Dr. Patrick: I want to discuss a seminal paper, what I think is a seminal paper of yours that you published back in 2004, you co-published with Dr. von Schacky about the omega-3 index and the omega-3 index being an important risk factor for cardiovascular disease. Can you explain to people what the omega-3 index is and let's get into why you thought and think it's a risk factor for cardiovascular disease?

Dr. Harris: Sure. Yeah. That's great. Just a little background on how Dr. von Schacky and I came up with this idea when we were together in 2002 in Chicago at the American Heart association meeting. And Dr. Christine Albert from Harvard had just presented her study where she'd looked at blood omega-3 levels in the physician's health study. And they had stored blood from when they recruited the men into this physician's health study. It was an observational study. And they had frozen blood samples, and after 17 years, they looked back and saw that they had a certain number of sudden cardiac death events in the physician's health study. And so the theory had already been out there from 10 years earlier that a high omega-3 would protect against sudden cardiac arrests. This is from animal studies and some human stuff. So the physician's health study said, "Well, let's go look at the blood that's in the freezer of these guys who died of sudden cardiac arrest and compare it to some controls who didn't die, you know, just case control study."

And they analyzed the blood and they found that those men who had the highest omega-3 levels at baseline when they started were like 90% less likely to be a case, experienced sudden cardiac arrest and sudden cardiac death. So Clemens [von Schacky] and I were sitting after this talk having a beer, talking about it. And we said, "Look, this is...the omega-3 level in the blood means something." I mean, it really does predict. And this is a second study that's shown it. But this is the first one that had been prospective. It really is just like a risk factor like cholesterol, except this is one that you can modify easily, you know, without taking drugs, without going on extreme diets, without having to change your lifestyle completely, you can just eat more fish or take supplements and you can raise your omega-3 levels and reduce risk.

So we said, "There ought to be...doctors ought to be able to know their patient's omega-3 level so they can do something about it." If you don't measure it, you can't control it, right? Manage it. So we kind of said, "Well, we got to make up a test." We both had laboratories so we could say, well, we can do this. So, ultimately, over the next two years wrote this paper, brought the evidence together and explained why we think and what we thought a target omega-3 level ought to be. And we called it the omega-3 index. We didn't really know what to call it. Didn't want to call it a red blood cell or EPA plus DHA is too much. And we picked red blood cells because that had been used in past studies and it makes sense because it's a long-term marker of omega-3 status because the omega-3s are in the membrane of the red cell and in most other tissues in the body, all other tissues.

So it was a good reflection of other tissues. And so we again wrote this paper, published it in Preventive Medicine in 2004, and said, here's the omega-3 index. There are ought to be...people ought to start looking at this like a risk factor. And that's kind of what's happened. It's slowly...I mean, this is now what, 17 years later. It's not certainly recognized by the American Heart Association or the NIH or anybody as an official risk factor, but hopefully, someday it will be in the same sense that CRP took a long time to be kind of considered a risk factor. Omega-3, I think, definitely deserves it for a variety of not just heart disease, for a variety of reasons. But that was the genesis of it. He started a laboratory in Munich called Omega Metrics, which is still going, which...and we started a laboratory in the U.S. called OmegaQuant. We use identical methods. And this is a big problem with just the diagnostic field. It's what's the method you're using because you get a different answer for different methods. So that's a problem. Standardizing, it's a problem. But he and I both started doing studies independently of each other, exploring the omega-3 index as a risk factor and I think the evidence has grown quite well.

Dr. Patrick: What's the biggest difference between measuring EPA and DHA in red blood cells, the omega-3 index versus you mentioned, you know, they're in the membranes of the cell, which is, you know, indicative of many things and it's also long-term. But most of the time, if people are going to go get omega-3, most people don't ever get the omega-3 measures. It's very rare. But if they do, they often get plasma omega-3 or phospholipid omega-3. What are your thoughts on the differences there?

Dr. Harris: There are differences. First of all, in plasma, of course, there are lipoproteins. All the lipids in plasma are in lipoproteins and lipoproteins have a membrane and that membrane has got fatty acids in it. Lipoproteins also contain triglycerides and cholesterol esters which also have fatty acids attached to different patterns of fatty acids. So the plasma certainly has omega-3, and you can express the plasma omega-3 content as a percent of total plasma fatty acids. It's just that the number you get, like a normal might be 2% for plasma EPA, DHA, whereas for red blood cell, EPA, DHA, which is just the red cell membrane, it might be 5% or 6% would be normal. So numerically, the values are different. They correlate pretty well. So if you put them on an X-Y graph, the plasma level and the red cell level, you'd get a pretty good correlation.

But what's confusing about it is the number is different. It's like saying you're...if you don't have the same units, you don't really know how to set a target if people are talking about different numbers in different lipid pools. One problem that I have with the plasma is it's just more noisy. Day-to-day, it varies because, especially if you're in a non-fasting state, if you've just eaten, you’ve got now triglycerides with fatty acids coming into the blood, changing the denominator. It's because it's a percent of total fatty acids and if you just had a big meal, that's going to change your plasma percent EPA where it won't affect your red blood cell. So red blood cell is very much like a hemoglobin A1C relative to a plasma glucose. It's the same concept. It's a more stable long-term marker. It's not affected by daily fluctuations, whereas plasma levels are. So that's one thing I don't like about plasma. Plus very few studies have really used plasma. It's hard to know what the target omega-3 level would be in plasma.

Dr. Patrick: Do you think the omega-3 index is indicative of EPA and DHA levels in every different organ, including the brain? Or is there some...

Dr. Harris: Well, yeah, you hit it. Almost every organ, probably, but the brain. The brain is...there's this blood-brain barrier, of course, which is very careful to take in what it wants. A brain has got a huge amount of DHA, almost no EPA in brain tissue. I mean, obviously in the blood flowing through the brain, it's there, but yeah, the correlation between the red blood cell and brain tissue is not nearly as good in brain as it is in heart, liver, muscle, every other internal organ where the red cell does reflect much better. Numerically, maybe a different value for red cell versus liver, but the correlation would be very good. The higher the omega-3 in the red cell, the higher the level of the liver. But it may not be the same number, same percent.

Dr. Patrick: Do you think the red blood cell omega-3, the omega-3 index is a better indicator of brain than plasma? I think I've...

Dr. Harris: Well, probably, yeah, probably better than plasma. But I think you just have to... Part of the brain just turns over so slow. You know, red cells turn over in 120 days. I don't know off the top of my head how fast brain cells turn over and are resynthesized, but I suspect it's quite a bit longer. Turnover time is much longer.

Dr. Patrick: So you've measured omega-3 index in, I mean, just many, many people through publications and OmegaQuant which people can then, you know, go and get their omega index quantified. Are there like huge variations in people that are given, or have the relative, like average amount of dietary intake of omega-3 is similar? Do you see that there's still variations in the omega-3 index?

Dr. Harris: Yeah. Right. And this is something we don't understand yet. There is quite a bit of background variability and we always say genetic, well, you know, what else are you going to say? Even though we know that there's... We, scientific group, have not discovered any genes that really control EPA, DHA levels well, like the standard Fatty Acid Desaturase, FADS gene have very little effect. Mutations in that gene have very little effect on omega. They affect omega-6 arachidonic acid levels pretty substantially. Those mutations and Fatty Acid Desaturase but they don't affect the omega-3s very much at all, 2% or 3% variability explained by that. So we don't know what it is. A probably an even bigger variability is the variability in response to taking an omega-3. So we look at the Delta, the change in omega-3 index with different dosage groups and it can be, you know, on average, it's a very nice, the higher the dose, the higher the omega-3 index. But if you look at the individual's splay across those increase, some people on 1800 milligrams of EPA, DHA they might go up from an omega-3 index of 4 to 4.3. Others might go up from four to eight. I mean, it's just huge variability. And we don't think it's compliance all the time. I think there's some actual, just a lot of land to cover between your mouth and your blood.

Dr. Patrick: Yes. So there is, and I'm going to look this up after this conversation because I don't remember the gene. But there has been one identified where there are SNPs in that gene and it does play a role in the response to supplementation of omega-3 and it's, you know, it's...

Dr. Harris: Sounds a little familiar, but anyway. Just look it up.

Dr. Patrick: Yeah. I'll text it to you.

Dr. Harris: We'll get back to you.

Dr. Patrick: Yeah. We'll put it in the show notes, but I will text it to you too because yeah, some people, and gosh, I wish I had looked this up before for the conversation. But yes, some people actually may require a much larger dose of omega-3. And it's really interesting because it comes back to that. And I did want to talk about this... I don't want to go off on this tangent right now, but the trial design, and, you know, when you're doing clinical studies in nutrition, as you know more than anyone, it's very complicated, it's not like a pharmaceutical, you know, the gold standard being a randomized controlled trial which is great for pharmaceuticals because nobody has any level of the pharmaceutical in their bloodstream before they start the trial.

Everyone has the same baseline. And for the most part, I mean, there are some SNPs in some of the, you know, xenobiotic metabolism, you know, genes and liver and things like that. But you don't have as, you know, wide variation like you do with nutrition where, you know, the thought is that people have sort of, you know, depending on where they come from, their ancestors, you know, they've evolved certain steps to kind of, you know, adapt to that region. But anyways, you know, so in an ideal world for every randomized controlled trial you do, you obviously need to measure something like the omega-3 index at baseline and, you know, after treatment and throughout, perhaps, but also measuring the SNPs and looking at that and including that, that would be something...

Dr. Harris: And I thought you were going to say, you know, measure omega-3 before baseline and you have to be below a certain level to get into the trial.

Dr. Patrick: Well, that would be another thing is also just, you know, analyzing the data for all that, like, you know, people that are low, you're probably going to, like you mentioned, with the hyperlipidemia effects are much more robust when they had hyperlipidemia versus someone that was like healthy and normal.

Dr. Harris: Right. Right. And we're seeing more studies now where they do a randomized trial with omega-3 and at the end of the day you do what you normally do, you compare the effects seen in the placebo group on whatever endpoint, death, Alzheimer's, whatever disease and the omega-3, you pair them and you get a P-value. And sometimes you don't get a very strong effect until you look at the achieved omega-3 index and say, "Okay, those people that achieved this omega-3 index in one group, how did they respond?" These people mostly in the placebo group, but not always, never got that high, what was their response? So in other words, your outcome is based not on your assignment of groups but on the omega-3 level achieved. And then you can really see much more clearly, oh, the people that got a high level, they did much better. And mostly it's people who were in the supplemented group, of course, but there were some people in the supplemented group who don't get a change at all and they're, by that analysis, they're in this control group thing because they didn't change and their outcome didn't change. And that's the best way to look at those kinds of trials if you have a test.

Dr. Patrick: And that would be the easiest actually. You wouldn't even have to then look at the SNPs because you have this quantifier of, you know, omega-3 levels and obviously for whatever reason, people not responding, there's non-responders, you know, for whatever reason. Yeah.

Dr. Harris: Yeah. It's why it's important to titrate the omega-3 on a given patient, you know, you just don't ask them how much fish they eat so you can call it good.

Dr. Patrick: I know we're going on a tangent here, but is there a way you can sort of talk to these lead researchers, you know, that are running these huge clinical trials we'll talk about, you know, the VITAL with REDUCE-IT and STRENGTH and say, like set up some kind of, you know, way for them to use OmegaQuant and measure the omega-3 index because this sounds like to me, you know, there's such heterogeneity in the research. In your thoughts, why do you think there's such heterogeneity? What are your thoughts on that?

Dr. Harris: Well, I mean, if we're talking about cardiovascular randomized trials with omega-3, that's where the heterogeneities you're talking about. Yeah, there's a lot of reasons why maybe over the last 10 years studies have not shown them...some studies have not shown an effect. Partly it's low dose, partly it's background omega-3 levels are higher in the population and they haven't controlled for that. Partly it's short-term treatment. I mean to me it's silly to think you can take somebody who's 65 years old and who's had a crappy diet their whole life and put them in a omega-3 trial, give them 840 milligrams of omega-3, like one capsule of Lovaza, and expect in three years to see a difference in cardiovascular endpoints. I mean, it's just ridiculous. So that's probably why those studies we'll talk about high doses have been effective because you've at least hit them with a bigger hammer.

But a lot of these studies... Plus the other thing that's happened is a background risk for heart disease has gone down. It's just continuing to drop. We're way below 1950s heart disease rates. A third of people die of heart disease now instead of half. And so the incidence of heart disease is down where we have much more powerful medications that are widely used in some of these...most of these trials had those background medications. So there's a lot of reasons why these early studies in the '90s, early 2000s may have worked and they're not working now when the same dose is used. So that is a problem. But I think if we would... And to your point about measuring omega-3 in the trial, both STRENGTH and REDUCE-IT did. Now, we did the analysis for STRENGTH at OmegaQuant. Another lab did it and REDUCE-IT. And I don't know if you want to get too far into REDUCE-IT, but the most successful omega-3 trial in years was REDUCE-IT with 4 grams of EPA. And they reported that the most striking, the only risk factor that they could measure or thing in the blood that they measured that would predict outcomes, it was better than cholesterol, better than triglycerides was the omega-3 level. It was the omega-3 level achieved that was the strongest predictor of benefit in the REDUCE-IT trial, which makes perfect sense. And so they're starting to move that way.

Dr. Patrick: So the REDUCE-IT trial, yeah. We can talk in a little bit, and let's get into the cardiovascular and I'll circle back, but, you know, the REDUCE-IT trial, you said it was 4 grams of EPA, so they were using Vascepa, Vascepa?

Dr. Harris: Vascepa.

Dr. Patrick: Vascepa. And is it the trial where there was like a 25% reduction in cardiovascular-related mortality?

Dr. Harris: Cardiovascular events mortality. Right.

Dr. Patrick: And was that correlated with the actual omega-3 index or was that just the program?

Dr. Harris: That was the standard approach, placebo versus active. They saw that difference.

Dr. Patrick: Did they do any sub-analysis with the omega-3 index?

Dr. Harris: Well, with the omega-3 levels, yeah. They measured omega-3 concentrations in the blood, not percent comp, but micrograms per mil. There's another confusion here. Well, okay. Your EPA is 10 micrograms per mil, well, how does that relate to the omega-3? And yeah, we know how it relates, but it's confusing for the medical world when you've got multiple metrics for omega-3 that have different units. That being the case, in REDUCE-IT, when they did look at their plasma EPA concentrations at the end of the study, people that had the highest biggest change in EPA levels in the blood had the greatest benefits compared to those who had minimal change. And to your point about how trial design, if we want to go there again, is different from drugs, not only do you not...when you do a drug trial, you don't have the drug in the blood in the control group. And if it's experimental drugs, they can't even go to the drug store and get it and cheat. But with omega-3, you're assigned to placebo, all you’ve got to do is bite into one pill and you know you're on the placebo. I mean, if you're on a five-year trial, right? It's going to be very clear that this is not fish oil. And if you already believe that fish oil is good and you see that now you're going to be five years on a placebo in this trial, you might want to go down to your local drug store and pick up a bottle of fish oil and just take it and don't tell anybody.

Dr. Patrick: Or at the very least, up the fish intake.

Dr. Harris: You can do that or start eating more fish, right? Exactly. But if you measure blood levels, you'll find that person. They're now in the treated group, you know. You don't measure blood levels, you have no idea.

Dr. Patrick: Exactly. Yeah.

Dr. Harris: So anyway, nutrition research is tough, but omega-3 is probably one of the easiest nutrients to study like a drug of all the nutrients because our background intake is so little and there's so little metabolism in vivo metabolism of omega-3. It's not controlled like calcium levels are controlled so tightly. Magnesium levels in the blood are controlled tightly. Glucose is pretty tightly controlled. You know, I mean, but omega-3 is not very tightly controlled. It's driven by diet, how much do you eat? So the reason that omega-3 has been probably like the fifth-most studied molecule in medicine is because it's been easy to study in the drug model, you know, plus it works.

Dr. Patrick: So you'd said something that kind of piqued my interest about it, you know, not being tightly regulated because, you know, it's controlled by your diet. Is there like an upper level to the omega-3 index. Can you saturate that? Like if you eat nothing but fish.

Dr. Harris: Yeah. Well, or eat 25 grams a day, which in that study, we don't know what the red cell was. We didn't measure them. We just did plasma. But yeah, in our experience at OmegaQuant, they were looking at thousands of dried blood spot tests for omega-3 getting up above more than 15%, 16%. So context, right? Average American's roughly 5% omega-3 index which is EPA and DHA in red cells as a percent of the total fatty acids in the red cell. So 5% of the fatty acids in the red cell membrane are EPA and DHA. In Japan, it's on average 9%, 8%, 9%, 10% because they eat so much more omega-3 than we do. Vegans are down around 3.5% as are U.S. military personnel. I'm sorry to say. When we've studied the soldiers, that's about the same as a vegan and you know they're not vegans. So they're not getting enough omega-3.

So 4%, we like to say be over 8%. That's the goal. That's been our target. So you can get up to about 15% or 16%. We have seen two or three people out of hundreds of thousands that are over 20%. Which is weird, but that's, I mean, a dolphin here at SeaWorld, which we studied and that's all they eat is fish, right? And they weigh about 200 kilograms. I mean, they're big mammals like us and they all these fish and their omega-3 index is around 18% or 19%. So I think that's about all that you can get into a cell membrane. There's only so much... The body will only let you put so much because when red cells are made, they're made to be able to perform a function and the fluidity of the membrane is very important and somehow or another bone marrow knows how much polyunsaturated fat can go into that membrane and it just is enough.

Dr. Patrick: And is there a difference between the amount of DHA versus EPA? I've always thought of, you know, DHA playing a more prominent role in membrane fluidity and, you know, in the membranes.

Dr. Harris: It's certainly there in a higher amount. DHA is always there in like four times the amount of EPA. I mean, unless you're just taking pure EPA, then they'll be one to one roughly. But in the normal situation, there's a lot more DHA than EPA. It doesn't mean one is more important than the other. It's just what it is. And when you take fish oil supplements, both EPA and DHA will go up. When you eat fish, both of them will go up. But typically in red cells. And I think in almost every other cell. I can't think of another cell type that's where EPA predominates over DHA. But still that doesn't say anything about the importance of them in biology. It's just what's in membranes.

Dr. Patrick: So you mentioned that target omega-3 index being around 8%. And let's talk about why that is. So I had my omega-3 index measured. I was telling you earlier. It was 11.7 and it said... I did it through WellnessFX and it says RBC omega-3 index. They called it that. So I'm assuming it's...

Dr. Harris: OmegaQuant was doing work with WellnessFX. It may still be. I'm kind of on the business stuff.

Dr. Patrick: This was literally like a week before everything shut down because of the pandemic in 2020. I had done this huge performance test where I had all these things measured and the omega-3 index was one of them. So I'm up there with Japanese.

Dr. Harris: Totally. How much omega-3 do you eat?

Dr. Patrick: Well, I eat salmon, I would say at least, you know, two, three times a week. I also eat sardines, like snack on those.

Dr. Harris: Oh, boy. That's a big one. That's a big one.

Dr. Patrick: Yes. And then I take a lot of fish oil. I take about 2 grams of EPA in the morning and 2 grams of DHA in the evening for a total of 4 grams.

Dr. Harris: Separately?

Dr. Patrick: I take them separately. Yeah. You know, I...

Dr. Harris: And where do you get pure EPA?

Dr. Patrick: A friend of mine. He is in Norway and he makes some pretty.

Dr. Harris: Okay. So you're not getting a prescription for Vascepa?

Dr. Patrick: No, no. Although I'm interested in doing that for my mother because I've been, you know, giving her mine and I'd like to keep mine and get her on something. But anyways, the omega-3 index and the 8%. So, you very recently published a study that correlated the omega-3 index to all-cause mortality, it was able to even predict mortality. Very, very interesting study. I shared it on social media, but I would love to talk about it.

Dr. Harris: Well. Yeah, yeah. Sure. It's going to be probably one of my capstone studies, I think. And in hindsight was a collaboration among 17 different cohorts, like the Framingham Study's a cohort. Women's Health Initiative's a cohort. MESA, EPIC. These are all and from all around the world. These are groups that have been recruited at one point in time, blood samples taken, fatty acid levels measured in that blood, and then the investigators follow this group of people over time, see what happens, what kind of diseases they get, you know, who dies, who doesn't. And so we had 17 of those pooled together and around 40,000, 45,000 people altogether where we had omega-3 levels at the beginning and then roughly the total follow-up time when you're looking at risk for death, all-cause mortality, you obviously look in a given window of time because if you wait long enough, it's 100%. Everybody dies.

So you can't wait forever. You got to wait. So we looked basically between ages 65 and 75, who died in that window of time. And we found that the people that had the highest omega-3 levels compared to the lowest were 15% or so less likely to die over that time. And it was very...when you look at quintiles of omega-3, it was very dose-dependent, the higher the omega-3, the lower the risk. And that was for total mortality. We then looked at cardiovascular mortality, cancer mortality, and then everything else, kitchen sink, you know, if it's not cancer, not cardiovascular, it's group three. And we saw the same thing in all groups... It wasn't as strong in cancer. It wasn't as stair-steppy like it was in cardiovascular. But the highest group in omega-3s did have a significantly lower risk of death from cancer. But interesting to me is the non-cardiovascular, non-cancer, all these other causes of death from electrocution to suicide, to car accidents, to kidney failure, you know, everything people die of. The higher the omega-3, just like cardiovascular, lower risk. So there's something very systemic, very protective across many systems in the body. Many diseases I think are just held somewhat in check by having a higher omega-3. It's not just heart disease. And I think that's the message to get out. It's not just heart disease.

Dr. Patrick: Right. And the 15% decrease in all-cause mortality, was that about a five-year? Was it translating to about a five-year?

Dr. Harris: In that study we didn't try to get at that because basically, that meant in that window of time, you were 15% less likely to die. How long you actually lived? We didn't follow people until they died all the time. But in another study we published from Framingham, just one cohort, we did see that there's roughly a five-year difference. If you're at the very lowest omega-3 versus the highest, your odds of dying are about five years earlier.

Dr. Patrick: Can you say again? So the omega-3 index for the lowest was...

Dr. Harris: It's probably under 4% and for the upper level roughly 7%. Again, this is observational and Framingham and nobody's supplementing. So we haven't got people, many people over 8%. This is, you know, people living in Boston. And so they don't have high omega-3 levels, but the highest quintile was about over 7%.

Dr. Patrick: You said the average in the United States was about five.

Dr. Harris: Five-ish.

Dr. Patrick: So five-ish. And what's the average intake of fish in the United States?

Dr. Harris: Fish, well, what is it? Thirteen pounds per person per year. And that's all fish and all...

Dr. Patrick: Awesome.

Dr. Harris: Right. So that includes, you know, shrimp which has zero omega-3 and white fish, Pollock, which is the fried fish that people get at McDonald's and salmon itself, which is one of the highest omega-3 fish. One of the highest that people actually eat, you know, that provides about one and a half grams per serving of omega-3. The average intake of EPA and DHA in America is something, you know, 100 to 150 milligrams a day. The median intake is zero. Okay. The average, because some people eat a lot and a whole lot of people eat none. You know, so the median is zero, at least to two decimal places. But the average intake is, say, 120 milligrams a day. In Japan, it's roughly 900 milligrams a day.

Dr. Patrick: Nine hundred milligrams. And...

Dr. Harris: For life, for minus nine months. I mean, because mom's doing it too. Yeah.

Dr. Patrick: And their, if I remember correctly, their average lifespan is about five years longer than the United States average.

Dr. Harris: Right. Despite the fact they smoke more, despite the fact they have more hypertension, despite the fact they have higher stress life, they still live four or five years longer.

Dr. Patrick: Does omega-3, is it known that if it has any effect on smoking in terms of like negating some of the negatives?

Dr. Harris: Well, in our most recent paper in Framingham, we asked the question... In general, we're trying to understand how much of a risk factor is omega-3 compared to things you already know for death. So we know cholesterol is a risk factor. We know blood pressure is a risk factor. We know diabetes, having diabetes. We know being a smoker is a risk factor for bad outcomes. So how does omega-3 compare to that? And we found that in the study we did in Framingham looking at all-cause mortality, that if you're a smoker and you have a low omega-3, you know, over the 10 years of the study, you're 50-50 chance of living. You're going to die at 50% chance of dying. If you have a low omega-3 and you're non-smoker, it's not so bad, your risk of death maybe is 30% over that [period].

If you're a smoker and you have a high omega-3, that's the other flip side, but you're a smoker, your risk is kind of like having a low omega-3 and being a non-smoker. And then if you've, best case you don't smoke and you have a high omega-3, your odds of dying are like 10%. So it's, in a way, having a low omega-3 is like being a smoker from a... I don't mean to say that taking omega-3 erases your risk of being a smoker. Don't want people to think you can do that. "Oh, I keep smoking. I just take some fish oil. I'm good." That's not the deal. We do know that smoking actually lowers the omega-3 index. Smokers have lower omega-3 index than non-smokers from other studies. And it could be because of the hyper-oxidative state of a smoker's blood that could actually destroy omega-3s potentially, or they just don't eat fish oil or they don't eat fish. That's the other explanation. So the general tack of both our study in "Nature Communications" on total mortality with our 17 cohorts and this latest one in "American Journal of Clinical Nutrition" in Framingham point to having a high omega-3 level is protective in the same sense that having a low cholesterol is protective, in the same sense that having low blood pressure is protective. It's about the same predictive value, which is...

Dr. Patrick: Wow. And that's about 8% of omega-3 index around...

Dr. Harris: Yeah. Again, it's over seven in Framingham but in the pooled analysis of those 17 cohorts, it was roughly about 7.8%. The highest quintile was roughly about the 8% target. So we felt that our original 2004 idea that 8% would be the target which is based on much less data back then has been vindicated and continues to be vindicated. It's been seen that that 8%, it's not perfect. I mean, in Japan, you actually get an additional reduction in risk at 10% versus being at 8%. Okay. That's good. But we're now going from this much risk to this much risk, you know?

Dr. Patrick: Well, that was going to be my question too, is like what if we get up into it, you know, 10% to 12% to 13% omega index, is that even greater? I mean...

Dr. Harris: It could be. We at OmegaQuant, we kind of say our target level is 8 to 12. And it's not because above 12 is bad. It's because we just have so little data to say that, if you get to 14, you're better than you're at 12. Or even to say that you're 12, you're better than 10. We don't really know that. It's just a reasonable target level. It's safe. I'm not concerned about that. And it's tough enough for people just to get up to 8, never mind get up to 12. And so we're not trying to say anything above eight, as far as you can go, the higher the better, I don't know, I can't say that. I mean, there may be adverse effects that pop up somewhere out there. You would think in theory, there could be, we just haven't seen them, but that doesn't mean they're not there. So be conservative.

Dr. Patrick: Have you looked at the correlation of the omega-3 index with inflammatory biomarkers?

Dr. Harris: Yeah. And as you expect, we, again, we did this in Framingham. We looked at 10 very different inflammatory biomarkers in the plasma in patients in Framingham and correlated it with the omega-3 index and all 10 of them, the higher the omega-3, the lower the marker. So it's across the board. It isn't just, you know, CRP. There's also some phospholipase A2...PPLA-2, you know, LpPLA-2 to this one which is a kind of inflammatory markers. Well, very different. It's not very different chemical than CRP. Some bone-related inflammatory markers were reduced in association with omega-3. So it's there. And giving omega-3 does lower inflammatory levels.

Dr. Patrick: Right. So I was going to say like for people like there's the mechanism by which these inflammatory markers lower...I'm sorry, which omega-3s lower the inflammatory markers and there's a wide variety of them. So you have, you know, for a long time, I always thought of EPA being the, you know, anti-inflammatory, omega-3, which isn't entirely accurate because all these metabolites of DHA and EPA are...

Dr. Harris: Are anti-inflammatory. Well, not just anti-inflammatory, they're pro-resolving of inflammation, which is the flip side of, you know, you can either prevent an inflammation from starting, which may not be good because inflammation at one level is important. But if you don't have the omega-3s onboard, the active process of shutting down the inflammation once it starts, that shutdown is inhibited. So the inflammation stays longer. So Charles Serhan is the guy who's discovered all of these, what he calls some specialized pro-resolving mediators, which with all due respect to Charlie, I think it's a silly name. I mean, there's no molecule in the body that doesn't specialize. Come on. Water's specialized. I mean, so if they're pro-resolving mediators, they're molecules made from EPA and DHA, that... And some that are made from arachidonic that are also suppressive. Lipoxin A which is the one from arachidonic. So that whole field of...it isn't just that they're anti-inflammatory, they're pro-suppression, pro-suppressing of inflammation, which is the important piece.

Dr. Patrick: Right. Because as you mentioned, you're talking about, you want to be able to activate your immune system when there's a pathogen, you know, that's there, but you don't want it to remain active and spiral out of control. But in the context of just, let's say not a pathogen, let's talk about this low level of just chronic, you know, immune activation in this chronic, you know, inflammation that can be caused from a variety of lifestyle factors.

Dr. Harris: Sure. Just obesity.

Dr. Patrick: Exactly. Obesity. What role do these specialized pro-resolving mediators, the SPMs as they're called and resolvins, and protectins and...

Dr. Harris: Protectins and maresins, and poxytrokins and poxytrins and...there's a bunch of them now. It's actually a bewildering array of molecules that have been discovered made from EPA and DHA that operate on different cell types and different receptors through different mechanisms but at the end of the day, they suppress an inflammatory response and keep it from getting out of control. So I don't really know the answer, how the presence of those resolving mediators plays into the chronic inflammation of someone who's just got a lot of adipose tissue. I assume it will just keep a damper on it, keep it down. And what we saw in Framingham was all these mediators are inversely related to the omega-3 level. And these people aren't chronically inflamed. Oh, well, I mean, they're Framingham people in their '60s, so maybe they are like typical Americans. So there's a ton of research to be done. And then, of course, drug companies are very interested in taking some of these molecules that are made from omega-3 and making them drugs that can be used. Okay, fine. Good.

Dr. Patrick: One of the reasons I'm asking is because, you know, this chronic inflammation is at the root of, you know, many different diseases, cardiovascular disease, you know, dementia, cancer, a lot of the diseases that you were mentioning in the Framingham study and also in your large, you know, 17 study cohort. And so, you know, the question is, is that, so let's talk about in the context of cardiovascular health, for example, you know, you mentioned the REDUCE-IT trial with the high EPA, there was a dramatic lowering of triglycerides.

Dr. Harris: No.

Dr. Patrick: No. That wasn't the REDUCE-IT trial?

Dr. Harris: It didn't lower triglycerides very much. I mean, it was 15%.

Dr. Patrick: Fifteen percent. Okay. So I guess that's not dramatic, but that's what a lot of people talk about when they think about cardiovascular and omega-3 and...

Dr. Harris: Think about triglyceride lowering.

Dr. Patrick: They think about triglyceride lowering.

Dr. Harris: That's the indication that the FDA gave these drugs because the only way to get these nutrients turned into drugs and approved by the FDA as a drug is it's got to affect some risk factor that the FDA believes in. And when it all began with Lovaza, they said, you lower "Oh, look, we can lower triglycerides by 20%." And that was enough to get them an indication for people with triglycerides over 500. That's the limitation. Only Vascepa is indicated for reducing risks for cardiovascular events because it's the only one that's been shown to do that. Lovaza has never been tested for lowering cardiovascular events. It's the EPA plus DHA product, but it's approved for triglyceride lowering because, I mean, that's what we saw back 40 years ago, is it does that, but I don't think that's the mechanism by which omega-3s are cardioprotective.

Dr. Patrick: What do you think the mechanism is?

Dr. Harris: I think it's much more likely to be an anti-inflammatory mechanism and anti-platelet. So thinner blood, less likely to clot. We've been fascinated recently to look at what's called the RDW, the red cell distribution width, and we're just preparing a paper on this now. The red cell distribution width is just a metric that comes out whenever you do a complete blood count, a CBC on a patient, they get their hemoglobin, the hematocrit, the mean cell volume on the red cells, and they get this thing called RDW, red cell distribution width, which is really just how varied are the red cell sizes in your blood? Ideally, red blood cell sizes should be all the same size. So the coefficient of variation would be very thin, very narrow. So if you divide the standard deviation by the mean, you get a coefficient of variation. And that's the red cell distribution width. So it's expressed as a percent, if you have a high percent distribution, you've got...it's a remarkable predictor of all kinds of adverse outcomes, independent of everything else. I mean, this is in the last 10 years. This has been discovered that for some reason, how your red blood cells, the variation size of your red cells is a big predictor of outcomes, bad outcomes. And if you have a lot of little cells and a lot of big cells, and so a wide bell curve of red cells, that is bad. You want to have a very steep, sharp distribution of red cells and the omega...

So we were interested in, since we measured the omega-3 in red cells, you know, maybe instead of just being a passive vehicle that's carrying omega-3s around the blood allowing me to measure omega-3 status, maybe they're actually affecting red cell biology. Maybe they're really changing the way red cells carry oxygen, pick up CO2, squeeze through capillaries because, you know, red cells got to squeeze through half its diameter as it goes through a capillary. So it's got to be very flexible, and omega-3s will help make that membrane more flexible. So it could be that we're mainly delivering more oxygen to tissues when you have a high omega-3, haven't tested this, this is all... I mean, I'd love to test this. So it is really very cool that... Again, we've seen that we've got a data set of 40-some thousand people. We see the very strong correlation between high omega-3 and lower, healthier RDW, and we're getting ready to submit that now. But the ways that omega-3s may be protective, we may have never thought of yet, which makes it hard to explain to people how they work. It's easy to say they lower triglycerides, and I get that. But so what?

Dr. Patrick: Exactly. So many mechanisms are doing so many things and that membrane fluidity with the red blood cell membranes itself, that's super interesting. Another thing I'm sure you're familiar with Dr. Ronald Krauss' work on small dense LDL particles and how those are more atherogenic and, you know, the larger buoyant LDL seems to be more cardioprotective because it is transporting, you know, fatty acids and cholesterol and things to cells and it's the small dense ones that really kind of get stuck in the arteries and start this inflammatory cascade. What he's also shown, him and his collaborators and colleagues, that, you know, inflammation can, you know, can basically cause a larger buoyant LDL to form a small dense LDL. The inflammation plays a role in that process. And so what I would love to see, I guess, this answers my question, you haven't looked at this yet, but the omega-3 index and small dense LDL particle.

Dr. Harris: We can look at that.

Dr. Patrick: Yeah. Because...

Dr. Harris: We'll get back to you on that.

Dr. Patrick: Yeah. Awesome. I think that would be, you know, because right now people go, when they go and get their cholesterol measured, it's usually just total LDL and, you know, there's some good LDL there like, you don't want no LDL.

Dr. Harris: Well, is it good LDL or just not as bad LDL?

Dr. Patrick: Well, the reason I say good is because, you know, like when you have a damaged cell, you want to repair that damage and your LDL is going to bring triglycerides and cholesterol and, you know, fatty acids and everything that cell the building...another membrane every time you make a new cell. I mean like, so it's serving a function, right? And so I guess, I don't know if good is the right word to describe it, but yeah. I mean, it's got a function that's important for normal health. So that would be very interesting to see if there's a correlation between omega-3 index and small dense LDL particle size. I would imagine you're going to see an inverse correlation.

Dr. Harris: I would think so. I would guess too, but we'll see.

Dr. Patrick: And it would be great to have that sort of panel in the physician's, you know, toolbox, right, where they measure the omega-3 index, they're measuring the small dense LDL. And, you know, it's like, "Oh, your omega-3 index is 3%. Well, you got to take some fish oil or..."

Dr. Harris: Right. And [inaudible] raising your omega-3 index is going to have implications all over the body that may not be even measurable in a blood test that are good, good things like this red cell biology, it just behaves better. It's a more efficient mover of gases or something like that.

Dr. Patrick: So you also had a recent study. I'm kind of going back to resolving the inflammation aspect. What I think is very relevant in, you know, our 2021 world that we live in.

Dr. Harris: COVID world.

Dr. Patrick: Oh, yes. The COVID world where we have a pathogen that is in some people causing a very bad cascade of inflammation. So you published a study looking at the omega-3 index and COVID-19-associated mortality.

Dr. Harris: Right. Right. We did that with colleagues here in LA. I don't know which way I'm pointing but...

Dr. Patrick: I probably should have said that pilot pre-print hasn't actually... Has it been peer-reviewed, it's not been peer-reviewed or?

Dr. Harris: Oh, no, it was peer-reviewed and published in January. It was published in January. Yeah. And it was a pilot study because we only had access to data from 100 people which was too bad, but we did have omega-3 index levels on 100 people that had been admitted to Cedar Sinai in LA with COVID. And so we asked the question, you know, "Is there any relationship between how they did, did they live or die, and their omega-3 level?" And, again, the distribution of omega-3 levels was very narrow. You know, like I think it probably went from a low of three to a high of five, something like that, you know, but the distribution was narrow. So we weren't able to see, you know, the older people had an 8%. Nobody there in the study had an 8%. And so we looked at the people who had the highest quartile of omega-3 levels, the 25% highest compared to everybody else who was lower. And those people were really half as likely to die as people who had... And it was 0.07 P-value, so it wasn't statistically significant by standard metrics, but in the race to understand what we can do about COVID, we'll put up with a slightly non-significant strong trend in the right direction with good biology behind it to explain it. Another paper's come out from Chile just confirming the same thing. We saw the same thing.

Dr. Patrick: Okay. What about Japan? Do you know what their...because their omega-3 index is higher, do you know their mortality?

Dr. Harris: I know a group has looked at this worldwide and they looked at WHO data on COVID death and they looked at reported fish intake in the countries. And they did it by six different regions around the world. And what they showed, you know, the higher the average fish intake, the lower the risk of death from COVID. Okay. It's hard to... There's so many variables here.

Dr. Patrick: Right. Of course.

Dr. Harris: But it sings the right song. What that paper, that specific paper was most interesting to me about was not this worldwide population thing, which was just their introduction. They were doing in silico experiments, looking at the spike protein on COVID and they found that there's two conformations, an open and a closed conformation. And if it's open, then they can interact with the receptor. It's closed, it can't. They found that DHA, again in silico experiments, if it's present, will hold that thing in a closed position.

Dr. Patrick: You're kidding.

Dr. Harris: No. So it will not interact with the receptor and not be taken in. I mean, that's the theory. So then...

Dr. Patrick: That's a huge deal. I mean, you know, the vaccines, at least the mRNA vaccines at Johnson & Johnson keep it in a close transformation spike protein. They inserted two proline amino acids to keep it in a closed.

Dr. Harris: Oh, I didn't know that.

Dr. Patrick: Yeah. So it can't interact with the ACE-2 receptor.

Dr. Harris: Interesting.

Dr. Patrick: Very interesting. It's a different spike. Very important because the whole... I'm not going to go off on this tangent, but like a lot of the, you know, terrible effects of the SARS COV-2 infection go through ACE receptor, and because a downregulation of that receptor occurs when the spike protein binds to it, endocytosis pulls it into the cell and causes downregulation which disrupts the whole renin-angiotensin system and lung injury.

Dr. Harris: That's a mess.

Dr. Patrick: I mean, heart injury. Exactly. That's a big mess. So.

Dr. Harris: Anyway, this is, you know, take this with a grain of salt because it was in silico experiment because it also showed that linoleic acid did the same thing.

Dr. Patrick: Can you send me that paper?

Dr. Harris: That's what prompted them to look at DHA. Somebody else had published linoleic acid had the same kind of effect, potential effect. And so they looked at DHA.

Dr. Patrick: And that's an omega-6 fatty acid for people that are not aware.

Dr. Harris: Correct. This is a classic omega-6. Right. So not all omega-6 are bad. Okay. Well, you all know. I'll send you that paper.

Dr. Patrick: Thank you. Yeah. I mean, the fact that both the DHA and linoleic acid could keep the spike protein in a closed.

Dr. Harris: Yeah. So, I mean, again, a completely different mechanism for suppressing inflammation, this would actually suppress infection if it's true.

Dr. Patrick: And well, not only... It would also suppress, you know, negative outcomes, severe outcomes through the renin-angiotensin system. Like that whole thing not happening, like the bad stuff. So very cool.

Dr. Harris: Yeah. It's cool stuff.

Dr. Patrick: Since you mentioned linoleic acid, and I kind of know there's so many people out there that talk about the omega-3 to omega-6 ratio and how... I'll never forget, I was submitting a paper for a review on omega-3s and I mentioned the omega-3 to omega-6 index ratio and, you know, how it could be negative and this was, you know, years ago and a reviewer just ripped me to shreds. I mean, totally came down with all this evidence that that was not true. Of course, you know, it blew my mind and I was like, "Wow, this seems to be convincing."

Dr. Harris: Well, I thought it was true. I wonder if I reviewed that paper. I don't know too many people or more.

Dr. Patrick: I think I do know who the reviewer was, but anyways, I can tell you off-camera. But I changed my mind basically. So, you know, this whole thought that the omega-3 to omega-6 ratio is so important, everyone's so concerned about eating too much omega-6, which, you know, the dietary sources, major net dietary sources these days are vegetable oils, refined oils, but, you know, getting them through and then people become scared about getting them through whole foods like eating nuts, and flaxseed, and healthy food.

Dr. Harris: Oh, yeah. It gets crazy.

Dr. Patrick: Yeah. So what do you think...what are your thoughts on this ratio?

Dr. Harris: I agree. I mean, the ratio, I mean, the concept... Well, we haven't got that much time. Makes some sense. It's just, it's very imprecise because when you say omega-3, you don't know what you're talking about, ALA, EPA, or DHA. Could be any of them. And then when you say omega-6, you don't really know. There's 7 omega-6 fatty acids in the blood, which ones are you talking about? And so you don't know what this ratio...you can't act upon it because you don't know what you're acting upon. The other problem is you can have a high omega-3 intake and a high omega-6 intake or low omega-6 and a low omega-3 and have the same ratio. So that doesn't help because the problem is that you can fix a bad ratio by taking more omega-3, and that's the right way to do it, but you cannot fix and improve your health by leaving your omega-3 intake alone and just lowering your omega-6, which that ratio, people tend to do that. They say, "Well, I got to fix it." Well, the way to fix it, there's only one way to fix it. It's a good way to fix it. So eat more EPA, DHA. That's fine. If you want to play that ratio game and fix it that way, okay. But don't take it any further than that.

Dr. Patrick: A hundred percent agree with you. That's my thoughts, is that really, it's the low omega-3 intake that's a problem and that you need to increase that omega-3 intake. And that's pretty much what the reviewer was arguing for with a little bit of a well, you know, omega-6 is good. It's part of the cell membrane and you need linolenic acid, you know, so there's some of that, but...

Dr. Harris: Yeah. We published two papers with this consortium of 17 or 20 cohorts. We've had several other papers all looking at fatty acids and some outcome. And one of them looked at linoleic acid levels in the blood and cardiovascular outcomes and found that the higher the linoleic acid, the lower the risk for cardiovascular disease. And another paper looked at linoleic acid levels and risk for developing diabetes. Higher omega-3... Excuse me, higher omega-6 linoleic, lower risk for developing diabetes. So when you look at that kind of data when you're talking about a biomarker, it's not a dietary intake questionnaire thing that everybody question. So looking at a biomarker of omega-6 intake, linoleic acid, you can't make it. And higher levels are associated with lower cardiovascular and diabetic risk. It's hard to say they're bad. I mean, you could turn that around and say lowering your levels of linoleic is going to increase your risk for atherosclerosis and...

Dr. Patrick: I think these were a couple of the studies that the reviewer used as an argument against, you know, like what they're not. So...

Dr. Harris: People love black hats and white hats though.

Dr. Patrick: Right.

Dr. Harris: And just feels good to have... I hate this one. I love this one. You can't love both of them somehow or another. Somehow, I like omega-6 and omega-3. And that's [inaudible]. We can't do that. You got to hate one of them. I don't know.

Dr. Patrick: So we do have a little bit more time. So there's a few more things that I would kind of love to get your thoughts on.

Dr. Harris: Sure.

Dr. Patrick: One is a question a lot of people will ask me or email me about...and it is about this 2013 paper that was published by Brasky.

Dr. Harris: Yeah. Brasky. Ted.

Dr. Patrick: Yes. And he looked at blood omega-3 levels. I don't know if it was plasma phospholipid.

Dr. Harris: Plasma phospholipid.

Dr. Patrick: Yeah. Omega-3 and the incidence of prostate cancer in a trial of people, it was called the SELECT trial where people were given high doses of tocopherol and/or selenium. And he found a correlation between the plasma phospholipid omega-3 and prostate cancer.

Dr. Harris: And it was statistically significant. It was...the range of high to low omega-3 was like this, like 4.6% versus 4.2%. Something like that. It's very, very, very narrow, very small, which makes it go well. That doesn't make any sense. Plus, I mean, my biggest... I don't criticize the results so much as the discussion in that paper because they said, therefore, ergo taking fish oil or eating high omega-3 fish is going to cause prostate cancer. They turned, A, an association into a cause and effect. In that study, you weren't allowed to be on an omega-3 supplement. Nobody in that study was on omega-3. These guys already had a bent that they didn't...they wanted to show something bad about them, supplements in general and omega-3 happened to be supplement du jour. And so their discussion and what they said on TV and what they said on other interviews was what went way beyond the data. The data itself have not been confirmed.

They'd been refuted by other studies. Those studies don't get any press, of course, and you're left with this weird thing hanging out from now, eight years ago that still pops up that, you know, hopefully this podcast will not cause somebody to go look at, because if you do look at it, realize that the levels of omega-3 are very tiny. Plus, I mean, we submitted a letter to the editor about that, me and Michael Davidson. And one of the things we pointed out was there's evidence that in some cancer cells, they can actually upregulate FADS activity and you might actually be making some more omega-3 because you got cancer. If, I mean, again, it's a very tiny difference in levels between those who did and those who didn't get cancer. But there are other mechanisms, one, if it was even true, then that you can explain it by.

Dr. Patrick: And once you have expected it to be repeated with yet, there were other studies, as you mentioned, that refuted that showed that actually omega-3s were more protective of even prostate cancer. But I don't know if...you want to know my thoughts too on this with the SELECT trial?

Dr. Harris: Yeah, sure. Am I allowed to ask right now?

Dr. Patrick: I mean, so, you know, the fact, the trial design, the fact that these men were actually...they were given, like, it was 400 IUs of alpha-tocopherol or selenium. I mean, the 400 IUs of alpha-tocopherol, my mentor Bruce Ames and one of his post-docs had shown that when you give a high dose of alpha-tocopherol much like... The RDA of it is like 25...

Dr. Harris: Fifteen milligrams. Yeah.

Dr. Patrick: Something like that. Yeah. That you basically deplete another tocopherol, gamma-tocopherol, which is anti-inflammatory. And so there's this, you know, it's actually not good to take mega doses of the vitamins...

Dr. Harris: The alpha-tocopherol.

Dr. Patrick: The alpha-tocopherol hormone, vitamin E. And so it's like, you're looking at blood samples from a very confounded, you know, cohort.

Dr. Harris: You're assuming a sling and alpha-tocopherol had no effect on its outcome. Right.

Dr. Patrick: Right. And we have no idea what could have happened, right?

Dr. Harris: I didn't know that. That's interesting.

Dr. Patrick: Yeah. And then plus the lack of confirmation of that study, it's just...I kind of want to like, you know, get this out there. I mean, this study, it was...

Dr. Harris: Right. Do not believe this study. Do not let them.

Dr. Patrick: Yeah. You know, it was a sensational headline as anything that is thought to be good for you but then it's not good for you and not only not good, could be bad for you, you know?

Dr. Harris: Totally. They love this.

Dr. Patrick: Yeah. It makes the headlines.

Dr. Harris: Glad we got that taken care of.

Dr. Patrick: Me too. So what does your personal omega-3 intake look like?

Dr. Harris: Two to three grams a day from supplements. I don't really have a favorite supplement. I kind of maybe like your friend in Norway, people send me supplements. Oh, yeah. "Try this." And then salmon, probably once a week for sure. Try to do more, but at least once a week. So my index is around 10. Mine is the...in our lab, we have high controls and low controls for our assays. And so they're always getting my blood for the high control. So they want to have a 10%, they want to have 3% when we do our assays at OmegaQuant. And so because of that, I have to keep it up. So I'm pretty diligent about taking my omega-3s.

Dr. Patrick: What are your... So we talked a lot about cardiovascular disease and some all-cause mortality. We didn't talk about all the studies. I mean, there were too many, I mean, the VITAL study. Well, I do want to get your thoughts on, you know, the STRENGTH study and why this was...they used Lovaza, what did they use?

Dr. Harris: No they used a thing called Epanova.

Dr. Patrick: Epanova.

Dr. Harris: Which is EPA plus DHA, same ratio as in Lovaza except they're free fatty acids, not ethyl esters. So they're unesterified EPA and DHA, which they had previously shown are more readily absorbed. You don't have to hydrolyze them, they're already free fatty acids. But the trouble with those is they're also pretty irritating. They're GI irritants. Free fatty acids are. So they had to enterically coat the pills. So that's fine. Why did STRENGTH, which was a bigger study than REDUCE-IT, but in virtually the same kind of patient, high cardiovascular risk, high triglycerides, on statins, that's...everybody had to be in there 13,000 people worldwide and placebo was olive oil, I believe stripped olive oil. They found no effect at all. They stopped the study early as a matter of fact for futility. And it was the biggest shock to everybody in the omega-3 world that it didn't work. And nobody really has a good understanding of why.

And, you know, people come up with ideas, you know, like they were healthier. Well, I mean, it was done like two years after REDUCE-IT was done. I mean, and probably recruiting out of exactly the same sites as well around the world, multiple countries are involved. I don't think that makes any sense. To me, if I had to guess, there may be some chronic, I mean, your GI tract is not designed to be taking in 4 grams of free fatty acids every day. It's just not designed for that. And that may induce some kind of chronic inflammatory response that's going on systemically from taking these detergents. And they've only been studied for 12 weeks in other studies and they show nice absorption, lower triglycerides. They do very well. But for four or five years of taking this every day, I bet there was just some kind of chronic inflammatory thing going on that erased any omega-3 benefits.

Dr. Patrick: And they didn't measure any inflammatory biomarkers.

Dr. Harris: CRP, even they didn't see any difference.

Dr. Patrick: CRP is not very sensitive.

Dr. Harris: Yeah. I mean, that's all they measured. So that's the only metric they have. So nobody knows. I don't know. Yeah. I don't know. Put it that way.

Dr. Patrick: So they cut off the study so early, and you said they were, you know, the participants were of the same sort of health status as the participants in the REDUCE-IT trial. But if you look at the adverse or the fatalities, there were much fewer. Is that because they stopped it earlier? Is that why? I mean...

Dr. Harris: No, no. I mean, yeah, I've got an interesting slide showing the event rate in REDUCE-IT in the placebo group, which is like this and the event rate in the treated group, which is lower, 25% lower. And then you look at the event rate in STRENGTH and both placebo and active were even lower than the event rates in the treated group and REDUCE-IT. So there's something...there were fewer events, a lot fewer events, and maybe...nobody knows how to explain that either. And you really, I mean, theoretically, you can't put these curves on the same graph. It's not the same study, but it was very close to the same study in my view.

Dr. Patrick: Well, the other thing is that the EPA versus the one that had EPA and DHA, and what are your thoughts? Like, you know, I hear people...I mean, you see headlines that say, oh, DHA can negate some of the positive effects of EPA.

Dr. Harris: I don't believe that. I mean, I think there's an effort by those who want to promote the EPA-only product to vilify DHA in any way they can. Which I don't think is appropriate. I don't think we have the evidence for it. Just because this study didn't work doesn't mean DHA counteracted the effect of EPA. Can't draw it. You need to do a study with DHA. That's what needs to be done. Pure DHA versus pure EPA versus maybe a combination would be optimal versus a placebo. So a four-arm group like VITAL, you know, VITAL at 225,000 people four arms in vitamin D. And I'd love to see if VITAL with four arms of EPA alone, DHA alone, the combination, and a placebo and see what would happen.

Dr. Patrick: And measuring the omega-3 index.

Dr. Harris: Totally.

Dr. Patrick: Yeah. I mean, that sounds good for a trial. I think with the VITAL study, you know, it made headlines because the...well...

Dr. Harris: Didn't work.

Dr. Patrick: Well, the primary outcome didn't work, but did it not work in your opinion?

Dr. Harris: No. It did work, in my opinion, it's just the primary outcome was a composite of multiple different kinds of outcomes. And if you look at the individual elements, there was benefit. It reduced major reduction in risk of heart attack. And even in people who didn't, who ate little fish or the lower half of the fish intake, they got a significant reduction in the primary endpoint. So there were good outcomes in that study from taking 840 milligrams. So it's a one-capsule Lovaza. And that's not much.

Dr. Patrick: It's not.

Dr. Harris: It's not much. So I think it was a positive study at the end of the day.

Dr. Patrick: Yeah. And that study itself kind of proves, because it was Lovaza, which is the EPA, DHA combo, that DHA can't be negating any because, you know...

Dr. Harris: Well, I suppose the other side can say, well, it would have been much better if it was just EPA, right? It's the 4 grams of...what was important with REDUCE-IT, it's 4 grams a day, which is really five times higher than anybody's ever used before for omega-3 dosing. And that showed benefit. And I think everybody said, "Oh, okay. That makes sense. You know, we got a high dose finally. Now we see some real serious benefits of omega-3." Just wish that STRENGTH had turned out with the same dose, 4 grams a day of EPA plus DHA. Wish it had turned out, but it didn't. So, you know, you take a big risk in these trials.

Dr. Patrick: Right. And you kind of just mentioned what your ideal trial would be with the DHA, the EPA, and the combination of the two and...

Dr. Harris: Who's going to fund that, I don't know.

Dr. Patrick: Any other clinical trial designs that if people are listening, scientists or...

Dr. Harris: Well, I mean, the fundamental thing to do is something you mentioned earlier is to measure omega-3 levels at baseline and only allow people in who've got a below normal, pick some number, exclude people with already high omega-3 because it's potentially not going to help. It's like recruiting people into a statin trial when their cholesterol is, you know, 100. It's silly. There's no nowhere to go. So I think that would be...that's one of the main things to do. And then, of course, to follow it up with an analysis based on blood levels achieved instead of just by group assignment.

Dr. Patrick: Yeah. Are there any other areas of omega-3 research, like maybe sports medicine, joint health, the brain that... I mean, we still have a little bit of time.

Dr. Harris: We do?

Dr. Patrick: We do.

Dr. Harris: Well, we're working on a paper right now again from one of our cohorts looking at the omega-3 index, predicting risk for Alzheimer's and dementia. And it does, which is nice. But that's kind of what you'd expect. We're looking for an interaction with the APOE4 genotype and not quite there. I think probably a sample size, not, but generally, I mean, if we control for APOE levels, we still have a significant benefit of high omega-3 if we control for it. But if we stratify by APOE4, non-APOE4, it looks like the benefit is a little better. The curve is steeper. The relationship is stronger in those that are at the higher risk, i.e., have E4, then those that have low risk. But I think because our sample size is too small at this point, you can't get an official interaction P-value.

Dr. Patrick: So it's actually the preventative power is better in people who are more predisposed, right, higher risk.

Dr. Harris: People who are at higher risk, which is kind of what you'd guess.

Dr. Patrick: And this is a great work because, you know, a lot of the omega-3 brain or dementia or Alzheimer's disease research has always been fixing someone who already has it trying to improve memory. And I mean...

Dr. Harris: Very hard to do. Forces out of the bar.

Dr. Patrick: It is. So if there, you know, people that people that do have a genetic risk for Alzheimer's disease, if they know that they can increase their omega-3 index by, you know, supplementing with omega-3 and/or increasing their, you know, fatty fish, like salmon or sardines that have high omega-3 in it to prevent and stave off dementia, I mean, that would be...it's very important and it's like low-hanging fruits, low-hanging fruit, you know?

Dr. Harris: It's a very safe way to help reduce risk, put it off for X years. We don't know how many years maybe you're putting off dementia. We'd like to try and figure that out.