Last month we discussed the latest research on the omega-6 fat linoleic acid with Dr. William Harris. Now we will look at the completed dietary fat picture and at the latest research on balancing omega-6 fats with optimal amounts of omega-3 fat. Dr. Harris has published his research on both omega-3 and omega-6 fats this year. We’ll begin with the latest research on the omega-3 fats EPA and DHA and cardiovascular disease.
Dr. William Harris is one of the world’s leading omega-3 fat researchers. He holds a Ph.D. in nutritional biochemistry from the University of Minnesota and began his omega-3 research in 1979 as a post-doctoral fellow in the laboratory of William Connor, M.D., at the Oregon Health Services University (Portland). Dr. Connor was a leading researcher at the time in nutrition, lipids (fats) and heart disease. Dr. Harris’ early research centered on the possible effects of large quantities of salmon oil on blood cholesterol.
Dr. Harris was the director of the Lipid Research Laboratories at the University of Kansas Medical Center (KUMC) and at the Mid America Heart Institute, both in Kansas City, MO, for 22 years, and was on the faculty at KUMC and at the University of Missouri-Kansas City School of Medicine. Between 2006 and 2011, he was the Director of the Cardiovascular Health Research Center at Sanford Research/USD (Sioux Falls, SD).
Dr. Harris’s research has focused primarily on omega-3 fatty acids and cardiovascular disease. He has been the principal investigator on five omega–3-related NIH grants, and is currently evaluating omega-3 blood tests as a possible new risk factor for cardiovascular disease. In 2004, he and his colleague Clemens von Schacky proposed that the Omega-3 Index be considered as a new cardiovascular risk factor, and in 2009, he founded OmegaQuant Analytics, LLC to offer the test commercially. He retains an academic appointment as professor of medicine at the Sanford School of Medicine, University of South Dakota in Sioux Falls and serves as the Chief Scientific Officer for OmegaQuant.
Over the years, Dr. Harris has published many major research articles and reviews on the marine lipids, EPA and DHA. A major discovery of Dr. Harris and his colleagues has been the elucidation of the Omega-3 Index as a risk factor in cardiovascular disease.
Dr. Harris’ leadership role in omega-3 research was the reason that Dr. Jørn Dyerberg (the discoverer of fish oil’s role in reducing cardiovascular risk) and I asked Dr. Harris to write the foreword to our 2012 book, “The Missing Wellness Factors: EPA and DHA” (Basic Health Publications, Laguna Beach, CA) (1).
Although during his career, he has focused on omega-3 fatty acids, Dr. Harris has also conducted research on the health effects of other families of fatty acids, notably trans fats and the cousins to the omega-3s, the omega-6 fatty acids. As regards the latter, he was the lead author on the American Heart Association’s 2009 Science Advisory on Omega-6 Fatty Acids and Cardiovascular Health (2). Dr. Harris was a member of the research team that just published a new study on the long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which will be the focus of this interview (3).
Passwater: Dr. Harris, there were three studies on EPA/DHA on cardiovascular disease published in late 2018 that were particularly interesting. One examined omega-3 fats on the risk for heart disease specifically in patients with diabetes (4). Dr. Harris, what can we conclude from this study?
Harris: This study was called, “A Study of Cardiovascular Events in Diabetes (ASCEND).” It randomized around 14,500 diabetic patients to either 1 capsule per day of Lovaza (omega-3 acid ethyl esters, GlaxoSmithKline; which provided 840 mg/day of EPA+DHA) or of a placebo oil, and then followed them for cardiovascular events over 7.4 years. The “primary” endpoint was what we call a “composite” measure, consisting of 1) non-fatal heart attack or stroke, 2) transient ischemic attack (mini-stroke), or 3) death from some vascular disease (heart attack or stroke or other). So, if any of these things happened to any participant during the study, it counted as one event. What did they find? First, there was no effect of treatment with Lovaza on the primary composite endpoint; therefore, the authors concluded (and the press reported) that “omega-3s didn’t work” in diabetic patients to reduce risk for heart and vascular disease. Unfortunately, this was a very limited view of the study outcomes. It is true that Lovaza had no effect on #1 or #2, but there was a statistically significant 19% reduction in #3—vascular fatalities. So although the authors concluded “no effect,” actually there was an effect—and a very important effect: reduced death from vascular disease. It is this kind of slavish attention only to the “primary endpoint” (which was chosen and defined before the study started) that often causes “failures” in omega-3 trials. Basically, the researchers box themselves in and say, “if fish oil doesn’t work on X, then it just doesn’t work—period.” Obviously, this can be very misleading.
Passwater: Then there was the study by Dr. JoAnn Manson and colleagues that examined the effects of omega-3 on both cardiovascular disease and cancer (5). What did this study teach us?
Harris: Yes, the “VITamin D And omega-3 triaL” (VITAL) was another study reported out in late 2018 that examined the effects of EPA+DHA omega-3 (and vitamin D)—each alone or in combination—on cardiovascular disease (CVD) and cancer. It included over 25,000 subjects, all without known CVD or cancer at baseline. This fact makes VITAL the first truly “primary prevention” study of omega-3 (or vitamin D for that matter) in CVD and cancer. “Primary prevention” means that the intent is to see if treatment will reduce risk for the first evidence of CVD or cancer; “secondary prevention” means that everyone in the study has already been diagnosed with either CVD or cancer, and the research question is, “can treatment prevent a recurrence of disease?”
The omega-3 arm of the study provided, as did ASCEND, one capsule per day of Lovaza (ethyl esters of the omega-3 fatty acids EPA and DHA found in fish oil) or a placebo. Also, like ASCEND, the primary CV endpoint was a composite—this time of 1) heart attack, 2) stroke, or 3) death from CV causes (or the development of cancer). The study lasted about 5 years. Again, the researchers reported this as a “no-effect” trial for both cancer and CV disease. There was no ambiguity about the non-effect in cancer, but the story with CV disease is more interesting. True, the combined CV primary endpoint was not significantly reduced, but if we look more carefully, we find some important benefits. For example, the risk for a heart attack was statistically significantly reduced by 28%, risk for any CV disease diagnosis was 17% lower, and risk for a fatal heart attack was 50% lower in the omega-3 group. Not surprisingly, it was people who reported lower background fish intake that benefited the most. A very surprising finding, and one that definitely needs to be re-tested in another study, is that African American subjects had a 77% reduction in heart attacks when taking Lovaza. So again, there were clear benefits of omega-3 treatment, but the headlines focused only on the “primary” endpoint, and if that isn’t affected, then “there was no effect.” Very unfortunate way to report the results of such a large trial.
Passwater: The third of this trio investigated the effects of EPA alone (not EPA+DHA like ASCEND and VITAL) on CV disease (6). What did they find?
Harris: REDUCE-IT (short for “Reduction of Cardiovascular Events with Icosapent Ethyl—Intervention Trial”) included about 8,000 individuals. These patients were all taking statin drugs (to lower their cholesterol) and had either a history of CV disease or had major risk factors for it. They all also had mildly elevated serum triglyceride levels. The trial lasted 4.9 years. Patients were assigned to take either 4 capsules per day of Vascepa (icosapent ethyl, which is another name for EPA ethyl esters; Amarin Corp.) or a mineral oil placebo. The investigators reported that the primary endpoint—major adverse CV events—was significantly reduced by 25%. This is by far the highest-dose omega-3 study yet performed, and its remarkable success, even in a statin-treated population (where CV disease risk is already reduced by cholesterol lowering) suggests that the failures to impact the primary endpoints of past studies (including ASCEND and VITAL) has been because too low a dose of omega-3 was given. This should not be surprising—if you give too little active agent, you’re unlikely to see an effect. To what extent the benefit was due to a high dose or the fact that only EPA was given (or both) won’t be known until another big study called STRENGTH is finished and reported in late 2020. (STRENGTH is giving 4 capsules per day of Epanova, a product that contains EPA and DHA but in a “free fatty acid” form to help with absorption). If STRENGTH is just as successful as REDUCE-IT, then it will suggest that it is the high dose that is responsible, not the presence of only one of the two omega-3s. If STRENGTH is less successful, then we may conclude that EPA alone is better than EPA+DHA. I’m betting on the former outcome, not the latter!
To summarize then, these three studies—ASCEND, REDUCE-IT and VITAL—have breathed new life into the omega-3 field. REDUCE-IT was an unambiguous winner, whereas ASCEND and VITAL (which gave an 80% lower dose of omega-3 compared with REDUCE-IT), were mixed winners. It is no longer possible to say, “fish oils don’t work.” They do work if the right dose is given to the right person and the effects are followed up for a long enough period of time. A very important additional consideration is safety. For almost all drugs, there is always a risk and a benefit, and the challenge is to see if the benefit is worth the risk. So, if a drug could cure cancer but in doing so also caused ingrown
toenails (to propose a silly scenario), the benefit would far outweigh the risk, and the drug would be approved by the FDA. For omega-3 fatty acid-based pharmaceutical products, there has never been any concern about safety—they are, after all, essentially nutrients and, although some vitamins and minerals in excess can be toxic, this is not known to be the case for EPA and DHA. So, if there is even a hint of a benefit with the use of a completely safe (and relatively inexpensive) “drug” then the benefit-to-risk ratio is favorable, and the products should be used to improve human health.
Passwater: Furthermore, in October, the “VITAL” researchers updated their previous meta-analyses by adding 3 recent large randomized controlled clinical trials which increased their sample size by 64% (7). They concluded that “Marine omega-3 supplementation significantly lowered risk for most cardiovascular endpoints, even after excluding a trial testing very high-dose supplementation. Risk reductions were linearly associated with dose of marine omega-3 supplementation.” They pointed out that the clinical implications were, “Daily marine omega-3 supplementation is effective in lowering risk for coronary and most other cardiovascular endpoints, including myocardial infarction, coronary heart disease death, total coronary heart disease, cardiovascular disease death, and total cardiovascular disease.” They also pointed out that “Greater cardiovascular benefits may be achieved at higher doses of marine omega-3 supplementation.”
Regarding the latter point, these studies are impressive, but how do we know that the optimal amounts of EPA and DHA were used? Didn’t your 2019 AJCN study suggest that two grams of EPA/DHA were healthier than only one gram (3)?
Harris: This is a great question, and it follows up the points made above about dose: If the dose is too low, then blood levels will be too low to provide protection, and the treatment “won’t work.” For EPA+DHA, the dose used in VITAL and ASCEND (840 mg per day) usually raises the Omega-3 Index (red blood cell membrane levels of EPA+DHA) from the intermediate zone (~5%) to maybe 6.5% or so; rarely will this dose get the majority of patients into the >8% cardioprotective zone. Interestingly, we have recently published estimates of the Omega-3 Index in REDUCE-IT (the authors did not report it), and we came up with an on-treatment Index of about 7% on average. This is a bit lower than the original target of 8%, but clearly (from the good outcomes of the study) that level—at least in people being given only EPA—is a healthy value. Most patients will very likely be >8% in STRENGTH because both EPA and DHA are being given (and DHA has a bigger impact on the Omega-3 Index than EPA). This is why we expect results at least as good from STRENGTH as were seen in REDUCE-IT.
Passwater: You are the developer of the Omega-3 Index. Is this an important indicator of cardiovascular risk?
Harris: Yes, it is. As noted earlier, an Omega-3 Index value of 8% or greater is what we consider to be in the heart-healthiest zone. The average in America ranges from about 4%-6% or so, and recent studies have shown that >95% of Americans are <8%. In our view, the Omega-3 Index should be viewed as important a “risk factor” for heart disease as cholesterol is, and our hope is to someday see this test included in all annual physical exams like cholesterol. Because it’s a more technically challenging test and not widely available, this will take some time, but I believe the day will come. In the meantime, people can order the Omega-3 Index test directly off our website—www.omegaquant.com. A collection kit will be sent to their home where they can collect a drop of blood on a card and drop it in the mail; there is no need for a special doctor’s visit.
Related: Omega -3, -6, -9 Update
Passwater: What did you find for the O3I heart-healthy Japanese compared to typical Americans?
Harris: When we have compared Japanese populations to those in the U.S., we found that the Japanese were about twice as high: 9.6% vs 4.9%. This is commonly seen in many studies and is explained simply by the fact that the Japanese eat fish much more often than Americans do.
Passwater: Can the O3I be misused by improving the ratio only by reducing the amounts of omega-6s?
Harris: This is an important insight. Yes. By focusing on the “omega-6:omega-3 ratio” instead of on EPA and DHA, it is very easy to lose focus. People with a low ratio can be tempted to reduce their intake of the primary dietary omega-6 fatty acid, linoleic, instead of addressing the real problem, which is the lack of EPA and DHA. This is a failed strategy on two levels: 1) They don’t get the benefits of higher omega-3 intakes, and 2) Based on recent research, they are likely to actually increase their risk for CV disease (and diabetes) by lowering their linoleic acid intake. So, for this and several other reasons, I’m not a fan of the ratio. I am a fan of the Omega-3 Index because it shines a bright light directly on the problem: too little EPA and DHA in the blood (hence, in the diet).
Passwater: You, my co-author Jørn Dyerberg, myself and others have published that there should be an RDI for EPA/DHA. Is there any progress for achieving this?
Harris: Not to my knowledge.
Passwater: What is your guidance for linoleic acid and EPA/DHA consumption?
Harris: We recommend pretty much what the American Heart Association supports for omega-6 (linoleic acid) consumption: Between 5% and 10% of total calories should come from this essential fatty acid. That translates into between 13 and 26 grams per day. The richest source for linoleic acid is vegetable oils. The best kinds would be soybean and corn oil, whereas rather poor sources would be canola, olive, safflower and sunflower oils.
Passwater: Dr. Harris, thank you once again for your research and for informing the public about healthy fat choices.
Note: The views and opinions expressed here are those of the author(s) and contributor(s) and do not necessarily reflect those of the publisher and editors of WholeFoods Magazine.
- Dyerberg, J. and Passwater, R.A. “The Missing Wellness Factors: EPA and DHA” Basic Health Publications, Laguna Beach, CA (2012).
- Harris WS, Mozaffarian D, Rimm EB, et al. Omega-6 Fatty Acids and Risk for Cardiovascular Disease: A Science Advisory from the American Heart Association Nutrition Committee. Circulation. 2009;119:902-907.
- Walker, R.E., Jackson, K.H., Tintle, N.L., et al., Predicting the effects of supplemental EPA and DHA on the omega-3 index. Am J Clin Nutr 2019;00:1–7. ( 2019).
- Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379(16): 1540–50.
- Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2019;380:23–32.
- Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, et al. Effects of icosapentethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol 2019;73(22):2791–802.
- Hu, Y., Hu, F.B., & Manson, J.E. Marine Omega‐3 Supplementation and Cardiovascular Disease: An Updated Meta‐Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. J. Amer. Heart Assoc. (October 1, 2019)8:19 https://doi.org/10.1161/JAHA.119.013543.