On July 8, the Washington Post published an article entitled “Fish oil pills: A $1.2 billion industry built, so far, on empty promises” (1). I could have sworn I read essentially the same article in the New York Times on March 8 (2). Apparently the writers at the Washington Post don’t read the New York Times, so let me share some of the important details so you'll know the facts once and for all.
The benefit of using fish oil in treating heart disease comes from its ability to alter inflammation. The leading experts in cardiovascular medicine all agree that inflammation is a powerful driver in heart disease; therefore, its reduction is probably a good thing. This is why every cardiologist recommends aspirin, (which doesn’t lower cholesterol) to help prevent a second heart attack (this is called secondary prevention). Unfortunately, their knowledge of inflammation in making that recommendation is somewhat primitive.
There are two distinct phases of inflammation. The first phase is the initiation of inflammation. The other phase is the resolution of inflammation (3). You need them both to be balanced to operate your inflammatory system with peak efficiency. In other words, you have to be able to turn on and turn off the inflammation response to lead a healthy life. Anti-inflammatory drugs, such as aspirin and even statins (they also have anti-inflammatory effects), slow down the initiation of inflammation. (Wait a minute. Aren’t aspirin and statins used in treating heart disease?) Unfortunately, they also inhibit the resolution phase of inflammation. This means that the initial inflammatory response continues to cause damage but at a lower level of intensity. That is why anti-inflammatory drugs (especially the non-steroid anti-inflammatory drugs) have side effects. In fact, the FDA just announced new, tougher labeling on over-the-counter anti-inflammatory drugs because of their increased risk of heart attack and stroke.
The reason why drugs are classified as drugs is because they have toxic side effects. Furthermore, there is a narrow dose range in which they actually work. If you take a placebo dose of a drug, you can expect to get placebo effects. If you take a toxic dose of the same drug, you expect to get toxic effects. Each drug has a zone that has some therapeutic benefits with hopefully tolerable side effects.
The quoted meta-analysis study from JAMA Internal Medicine showed that 22 out 24 studies demonstrated no benefit (but also no toxicity) (4). The reason was because virtually all the studies mentioned (except one that I will get to later) used in the analysis were using placebo levels of omega-3 fatty acids. As a result, the levels were not sufficient not only not to reduce the initiation of inflammation, but also too low to promote increased resolution.
So what’s a therapeutic amount of fish oil? In my opinion, the minimum amount would be the level required to reduce the arachidonic acid (AA) to eicosapentaenoic acid (EPA) ratio to the level known to reduce the generation of inflammatory cytokines. The AA/EPA ratio that reduces cytokine formation appears to be less than 3.
The first study to demonstrate this was done by Harvard Medical School researchers some 25 years ago and published in that rather obscure journal known as the New England Journal of Medicine (5). This study measured the levels of inflammatory cytokines, and in particular tumor necrosis factor (TNF) that are released by cells when they are inflamed. The starting levels of the subjects in that study had an AA/EPA ratio of 21, and after 10 weeks of taking 5 grams of omega-3 fatty acids per day, their average AA/EPA ratio dropped to 2.4. However, with that decreased AA/EPA ratio came a significant drop in TNF levels. Keep in mind three of the top-ten selling drugs of all time are injections of anti-TNF antibodies (Humara, Enbrel, and Remicade) to treat rheumatoid arthritis, and their reduction of TNF is about the same level as demonstrated in this Harvard study some 25 years ago. The sale of these injectable drugs to treat rheumatoid arthritis was about $25 billion dollars in 2012. So unless you are taking at least 5 grams of omega-3 fatty acids per day, you will be taking a placebo dose for reducing the initiation of inflammation in cardiovascular disease.
However, reducing the initiation of inflammation is only part of the story. The more intriguing benefit of high-dose fish oil is its ability to increase the resolution of inflammation. This is accomplished by the generation of a unique class of hormones known as resolvins. These resolvins are primarily generated from omega-3 fatty acids, but only if you have adequate levels in the blood. Again, the AA/EPA ratio can guide you if you have high enough levels to increase resolvin synthesis. If you can get the AA/EPA ratio even lower to about 1.5, then resolvin synthesis increases; however, to get your AA/EPA ratio to those levels requires even more fish-oil consumption.
Yet at this lower AA/EPA ratio almost magical things begin to happen. We know this from studies from an animal model known as the fat-1 mouse. This animal model has been genetically modified to convert omega-6 fatty acids into omega-3 fatty acids so that the AA/EPA ratio in these animals is approximately 1. These genetically modified animals appear to be dramatically resistant to developing chronic diseases associated with inflammation, such as diabetes, heart disease, and Alzheimer’s (6-8). You don’t need a gene transplant to the give the same benefits as you can achieve the same AA/EPA ratio by taking enough fish oil.
Also overlooked in this fish-oil bashing article is that there is a FDA-approved prescription omega-3 fatty acid drug for treating cardiovascular disease (elevated triglyceride levels) that has sales far greater than $1.2 billion quoted for the fish-oil products sold in health-food stores. I guess these prescription drugs are popular with physicians for their patients. Perhaps some one at the Washington Post should inform the FDA that they have approved a bogus drug. However, to get to 5 grams of omega-3 fatty acids per day using this approved drug would take about 6 capsules per day. To get to an even lower AA/EPA ratio to increase resolution, requires even more (9). Even through there is an FDA-approved drug that can do that, it is unlikely your insurance company will pay for it.
Besides studies with fat-1 mice, what clinical data exists indicates that lowering the AA/EPA ratio is important in cardiovascular disease, especially by making it less likely you are going die from a heart attack. Let me use some data from my earlier blog (Part 1) that compared mortality from heart disease in 2004 versus various cardiovascular parameters in both Japanese and America male populations (10).
| CHD Parameter | Japanese | Americans |
| Total Cholesterol (mg/dl) | 218 | 213 |
| LDL Cholesterol (mg/dl) | 132 | 135 |
| Smokers | 49% | 8% |
| AA/EPA ratio | 2.6 | 11 |
| CHD Mortality (per 100,000) | 46.2 | 160 |
Keep in mind by 2004 the use of statins and aspirin (both anti-inflammatory drugs) to treat heart disease were in full force in both countries. Yet somehow the dramatic reduction in CHD mortality in Japan compared to the United States seems be far better correlated with the differences in the AA/EPA ratio than cholesterol levels (unless you want to make the assumption that smoking decreases heart disease mortality).
Maybe the Japanese are simply genetically protected against heart disease. That was dismissed with one of the largest cardiovascular trials ever done, the JELIS study (11). This is one cardiovascular trial that had a benefit, according to the article in JAMA Internal Medicine (4). So what made this exceptionally large trial so successful whereas all the others mentioned in that article were not? This particular trial had 18,000 Japanese all taking statins. In essence, statins were the placebo. Half these subjects took a large daily dose of EPA, and the other half an equivalent amount of olive oil. The average AA/EPA ratio of both groups at the start of the study was 1.6. At the end of 3 1/2 years the Japanese taking both statins and extra EPA decreased their AA/EPA ratio to 0.8 and had 20% fewer cardiovascular events than the Japanese taking statins and olive oil and whose AA/EPA ratio remained at 1.6. Based on one of the largest cardiovascular trials ever done and in the era of “evidence-based medicine”, it should be considered bad medicine if a doctor didn’t prescribe extra omega-3 fatty acid with statins. Maybe that is why prescription sales of omega-3 fatty acid drugs are so high.
A little additional homework done by searching Pub Med (the free national medical database) provides many recent references demonstrating the decrease in the AA/EPA ratio consistently generates improvement of cardiovascular conditions (12-16). Or they could have simply read my book The OmegaRx Zone, which started the exponential growth in fish oil sales in America when it was published in 2002 (17.) But the only way you can decrease the AA/EPA ratio (especially for Americans) is to take large doses of omega-3 fatty acids, much larger than in any of the studies cited (except for the JELIS study).
Bottom line is unless you get your AA/EPA ratio into a therapeutic zone (between 1-3), you will never see any cardiovascular benefits because you are using a placebo dose of omega-3 fatty acids. If you are starting from a relatively low AA/EPA ratio, it doesn’t take as much omega-3 fatty acids to bring you into that therapeutic zone compared to the amount you would need if you were starting from a higher AA/EPA ratio. Since the average AA/EPA ratio in Americans is about 18 (18), it will take a lot of fish oil to bring the AA/EPA ratio in Americans down to the minimum AA/EPA ratio of 2.5 where you will start to see cardiovascular benefits.
When you give a placebo level of fish oil, you can expect placebo effects. Considering that heart disease is still the number-one killer of Americans, perhaps based on the “evidence-based medicine” coming from the JELIS study and other studies on the role of the AA/EPA ratio in treating heart disease, we should be suggesting that Americans should be taking a therapeutic dose of fish oil to get our death rates near those of the Japanese instead to writing articles for the general audience based on flawed studies that gave placebo doses and somehow generated placebo results.
Revisit: Fish Oil & Heart Disease: The Real Facts (Part 1 of 2)
References:
- Whoriskey P. “Fish oil pills: A $1.2 billion industry built, so far, on empty promises. Washington Post. July 8, 2015.
- O’Connor A. “Fish oil claims not supported by research.” New York Times. March 30, 2015.
- Serhan CN. “Pro-resolving lipid mediators are leads for resolution physiology.” Nature 510:92-101 (2014).
- Grey A and Bolland M. “Clinical trial evidence and use of fish oil supplements.” JAMA Internal Medicine 174:460-462 (2014).
- Endres S et al. “The effect of dietary supplementation with n-3 polyunsaturated acids on synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” New Engl J Med 320:265-271 (1989).
- Bellenger J et al. “High pancreatic n-3 fatty acid prevent STZ-induced diabetes in fat -1 mice.” Diabetes 60:1090-1099 (2011).
- Wan JB et al. “Endogenously decreasing tissue n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apolipoprotein E-deficient mice by inhibiting systemic and vascular inflammation.” Arterioscler Thromb Vasc Biol 30:2487-2494 (2010).
- Lebbadi M et al. “Endogenous conversion of omega-6 into omega-3 fatty acids improves neuropathology in an animal model of Alzheimer’s disease.” J Alzheimer’s Dis 27:853-869 (2011).
- Yee LD et al. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91:1185-1194 (2010).
- Sekikawa A et al. “Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanese, Koreans, and Americans.” Prostaglandins Leukot Essent Fatty Acids 87:11-16 (2012).
- Yokoyama M et al. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis.” Lancet 369:1090-1098 (2007).
- Hasegawa T et al. “Serum n-3 to n-6 polyunsaturated fatty acids ratio correlates with coronary plaque vulnerability: an optical coherence tomography study. Heart Vessels 29:596-602 (2014).
- Domei T et al. “Ratio of serum n-3 to n-6 polyunsaturated fatty acids and the incidence of major adverse cardiac events in patients undergoing percutaneous coronary intervention.” Circ J 76:423-429 (2012).
- Hayakawa S et al. “Association of plasma n-3 to n-6 polyunsaturated fatty acid ratio with complexity of coronary artery lesion.” Intern Med 51:1009-1014 (2012).
- Ninomiya T et al. “Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: the Hisayama Study.” Atherosclerosis 231:261-267 (2013).
- Fontani G et al. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with Omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35:499-507 (2005).
- Sears B. “The OmegaRx Zone”. Regan Books. New York, NY (2002).
- Harris WS et al. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88:257-63 (2013).
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