Today, most people know that the omega-3 fatty acids, such as are found in cold-water fish, are good for us. In fact, these are among the “stars players” of health supplements. The omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) have been widely studied in connection with cardiovascular, joint, immune and brain health. Numerous scientific findings have demonstrated that omega-3 fatty acids are important for a healthy inflammatory response. In fact, research on omega-3s is so compelling that the FDA has granted a qualified health claim to the effect that consuming omega-3s reduces the risk of heart disease. For more than a decade, many of the benefits of omega-3 fatty acids have been largely beyond reasonable doubt. This year, that certainty has been called into question.

Publications from early 2015 challenge, or at least appear to challenge, two of the most important assertions often made for omega-3 fatty acid supplementation. These are the assertion that fish oils are valuable assets in reducing key components of cardiovascular disease and the assertion that these oils are useful supplements for preventing cognitive decline. The first shoe fell on March 31 with the publication in the New York Times of the essay, “Fading claims on fish oils.” This article was quite direct in judging that “no evidence that fish oil lowers risk for heart attack or stroke” has been found according to the majority of clinical trials that have been conducted on the topic.

The second shoe fell on August 26 in the form of a Newsweek article entitled “Omega-3 Supplements Are a Waste of Money.” The basis of this judgment was a medical study published in August 2015 in which the authors Chew et al. concluded, “oral supplementation with LCPUFAs (long-chain polyunsaturated fatty acids) … had no statistically significant effect on cognitive function.” 1 The same research group the previous year, based on the same trial design and data, had concluded that omega-3 supplementation “did not reduce the risk of CVD in elderly participants with age-related macular degeneration.” 2 This study, dubbed AREDS2, was a large double-blinded randomized study involving more than 4,000 subjects in its overall design and lasting approximately five years. On the surface, the results appear to be definitive. As often is the case, however, appearances can be deceiving.

The latest studies are not always the best or the most definitive studies despite the breathless hype so often found in the popular press. As usual, the devil is in the details with both of the negative judgments in the above paragraphs. The following sections provide a bit of guidance for the perplexed.

Omega-3s versus Cardiovascular Disease

In evaluating the findings of clinical trials, it is necessary to consider a range of questions regarding the basis and the aims of the trials in question. For instance, was a given trial performed in the right subject population to support its conclusions? The AREDS2 study mentioned above for its CVD conclusions used a population of participants who were “primarily white, married, and highly educated, with a median age at baseline of 74 years” that included “participants with stable, existing CVD (>12 months since initial event)” to determine a “composite outcome of myocardial infarction, stroke, and cardiovascular death…” “Approximately 19% had a history of CVD; 44% reported taking a statin medication; and 14% reported taking any type of medication for congestive heart failure, CVD, or cerebrovascular disease.” Several issues should be flagged immediately with this study population.

First, it was a group that might be expected to already have adopted dietary changes, such as eating fish two or more times per week and preferring olive oil for cooking and salads, that would have reduced the impact of supplementation with additional omega-3 oils. The average American may eat a diet highly unbalanced in the ratio of omega-3 to omega-6 fatty acids, high in saturated fats and low in magnesium, low in vegetables and fiber, etc., but the study population would have been much less likely to be following the standard American diet. Did the researchers check? Not as far as I could tell from reading the methods section. My suspicion is that a substantial percentage of the subjects already were consuming considerable omega-3 fatty acids in their diets and already had adopted a more healthful ratio of omega-3 to omega-6 fatty acids than is true of most Americans.

Second, 44 percent of the study group already was taking a statin medication and 14 percent (whether overlapping the statin takers is not indicated, but the implication is “not”) were taking other CVD medications. In other words, this was not a medically “naïve,” i.e., pharmaceutically untreated, starting population. The researchers in AREDS2 did try to control for some of these issues (see Figure 3 in the study), yet their data in this regard are a bit odd. Despite the non-significance of the statistics regarding the number of cardiac events between omega-3 and non-omega-3 arms with regard to, say, statin use, there were statistically significant differences between the arms involving hypertension history (a proven benefit of omega-3 supplementation, P = 0.02) and cardiovascular disease history (P = 0.04) implying a medical treatment effect not captured in the write-up. The authors, by the way, do admit the data that I mention imply potential benefit from omega-3 supplementation, but then try to explain this away without pursuing the implications regarding their collected data and its reliability regarding the impact of medications and lifestyle changes.

Another issue involves the endpoints selected for evaluating the outcome of a study. Surely, the meta-analyses have been conducted to evaluate the quite massive volume of clinical research, which has been performed with omega-3 fatty acids. This research consistently has found that fish oil consumption reduces cardiac death risk between approximately 10 and 30 percent with a low of nine percent and a high of 35 percent.3 These figures surely are not bad for a simple and safe dietary supplement!

With regard to other important CVD risk factors, omega- 3s have been found to consistently perform well. Omega-3 supplementation reduced blood pressure in studies in the general population approximately 4.5 mm Hg, which similar to lifestyle changes, including reduced intake of dietary sodium, increased physical activity and a reduction in excessive alcohol consumption. High fasting triglycerides were reduced by 30– 40 percent, yet another healthful change.4

Again, it must be remembered that study populations are important for outcomes. If one focuses on populations with advanced cardiovascular disease, this will be quite misleading with regard to the benefits of taking a nutrient, in this case, omega-3 fatty acids, over a significant period of time starting before the disease has manifested. This, of course, is precisely the role of supplements as opposed to drugs. The New York Times article applied the wrong model and created a controversy by doing so.

Omega-3s and Cognition

Let’s return to the citation above in which Chew et al. concluded, “oral supplementation with LCPUFAs (long-chain polyunsaturated fatty acids) … had no statistically significant effect on cognitive function.” The authors actually state in another spot, “Contrary to popular belief, we didn’t see any benefit of omega-3 supplements for stopping cognitive decline.”

The study by Chew et al. refers to its experimental supplementation as a “high dose,” yet the truth is that only 350 mg of the dose was DHA and the other 650 mg was EPA. This matters because these two omega-3 fatty acids do different things. To combat depression, which the AREDS2 study did not examine, EPA is the more significant nutrient. Trials using a mixture of the two mostly have been successful.5 Nevertheless, in a face-off of the two omega-3 fatty acids, EPA is the stronger anti-inflammatory in the brain and may deliver better results against depression.6

For cognition, the reverse is true: DHA outperforms EPA. This should not come as a surprise given that DHA plays a major structural role in brain cellular membranes and in the neurologic system more generally. In a study of 22 healthy adults, 12 weeks of daily dietary supplementation with either 1 g DHA-rich or 1 g EPA-rich fish oil (FO) or placebo (1 g olive oil) were assessed with the result being that DHA consumption leads to greater blood flow and activity in the prefrontal cortex during cognitive tests than does EPA.7 In older adults, episodic memory outcomes in adults with mild memory complaints are improved with the intake of greater than 1 gram DHA/EPA per day.8 In other words, the study by Chew et al., focused on the wrong omega-3 fatty acid to better influence cognition and was below an accepted threshold for the dosage for some aspects of cognition and memory.

To be fair to Chew et al., their trial was designed before papers became available that demonstrated that higher dosages of DHA and/or DHA/EPA improved cognition and memory, whereas lower dosages did not. A clarifying discussion of the issues involved has been published under the title “Omega-3s and Cognition: Dosage Matters.”9 For those interested in pursuing this issue further, a table of relevant papers can be downloaded from http://goedomega3.com/files/download/334/memory-and-cognitive-functionpapers-table.pdf.

Conclusion
The misleading conclusions of the New York Times article on fish oils and cardiovascular disease and the Newsweek article on DHA and cognition are cautionary tales regarding the interpretation of studies. In reality, adequate intakes of omega-3 fatty acids reduce CVD mortality by 10 to 30 percent, although supplementation may not deliver this same degree of benefit in populations already suffering from active CVD, already taking numerous medications or already having adopted appropriate diet and lifestyle modifications. Similarly, DHA supplementation significantly improves some aspects of cognition and memory, but only at intake levels above 1 gram per day in older individuals. Younger adults may benefit from 1 gram mixed DHA/EPA with the proviso still in place that for this purpose DHA is more active than is EPA whereas for depression, the opposite is true.

Endnotes:

  1. 1. Chew EY, Clemons TE, Agron E, Launer LJ, Grodstein F, Bernstein PS; Age-Related Eye Disease Study 2 (AREDS2) Research Group. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. JAMA. 2015 Aug 25;314(8):791.801.
  2. 2. Writing Group for the AREDS2 Research Group, Bonds DE, Harrington M, Worrall BB, Bertoni AG, Eaton CB, Hsia J, Robinson J, Clemons TE, Fine LJ, Chew EY. Effect of long-chain ƒÖ-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA Intern Med. 2014 May;174(5):763.71.
  3. 3. Ismail A. The real story of omega-3s in heart health. April 3, 2015. http://goedomega3.com/index.php/blog/2015/04/the-realstory-of-omega-3s-in-heart-health
  4. 4. Ibid.
  5. 5. Yang JR, Han D, Qiao ZX, Tian X, Qi D, Qiu XH. Combined application of eicosapentaenoic acid and docosahexaenoic acid on depression in women: a meta-analysis of double-blind randomized controlled trials. Neuropsychiatr Dis Treat. 2015 Aug 10;11:2055.61.
  6. 6. Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr. 2009 Oct;28(5):525.42.
  7. 7. Jackson PA, Reay JL, Scholey AB, Kennedy DO. DHA-rich oil modulates the cerebral haemodynamic response to cognitive tasks in healthy young adults: a near IR spectroscopy pilot study. Br J Nutr. 2012 Apr;107(8):1093.8.
  8. 8. Yurko-Mauro K, Alexander DD, Van Elswyk ME. Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One. 2015 Mar 18;10(3):e0120391.
  9. 9. Ismail A. Omega-3s and Cognition: Dosage Matters. August 31, 2015. http://goedomega3.com/index.php/blog/2015/08/omega-3s-and-cognition-dosage-matter

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