risk of fatal coronary heart disease. Furthermore, DPA levels (but not DHA or EPA levels) were associated with a significantly lower risk in the incidence of total coronary heart disease.

Italian researchers similarly found significant benefits in a meta-analysis of randomized placebo-controlled trials involving 11 studies administering at least 1 g/day of omega-3 fatty acids for one year or more to patients with existing cardiovascular disease.⁸ Overall, the trials included 15,348 individuals with a history of cardiovascular disease. While no statistically significant effects were seen for all-cause mortality or stroke incidence, the meta-analysis revealed strong protection against cardiac death, sudden death, and myocardial infarction, indicating that daily doses of omega-3 fatty acids above 1 g may be increasingly beneficial.

Furthermore, in a meta-analysis led by Luc Djoussé from Brigham and Women’s Hospital (Boston, MA), researchers looked at seven prospective studies to assess the impact of fish intake and omega-3 fatty acid intake relative to the incidence of heart failure.⁹ After analyzing the data from the identified studies (which in total included 176,441 individuals), the authors concluded that higher marine omega-3 intakes were associated with a significantly lower risk of heart failure.

Given positive evidence like this, in April 2015 the association the Global Organization for EPA and DHA Omega-3s (GOED; Salt Lake City) issued a statement summarizing the fact that 10 meta-analyses of gold-standard, randomized clinical trials published between 2006 and 2014 all showed significant effects of omega-3 consumption for reduced cardiac death risk.¹⁰ The range of risk reduction was impressive, varying between 9%–35%.

Of course, omega-3 fatty acids have been found to reduce additional risk factors for cardiovascular disease as well, including triglyceride levels and blood pressure.

Triglyceride Reduction
With regard to triglyceride reduction, a recent review indicated that omega-3 fatty acids (average dose of 4 g/day) consistently lowered triglycerides by a range of 25%-34% in placebo-controlled clinical trials.¹¹

In the United States, approximately 33% of the population has elevated triglyceride levels, which is considered an independent risk factor for cardiovascular disease. A current meta-analysis evaluated the effects of triglyceride-lowering on cardiovascular disease risk and found that lowered triglycerides are consistently associated with cardiovascular risk reductions, indicating a protective effect against cardiovascular events.¹²

Blood Pressure Reduction
In terms of blood pressure, Anne Minihane and colleagues in the United Kingdom recently conducted a retrospective analysis of data from a multicenter, placebo-controlled randomized clinical trial.¹³ During the trial, healthy men and women consumed fish oil containing 0.7 g or 1.8 g of EPA plus DHA daily for eight weeks. In those adults with isolated systolic hypertension, the 0.7-g dose led to clinically meaningful reductions in blood pressure averaging 5 mm Hg. The authors indicated that this magnitude of blood pressure reduction in middle-aged individuals is associated with an approximate 20% reduction in the risk of cardiovascular disease.

Bo Yang and colleagues from Zhejiang University (Hangzhou, China) conducted a meta-analysis of eight prospective cohort studies involving 56,204 adults and found that higher circulating levels of long-chain omega-3 fatty acids (and DHA in particular) were significantly associated with a lower risk of elevated blood pressure, indicating that optimal intake of omega-3s could potentially serve as a primary means of preventing hypertension.¹⁴

These findings are buttressed by an earlier meta-analysis of 70 randomized controlled trials, which indicated that supplementation with EPA and DHA led to significant reductions of systolic blood pressure, while higher doses (more than 2 g/day) also significantly reduced diastolic blood pressure.¹⁵

High blood pressure is a leading cause of stroke¹⁶, and decreases associated with consuming omega-3s could lead to clinically meaningful risk reductions in this area.

Reconciling Current Findings
Research supports the benefits of omega-3 fatty acids for reducing several risk factors associated with cardiovascular disease. Why, then, do some researchers find potential discrepancies when analyzing the data, and, more importantly, how does one go about reconciling the divergence between positive and negative findings? Some experts have postulated several reasons for the seemingly disparate results.

Differences in study populations certainly may play a role. Factors-including genetics, ethnicity, and background dietary intake of omega-3 fatty acids-all may have an impact on findings. In comparing the results of long-term clinical trials of omega-3s in western countries (which have often had neutral findings) to results from Japanese trials (which generally have positive findings), Akira Sekikawa of the University of Pittsburgh (Pittsburgh, PA) postulated that the doses used in the studies played a significant part and, importantly, that higher doses may be needed to ensure the greatest cardio-protective benefits. For example, the author, pointed out, dosages administered in the Japanese trials were generally higher than those in the western trials. In a recent trial in Japan showing a cardiovascular risk reduction of 19% with omega-3 fatty acid supplementation, the dose of omega-3 fatty acids given in the study was 1800 mg/day-this is in addition to the relatively high omega-3 dietary intake in the Japanese population of greater than 1,000 mg/day.¹⁷ By comparison, in western studies, the dose range was generally 300-900 mg of omega-3s per day, and the intake of omega-3s in western populations is generally less than 300 mg/day.

In recent intervention studies that have had neutral findings, another reason there may have been unfavorable results may be due to bioavailability issues associated with when the omega-3 supplements were administered. In a commentary on the discrepancies between recent intervention trials looking at cardiovascular risk reduction versus positive findings from epidemiologic studies, Clemens von Schacky from Ludwig-Maximilians-University (Munich, Germany) suggested that many of the intervention trials advised participants to consume their supplements with breakfast, which is often a low-fat meal.¹⁸ This could have significant impacts on omega-3 bioavailability because omega-3 absorption is dependent on the fat contained in foods and could partially explain the neutral findings. He advocated for new intervention trials to assess the real effect of omega-3s, keeping in mind the issue of bioavailability as well as controlling for the background dietary intake of study populations.

Jason Wu and Dariush Mozaffarian of the Harvard School of Public Health (Boston, MA) further speculated that another likely reason for neutral findings in recent studies versus older, positive trials may be the aggressive use of antihypertensive, lipid-lowering, and antiplatelet medications in later trials.¹⁹ Since many of the risk factors addressed overlap between the effects of these medications and the effects of omega-3 fatty acids (reduction of blood pressure, blood lipids, and circulation benefits), any additional effects of omega-3 fatty acids could have been masked by drug therapy. Researchers in the field should take these and other factors into account as they design further intervention trials assessing the benefits of omega-3s for cardiovascular health.

Plenty of Promise
In spite of the mixed findings of some recent trials, omega-3 fatty acids clearly play a role in cardiovascular wellness due to their mechanism of action on cardiovascular health parameters. Epidemiological studies consistently have shown positive associations with omega-3 supplementation, and clinical trial evidence from studies conducted around the world speaks to the impressive effects of omega-3 fatty acids on heart and vascular health.

Additional research will continue to provide specific evidence to assess the magnitude of omega-3’s true benefits. In the meantime, as supplement users consider the low risk associated with omega-3 supplementation and the potential upside of promoting heart health, increasing dietary and supplemental intake should make sense. These important nutrients remain a prudent choice for improving health and well-being.  

Also read:

2016 Omega-3 Market Update: Fish Oil, Krill Oil, Astaxanthin, and More

2016 Omega-3 Science Update

“Mixed Results” of Omega-3s for Cardiovascular Health in New Government Report

Adults Should Consume 500 mg EPA and DHA Omega-3s Daily, GOED Says

Disclosures:

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• O’Connor, Anahad, “Fish Oil Claims Not Supported by Research,” The New York Times, March 30, 2015. Available at http://well.blogs.nytimes.com/2015/03/30/fish-oil-claims-not-supported-by-research/?_r=1. Accessed October 17, 2016.
• Whoriskey, Peter, “Fish Oil Pills: A $1.2 Billion Industry Built, So Far, on Empty Promises,” The Washington Post, July 8, 2015. Available at https://www.washingtonpost.com/business/economy/claims-that-fish-oil-boosts-health-linger-despite-science-saying-the-opposite/2015/07/08/db7567d2-1848-11e5-bd7f-4611a60dd8e5_story.html. Accessed October 17, 2016.
• Agency for Healthcare Research and Quality. “Omega-3 Fatty Acids and Cardiovascular Disease: An Updated Systematic Review-Research Report-Final | AHRQ Effective Health Care Program.” Available at https://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=2262. Accessed October 17, 2016.
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• Djoussé L et al., “Fish consumption, omega-3 fatty acids and risk of heart failure: a meta-analysis,” Clinical Nutrition, vol. 31, no. 6 (December 2012): 846–853
• Global Organization for EPA and DHA Issues Statement Reiterating Heart Health Benefits of Omega-3s | Business Wire. Available at http://www.businesswire.com/news/home/20150403005150/en/Global-Organization-EPA-DHA-Issues-Statement-Reiterating#.VR7UZvnF91Z. Accessed October 17, 2016.
• Ito MK, “Long-chain omega-3 fatty acids, fibrates and niacin as therapeutic options in the treatment of hypertriglyceridemia: a review of the literature,” Atherosclerosis, vol. 242, no. 2 (October 2015): 647–656
• Maki KC et al., “Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia,” Journal of Clinical Lipidology, vol. 10, no. 4 (July–August 2016): 905–914
• Minihane AM et al., “Consumption of fish oil providing amounts of eicosapentaenoic acid and docosahexaenoic acid that can be obtained from the diet reduces blood pressure in adults with systolic hypertension: a retrospective analysis,” The Journal of Nutrition, vol. 146, no. 3 (March 2016): 516–523
• Yang B et al., “Fish, long-chain n-3 PUFA and incidence of elevated blood pressure: a meta-analysis of prospective cohort studies,” Nutrients, vol. 8, no. 1 (January 21, 2016)
• Miller PE et al., “Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials,” American Journal of Hypertension, vol. 27, no. 7 (July 2014): 885–896
• Stroke and High Blood Pressure. Available at http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/WhyBloodPressureMatters/Stroke-and-High-Blood-Pressure_UCM_301824_Article.jsp#.WAQaocnG-mp. Accessed October 17, 2016.
• Sekikawa A et al., “Recent findings of long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFAs) on atherosclerosis and coronary heart disease (CHD) contrasting studies in Western countries to Japan,” Trends in Cardiovascular Medicine, vol. 25, no. 8 (November 2015): 717–723
• von Schacky C et al., “Omega-3 fatty acids in cardiovascular disease-an uphill battle,” Prostaglandins Leukotrienes, and Essential Fatty Acids, vol. 92 (January 2015): 41–47
• Wu JHY et al., “Ω-3 fatty acids, atherosclerosis progression and cardiovascular outcomes in recent trials: new pieces in a complex puzzle,” Heart, vol. 100, no. 7 (April 2014): 530–533