Dr. Jorn Dyerberg – An Omega-3 Legend
OmegaMatters: Episode 8, Part 2
Hosts: Drs. Bill Harris & Kristina Harris Jackson
Guest: Dr. Jörn Dyerberg
Background and key takeaways:
Dr. Bill Harris and his daughter, Dr. Kristina Harris Jackson, are joined by Dr. Jörn Dyerberg. In part 2 of this series, Dr. Dyerberg discusses the rollercoaster of omega-3 research of the past 40 years with Dr. Bill Harris. They discuss each landmark study that had a heavy impact, either positive or negative. It’s been a wild ride.
Dr. Jörn Dyerberg:
Dr. Jörn Dyerberg is a pioneer in the omega-3 fatty acid world, having made the discovery of their important heart health benefits more than four decades ago while researching the native Greenland Inuit. Along with his colleague, Dr. Hans Olaf Bang, the two embarked on an adventure that started in the late 1960s and trickled well into the 1970s. It started with their curiosity about the Inuit’s high fat diet and their very low incidence of heart disease. Their goal was to examine their blood and their diet. At the time, the Inuit subsisted mainly on a diet of high-fat seal and fish, however, the rates of heart disease were staggeringly low compared to Americans eating a much different diet but had much high rates of heart disease. Their first publication appeared in the Lancet in 1971. What this research showed is that the Inuit actually had favorable lipid levels despite their high-fat diet. It was in a subsequent publication in 1975 in the American Journal of Clinical Nutrition that they detailed the specific omega-3s eicosapentaenoic acid (EPA) and docosahexaenoic (DHA). This led to several landmark publications during the following decades and a stream of interest in these newly discovered molecules.
Dr. Bill Harris: Hello again everyone. Welcome back to Part 2 of our Omega Matters discussion with Dr. Jorn Dyerberg, the pioneer who, along with is mentor, Dr. Bang, really started the whole omega-3 rollercoaster. They certainly began the story back in the 1970s, with a 1978 publication that really started, lit the fuse I think we could say, so welcome back Jorn. Thank you for joining us again.
Dr. Jorn Dyerberg: Yes, I enjoy joining this sort of thing.
Dr. Bill Harris: Good. All right, I’m going to share a slide that will serve as our template for talking through the lasts 40 years of omega-3 and see if we can do this in 20 or 30 minutes.
Dr. Jorn Dyerberg: I see the rollercoaster.
Dr. Bill Harris: Rollercoaster. All right, well, let’s begin. First of all, just to orient the audience here, this is a very rough sketch of what we’ll call the popularity index are on the Y axis and that’s general popularity in the medical community and the public in general. So, what I’m going to do is I’m going to click the button and we see our first happy face down here, just before 1980 and that is for the publication of this paper. It’s kind of hard to see these, I’m afraid, but this is a paper entitled “Eicosapentaenoic Acid and Prevention of Thrombosis and Atherosclerosis?” With a very modest question mark.
Dr. Jorn Dyerberg: Yeah, a modest question mark.
Dr. Bill Harris: Just briefly tell us about this paper?
Dr. Jorn Dyerberg: Yeah, yeah. This was a breakthrough paper where we published our new data that we found during the years before that, based on the theory or the findings by Hamburg and Samuelsson and then Vane, in England, that from arachidonic acid there could be generated prostaglandins that were either pro-aggregatory or anti-aggregatory, defining a, sort of, balance between pro and anti-aggregatory, pro and anti-thrombotic events in the circulation. And we were sitting there, with our data on fatty acids and suddenly looked at our EPA that was high in Eskimos. That was a 20-carbon fatty acid with not four but five double bonds, with the last one in a three position and we thought, “What if there is a balance of prostaglandins made from eicosapentaenoic acid that has another thrombotic balance?” And we then added eicosapentaenoic acid to platelets and made them aggregate and then we added eicosapentaenoic acid to cellular tissue harvested from the umbilical cord in newborns at the birth department and we could then extract the component that was anti-aggregatory.
Dr. Jorn Dyerberg: But the pro-aggregatory EPA type of prostaglandin wasn’t nearly as effective as the thromboxane from the arachidonic acid, whereas the anti-aggregatory effect was quite equal to that made by the arachidonic acid. So, we had a shifted balance that could point at an anti-thrombotic state and the next thing we, of course did, was to search for money for a new expedition to Greenland to measure their aggregatory potential by measuring the bleeding time. This was another paper but in that we found a higher level of EPA and DHA in the platelets of Eskimos and a longer bleeding, cutaneous bleeding time than the Danes, and this added up to this paper, coined it as the explanation of why we found a lower coronary heart disease frequency in Eskimos, compared to Danes. And I guess this opened up the whole omega-3 story.
Dr. Bill Harris: It opened it, right. I think it’s the first page of this particular issue of Lancet, with the first article that really did start the story. I’ll go on to the next step in my little thing, which was May 9th, 1985. That was an important day when there were actually three Omega-3 papers published back-to back, in the same issue of New England Journal of Medicine.
Dr. Jorn Dyerberg: Yeah, yeah.
Dr. Bill Harris: And this one was Dan Kromhout’s epidemiologic study in looking at fish intake over 20 years and mortality. This one was very favorable from an omega-3 point of view.
Dr. Jorn Dyerberg: True.
Dr. Bill Harris: The second one was from Frank Austin’s lab in Boston where they were looking at EPA and DHA here and their effects on neutrophil and monocyte function and leukotriene formation, so this was, again, breaking into this, the whole field that you started there with the eicosanoids.
Dr. Jorn Dyerberg: Yeah.
Dr. Bill Harris: And the third paper in there was one where I was one of the co-authors but we gave very high amounts of fish oil in our study in Portland, Oregon under Bill Connor’s leadership. Very high omega-3, 25 grams a day or so, to people with very high triglyceride and saw a fantastic drop in triglyceride levels.
Dr. Jorn Dyerberg: Did you also find the lowering of the cholesterol, LDL-cholesterol?
Dr. Bill Harris: Well, LDL didn’t go down particularly well. LDL went down if you took out the saturated fat, that’s true, but it wasn’t really because of the omega-3s it was because you took out the saturated fat.
Dr. Jorn Dyerberg: Yeah, sure.
Dr. Bill Harris: But that was a red-letter day for the omega-3 story, May 9th of ’85. You don’t see that happen in New England Journal very often, where you have three papers on the same topic. So, something really got going. We have a little down peak here but it probably is not worth talking about because it was a small study I did where we found that fish oil supplements raised LDL in some people and that got a little bit of press and there were some unhappy people thinking, “Oh no. We thought fish oil was good for you.”
Dr. Jorn Dyerberg: Yeah, yeah, yeah.
Dr. Bill Harris: That was a minor downturn.
Dr. Jorn Dyerberg: Again, there is a mechanism behind that because now it has been documented that increased long-chain omega-3 enhances via the conversion or breakdown to LDL.
Dr. Bill Harris: Right, but no evidence that that increase in LDL was atherogenic.
Dr. Jorn Dyerberg: Nope, nope, nope.
Dr. Bill Harris:
Yeah, that’s important.
Dr. Bill Harris:
Okay, the next study, was the DART study. Tell us how you felt on this day?
Dr. Jorn Dyerberg: Yeah, I was so happy when it came because it came on my birthday, the 30th of September.
Dr. Bill Harris: 30 September. I’ll remember that.
Dr. Jorn Dyerberg: That was the first intervention study with finding a lower cardiovascular risk in the group that was given either a fat-rich diet or if they hated fish, a supplement. I can’t remember the exact dose of fish oil… But they found a lower coronary risk incidence in the group on the high-fat, high-fish, high-fish oil supplement diet.
Dr. Bill Harris: Right, right compared to a high-fiber diet which didn’t work, compared to a low-fat diet which didn’t work, the high-fish oil, high-fish diet did work.
Dr. Jorn Dyerberg: It did work, yeah, yeah.
Dr. Bill Harris: In just two years there was a remarkable effect and that was a fantastic finding as well.
Dr. Jorn Dyerberg: That was a good finding, yeah. Then again, I must say, there was a DART II study that came later that was more dubious and had many issues with study design and outcome, but DART, DART I was the study to beat.
Dr. Bill Harris: Yes.
Dr. Bill Harris: Okay and then it looks like we go up again one more time to Lancet 1999 and this was the GISSI-Prevenzione trial.
Dr. Jorn Dyerberg: Yes, the GISSI studies. There were two GISSI studies.
Dr. Bill Harris: This was the first one published, I think GISSI-Heart Failure was later, right.
Dr. Jorn Dyerberg: Yeah, yeah but they were both positive and they just supported the findings and we were on an uphill on this rollercoaster and we nearly reached the top there with the GISSI studies.
Dr. Bill Harris: Right. And what was different from DART was this was just mega-3 supplements.
Dr. Jorn Dyerberg: Right. It was 1.8 grams of ethyl esters of EPA and DHA.
Dr. Bill Harris: No, wasn’t it just one capsule of Omacor?
Dr. Jorn Dyerberg: Yeah, it could have been. I remember it as two but, but you might be right.
Dr. Bill Harris: I was thinking it was just one. They tried to mimic the presumed omega-3 intake in DART.
Dr. Jorn Dyerberg: You might be right. I can’t remember exactly.
Dr. Jorn Dyerberg: Yeah, in the JELIS trial, they used pure EPA. That was the first pure EPA study finding a positive effect, in the JELIS study, so these three actually, so to speak, for us cemented that. I mentioned the platelet aggregation, you mentioned the triglyceride lowering and at the same time came, also, the addition of omega-3 fatty acids lowers the inflammatory response or activity. At that time, also, studies in rheumatoid arthritis were showing that they dampened the inflammatory reaction, which also is a part of the mechanism behind coronary artery disease, so we had studies, we had mechanisms and we had epidemiological findings, so we were uphill and happy.
Dr. Bill Harris: Were you consulted by the folks in Japan as they were designing their studies?
Dr. Jorn Dyerberg: I was consulted by the folks because of the EPA side. I was over there discussing with them, but I was not in the group planning the JELIS study.
Dr. Bill Harris: Right but that was the reason Mochida came out with an EPA-only product, at the very beginning, and was probably based your original hypothesis.
Dr. Jorn Dyerberg: That was the original hypothesis and Welcome tried to make a patent on EPA. The Welcome Institution, with John Wayne as Scientific Director and they gave up and they sold this patent to Mochida.
Dr. Bill Harris: Oh.
Dr. Jorn Dyerberg: So, that’s why Japan focused on EPA because they hoped, which they didn’t succeed in, to get a patent on EPA. This was maybe a bit naïve because it’s a naturally occurring component and I mean, you can’t patent Vitamin D or anything like that.
Dr. Bill Harris: So, you couldn’t patent even an ethyl ester, which is not natural?
Dr. Jorn Dyerberg: No, no but they tried to patent derivatives and the production system but they didn’t succeed in that but, nevertheless, that’s why Japan’s studies were focused on EPA.
Dr. Bill Harris: Yeah. Can you remember back to when you first heard the results of the JELIS trial, what you thought?
Dr. Jorn Dyerberg: Yeah, I was happy.
Dr. Bill Harris: I was amazed. I was betting that there would be no benefit, in Japan. That you couldn’t actually do better than what the normal background is (because their diet is already high in fish and hence omega-3s).
Dr. Jorn Dyerberg: Yeah, yeah, you’re right. They have one of the highest fish consumptions in the world.
Dr. Bill Harris: Right, yeah, so that was a real shocker.
Dr. Jorn Dyerberg: Too much of a good thing is wonderful, as Mae West said… but…
Dr. Bill Harris: I think we probably would agree that in the early 2000s is really when the peak of the rollercoaster. And then we had some problems.
Dr. Jorn Dyerberg: Crossing the century, we were on virgin soil when compared to people taking fish oil supplements. Nobody did that. And then came these major studies and they were referred to in the newspapers and people began to take fish oil capsules and the industry began to grow. From that point on we were leaving virgin soil when we are doing our intervention studies, that is, because from now on we cannot be sure that the placebo group hasn’t taken EPA and, or DHA as compared to the intervention group, which can only be found out by determining the resulting levels in the intervention group and the placebo group, which none of the studies that is lined up here, the negative studies, Ascend, Vital, AREDs, ORIGIN — these studies did not do what should have been done, which would be to measure the omega-3 level in the intervention and placebo groups at baseline and the end of the study. There is a difference in that point forward when it comes to study outcomes being more negative than positive.
Dr. Bill Harris: You’re right, you’re right and we have here, I think, Ascend and Vital, not in red but in yellow and I did that because there were some of the really pre-specified secondary end-points were very favorably affected, it’s just their composite endpoint was not and that’s an unfortunate way of looking at the data.
Dr. Jorn Dyerberg: Sure, sure, yeah.
Dr. Bill Harris: There was good news there.
Dr. Jorn Dyerberg: Yes, there were good news in these. Yeah.
Dr. Bill Harris: Yeah. So, let’s see, those were bringing us down basically between 2010 and 2018, 2017, in that area. Another one that was a big hit was the prostate cancer study.
Dr. Jorn Dyerberg: The prostate cancer study was a crazy study. We shouldn’t say that but this publication indicated that giving fish oil would increase the risk of prostate cancer in the SELECT trial. The difference between the intervention group and between those with cancer and those without, was minimal.
Dr. Bill Harris: It was minuscule, right.
Dr. Jorn Dyerberg: Minuscule, yeah. Later, studies have actually found that, for example, Japanese have a low prostate cancer incidence. When they move to the USA having lower EPA and DHA intake, they have a higher risk, so epidemiology pointed in directly the opposite direction but it got a lot of attention.
Dr. Bill Harris: It got a lot of attention and it hurt a lot.
Dr. Jorn Dyerberg: A lot of attention and it didn’t deserve this attention. Actually, a follow-up study has disproved the relationship between increased intake of omega-3 long-chain and prostate cancer.
Dr. Bill Harris: Yeah.
Dr. Jorn Dyerberg: Actually, the data to me seems as it’s quite the opposite.
Dr. Bill Harris: That omega-3s might be favorable, right.
Dr. Bill Harris: Second study here, this is the Rizos meta-analysis in JAMA.
Dr. Jorn Dyerberg: Yeah, which showed no association between long-chain omega-3 in the meta-analysis of the intervention studies.
Dr. Bill Harris: And as I recall, I think we commented earlier before the discussion, that there were some questionable statistics here?
Dr. Jorn Dyerberg: Yeah.
Dr. Bill Harris: In these because the bar was raised very high, inappropriately.
Dr. Jorn Dyerberg: Yeah, inappropriate.
Dr. Bill Harris: Yeah and they wanted to have a no-effect outcome and all they had to do was change their statistics to get it. Very unfortunate but it got a lot of press too.
Dr. Jorn Dyerberg: Yeah, they got a lot of press, so we were downhill from there.
Dr. Jorn Dyerberg: Now, two very big findings. First of all, the major risk reduction in the study of giving four grams of EPA per day was it four years or whatever?
Dr. Bill Harris: Yeah.
Dr. Jorn Dyerberg: A major reduction, 25% reduction in cardiovascular risk and then, of course, the Cochrane publication of the risk for premature birth in females, concluding that there’s no need for further studies. That’s rather rare that you read that in the conclusion.
Dr. Bill Harris: Right.
Dr. Jorn Dyerberg: “We have found out there’s no need for further studies.”
Dr. Bill Harris: Of course, then the next study that comes out doesn’t confirm the findings, so-, for good reason though, bad compliance, I think that was the problem. So, that was a happy time. Oh yeah, this was a down swing here.
Dr. Jorn Dyerberg:
From the Strength Study.
Dr. Bill Harris: So, Strength was 4 grams a day of a free fatty acid form of omega-3. What happened here?
Dr. Jorn Dyerberg: I don’t know. No effect but we have never seen, again, we’ve never seen the effect on Omega-3 index or phospholipid, omega-3 content in the intervention and the placebo group.
Dr. Bill Harris: You know what, our lab did these analyses and they did show a good increase in the Omega-3 index in the treated group.
Dr. Jorn Dyerberg: Okay.
Dr. Bill Harris: My concern is there may be other things going on with a free fatty acid form. Regardless of the benefits of omega-3, there may be some adverse effects of free fatty acids on the inflammatory system that might have overwhelmed the effects of omega-3, right. We don’t know but it was a disappointing finding.
Dr. Jorn Dyerberg: Yeah, it was, it was indeed.
Dr. Bill Harris: And I think I just for personal reasons, I put on here, to end in 2021 with a study from our group. There’s been a large group of us (FORCE Consortium) looking at omega-3 levels and total mortality and finding very a strong relationship between the higher levels of omega-3 and lower risk for disk from anything.
Dr. Jorn Dyerberg: Yeah, especially also for cardiovascular disease but including cancer, actually, yeah?
Dr. Bill Harris: Including cancer and all other causes.
Dr. Jorn Dyerberg: Oh, okay. Yeah, yeah, yeah.
Dr. Bill Harris: So the rollercoaster could still keep going up here.
Dr. Jorn Dyerberg: Yeah, indeed.
Dr. Bill Harris: Keep going but it’s been quite a run.
Dr. Jorn Dyerberg: It’s been a long run and I’ve enjoyed the privilege of being part of it, since way back.
Dr. Bill Harris: Yeah.
Dr. Jorn Dyerberg: Since way back. So, I said, “Oh well,” I can lean back and say, “Okay, rollercoaster but with positive impact.” What I would add, if I should add something on top of it all, it’s very essential, with cardiovascular disease, it’s very essential with inflammatory disorders and giving pregnant females long chain omega-3s to correct their deficiency, that’s a point I would like to make too. That has shown me that it could be so that the newborn kids are better, better cerebral function. If it is so, for me, outweighed whatever else we could think of beneficial effects.
Dr. Bill Harris: That’s sweet.
Dr. Jorn Dyerberg: The brains of the newborn — there are no documentations on that but there are things pointing in that direction and it’s worth finding out which makes, for me, the issue that long-chain omega-3 is not a treatment, it’s correcting a deficiency.
Dr. Bill Harris: Yeah, very good point. It’s very good point. We’re not treating like a drug.
Dr. Jorn Dyerberg: No, it’s correcting a deficiency, like, I would put it on the major deficiencies, like Vitamin D, like Iodine, like Iron. We have this omega-3 deficiency in the rest of the world at least.
Dr. Bill Harris: We have to think about it that way. That’s great. Well, thank you again for this ride. You, I guess, were probably in the front car of the rollercoaster, you got to see all of this.
Dr. Jorn Dyerberg: I am.
Dr. Bill Harris: … And it’s only one car at the beginning.
Dr. Jorn Dyerberg: Fun to see, good to see, interesting.
Dr. Bill Harris: Absolutely. Well, and I understand your 84th birthday is impending on September 30th?
Dr. Jorn Dyerberg: Yes, thumbs up on that.
Dr. Bill Harris: That’s great, you’re looking good and you’re sounding great-
Dr. Jorn Dyerberg: Thank you.
Dr. Bill Harris: … And staying strong.
Dr. Jorn Dyerberg: Hopefully last a bit longer.
Dr. Bill Harris: How’s your Omega-3 index these days?
Dr. Jorn Dyerberg: 10.
Dr. Bill Harris: 10?
Dr. Jorn Dyerberg: Yeah, 10.3 or something.
Dr. Bill Harris: Yeah but I think Lisa beat you, didn’t she?
Dr. Jorn Dyerberg: Yeah, yeah, beat me by 0.4 or something.
Dr. Bill Harris: Oh my gosh. These women, they’re always-, you know. Well, I’m going to have to end our little chat. Thank you so much for our time together and we’ll stay in touch.
Dr. Jorn Dyerberg: See you. Bye.
Dr. Bill Harris: Bye-bye.