FOR THE TWELVE DAYS OF CHRISTMAS MY TRUE LOVE CHALLENGED THE CONCLUSION OF THE 2012 JAMA META-ANALYSIS, WHICH IMPLIED THAT OMEGA 3 FISH OIL WAS BASICALLY USELESS
On the first day of Christmas, my true love pondered…
Of all the supplements out there, fish oils are one of the best accepted and most widely used because the research on it is so plentiful and compelling. Modern man has flipped the intake of “good” anti-inflammatory omega 3 fatty acids with “bad” pro-inflammatory omega 6 fatty acids, not unlike how we’ve negatively flipped intake of potassium and sodium. (We’re the only mammals to accomplish this feat!) In 2009 Harvard School of Public Health estimated that omega 3 deficiency contributed to 84,000 US deaths per year!1 And interestingly, according to CDC/NHANES data, those most likely to be severely deficient are heart failure patients!
But on the second day of Christmas, my true love exclaimed: The Rizos, et al., meta-analysis concluded that, “Overall, omega-3 polyunsaturated fatty acid (PUFA) supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.” 2 Whaaaa?
So, on the third day of Christmas, my true love asked: What is wrong with that Journal of the American Medical Association (JAMA) omega 3 fish oil meta-analysis?
On the fourth day of Christmas, my true love noted that the dosage of fish oil used in at least 20% of the trials was LESS than 900mg EPA/DHA per day. I mean, seriously. This is not a sufficient amount to achieve good therapeutic benefit.
On the fifth day of Christmas, my true love also noted that the placebo used in at least 30% of the trials was OLIVE OIL, which has been demonstrated to be anti-inflammatory and cardio-protective. Olive oil is rich in polyphenols, among other heart-healthy compounds.3 (If the placebo shows benefit — it’s supposed to be totally neutral — that will make the fish oil appear to be less beneficial than we know it to be.)
On the sixth day of Christmas, my true love commented that the Rizos, et al., meta-analysis includes only those individuals who have already sustained a major cardiovascular event and are on medications. It’s not a clean investigation in that regard, as drug/nutrient interaction possibilities must be taken into consideration. Additionally, limited nutrient interventions — such as only using fish oil — as an attempt to influence late-stage cardiovascular disease, is likely to be insufficient to turn around the course of the disease. This brings to mind the SEARCH trial which looked at B12 and folate in those having sustained a myocardial infarction.4 The outcome was similarly underwhelming. One criticism levied against SEARCH was that the vitamin intervention, although it did modestly reduce homocysteine levels, was “too little too late.”
And on the seventh day of Christmas, my true love mentioned that it is also interesting that the P value used in the meta-analysis was set at an inexplicably low 0.0063. (This basically means it’s needle-in-the-haystack hard for this study to have achieved significance. Generally, p-values are 0.05, which is a whole order of magnitude higher!) As the National Lipid Association pointed out, “There really isn’t a good discussion as to why the authors made this choice, which makes accepting the conclusions difficult.”
On the eighth day of Christmas, my true love exclaimed: Why on God’s earth was the Alpha Omega Trial (AOT) included in this meta-analysis? Honestly, people! The AOT used different combinations of polyunsaturated margarines, analyzed collectively and shown to be ineffective in reducing the rate of cardiovascular events. Some of the margarines had very, very low amounts of EPA/DHA, and ALL of the margarines contained heart-toxic trans fatty acids!5
And on the ninth day of Christmas, my true love was like, HEY! Why do supplement trials with negative results get such publicity? There is a well-documented historical bias towards supplements and integrative medicine in general from the greater medical community, but many of the researchers conducting these massive government-sponsored supplement trials speak of their disappointment with outcome. The researchers are hoping to demonstrate the benefits of the nutrients we eat in food. However, the study designs are usually pretty simplistic in an effort to control variables (for example, only one or two supplements are used), which means these trials are more likely destined for poor outcome. The need to control variables is the cornerstone of the scientific method, but it’s just not a great model for studying nutrients. The emerging Systems research models are better suited for multi-variable, high complexity investigations.
On the tenth day of Christmas, my true love mentioned to me that information about the quality of the fatty acids used in the trials isn’t readily available. Quality can make a significant difference in outcome. These delicate fats can become oxidized. And there is the potential for problem contaminants (PCBs, toxic metals) if the product is of lower quality. Additionally, there is a big difference in the bioavailability of EPA + DHA as ethyl esters versus re-esterified triglycerides, where the former is far less efficiently absorbed and utilized than the latter; and such a difference must be compensated for by using a higher total dose of ethyl esters. (Which I never see happen, do you?)
On the eleventh day of Christmas, my true love revealed: One of my favorite papers looking at EPA+DHA was in rheumatoid arthritis patients. It was a meta-analysis that demonstrated that pain reduction with as little as 2.5 grams of EPA + DHA per day was as effective as Humira! They also showed that up to 4.5 g/day was associated with a high rate of remission. The take-home of this meta-analysis is clear: Get all your RA patients on 2.5 grams now!6 (With adequate antioxidants, of course.)
On the twelfth day of Christmas, my true love waxed theoretical: Omega 3 fatty acids are needed by most of us, and generally in much higher quantity than we are getting. New research on the mechanisms of their efficacy is always emerging and very fascinating. For instance, there are new classes of “atypical” eicosanoids and decosanoids being discovered that actually resolve the inflammatory process; that is, they clean up after the inflammatory event. Newer thinking is that “inflammation is a failure of resolution.” 7 Because bioavailability of PUFA can vary widely from person to person, evaluating appropriate biomarkers, such as RBC fatty acids, can be very useful to gauge status both pre- and post-supplementation.
In conclusion, my true love has convinced me… fish oil for all this Holiday season!
1. Danaei G, Ding EL, Mozaffarian D, et al. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med. Apr 28 2009;6(4):e1000058.
2. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. Jama. Sep 12 2012;308(10):1024-1033.
3. Stark AH, Madar Z. Olive oil as a functional food: epidemiology and nutritional approaches. Nutr Rev. Jun 2002;60(6):170-176.
4. Armitage JM, Bowman L, Clarke RJ, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. Jama. Jun 23 2010;303(24):2486-2494.
5. Kromhout D, Giltay EJ, Geleijnse JM. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. Nov 18 2010;363(21):2015-2026.
6. James M, Proudman S, Cleland L. Fish oil and rheumatoid arthritis: past, present and future. Proc Nutr Soc. Aug 2010;69(3):316-323.
7. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. May 2008;8(5):349-361.
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