#83 – Bill Harris, Ph.D.: Omega-3 fatty acids

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [intro music]

2. 0:04 – 6:51

   Why the podcast runs on subscriptions, and meet Bill Harris

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [intro music] Hey, everybody. Welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I, I, I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will get back more than you give. So for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone. But instead, what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all, but my hope is that many of you will find enough value in, one, the podcast itself and, two, the additional content exclusive for members. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Dr. Bill Harris. Bill is an internationally recognized expert on omega-3 fatty acids and how they can benefit patients across a broad range of medical conditions and, but, but in particular with attention to heart disease. He's a professor in the Department of Medicine at the Sanford School of Medicine in the University of South Dakota. He's also the president and CEO of OmegaQuant, which is a company he started about 10 years ago that we spent a little bit of time at the very end talking about. And again, the caveat being, of course, he does have a, a vested interest and therefore a conflict with respect to involvement of his company. But, you know, I can say I've known Bill for, for 10 years, and I know people who have known Bill for much longer than that. And his reputation amongst his peers is really someone who is a very honest broker of the science. And he's been the recipient of five NIH grants for the study of the effect of omega-3 fatty acids, particularly EPA/DHA, on human health. He's published over 300 papers on the topic, and we discuss just a couple of those here, some of the really interesting ones. And he was also the author on two of the American Heart Association scientific statements on fatty acids. He earned his Ph.D. in human nutrition from the University of Minnesota and did a postdoc in clinical nutrition and lipid metabolism with Bill O'Connor at Oregon Health Sciences. I was introduced to Bill, like I said, probably nine years ago from Tom Dayspring, and this was around the time that I was really searching for insight around the polyunsaturated fats and in particular EPA and DHA. And since that time, Bill has been a very generous, generous mentor to me with respect to just one of those guys, you send him an email with a simple question and he responds with a very thoughtful, you know, 600-word response that contains more insight than anything I could have drummed up. We talk about mostly the landscape of polyunsaturated fats here, but this is a great episode. You don't have to know anything going into this episode when it comes to fats. We're gonna explain what saturated fats are, monounsaturated fats, polyunsaturated fats, omega-3s, omega-6s. You're gonna come out of this and have a better understanding of this topic than if you went to med school and took a course in this subject matter. I think I'm just gonna leave it at that. The show notes will be very helpful for this episode because some of this stuff, it really makes sense to be able to look at a diagram as we go through it. And then of course, as usual for, for subject matter like this, we're gonna go heavily into studies, so you'll want to be able to reference those studies and see that. So without further delay, please enjoy my conversation with Bill Harris. [outro music] Bill, thank you so much for making the time to talk about a subject matter that I think is incredibly confusing and incredibly important. That intersection of things that are confusing and things that are important tends to be a very important and sometimes overlooked intersection in medicine. So with that, I want to thank you for making the time.

   2. BHBill Harris6:50

      Yeah, my pleasure.

3. 6:51 – 11:04

   Harris's first salmon oil study and the start of his career

   1. PAPeter Attia6:51

      How long have you been the guru of this? I mean, for the listener, in the background, I give a little bit of your background, but I was introduced to you in, I think, 2011 from Tom Dayspring, who basically said anytime I had a question that had to do with, you know, anything around fatty acids, you were the guy to ask. And over the past eight years, you've steadfastly answered more questions than I can count. Tell me a little bit about how you, how you got to be the guy that knows so much about this.

   2. BHBill Harris7:18

      Just hanging around a long time. So I, I got, uh, my Ph.D. in nutrition in 1978, and I went to work with Bill Connor in Portland, Oregon, for my postdoc. His first assignment for me was to study the question of what is the effect of salmon oil on cholesterol levels? 'Cause we were very familiar with the effects of vegetable oil on cholesterol and animal fat, saturated fat, but we really didn't know what a, a fish oil would do to cholesterol. So my first really metabolic ward study, I organized, recruited subjects, uh, did the protocol, and we fed people huge amounts of salmon oil, basically all of the fat in the diet. So people were eating salmon steaks twice a day, and this was a 28-day inpatient feeding. Well, excuse me, outpatient feeding, but metabolic ward. And beyond the salmon steaks, they were drinking about a, a hundred milliliters a day of co- of salmon oil, just drinking it straight. And so it was a, a huge load, 25 grams of EPA, DHA per day. And we found that the omega-3s lowered... Well, actually, salmon oil did lower cholesterol relative to the saturated fat diet, and it was about the same lowering as we saw with the vegetable oil diet. But the thing that was unique about salmon oil was that it lowered triglyceride levels, and nobody had known that at that time. So we published our first paper on that in 1980. That's really coincident with the time that the, uh, Greenland Eskimo studies were finally becoming well-known from Dyerberg and Bang, and the omega-3s had been sort of discovered, in a sense, at that time. And so we started chasing omega-3 effects on lipids and platelet function and all kinds of other things. And so I've just been able to stay with it. I've had five grants from the NIH to study omega-3-related questions. And so just again, it's, it's been a field that's continued to be fascinating and ups and downs, but, uh, en- enriching. And as you said, it's confusing right now. It's, it's been confusing for most of its history.

   3. PAPeter Attia9:25

      [chuckles] That's kind of an amazing story, and I want to come back to that study because it's possible the listener right now doesn't understand the context of what 25 grams of EPA would mean. But that's-- I mean, that's a dose of a type of fat we're gonna talk about when we get into the nomenclature that is almost unprecedented. And I already have a dozen questions for you about that exact study and were there any side effects such as bleeding noses and anti-anabolic effects, all these things, which... But I'll, I'll refrain from going down that path to instead, uh, make sure we can get everybody on the same playing field. So I'm gonna start and give a little bit of a framework, but I'm gonna very quickly hand the baton over to you to get into the weeds on this a little bit. So obviously, fat is one of the four or five, depending on how you look at it, macronutrients, right? So fats, proteins, carbohydrates, ketones, alcohol. And I think most people know that fats come in different chemical families. So you've already alluded to one of them called a saturated fat. And then everybody's probably heard of a monounsaturated fat. And then there are these things called polyunsaturated fats, which then get further divided into these omega-3s and 6s typically, but there are others. Do you want to say a few words about what separates a saturated fat from a monounsaturated fat from a polyunsaturated fat, and then how we further subdivide those polyunsaturates into the omega-3s and 6s? And I guess if you can answer the question, Bill, not just through the chemical explanation, though I'd like you to provide that, but also through some of the examples and characteristics of each of them so that folks have a sense of what we're talking about.

4. 11:04 – 20:03

   Saturated, monounsaturated and polyunsaturated fats; omega-3 vs omega-6

   1. BHBill Harris11:04

      From a chemical structure point of view, a saturated fatty acid is a long single chain of carbon atoms all hooked together. And there are what we call single bonds between each carbon atom. You-- In chemistry, you can have single bonds, you can have double bonds, you can have triple bonds. But in a saturated fatty acid or a sat- and a saturated fat like lard or butter, any of those saturated fats have the vast majority of fatty acids that make up those fats are saturated, meaning they have long single chain. Uh, and they're solid at room temperature. I think that's the most common characteristics. The simplest way to detect a saturated fat is at normal room temperature, they're solid. Monounsaturated fats, fatty acids are the next class, and these have the same long carbon chain. It can be 12, 14, 16, 18 carbons long. And there's one double bond in a monounsaturated fatty acid. So w- when there's a double bond in a molecule, it now has a point of unsaturation. And why they picked that nomenclature is not worth talking about at the moment, but that's what that means. The classic oil that is rich in monounsaturated fatty acids would be olive oil and canola oil now too. Those are both very rich in monounsaturated fatty acids. They are liquid at room temperature, but you put them in the refrigerator, and they'll get hard. That's kind of a, a way of telling a monounsaturated rich oil. If it's out at room temperature, it'll be liquid. In the fridge overnight, it'll get solid or certainly get very cloudy. The polyunsaturates, the next group, it's really instead of one double bond, now we have two or more double bonds, and that's the poly. So again, the same long carbon chain with now two or three typically. Actually, in foods, all you really find is two double bonds. The oils that contain polyunsaturated fatty acids are liquid at room temperature, and they're typically liq- liquid in the refrigerator too. You have to put them in a freezer to get them to get solid or to get cloudy. Even some fish oils will not get solid even in a freezer. The polyunsaturated fatty acids are... Again, they, they are what you find in oils. We say fats and oils. When we say fats, we're usually talking about things that are solid at room temperature. Oils, we're talking about things that are liquid at room temperature. And again, the oils are gonna be mono or polyunsaturated rich, and the fats will be saturated fat rich. Again, we're now in the polyunsaturated fat world, we have two families, two major families. It's called omega-6 and omega-3. And they're called omega because when chemists start, first started naming chemicals, naming fatty acids when they were discovering the structure of them, there was the beginning and the end of the molecule. And the way they designated what was the beginning of the molecule, they called that was the alpha carbon, the first carbon. And the last carbon in the molecule was always the omega carbon, taking from the Greek alphabet, the alpha and the omega, the beginning and the end. So the omega carbon was at the end. If you have an omega-6 fatty acid, it's actually s- said omega minus six, means that if you count back six positions from the omega or final carbon, you get the first double bond in the molecule. And that's specific for all, all the fatty acids that are omega-6 family. They all have that characteristic. First double bond, six counting back from the omega or final carbon. And the omega-3 fatty acids all have the first double bond in the third position. And that sounds like it really shouldn't... You know, so what? But actually, chemically, it makes quite a bit of difference in the physical properties of the oils as well as the other molecules or, or metabolites that these fatty acids are converted into by enzymes in the body. So that's the omega-6, omega-3 family. Fish oils are the ones that contain omega-3 predominantly. Vegetable oils, safflower oil, corn oil, sunflower oil are rich in omega-6 fatty acids.

   2. PAPeter Attia15:15

      It would've taken me an hour to have tried to explain that, Bill, and it would've been half as clear, so thank you for that. [chuckles] The thing that's always amazed me is how many different pieces of information can be conveyed in the nomenclature of fatty acids, because you're dealing with the extent or degree of saturation, anywhere from fully saturated to not, as mono and poly. You then have the actual number of carbons in the molecule, and then you have the position of that first double bond in the case of the monos and the polys. So even for someone who's taken a course in organic chemistry, like it still requires a little bit of thought when you're looking at detailed chemical drawings of these things. And I suspect that represents at least some fraction of the challenge that people have when talking about this, is we tend to distance ourself from what we're talking about because of the confusion. But as you point out, it sounds like it shouldn't make that much of a difference, right? The difference between coconut oil and olive oil is one double bond, and yet their properties are almost entirely different. I don't know if you have insight into this, but from a nutrition standpoint, does the specificity of enzymes for these fatty acids, is that kind of unique in terms of just how much difference you can see in the output relative to the starting structure? Or do you see that to be relatively conserved across all of nutrition? Outside of fats, that is.

   3. BHBill Harris16:41

      No, I think it's probably a, a truism that every molecule is unique, every molecule is special, in our foods, in our bodies, from water, which is probably the most special molecule in the world or in the universe, which makes up, what, 70% of our bodies, to down to the fats and fatty acids. And of course, carbohydrates and proteins are all very unique molecules. And I appreciate you mentioning the numbering. I should mention how they are numbered in case people ever see them written out in the number format, because any saturated fatty acid... Let's take a fatty acid that has 16 carbons, and it's a saturated fatty acid. Its, its common name is called palmitic acid. It comes from, primarily from palm trees, palm oil. So it's called palmitic acid. Its designation is 16 colon zero. 16 means how many carbons are in the molecule. The colon-- What follows the colon is the number of double bonds in the molecule. So all saturated fats is just a number, colon, and then a zero. When you get into monounsaturated fats, again, it's the carbon number first. Like the most common one is 18 carbon fatty acid, 18 colon one, and the one tells you there's one double bond. That fatty acid's called oleic acid. We get oleo from that word, oleomargarine. Once you start putting a double bond in a molecule, now you have to tell the reader where it is in the molecule. And to your point, when you have a 18 colon one, you gotta know where is that thing, and in this case, it's at position number omega-9. It's the ninth position back from the, the end. So that'd be 18 one colon N... Oh, yeah, here we go. Here's the other confusing part of... We say omega. We like to say omega-3, omega-6, omega-9, but chemists like to talk about them using the term N, like the letter N. It's the final carbon in the molecules, the nth carbon. It's the last one. It's just the nth one. Again, exactly where that came from, I don't know. Sometimes you'll see an omega-3 fatty acid called an N minus 3 fatty acid, N dash 3 fatty acid. Same thing. We're talking about the same molecule.

   4. PAPeter Attia18:53

      I think there's mathematicians that have snuck in there so that the nth terminus is where that N must have come from in a geometric series or sequence.

   5. BHBill Harris19:02

      Yes.

   6. PAPeter Attia19:03

      We're gonna include a lot of figures in the show notes that go through what these pathways look like because at least for me, I don't find I can wrap my head around these things without actually looking at the chemical structures. And I still remember probably a figure you sent me eight years ago that really walked through the pathway from linoleic acid and alpha-linoleic acid all the way down through the desaturases, elongases, all of these enzymes. And I, I think I just had to decide, like, look, I'm gonna sit here and I'm gonna learn this. And I remember printing it out, laminating it, carrying it around with me, and just going through it. It's like, okay, well, it's a desaturase. Okay, that makes sense. It's an elongase. It's gonna elongate here one, da, da, da, da, da. And at least for me, that was just sort of the way to do it, which was just I'm not gonna be intimidated by all of these names that by themselves don't mean much to me. But if I can look at them in the context of what you just said, which is they're simply referring to positions of double bonds and things, it, it makes it a little easier. Now, of course, I think most people

5. 20:03 – 23:55

   Membranes, tissue-specific fatty acid patterns, and diet vs. membrane composition

   1. PAPeter Attia20:03

      listening to this are gonna be like, "Okay, guys, why are you going so far into this?" And I think the answer is these fatty acids basically make up the most important parts of our body, right? I mean, every membrane of every cell is formulated with these, and it seems that they have a profound impact on our health.

   2. BHBill Harris20:23

      They do. And we're finding-- we're just discovering that more and more.

   3. PAPeter Attia20:26

      And there seem to be quite differences. I mean, on the one hand, I'm struck by the relative convergence that you can see across people consuming vastly different things. So there's sort of a dampening effect, if you will, that the body can do where it kind of converges all sorts of inputs to modestly banded outputs. But at the same time, I'm struck by the differences. So I'll give you one example, which is in the weeds clinically, but it's hopefully for the listener gives them a sense of why we wanna understand this. So when we do blood tests on patients, one of the things we always like to do is look at the EPA, DHA, AA levels in their red blood cell membranes. And the laboratory will spit out what percentage is EPA, DHA, total saturates, total monounsaturates, et cetera, et cetera. The ranges on those are not that big, and most people tend to fall within them no matter how much they're eating, but they can be at really different ends of those ranges. So you don't have people that differ by two and threefold, but people can definitely differ by 20 or 30%. Is that-- That's my observation. Is that fair?

   4. BHBill Harris21:33

      That's true. That's true. And because when you're talking about a blood test, and specifically you're talking about a red blood cell, which is the, the, the test we, we like to do, uh, and measure the fatty acid composition of the membrane, every... As you alluded to, every membrane of every cell is made up of fatty acids. And I would venture to say that there is a unique suite of fatty acids, a unique pattern of fatty acid for every type of tissue in every cell. It's not the same anywhere. They're all a little bit different. And that's because the body and the way the, the, the wisdom of synthesizing cells, each cell has its own role to play in metabolism. The membrane has to have certain physical characteristics, being real loose and floppy or being real stiff, depending on the need of that cell. And the fatty acid composition is unique to, uh, afford a certain kind of chemical flexibility. It's an amazing thing. There is certainly much wider variation in the fatty acids we eat than what we see in our blood. That's because the body is making the membranes from the raw materials we eat, and it picks what it wants, and it puts the fatty acids largely where it wants them to be. When you're making a red blood cell in the bone marrow, the fatty acids that are selected and put into that membrane are taken out of the blood, and the bone marrow takes what it wants. You can influence it a little bit, but you can't influence it, like, two and threefold different for most fatty acids.

   5. PAPeter Attia23:08

      To give you one real example that is just a, a great illustration of this, if you take somebody who is on the lowest fat diet in the world, or specifically someone who, for example, goes out of their way to avoid saturated fat, someone who's consuming in the neighborhood of 10 grams per day or less of saturated fat, and you counter that with someone who's on a super high fat diet that's eating 75 grams a day of saturated fat or more, you might see a 20% difference or a 10% difference in the amount of saturated fat within their cell membranes. As you said, the body tends to be a heck of a lot smarter at putting things together than just doing it based on what's available in the diet.

   6. BHBill Harris23:53

      Yeah. Thank God that's true.

6. 23:55 – 28:08

   The 1970s–80s low-fat era and how fats affect LDL

   1. PAPeter Attia23:55

      Let's talk about why this stuff matters, and let's maybe take a step back and go to, uh, back to 1980. So you do this experiment where... And, and I guess just to set the context for listeners, in 1980 is really we're witnessing the height or, or I would say sort of the wave is about to crest in the major fat phobia 15, 20 year run that's about to sweep over America. In 1977, George McGovern presiding over the Senate Select Committee on Health basically comes to the conclusion that even though the evidence against or implicating saturated fat and heart disease, even though that evidence is not great, it's good enough and they have to make an-- make a decision, and the decision that's put forth at that time is that Americans should greatly reduce their intake of saturated fat. I suspect that it's that decision that largely triggers an enormous interest in the type of work that you carried out as that first paper, that first major experiment you led as a freshly minted Ph.D. student, which was, well, gosh, if saturated fat is gonna do this, does polyunsaturated fat do the reverse? And at that point in time, Bill, if I'm not mistaken, there had already been a number of studies that had suggested that broadly speaking, polyunsaturated fats, mostly omega-6s, actually showed a reduction in total cholesterol. Is that correct?

   2. BHBill Harris25:19

      That's correct. In fact, in, in those days, even starting back in the '70s, people were taking tablespoons of vegetable oil to lower their cholesterol. It was taken as a medicine.

   3. PAPeter Attia25:29

      What is the mechanism by which taking tablespoons and tablespoons of sunflower oil or corn oil would lower a person's cholesterol?

   4. BHBill Harris25:37

      [chuckles] It's, it's complicated. It's, it's, it's been fairly well worked out since, but what that does, again, we mentioned what you eat is not directly reflected in your cell membranes. But when you're taking the om- the omega-6s or the omega-9s, the po- the monounsaturates, you're replacing some saturated fatty acids in the membranes. If you're reducing your f- saturated fat intake, like McGovern et al. suggested or said we should do, you're reducing the amount of saturated fat to an extent in your membranes, and that has ef- effect on the physical, chemical fluidity of the membrane. And there is buried within all of our cell membranes hundreds and thousands of these receptors, proteins that are sitting right in the middle of membranes. One of these is called the LDL receptor, low-density lipoprotein, which is the primary lipid particle that carries cholesterol in our blood. And that receptor is sitting there in the liver membrane. And if you remove saturated fat or lower the amount of saturated fat in that membrane, changes the properties of the membrane so that that LDL receptor is more efficient at removing a- and binding to and removing LDL particles from the blood. That essentially lowers your cholesterol level.

   5. PAPeter Attia27:01

      So the cholesterol lowering comes through more lowering of the LDL than the HDL?

   6. BHBill Harris27:08

      Correct. It's the LDL that's affected by, primarily by the saturation of fats. There's some effect on HDL cholesterol, but most of it is LDL.

   7. PAPeter Attia27:16

      On the surface, that would sound like a very positive thing, so as tempting as it is to sort of look back at the low-fat mania that swept across America 30 years ago or 40 years ago and just sort of dismiss it as buffoonery for a handful of reasons, especially with the sort of substitution of what became the go-to default, based on just the mechanisms and the studies of the day, it was not an entirely unreasonable thing to suggest.

   8. BHBill Harris27:43

      No, but particularly, as, as you said, McGovern's committee said saturated fat should be reduced. Didn't say all fat. I think that's where the message got mixed, because if you, if, if Americans had just reduced saturated fat and replaced it with mono and polyunsaturated fats, we wouldn't have had this problem.

   9. PAPeter Attia28:02

      It seemed to get replaced by sugar was the, one of the big things that got-

   10. BHBill Harris28:05

       Right. It was take all the fat out, and that was

7. 28:08 – 40:20

   The omega-6 and omega-3 pathways: LA to AA, ALA to EPA to DHA

   1. BHBill Harris28:08

      the mistake.

   2. PAPeter Attia28:09

      The question you were trying to ask when you did that study where patients were consuming, in the end, I think you said 25 grams of EPA, and I guess I should, before you answer this, maybe let's go back and explain what EPA, DHA, and all these other things are. And again, assume for a moment, Bill, that there will be a large figure. Multiple figures, in fact, will be in the show notes. We'll have the really detailed chemical ones, but we'll also sort of have the cartoony ones. So let's assume that someone's looking at the cartoony figure that takes linoleic acid down to arachidonic acid and then the one that takes alpha-linoleic acid down to EPA and then down to DHA. Can you, can you explain what's happening there? And let's start with the omega-6 one, I suppose.

   3. BHBill Harris28:51

      Sure. The left-hand side of the slide that I have in my mind, and I think you have in your mind-

   4. PAPeter Attia28:56

      I'm probably have in my mind a slide you've shared with me, but we will make sure we use exactly whatever you're speaking from in memory now

   5. BHBill Harris29:02

      [chuckles] It's, it's always done this way for some reason. Left hand, uh, the left hand is always the omega-6. And so it starts with linoleic acid, which is the, an omega-6 fatty acid. It's the principal omega-6 fatty acid in our diet. It is an essential fatty acid in the, with a capital E, essential, meaning we cannot make it. Uh, it's very much like a vitamin. Can't be made from scratch, and it, it is important for metabolism. So it is an essential fatty acid, and we have to eat some omega-6.

   6. PAPeter Attia29:31

      And what are the dominant sources of that, Bill?

   7. BHBill Harris29:34

      Vegetable oils. Soybean oil is probably, what, 80% of where we get our linoleic acid in, in our diets.

   8. PAPeter Attia29:41

      So sunflower, corn, soybean, cottonseed would be the big four, right? As my recollection-

   9. BHBill Harris29:47

      Yeah, actually, sunflower and safflower nowadays are not... Linoleic has been pretty much stripped out of those oils. Now they're what's called high oleic sunflower, high oleic sun- safflower. Doesn't say it on the label, but what's in the bottle has vastly changed from what it, the natural fatty acid pattern. But corn and soybean are still high omega-6, meaning 50, 60% of the fatty acids in that oil are linoleic acid. And linoleic is a 18, which, so 18 carbons, so it's 18 colon 2, two double bonds, omega-6 position. So what happens is you eat that, and a portion of it is glommed onto by certain enzymes in the liver that want to make a longer fatty acid. And so they add two carbons, and they get a 20-carbon fatty acid now. And then they add... The liver has enzymes that will add, instead of having two double bonds, it'll now have four double bonds. It goes through a, a three double bond molecule. Now we're at a four double bond. When you get to this molecule, it's an omega-6 family 20 carbons, four double bonds, that's called arachidonic acid, and that is a extremely important fatty acid in metabolism. If your listeners have ever heard of prostaglandins, this is the stuff of which all prostaglandins, well, most prostaglandins are made. It's the substrate. It's the beginning and, and it's terribly important throughout the body. The liver can even take that molecule and make it even longer, 22 carbons, and add more double bonds, up to five double bonds, but there's not much of that around, and we really don't know what it does. I think the most important endpoint of om- omega-6 metabolism is to produce arachidonic acid, 20 carbon, four double bond.

   10. PAPeter Attia31:35

       Well, the way you explain it, like, I think going back to the biochem, anyone who's listening to this who's a college student or a med student or something, I mean, that's not rocket science, right? You elongate it with the elongase enzyme, and then you further desaturate it, take two of the saturations out, and there you go. So you go from 18:2 to 20:4. Now, arachidonic acid has a real bad rap, doesn't it?

   11. BHBill Harris31:56

       It has, yes. [laughs]

   12. PAPeter Attia31:58

       We'll get into it in detail, but just is it safe to say that that's a bit misunderstood and that the binary view of arachidonic acid might not be the whole story?

   13. BHBill Harris32:09

       That's safe to say.

   14. PAPeter Attia32:10

       All right.

   15. BHBill Harris32:10

       I would agree with that. We'll get into that later then.

   16. PAPeter Attia32:12

       [laughs] So we'll come back to the, the demonization of arachidonic acid. Let's go over to the right-hand side of the picture we both have in our mind that is hopefully about the same picture. [laughs]

   17. BHBill Harris32:23

       It is. You're right. Now we have at the top instead of linoleic acid, we have linolenic acid. Just add one N to the name and you get linseed oil is... Most people are familiar with linseed oil. That is rich in this particular fatty acid. Flaxseed oil is, is, uh, similar. Chia seed oil but... are all sources of this linolenic acid. It's 18 carbons, again, same length as the omega-6 cousin. It has three double bonds instead of two, and the first double bond's in the omega-3 position, so it's an 18 colon three N minus three fatty acid. It also is essential in the same sense that the omega-6 cousin linoleic is essential in the diet. Alpha, this is called alpha linolenic acid, is also essential. We can't make it, and it's important for metabolism and, and health. And so the same game happens. This 18 alpha linolenic acids, we call it ALA, thank God. ALA is consumed and then, again, goes to the liver and is elongated. In other words, an- two more carbons are added and more double bonds are added to the molecule, so it goes from three to four to five double bonds. And now you have 20 carbon, five double bond omega-3 fatty acid, and that's called EPA. The EPA stands for eicosa, E-I-C-O-S-A, which is 20 in Greek. Penta is five. So there's 20 carbons, five double bonds, and then we say -enoic acid means it's a fatty acid. So it's a 20 carbon, five double bond molecule, and that's EPA, one of the most, two most important of the, quote, omega-3 fatty acids. That fatty acid then, EPA, can then be further converted to two more carbons. Again, elongates the chain and desaturases replace single bonds with double bonds, so you end up with a 22 carbon, six double bond molecule, and that's called DHA, which stands for docosa, 22, hexa, six, -enoic acid. So it's a 22 carbon, six double bond. So EPA and DHA are the two... When people talk about omega-3s, that's what they mean. Those two fatty acids are the principal ones.

   18. PAPeter Attia34:36

       Going forward, just to make everybody's life easy, we're gonna talk about ALA, alpha linolenic acid, as the omega-3 that you get mostly out of flaxseed and chia seed, I think. Are there any other sources of high, high dose of ALA?

   19. BHBill Harris34:54

       Well, no, not a high, high dose, but if you look at what's the principal source in the American diet, it's soybean oil.

   20. PAPeter Attia35:01

       Soybean and maybe canola to some extent has a little bit?

   21. BHBill Harris35:03

       To some extent. To some extent, yes. But soybean is such a... It's the gorilla in the room when it comes to vegetable oils in America, and it's about 7% of the fatty acids in soybean oil are ALA.

   22. PAPeter Attia35:15

       ALA goes through a number of steps, adds a couple carbons, desaturates a couple bonds, and you have EPA. Though I don't think you stated this, I do believe there's an equilibrium. EPA and DHA can go back and forth between each other, or is that mostly a one-way street?

   23. BHBill Harris35:31

       We thought they kind of went back and forth, but now I think we know based on a paper that was published a couple months ago, it looks like EPA goes to DHA. DHA does not... What they used to call it is gets retroconverted, in other words, goes from a 22 carbon, six molecule to a 20 carbon, five double bond molecule. That- that's retroconversion, going backwards. We thought it happened. We don't think it happens anymore.

   24. PAPeter Attia35:55

       It's more straightforward than what I used to-

   25. BHBill Harris35:58

       Yes

   26. PAPeter Attia35:58

       ... my laminated sheet's gotta be updated. So it's basically ALA to EPA to DHA on the right-hand side of the page. That's your omega-3 family. And then for the sake of simplicity, we're basically going from LA, linoleic, not linolenic, linoleic acid, down to arachidonic acid, AA. So LA to AA is your big omega-6 pathway. We'll pause there for a moment. With all of that said, what was your state of understanding circa 1978-ish, whenever you probably started this study, about EPA and DHA? Which today we know a lot about, and we'll talk about it, but what did you know then?

   27. BHBill Harris36:39

       I didn't know anything about them. All I knew was we were using salmon oil, and I don't remember... I, at the beginning of our experiments to see what the effect of salmon oil was on cholesterol, I'm not sure I even knew EPA and DHA existed. A very simple-minded way, we were asking the question We know animal fats that are solid at room temperature raise cholesterol levels, and we know that vegetable oils, plant fats basically, plant oils lower cholesterol, and they're liquid at room temperature. So we have animal and solid, and we have vegetable, plant, and liquid. So is it the liquidness that's important or is it the animalness, animal versus plantness that's important in controlling cholesterol levels? And so the uniqueness of fish oil is it comes from an animal, but it's a liquid.

   28. PAPeter Attia37:34

       That's really a funny and cute way, yet an elegant way to think about it, right? It's a two-by-two of solid versus liquid, animal versus plant-derived, and the fish oils sit in a unique part of that two-by-two, as you said, liquid but animal-derived. Okay, so that makes sense.

   29. BHBill Harris37:50

       That was the question. So d-- is it the animalness or the liquidness of the oil that lowered cholesterol? It turns out that fish oil lowered cholesterol, and it's an animal fat. So it's the liquidness that was important, not the source, not whether it's a plant or an animal. It's, it's the physical property of the oil that's the important thing. But EPA and DHA, we really... I mean, I don't remember knowing anything about them until well into our study and I started reading the papers from the Greenland Eskimo studies. And that's when I said, "Oh, these things have EPA and DHA in them. How about that?" [chuckles]

   30. PAPeter Attia38:22

       Now, the average American today who is not supplementing with fish oil will get approximately how many grams of EPA and DHA in their diet?
8. 40:20 – 52:12

   Findings of the early studies: platelets, Eskimos, and the LDL rise

   1. PAPeter Attia40:20

      What was the magnitude of the reduction in total cholesterol, LDL cholesterol, and triglyceride that you saw in that study? Not to put you on the spot with something you did 100 years ago, but directionally, was it significant? Not just statistically, but clinically.

   2. BHBill Harris40:32

      Oh, no, it, it, it wasn't marked. Like, cholesterol might have gone from 250 to 230, let's say.

   3. PAPeter Attia40:40

      Okay. What about triglycerides?

   4. BHBill Harris40:41

      Triglycerides went from about 100 to 75.

   5. PAPeter Attia40:44

      Okay. So that's a pretty big reduction in triglycerides. That's a, you know-

   6. BHBill Harris40:47

      As a percent, it is.

   7. PAPeter Attia40:48

      Yeah. Yeah. Any other phenotypic changes you observed in those subjects, or was that... those were your primary endpoints, that's all you had the budget to study?

   8. BHBill Harris40:58

      You alluded to it earlier. Platelet function. Bleeding was something we looked at because that-- by that time, Jørn Dyerberg had published a paper in Lancet 1978 proposing that EPA was an antiplatelet or, like, a blood-thinning fatty acid, and that that is why it prevented blood clots, and that is why Eskimos didn't have heart attacks. That was the proposal. And EPA had been shown by that time to be antiplatelet. So we were very interested in the effect on bleeding, and we saw a significant prolongation of an old-fashioned test called the bleeding time test, where we actually cut the skin and count how many seconds it takes to stop bleeding. It didn't prolong it any longer than aspirin did, so not outrageous, except in one patient. It wasn't a patient, it was a college student. But he had a, um, a marked drop in his platelet count. We wrote a whole paper on this guy. He had a marked drop in his platelet count, a really prolonged bleeding time, and we stopped him on the omega-3 diet because of that. But everybody else had a, a just kind of a mild prolongation of bleeding, which was an inhibi-- so the platelets were less reactive, less likely to clot, which is a good thing. So that fit with the idea that these are protective against heart attacks.

   9. PAPeter Attia42:19

      Now, if I did the math somewhat correctly on your salmon burger versus salmon oil distinction, is it safe to say they were getting about two-thirds of their EPA and DHA through consumption of salmon and about a third of it then through actual concentrate oil?

   10. BHBill Harris42:35

       It'd probably be the reverse because let's say they were getting two four-ounce servings a day of salmon, and let's just ballpark that at two grams. Let's be generous. Say that each one of those has two grams of EPA and DHA. So there's four grams, and then they were getting 20 grams from the liquid oil they drank. It was almost-

   11. PAPeter Attia42:55

       Oh, okay. I s- I don't know why-

   12. BHBill Harris42:55

       ... you know, half a cup

   13. PAPeter Attia42:55

       ... I thought it was only 10. Okay. So that was the reverse. So they're getting most of it in concentrate. They're getting, you know, maybe a quarter of it or even less potentially through consumption of salmon. Going back to the Eskimo for a second Do you have a sense from those studies what percentage of their total calories were fat and then how much of that was saturated versus poly? And I'm guessing mono was not a, a very abundant source in the North Pole.

   14. BHBill Harris43:20

       Very high-fat diets. Again, I'd have to look it up, but their diet was largely seafood, and we're talking about seal blubber and whale meat and some fish. This is pretty much what they ate. You know, Greenland, you don't grow anything, at least not until global warming comes along. But for now, they, they didn't grow anything. So fruits and vegetables and grains were... You could get them at an, an occasional store, but fundamentally they were living a traditional lifestyle and eating what they killed out of the sea. So they were probably 80% of their calories were fat.

   15. PAPeter Attia43:56

       And of that, do you have a sense of how much was polyunsaturated versus saturated?

   16. BHBill Harris44:01

       Probably about maybe six or seven grams a day out of, let's say, let's say they ate 100 grams of fat a day. So, so 6 or 7% of it might have been the omega-3, the polys, polyunsaturated. Very little omega-6. And probably 70% of the fat was saturated. Huge amount. I mean, this is what was so amazing about the Eskimo studies because we had this paradigm that high fat, high saturated fat, high cholesterol, of course eating very high cholesterol diet because everything was from animals, those are bad diets. And yet the evidence, which has been challenged nowadays, but at the time the evidence was these Eskimos were al- virtually free of acute myocardial infarction, of heart attacks. It just didn't make any sense, which is why the couple of Danish investigators went over there and started studying them, measured their plasma, their food, and they kind of discovered omega-3 fatty acids.

   17. PAPeter Attia44:59

       So was your conclusion from the study in 1980 that the high amounts of EPA and DHA in their diet were offsetting or protective to the high amounts of saturated fat? Or was your conclusion that maybe the saturated fat, because it came from fish, was somehow different from, say, dairy or land animals? I mean, how did you reconcile your experiment with this broader volume of data, though, you know, they're obviously asking very different questions and looking at very different things. I mean, how did you begin to square those things?

   18. BHBill Harris45:36

       For one thing, again, we didn't feed any blubber or any whale, whale meat or seal meat, any of that really high... We were feeding salmon oil.

   19. PAPeter Attia45:45

       Your subjects didn't really have a significant increase or change in macros, really. They were just basically getting an extra 25 grams of fat that happened to be polyunsaturated omega-3, but they weren't-

   20. BHBill Harris45:57

       Largely true. Largely true.

   21. PAPeter Attia45:59

       So where do you go next, Bill? So obviously... Well, you've never stopped looking at polyunsaturated fat since, so tell me how that study basically, uh, piqued your curious-

   22. BHBill Harris46:08

       I think the interesting thing the way that played out is actually 1985 was a turning point year for omega-3. In that year, in May of that year, the New England Journal published three back-to-back omega-3 studies. One was our study in, in giving very high doses of omega-3 and looking at effects on lipids. And we, we showed huge drops in triglycerides as we were studying people. Some of the... The study I did was with normal volunteers. We later did studies with people who had lipid disorders, had very high triglyceride levels, for example. And we found that giving them fish oil just, just knocked the socks out of their triglyce- instead of their triglycerides being 2,000, they were down to 250. It was a huge effect.

   23. PAPeter Attia46:59

       And how much EPA and DHA did you have to give them?

   24. BHBill Harris47:02

       That was the 18 to 20 gram. We were still doing-- playing the same game. We were still giving high doses of salmon oil. So New England Journal publishes our paper, it publishes a paper on kind of arthritis or inflammatory disease, and it publishes a paper on kind of molecular biology cell, the effects of EPA on what's called leukotrienes in inflammatory molecules. It was a basic science paper. But it was bang, bang, bang, three papers in a row, literally in the magazine in a row, in May of 1985 that just put omega-3s in lights on the map, and people got very excited about them. What we did subsequent to that, instead of patients completely controlling their diet, by that time we were able to... Because omega-3 supplements, concentrated pills were now becoming available. And so we did some studies just giving 18 capsules. So we were giving 6 grams a day of EPA and DHA in capsule form without changing anybody's diet. What happened in that setting was very different. In that setting, where we didn't change their background fat intake, just added omega-3s, triglycerides still came down very nicely, but the, the conundrum was LDL cholesterol, the bad cholesterol, started to go up. That was one of the downsides of the omega-3 story, because all of a sudden we published this, it gets a lot of press, American Heart Association, and the, and these fish oil companies that were just starting to advertise their product as cholesterol-lowering based on our earlier studies and others, it's not just us. Fish oil folks were marketing their fish oils as cholesterol-lowering products, and then we show, when we directly test them, that they don't lower cholesterol. In fact, in some people, at high dose, they will raise cholesterol. So FDA sends out all these letters to these companies and says, "You can't... You're false advertising. You can't say this anymore." So that was what they call a gut punch to the industry at that point.

   25. PAPeter Attia49:08

       At the time, was it clear whether LDL cholesterol alone was going up? Was ApoB going up as well? What other parameters of the, of the lipoproteins were changing?

   26. BHBill Harris49:20

       LDL cholesterol and ApoB. So there were more particles

   27. PAPeter Attia49:23

       How much were they going up based on just the six grams of additional EPA and DHA?

   28. BHBill Harris49:28

       They might have gone from an LDL of 120 to 140 or 150.

   29. PAPeter Attia49:34

       That's amazing. I mean, we're talking about six additional grams of a very specific type of fat having that much of an impact on LDL cholesterol, and presumably, as you said, the particle number or ApoB. So mechanistically, what do you think was happening there?

   30. BHBill Harris49:49

       That's been hard to figure out, but, uh, more recent studies have suggested that there's actually an effect primarily of the DHA component on LDL receptor activity. It actually can slow down the action of LDL receptors, so the D- LDL receptors are not removing LDL particles from the blood as fast as they used to be, so the blood levels go up. So it's an effect on clearance, not an effect... It's not an effect on production.
9. 52:12 – 1:01:57

   Prescription omega-3s versus supplements and EPA's heart benefits

   1. PAPeter Attia52:12

      But today, the largest dose of EPA that is given pharmacologically is about four grams. Is that correct?

   2. BHBill Harris52:19

      Four grams.

   3. PAPeter Attia52:20

      Isn't that indicated primarily for people with elevated triglycerides?

   4. BHBill Harris52:25

      It's indicated for people with very high triglycerides. So we got two levels of high triglycerides. You got garden variety high triglycerides, which is maybe 200. So a normal triglyceride may be 100, 150. Yeah, I mean, maybe that's not optimal, but that's kind of normal. 200 to 500 is what we call hypertriglyceridemia. And over 500 is now very high triglycerides. And there's kind of a bright white line. The FDA indicate... W- when the first omega-3 drug was approved, it was Lovaza or Omacor, and it was approved by the FDA for treating triglycerides over 500. Not under 500, over 500. And it was approved at this dose of four grams a day because that's the dose that the company did the studies at. They could get better triglyceride lowering with higher doses, but now you're talking six or eight pills a day, and it becomes totally impractical. So they... It was a compromise. Let's make the dose four grams a day. It, it does lower triglycerides, and it, it works to some extent, and so that's what the FDA approved. And so FDA has now set four grams as the standard dose.

   5. PAPeter Attia53:36

      Their product, is it any different from what one buys over the counter?

   6. BHBill Harris53:41

      [laughs] That product that I was just talking about, what's called Lovaza, it's now Lovaza, that's about 85% EPA plus DHA. It's ethyl esters. You can buy, uh, over the counter or dietary supplement essentially, more, more accurately, dietary supplements that have that much EPA and DHA as ethyl esters in one pill. Typically, you have to buy... The pill is not a one gram pill. So I-- maybe we're gonna get into this, the, the confusion about 1,000 milligrams of fish oil. But a, a... The, the standard drug, the Lovaza drug, is 1,000 milligram capsule, of which 850 or 85% is EPA and DHA.

   7. PAPeter Attia54:29

      Oh, yeah. No, we, we should definitely cover that now. So if you go on Amazon... I mean, I'll just share my bias. I've talked about it before. The two brands I typically recommend to patients are Carlson's and N- Nordic Naturals, and I'm sure there are several brands out there that are quite reputable. Anahad O'Connor at The New York Times wrote a story on this probably four or five years ago looking at lots of different brands of, of fish oil, and it was looking to basically see how many of these were made at GMP standard, how many of them actually had in them what they said they contained from a content perspective, what was the level of contaminant, all sorts of variables. But for whatever reason, again, those two brands I've just gotten to know and I've gotten to trust. But you still have to read the label very carefully because, one, these are very large capsules. Two, the entirety of the capsule is not EPA and DHA, so we tend to think about how much EPA and DHA we want, and we then have to sort of reverse engineer it out of the capsules. If you're taking 2,000 milligrams of ... a fish oil and let's say 1,600 of that is true EPA and DHA, which is 80%. That's not an uncommon finding. What's the other 400 milligrams?

   8. BHBill Harris55:41

      It would be a mixture of some monounsaturates and some polyunsaturates, just a, kind of general standard fatty acid you'd find in most foods. It's just, just a very small fraction of what's in a fish oil, particularly a fish oil concentrate.

   9. PAPeter Attia55:54

      Now, am I being paranoid about this stuff or do, do you think that most of these things that are sold as dietary supplements are, are reasonably safe or, or what, what is your view on that?

   10. BHBill Harris56:04

       I don't have a problem with dietary supplements. I think that the vast majority of them, when they've done consumer reports testing, they've done it twice in my memory, their final conclusion is generally the products have pretty much as much EPA and DHA as they say and with some, some variation, and they're free of, of toxins and any meaningful levels of environmental pollutants. So w- I, I don't have a, a problem with it. If... The challenge is if you're gonna try and get four grams a day of EPA, DHA, which... or three and a half grams is really what four capsules of Lovaza would give you, 'cause it's, again, 85%. So y- you're gonna be taking a whole lot of dietary supplem- a lot of pills, because most pills are not that concentrated typically. Nowadays, you can find very highly concentrated products, and it-- the line between a drug and a dietary supplement's getting a little bit fuzzy, which is something some of the, the drug manufacturers are pointing out more and more loudly, that there's a lot of products that are being sold as dietary supplements that fundamentally have the same chemical composition as, uh, FDA-approved drugs. There's gonna be a fight about this coming on. But the processing of omega-3 rich oils has advanced tremendously over the last 20, 30 years, and they can really concentrate these. Take a raw fish oil, which might have 30% of its fatty acids, EPA and DHA, and you do lots of processing to get rid of all the other fatty acids, and all you have left is EPA, DHA, and you're really highly concentrated, and that's not all that different than the composition of some of these drugs. It's gonna be confusing, I think, to the consumer.

   11. PAPeter Attia57:45

       Bill, what is our current understanding of the health benefits of EPA specifically? I wanna actually talk about this and then do the same thing on DHA, and then do the same thing on arachidonic acid, so cover these three end products of the, uh, omega-3 and omega-6 pathways. But let, let's come back to omega-3 'cause it-- or pardon me, to EPA, 'cause that's sort of where we got off on this little side tangent. Today, is the consensus view that EPA is a, quote-unquote, heart-healthy oil?

   12. BHBill Harris58:17

       Yes, and, yeah, you could say the same for DHA, in my view. But yeah, EPA is heart healthy. Its, its mechanisms by which it is heart healthy are, are multiple, and they include being converted into, again, some metabolites, some prostaglandin-type molecules that make the platelets, the blood platelets, less likely to get sticky. And so there's a reduced... It's kind of like taking aspirin without some of the side effects of aspirin. So that's one of the arms of the benefit. The EPA is also able to produce a s- a whole series of molecules that we call resolvens, like, because they resolve inflammation, so they're kind of anti-inflammatory in that sense. They also-- When, when EPA becomes incorporated into cell membranes, it, it changes the flexibility, the fluidity of the membrane, just because of its own physical properties, and that changes the way the enzymes that live in the membranes work in such ways that makes cellular metabolism run more smoothly. I mean, to try to simplify this. Those are really primary ways that EPA, I think, is heart healthy. Um, we've only had one big study with EPA only, free of DHA.

   13. PAPeter Attia59:36

       Let's talk about that one now, and then I wanna come into potential risks of EPA, and then I wanna circle back to DHA. But let's talk about the EPA only study. What was the patient population, what was the dose, and what was the objective of the study?

   14. BHBill Harris59:50

       The study was called REDUCE-IT, which it was an acronym, as they all are, for, for something. REDUCE-IT was the name of the study. The product was called Vascepa, like vascular EPA, V-A-S-C-E-P-A. Uh, the company that makes the drug is called Amarin. And the way the study was done, they gave four grams a day of this EPA. It's EPA ethyl ester, so it's a very purified EPA that has a ethyl ester, which is the typical way that they use, they concentrate omega-3s nowadays. Four grams a day versus the four grams of a mineral oil placebo, which has had some controversy as to whether that's a real placebo or not. Roughly 8,000 patients who all were on statin drugs to control their cholesterol levels, and they all still had triglycerides between two and 500, roughly, 150 to 500. So triglycerides were still elevated even though they were on a statin. Cholesterol, LDL cholesterol was roughly in the 70s, so there was low or, or healthy levels of LDL. And they also had to have either a history of heart disease or some s- other risk factors, like having diabetes, for example, was another way you could get in. So if you met that criteria, that kind of patient, you were given either four grams of placebo or four grams of, of Vascepa.

   15. PAPeter Attia1:01:10

       Do we know what fraction of those patients were metabolically ill? I assume most of them were. And I, th- I know this study's only about a year and a half old, right? I mean, I remember this when this came out.

   16. BHBill Harris1:01:19

       Well, it was reported in N-November, so s-six months ago.

   17. PAPeter Attia1:01:23

       Oh, wow.

   18. BHBill Harris1:01:23

       So eight months ago.

   19. PAPeter Attia1:01:24

       Yeah, yeah. So almost a year, but okay. That's... Yeah, I've, uh, time, I've lost track of time.

   20. BHBill Harris1:01:28

       Time flies, right. Exactly.

   21. PAPeter Attia1:01:30

       But how many of these people were sort of metabolically super healthy but just happened to have these genetic triglyceride elevations?

   22. BHBill Harris1:01:36

       And nobody checked in the study what any kind of-- they may be someday. They probably have blood for them and they'll check things later. But as a recruitment strategy, they just took people who met those criteria. You c- you're on a statin, you have triglycerides between one fifty and five hundred, and you've got some other risk factors for heart disease, and that's it, and you're in.

10. 1:01:57 – 1:11:22

    REDUCE-IT: pure EPA and cardiovascular events

    1. PAPeter Attia1:01:57

       What did the study show? Because it sure made a lot of headlines.

    2. BHBill Harris1:02:00

       It should have, and it did. It showed a twenty-five percent reduction in risk for overall cardiovascular events over about a f- four or five-year period, which is not that long, and it was effective ac-across, you know, myocardial infarction, need for angioplasty, a variety of different cardiovascular unfortunate outcomes. So it was a big hit. It was really... For the last fifteen years, we've been searching for other lipid-lowering drugs that... or other, other drugs that will improve the outcomes over statins. The statins have been established in the eighties and nineties and two thousands as very, very effective in reducing risk for heart disease. But there's still people even on a statin that still have events, cardiac events. So that's called residual risk. They have leftover risk. So what do we do for that? And they've, there's probably been ten or fifteen drugs that have been tested to try to improve upon a statin. Really, none of them have worked, without going into all the details. But this one, pure EPA, worked, and it worked great, and it worked with virtually no side effects. And you can take it with any other medications. It doesn't have any drug-drug interactions. I think it was a big hit and well-deserved. I should mention the name, the, the trade name of the drug is Vascepa. The generic name is called icosapent ethyl, two words, and it's spelled, starts with an I, I-C-O-S-A, icosapent. It, it's, it's, it's really just a flipping around of the spelling of icosapentaenoic acid or EPA.

    3. PAPeter Attia1:03:40

       Now, Bill, one of the issues with this study, of course, is the inclusion criteria assumes that the patients have very high triglycerides. I, I must have received twelve emails in the span of a day from patients of mine saying, "Hey, should I be taking this?" To which my answer was, "Well, your triglycerides are eighty-six, so I'm gonna go with no on that because I can't infer that the mechanism by which this worked in these patients is going to have a benefit in you." Do you know if there's any plans to repeat that study or a study like it in a normal triglyceride population?

    4. BHBill Harris1:04:17

       I don't. I know that what's, what's fundamentally being reproduced is the s- the same type of patient, but with a EPA plus DHA product.

    5. PAPeter Attia1:04:27

       Why was that study done with only an EPA versus a combined?

    6. BHBill Harris1:04:31

       Well, [chuckles] in the late eighties, a EPA-only drug was approved in Japan called Epadiel, which is essentially, it's exactly the same thing as Vascepa. And the Japanese, back in the nineteen eighties, believed that it was EPA that was the active agent in fish oils. So a drug company called Mochida developed an EPA drug, and they got it approved, and they've been using that EPA drug for years and years. And the JELIS trial, which was done, published in two thousand seven, which was a Japanese omega-3 trial, used this product. It's called Epadiel. We call it Vascepa. And it was successful. This company in Ireland, which, Amarin, has the same molecule essentially. I think they're trying to carve out a unique niche in the omega-3 world that they can get an approved drug. EPA plus DHA is already approved. That's Lovaza, Omacor. They say, "Well, let's just try the EPA part, see what that does," and it works well. What nobody's ever done and nobody is done, doing yet is the counterpart-

    7. PAPeter Attia1:05:43

       The DHA only. Yeah

    8. BHBill Harris1:05:43

       ... a DHA-only study.

    9. PAPeter Attia1:05:45

       What is your take on this from two standpoints? The first is, if you can speculate for a moment, do you believe that EPA and DHA, from a cardiovascular standpoint, are as beneficial or have benefit in people with normal triglycerides?

    10. BHBill Harris1:06:02

        Yes. I don't think the me-- I don't think the benefit, the cardiovascular benefit comes from lowering triglycerides. In fact, in this study, the REDUCE-IT study I just talked about with EPA, triglycerides were lowered fifteen percent maybe. You know, it w- it was not a huge drop in triglycerides by any means.

    11. PAPeter Attia1:06:22

        What was the reduction in LDL-C and ApoB? I, I don't recall.

    12. BHBill Harris1:06:26

        Yeah, virtually no change.

    13. PAPeter Attia1:06:28

        So unlike PCSK9 inhibitors, which really have had the biggest impact on residual risk in cardiovascular disease over the past five years, very similar population to what you've described in FOURIER more so than ODYSSEY, where they started with patients already maximally statinized. These patients, it was independent of their triglyceride level, but they had to be sort of maximally statinized. I think they came in with an average LDL cholesterol of seventy-four milligrams per deciliter. And in a very short period of time, you know, something to the neighborhood of two and a half years, saw an amazing event risk reduction.

    14. BHBill Harris1:07:03

        But the event risk reduction in REDUCE-IT was greater than the PCSK9 studies.

    15. PAPeter Attia1:07:09

        Yeah. It was a longer study. Wasn't it about five years in REDUCE-IT?

    16. BHBill Harris1:07:12

        Yeah. Right, right.

    17. PAPeter Attia1:07:13

        Yeah.

    18. BHBill Harris1:07:13

        Right.

    19. PAPeter Attia1:07:13

        And FOURIER was like two point two, and ODYSSEY was about two point four, which again, I think all of those are amazing. I'm not saying that to be one up on REDUCE-IT or one down. I, I actually just... I think most people don't understand the time course of cardiovascular disease well enough to appreciate the fact that you can take a, a disease that is a time course disease that starts at birth and in somewhere between two years and five years actually reduce events. It shouldn't happen. And in fact, I remember I don't know if I actually said it out loud. It would be great if I did, 'cause I could go back and f- you know, maybe someone would remember. But, but I certainly remember thinking FOURIER is going to fail because not that I didn't have faith in the mechanism of PCSK9 inhibition, but because I simply didn't think you could bend the arc of a disease like cardiovascular disease in two years on a group of patients who had an LDL cholesterol in the 70s. That, that just struck me as impossible. It is really quite amazing that all of these things work, and in some ways it's even more amazing, frankly, that just pure EPA could have this effect, which again, I'm bringing you back to the question that I keep interrupting you [chuckles] when you start to answer. I apologize. Why in the world would four grams of EPA reduce events, especially as you said, when it's not the obvious mechanism of, hey, we're gonna drop triglycerides, which all things equal should drop ApoB. And by the way, you're seeing a greater magnitude of event reduction than you're seeing with aspirin, so the pure antiplatelet effect also seems a bit counterintuitive. What else do you think is going on here?

    20. BHBill Harris1:08:52

        Right. Right. It, it's not enough. Whatever role inflammation... And, and it's, it's such a, a slippery word that's thrown around so much, but EPA definitely gives rise to molecules that are pro a resolution of inflammation. So inflammation starts, the EPA will, will shut it down. To whatever extent a, a cardiovascular event is, is precipitated by an inflammatory event, the omega-3 EPA could, could participate in that. It could stop it. Um, the omega EPA could also play a role in, uh, even like the control of the heart rate. The, uh, heart rate variability can be reduced. I'm not sure in this study they measured it, but we've done studies with omega-3 showing heart rate variability, which is a marker of autonomic nervous system control of the heart, uh, i- is improved. So that's, uh, another piece of the puzzle. It, it could just be several different things that in an-

    21. PAPeter Attia1:09:47

        That start to add up

    22. BHBill Harris1:09:48

        ... each one in of itself. They add up, and they multiply.

    23. PAPeter Attia1:09:51

        A- and you said heart rate variability improved. Before that you said reduced, but I think you mean improved or increased, right? Is that what, uh-

    24. BHBill Harris1:09:57

        Correct.

    25. PAPeter Attia1:09:57

        Yeah.

    26. BHBill Harris1:09:57

        Correct.

    27. PAPeter Attia1:09:58

        Do you recall if in REDUCE-IT they measured other cytokines, inflammatory cytokines beyond the usual suspects? Like did they look at the, all of the suite of interleukins and things like that? Was that published in the original study? So presumably, as you said, they've got a biobank that may be able to look at other markers of what... What was the signature of this event reduction? Going down this path you just described, it'd be great to see what happened to IL-1, IL-6, TNF. You know, if you look at all of these other things that could be playing a role in the inflammatory component of atherosclerosis, that would be interesting to see, right? 'Cause then it would give you more confidence that this is, this has broader applicability than just people with sky-high triglycerides.

    28. BHBill Harris1:10:43

        Back again to the inclusion criteria, these are not sky-high triglycerides, and this is not triglycerides over 500. These, these are not people at risk for pancreatitis. This is much more garden variety hypertriglyceridemia.

    29. PAPeter Attia1:10:54

        I don't know. In my practice, Bill, one- 150 to 500 is sky-high. [chuckles]

    30. BHBill Harris1:10:59

        Okay. Well, I guess I'm used to hearing, you know, type, you know, 500, 1,000, 2,000. You know, it's... Pe- people have that. But, um, that's the place the omega-3s first got their approval, in that very high triglyceride world. And so when we bump it down to under 500, to me it seems like kind of garden variety. But-
11. 1:11:22 – 1:17:26

    Red blood cell testing and the limits of ALA conversion

    1. PAPeter Attia1:11:22

       Did that study, did it look at how much of that EPA converted to DHA? In other words, one of the advantages presumably of giving mega dose of EPA versus mega dose of DHA is you're higher up the food chain, so presumably you're covering any benefit that's unique to EPA, if you believe there may be one, and then you're also transmitting into DHA and getting that. Or do you believe that all of the benefits of EPA are transmitted through DHA?

    2. BHBill Harris1:11:50

       I think it's probably m- all the benefits of EPA are transmitted through EPA, not through conversion to DHA.

    3. PAPeter Attia1:11:56

       Not through the conversion to DHA.

    4. BHBill Harris1:11:58

       No, no. In fact, when you look at, um, a couple of, a couple of papers looked at the effects of giving pure EPA, four grams, on, on red blood cell DHA levels, for example, and DHA levels actually go down a little bit. EPA goes up, of course. You're feeding EPA. But the DHA component in the red cell membrane goes down or, or in other studies stays the same, but doesn't go up. You're not, not increasing DHA tissue levels.

    5. PAPeter Attia1:12:29

       That's really interesting. So in other words, if EPA is being converted to DHA, which I assume we still think it is, it's not necessarily... I mean, it's just increasing the substrate pool of DHA, but not necessarily the incorporation into cell membranes.

    6. BHBill Harris1:12:43

       Right. Right.

    7. PAPeter Attia1:12:44

       That's interesting, and that actually explains, I think, some of what I, I guess I would see when I look at people's laboratory values. While we're on this topic, if I consumed staggering amounts of flaxseed oil... By the way, a friend of mine once gave me a recipe to make flaxseed tea, and I... A, it tasted really good when I had it at her place, so part of it is just it was really amazing, and part of it is the recipe was so complicated that I took pride in, like, taking two days to make a vat of flaxseed tea that could feed a small village. I was never able to get it quite right, but let's assume I could get it right and I could consume a near infinite amount of flaxseed oil. Could that amount of ALA ever give me sufficient enough substrate EPA and DHA to rival what we're talking about in these supplemental doses of four grams?

    8. BHBill Harris1:13:40

       No, it's never... When people have tried giving 12 grams of ALA Or not just flaxseed oil, A- ALA

    9. PAPeter Attia1:13:48

       Just straight ALA. Yeah

    10. BHBill Harris1:13:49

        Yeah, you d- you don't even get... You might take an EPA level of 1% in a red cell and maybe drive it to 2%.

    11. PAPeter Attia1:13:57

        There's two questions I have, and I hope I'm gonna remember the second one. Is there a risk that looking at the red blood cell, which of course is the most obvious and easy cell for us to access the membrane in, is there a risk we're missing something that's not occurring in cells that we can't access, like, as easily? We can't look at the membrane of adipose cells or muscle cells, and we typically... Even though it would be just as easy to look at leukocytes, I assume we don't look at them, at least clinically or commercially. Do we run the risk of just looking at one, one pony here?

    12. BHBill Harris1:14:28

        Right. E- everything's a compromise. So the red cell is the easiest cell type to get at. Leukocytes are not that easy to get at.

    13. PAPeter Attia1:14:35

        Right. You need some apheresis or something like that.

    14. BHBill Harris1:14:37

        In a, in a clinical, clinical lab. Right. Right. In just a clinical lab, lab setting is very difficult. Red cells are thrown away by the gallon day by day just 'cause y- all you really wanted was the plasma, right? So you, the red cells go to the bottom and you take the plasma off and you throw them away. Red cells are... W- we've shown red cells correlate with quite a few other tissues in terms of the omega-3 levels. So they are a good reflection of other tissues. Probably the only one that's the least reflective of is the brain, at least in the adult. Uh, it's hard to get the fatty acid composition of the brain.

    15. PAPeter Attia1:15:08

        Yeah, I don't think anyone's gonna sign up for the brain biopsy. So what are some of the tissues that you've seen high correlation with, with RBC?

    16. BHBill Harris1:15:14

        Well, w- we did it originally with the heart using heart transplant patients who were being followed up every six months with a heart biopsy to see how their heart was doing, of course. And we were able to get their red cells and the heart biopsy and measure the omega-3 content and show the nice correlation. The higher the omega-3 in the red cell, the higher the omega-3 in the heart. Other people have done this, too. And you can do it in animals, of course.

    17. PAPeter Attia1:15:37

        Yeah.

    18. BHBill Harris1:15:37

        You can do it in lots of different tissues.

    19. PAPeter Attia1:15:38

        Is there a s- is there a high, uh, correlation with liver as well as myocyte, skeletal myocyte?

    20. BHBill Harris1:15:42

        Right. Muscle and liver and guess small intestine, large intestine.

    21. PAPeter Attia1:15:47

        Wow. Okay. We'll make sure we include all these papers, Bill, as well in the show notes 'cause this is, uh-

    22. BHBill Harris1:15:52

        Sure

    23. PAPeter Attia1:15:52

        ... that's actually something I've just been too lazy to personally go back and check. It's on my list of 2,000 things I want to go and check, and that's one of them is I always wanted to go back and look at what the association between RBC membrane level was and other tissues. The other question I had was what are the... We've kind of glossed over it 'cause it's a little bit of the stepchild, but what are some of the direct benefits, if any, of ALA by itself? 'Cause you just noted that it's not that having all the ALA in the world is not really meaningful to conversion to EPA. So if there's benefit to ALA, it needs to be through ALA, right?

    24. BHBill Harris1:16:25

        We don't really know. There's certainly some hints in some of the population, uh, epidemiologic studies that higher ALA intakes, presumably independent of EPA and DHA intake, is associated with reduced risk for disease. So that's, that's a good thing. I have no problem with ALA. I just have a problem with it being a substitute for fish oils or omega-3, long-chain omega-3s, 'cause it, it doesn't. But A- ALA itself, I mean, I don't think it's a bad idea to take ALA products, rich, rich oils, as well as take fish oils. But we don't really know the mechanism, but I think there's probably going to be some, uh, metabolites of ALA itself in, in the same sense that there are prostaglandins, leukotrienes, and other metabolites from EPA and DHA. There probably are from ALA, too, that are doing things we don't know about. It's all dark on the inside, so we don't really quite know what's going on. I think there's gonna be benefit, but it's, it's not because it's converted to EPA and DHA as far as we know.

12. 1:17:26 – 1:23:37

    DHA, the omega-3 index and individual variability

    1. PAPeter Attia1:17:26

       And speaking of which now, let's talk, let's, let's go down the bottom of that chain. We've talked about EPA. Let's talk about DHA. As you said, we haven't had the study that takes four grams of DHA, administers it in either a high, low, or normal triglyceride population. But based on studies that have looked at high doses combined and maybe trying to contrast with high-dose EPA studies, plus looking at all the animal and mechanistic studies, what is your best guess as to what a high dose of DHA is doing?

    2. BHBill Harris1:17:59

       In a sense, much the same thing as EPA. There are parallel mirror image molecules being made. What DHAs are called instead of resolvins are called protectins. These are the metabolites that are very active in anti-inflammatory processes. DHA will improve platelet function, make platelets less sticky, the same way that EPA does. Uh, but a d- different mechanism, but the same outcome. DHA is probably better at actually lowering triglycerides and raising HDL than EPA is. So there could be actually a, a lipoprotein benefit there. Although DHA does raise, uh, particularly in people who are hypertriglyceridemic, taking fairly high doses of DHA, there will be an LDL raising effect. Uh, whether that's a bad thing or not, nobody knows, but it's been observed, and that's one of the differences between an EPA only product and a EPA plus DHA is there have been folks who've been trying to say that the EPA plus DHA products are not good for you because they have DHA, which can raise LDL. But I think that's a, a big stretch, and this is a lot of caveats. But nevertheless, that's part of some marketing programs now, which I find unfortunate. DHA is certainly, if you look at biology at the membranes of any of our membranes, red cells or heart, DHA is by far the most common, much higher levels of DHA. Like, the, the red cell, 85% and 15% if you look at the t- total of EPA plus DHA.

    3. PAPeter Attia1:19:30

       Yeah, I usually think of it in terms of absolute, so I know... I was looking at my labs from... I draw my labs every once in a while. I think the last check was a few weeks ago, and my, my red blood cell EPA level was about 2.2% and DHA level was about 8%. So it's, uh, comparable to what you're saying for a total of about, you know, a little over 10%, 10 to 11%. At what point do you worry? Is it too high?

    4. BHBill Harris1:19:58

       We really haven't seen any adverse effects in higher doses, and there are major international bodies that are saying up to five or six grams a day of EPA, DHA is no, no problem.

    5. PAPeter Attia1:20:08

       And five or six grams of EPA would give you what level in the RBC? The highest level I've ever seen in RBCs about-- I've had a patient who was just taking this stuff by the truckload and which means he was probably taking about three grams a day, maybe four, I'm not sure, but, you know, was sitting there at about 16% EPA plus DHA in the red blood cell. Is that com-

    6. BHBill Harris1:20:28

       We, we have seen higher, but that is very-- y- that guy is probably ninety-nine point nine percent percentile. We've seen people over twenty who are not taking fish oil [chuckles] , which is pretty... So there's some interesting biology here.

    7. PAPeter Attia1:20:41

       What, what, what do you think is going on in there? How is that happening? Are they just eating a lot of fish or?

    8. BHBill Harris1:20:45

       This particular lady I'm thinking of was-- when we interviewed her, said, yeah, she eats maybe fish once a week, you know, some salmon. But it's not like [chuckles] she's not doing anything Eskimo, and she wasn't taking a supplement. She was a woman of Indian, East Indian extraction and drank a lot of... The thing that really stuck out, she drank a lot of kefir, liquid yogurt. But, uh, what in the world that would have to do with omega-3, I have no idea. So we don't know what happened to her, uh, why she's that way, and there's other people that have been up that level. I think it's just genetic. I mean, that's, that's a cop-out word, I know.

    9. PAPeter Attia1:21:20

       I know. It, it is funny, but I was just about to say the ubiquitous cop-out of genetic. But I've absolutely seen patients who eat one serving of fish a week and need four mega EPA, DHA, and it's the same brand, so it's not a brand issue. They'll take a, you know, mega dose, four capsules a night of the big stuff, and you might get them up to seven percent. And then I've seen other people who eat fish twice a week, and they walk around at nine percent. You're seeing this as well, and you're equally stumped by it.

    10. BHBill Harris1:21:52

        Yeah, right. Yeah, we, we published a paper recently looking at in something like thirty-five hundred people that have submitted blood to us and have told us how much oily fish they eat and whether they take a supplement or not. And that's all we asked. And we found out that the group that has the fifty/fifty chance of an eight percent omega-3 index were eating three-- reported eating three oily fish meals a week and taking a supplement. But below that, the chances of having eight percent are diminished, diminished. But there's even within the category of people that were not taking any supplements and eating maybe one o- one fish meal a week, there were some people that had eight percent. It's just they're real outliers. There's a tremendous variability in the level in the blood compared to what's in the diet.

    11. PAPeter Attia1:22:42

        Bill, just based on your knowledge around this, and I-- we haven't fully finished the DHA stuff, so w-with that caveat, do you have a, a recommendation for physicians or patients who are monitoring EPA and DHA levels in red blood cells for a target? I mean, the lab that I use, I think gives a, a range of eight to ten percent as ideal. Do you have a, a view on this?

    12. BHBill Harris1:23:03

        We think, uh, in, in what we call the omega-3 index, which is EPA plus DHA in red cell membranes, our target is eight to twelve percent. Just that's a, a range we think is the healthy range. Average American is around five percent maybe, four or five percent, twice as high as normal.

    13. PAPeter Attia1:23:22

        I've seen people at two percent, which are obviously people who don't supplement and don't eat fish, but I've also seen people who don't supplement, don't eat fish, and they're at five to six percent, which again comes back to this sort of question of, of the role of genetics in, in driving this.

13. 1:23:37 – 1:30:26

    DHA and the brain, choosing fish, and mercury

    1. PAPeter Attia1:23:37

       So let's come back to DHA for a moment. A few years ago, there was certainly a little bit of hoopla around the neuroprotective benefits of DHA. What, what is the state of the art and science around that particular question?

    2. BHBill Harris1:23:51

       So it begins with the observation that the brain and the retina, which is really just an extension of the brain, are very rich in DHA. Virtually no EPA in the brain. Beginning with that, you ha-- the la-logical conclusion is E- DHA is important in the brain and the eye because they're there. People have then tried to jump to the conclusion that therefore, if you give more DHA, you're gonna get better brain health and better eye health. Well, that's not necessarily panned out, particularly like in depression studies. Uh, that's the most clear area at the moment where folks who have tried to give high DHA products to try to affect depressive symptoms, and they don't really work. The products that seem to work to actually have an effect on depressive symptoms are ones that are richer in EPA than DHA. And, you know, when-- So you look at a meta-analysis, like a compilation of lots of different studies, the positive ones are the ones that are richer in EPA, but there's no EPA in the brain. The logic was that if the meat of the brain has got DHA in it, the actual physical flesh of the brain is DHA, well, then DHA should be given, and it would be beneficial, but that's, that's not a logical assumption. I think what's happening is EPA is probably providing some unique and anti-inflammatory effects in, in the brain circulation that's affecting... 'Cause we don't understand depression at all, but it's somehow affecting the expression of depressive symptoms like DHA doesn't. I can't say that DHA is the brain omega-3 and EPA is the heart omega-3. I don't think that's true. I don't think we can at this point say one of them is better than the other for any given system. They come together in nature. In all fish that provide con- that contain EPA and DHA ha-has both of them. It's not fifty/fifty. It's usually sixty/forty or forty/sixty in, in terms of ratio, EPA and DHA. So I think that's the best thing to do is to get both of them at this point for any condition, all conditions.

    3. PAPeter Attia1:25:56

       Because you've done a Ph.D. in nutrition, I'm gonna ask you a nutrition question. If you recommend ... fish for people to eat. If someone says, "Look, I wanna get as much of the EPA, DHA as I can through my food intake as opposed to supplement intake," and then being mindful of fish that contain toxins, particularly mercury, what's the best yield for safety and then high quantity of EPA, DHA? I mean, salmon seems to be at the top of that intersection, right? Is there other fish you'd put there?

    4. BHBill Harris1:26:25

       Sardines, herring, mackerel. Almost all the oily fish are gonna b- have high EPA levels just simply 'cause they have high oil, 'cause they have fat in their flesh, in their tissues. There's really only about four or five fish that are, because of the mercury, have a mercury concern, and they're fish that are really very rarely eaten. Tilefish, swordfish, king mackerel, and shark. So those are the ones that everybody agrees that pregnant women, lactating women should not eat because they affect neurodevelopment of the brain. There's anecdotal stories of people eating vast amounts of tuna and getting high levels of mercury, and sure, I'm sure that can happen. But by and large, albacore tuna, for example, is twice as much EPA and DHA as chunk light tuna. It's more expensive, so it's a great source of EPA and DHA, but it has more mercury than chunk light tuna has. I think people get that balance way out of whack. They're far more concerned about minuscule amounts of, of mercury, and they will forego the good benefits of EPA and DHA in a food like, like albacore tuna, white tuna because they're afraid of the small amount of a toxin. The benefits of eating fish, even if there's some mercury in it, far outweigh the downside of the mercury.

    5. PAPeter Attia1:27:51

       Yeah, I probably need to go a little further down this rabbit hole, but, but a- again, this is another example where I've seen amazing individual variability. I've seen people who eat three servings of tuna a week who have a mercury level below 10, you know, on a, on a laboratory assay like LabCorp where the upper limit of normal is 15, and there are people that walk around at 10, so they're perfectly fine and they're eating tuna three times a week. And then I've seen people who consume tuna twice a month, and they're right at the upper limits. There's a lab called Quicksilver that we use to further scratch at that a little bit and look at the inorganic and the organic, but one of the things we've learned through that is clearance matters a lot. In fact, clearance seems to matter at least as much, and maybe not surprisingly, as intake. So the, the, the Quicksilver test looks at the hair, urine, blood. It basically quantifies how they're clearing inorganic and organic, and then you get a sense... And then you're measuring organic and inorganic, so you're getting a sense of is this coming in through food, is this coming in through, you know, the environment. But yeah, it's another one of those things that's complicated. I mean, I-- my general rule and advice to patients is, is sort of salmon and small baitfish is sort of open field running. Um, and if you're gonna go haywire on tuna, which I could do, I could eat tuna every day, I love it so much, I don't, you're probably best to at least measure your levels. But to your point, uh, maybe we don't know exactly what the toxicity curve looks like. It's, it's worth exploring. I do wanna come back to something else on the, the omega-3 broad front, which is there are a handful of studies. I, I sort of-- I've seen one of them, but I believe there are others. I think one of them was the Honolulu Heart Study or something about, this has got to be over 20 years old now, that actually looked at a reduced amount of lung cancer in smokers who had high omega-3 levels. Am I getting that right?

    6. BHBill Harris1:29:45

       I've not seen that. I'd like to see that. But I've seen papers recently looking at smokers. Some of the adverse effects of smoking seem to b- be mitigated by a high omega-3 intake. Sort of the same idea.

    7. PAPeter Attia1:30:00

       It's the same idea, yeah, and maybe I'm just not remembering the study correctly. But I... It sort of goes down this theme of there was a protective benefit of high amounts of EPA and DHA. Let's pivot back over now to the other side of the axis. So we talked about linoleic acid, or LA, as an essential fatty acid. I believe you said we get the lion's share of it from soybean and corn oil, correct?

    8. BHBill Harris1:30:25

       Right.

14. 1:30:26 – 1:44:55

    Arachidonic acid, omega-6 ratios, and seed oils

    1. PAPeter Attia1:30:26

       Linoleic acid you described through the process of elongation, desaturation, ultimately becomes arachidonic acid. How did arachidonic acid get such a bad name? Is that, is that all Barry Sears that we have to thank for that?

    2. BHBill Harris1:30:40

       [laughs] Partly Barry, partly Bill Lands, partly Artemis Simopoulos. The way I look at it is if we think back to the 1960s and '70s, we had this thing called the P to S ratio in oils. Um, do you remember that? Polysaturates, right. For heart health, you wanted to eat high P to S ratio foods, oils. The ratio mentality was, that was the idea. And it made sense. We want less saturated fat, more polyunsaturated fat was good for your health, good for your heart. We move a, a couple decades in, now, now we have the omega-6s and the omega-3s, and we know that they... E- the L- linoleic and ALA on the omega-3 side compete with each other for enzymes to metabolize up to other EPAs and arachidonics. And so there's a competition there. So people like ratios, black and white, you know, black hat, white hat. Arachidonic acid does give rise to several or many, um, pro-inflammatory compounds. Uh, no question. It's a good thing. It's what it's supposed to do. The concern is does that get out of whack, and does it go on and on and on and never get resolved? So arachidonic got this black hat idea. It's the pro-inflammatory one, and then EPA and DHA are the anti-inflammatory ones, so let's just do an omega-6, omega-3 ratio. I have a lot of problems with that ratio. I think it doesn't make any sense Partly because it presumes that the omega-6s actually are bad, and they really aren't. The evidence now coming out from large meta-analyses where people are-- and we were part of this study, where they looked at plasma linoleic acid levels or, or, or blood linoleic acid levels, so omega-6 levels in the blood, and arachidonic levels in the blood. And they, they measured it in, in thousands and thousands of people, and they followed them for the development of heart disease and diabetes over between five and thirty years. And a very clear signal that the higher the level of linoleic acid, meaning the more you eat, that's the only way you can raise it, is by eating more. The higher the level of linoleic acid in the blood, the lower the risk of heart disease, the lower the risk of myocardial infarction, the lower the risk of diabetes. And arachidonic acid levels were unrelated to either of those outcomes. It was neutral. It wasn't higher or lower. It didn't make any difference.

    3. PAPeter Attia1:33:00

       So what's the correlation between arachidonic acid level and linoleic acid level? And what's the correlation between arachidonic acid level and ingested linoleic acid?

    4. BHBill Harris1:33:11

       Virtually none. Even though we know arachidonic can be made from linoleic acid, only less than 1% of the linoleic we eat gets made into arachidonic. Very little of it's ma-made.

    5. PAPeter Attia1:33:22

       And you may have already said this, and I was too busy trying to think about something you previously said, but just as ALA conversion to EPA is virtually irrelevant, is that a similar statement for LA conversion to AA?

    6. BHBill Harris1:33:37

       The same idea. When the people have given, you know, radioactive tracers and, and measured how much actually goes from LA to AA, very-- less than a percent. Very little. Um, so-- and people have, uh, also looked at, you know, if you give a huge dose of LA in the diet and then you measure the effect on a plasma arachidonic, no effect. If you completely strip the diet for, you know, weeks and weeks of LA, arachidonic levels don't go down. It just doesn't respond. So arachidonic is very tightly controlled, and it's not driven by a linoleic acid.

    7. PAPeter Attia1:34:15

       While we're on the subject of ratios, Bill, one of the other ratios that people like to talk about is the ratio of AA to EPA and AA to DHA. Do you put that in the same category of helpfulness as total omega-3 to total omega-6, or...?

    8. BHBill Harris1:34:35

       It's a little bit better. One of the problems with the total omega-6 to omega-3 is it doesn't define what the fatty acids are.

    9. PAPeter Attia1:34:42

       Right. Because the omega-3 can be dominated by ALA, which is what it is. That number could be dwarfed by how much is EPA and DHA.

    10. BHBill Harris1:34:51

        Correct. Right. And, and the same on the omega-6 side. There's seven different omega-6 fatty acids you throw into that recipe. Which one are we talking about? And, and so that's a problem. The fact that you can have the same ratio of EPA or of omega-6 to omega-3 with very high levels of omega-6 and omega-3 or very low levels of omega-6 and omega-3, same ratio, doesn't make any sense. And it's very hard to... The other problem is it presumes that the omega-6 is bad and the omega-3 is good. I, I love a quote I read somewhere then what-- it said-- the guy said, "What's the point of the omega-6 to omega-3 ratio? It's good versus good." So why are we doing this? AA/EPA ratio is, is better because it at least defines which fatty acids you're talking about. That's good. I don't think it's any more informative. It leaves out DHA completely, which I think is unfortunate. Again, it's a ratio that presumes arachidonic's bad, and I don't think we can presume that, because arachidonic is not only made into pro-inflammatory, it's made into anti-inflammatory molecules too.

    11. PAPeter Attia1:36:00

        What drives that balance? First of all, what are the top two or three things that drive the pool of arachidonic acid? And then secondly, what are the top two or three things that drive its destination, either pro or anti-inflammatory?

    12. BHBill Harris1:36:16

        That's tough to say. I don't know what controls arachidonic levels to-- substrate levels to begin with.

    13. PAPeter Attia1:36:22

        That's, that's kind of amazing, right?

    14. BHBill Harris1:36:24

        Some that you make. The tissues get incorporated with a certain amount of arachidonic, and the body likes a certain level, and it's released from membranes when you have a stressor of some kind and you make prostaglandins and... But there are like a hundred different metabolites you get made from these molecules, and you-- it's almost virtually impossible to study all of them in vivo together. You can take one particular metabolite and sprinkle it on a cell in a test tube and see what it does, and then write a paper on it, but it may have nothing to do with reality, because in reality, you've got a, a hundred different molecules all banging on the door, fighting with each other, one balancing the other. It's, it's an incredible dance that you can't replicate outside of the body, and people draw these conclusions about this fatty acid's bad and that fatty acid's good based on really naive views, I think, of the complexity of the biology. What's most compelling is let's look at blood levels of fatty acids and who's actually having diseases. Who's getting sick? I mean, I don't care about looking at metabolic charts and what pathway intersects with what pathway or competes. That's swell. But at the end of the day, if omega-6 levels are high and that's associated with reduced risk for diabetes and heart disease, that's a very powerful testimony to me that the omega-6s are good.

    15. PAPeter Attia1:37:54

        When you say omega-6 in that situation, is the bulk of it made up through LA or is it a proxy metric of LA plus AA?

    16. BHBill Harris1:38:02

        LA 'Cause that's what we eat. Again, we eat, you know, on average we eat maybe 15 grams a day of LA, and we eat about a 10th of a gram a day of arachidonic.

    17. PAPeter Attia1:38:13

        You have a bit of a contrarian view of the sort of plant oils, the, the canolas, the safflowers, and the sunflowers, et cetera. Many people view these as sort of unhealthy oils. Do, do you view any of those oils, when consumed in the quantities that Americans consume them, as unhealthy?

    18. BHBill Harris1:38:32

        I thought you were gonna say people... When you're talking about canola and olive oil, people think those are great 'cause they're mono. They're mono rich oils.

    19. PAPeter Attia1:38:39

        Well, yeah, that's actually funny. The canola and the safflower, at least in its original form, and olive oil are virtually indistinguishable by ma- by fatty acid composition.

    20. BHBill Harris1:38:50

        Well, canola and olive, yeah. But in a safflower, it was like 77% linoleic acid originally, and now it's down to like 15%.

    21. PAPeter Attia1:38:59

        Right. And isn't it largely boosted in omega monounsaturated now, omega-9?

    22. BHBill Harris1:39:04

        Monounsatur- right. They call them high mono, high mono saff and high mono sa- uh, sunflower. And I think those are a problem. I'm sorry to see that happening. I know what's happening because, partly because the omega-6 fatty acids are unstable or are more likely to go rancid, so they'd like to get rid of them, which led to the whole trans fatty acid thing, but we're not gonna go there today. So we're reducing omega-6 levels in our oils, which is gonna reduce them in our blood, which in... If the evidence is pointing in the right direction, that's gonna show lead to an increased risk for these major diseases.

    23. PAPeter Attia1:39:39

        Wasn't there a day when we really didn't have much omega-6 in our diet?

    24. BHBill Harris1:39:43

        Sure.

    25. PAPeter Attia1:39:44

        Isn't it a relatively recent thing? Like more than a hu- a few hundred years ago, wouldn't we have only been consuming saturated and monounsaturated fats primarily in addition to EPAs and DHA?

    26. BHBill Harris1:39:57

        Right. Right. We didn't live very long either.

    27. PAPeter Attia1:40:00

        Well, is that really true though? I mean, the mortality curve had more to do with infectious diseases, infant mortality, and things like that, but we, we certainly weren't dying of chronic diseases either. Do you... Are you suggesting that the addition of plant seed oils is protective against the things that were killing us, or are we surviving despite them?

    28. BHBill Harris1:40:19

        I don't know what the case is. I know that people have shown huge increases in linoleic acid intake over the 20th century. They do that with the intent of, of scaring people. Look at how unnatural this is, but then you look at death rates from heart disease. Heart disease rates as, as the levels of LA go up, they seem to go down. [laughs]

    29. PAPeter Attia1:40:42

        Although it's so hard to look at... I mean, the problem with that type of data is that, you know, we superimpose the use of statins and advanced cardiac life support and defibrillators and smoking. Yeah, so I, I think it's very difficult to do that. But if we look at the literature as far as what we can say, I mean, it seems that we're on more stable ground saying that EPA and DHA are probably protective. I'm still at a bit of a loss as to what to say about omega-6. I mean, on a personal level, I just find them kind of disgusting, if I'm gonna be brutally honest. Like-

    30. BHBill Harris1:41:17

        [laughs]
15. 1:44:55 – 1:53:16

    Fish versus supplements and the VITAL trial

    1. PAPeter Attia1:44:55

       What do you think is the best case for and against the notion that... I mean, the REDUCE-IT study, in addition to at least one or two other studies, makes a pretty compelling case that you don't have to eat fish to get these benefits. You can get the supplements. I know that prior to a year ago, when REDUCE-IT came out, there was still a piece of me that wondered, did you have to actually eat the fish? And is the consumption of fish itself and the EPA, DHA level that rises with it more of a proxy for some subtler thing that we're not measuring?

    2. BHBill Harris1:45:34

       Is the omega-3 content of fish, and hence of your blood levels, really just a marker of fish intake and there's nothing really beneficial in fish other than omega-3 that's really doing the good work? Or something we-

    3. PAPeter Attia1:45:46

       Or even complements it. Yeah. So, so even if you posit that the EPA and the DHA are part of the benefit from eating fish, is there something else in the fish or other things that one would eat with it that augment or transduce that benefit that you could be missed? And again, REDUCE-IT now makes that question much less likely, or makes the answer to that question being yes much less likely. But just wanna, I wanna round that out and make sure that you haven't forgotten anything you wanted to talk about there.

    4. BHBill Harris1:46:12

       I agree with you. I, I think it can be done with-- We prefer to do it with fish if possible, but there's a lot of challenges with that. Not only just personal taste and cost and, but e-ecological issues. So yeah, you can do it from EPA and, and I think you can do it from EPA plus DHA supplements. I think we need to talk about the other study, though, the VITAL study, which was reported out at the same meeting as REDUCE-IT, and it was widely reported. It was not done in people with high triglycerides. It was done in normal, relatively healthy Americans in about, uh, you know, twenty, twenty-five thousand of them.

    5. PAPeter Attia1:46:46

       What was the dose that was used?

    6. BHBill Harris1:46:48

       It was one Lovaza capsule, so eight hundred and fifty milligrams of EPA, DHA.

    7. PAPeter Attia1:46:52

       Yeah, and that study didn't find a difference, did it?

    8. BHBill Harris1:46:56

       Well, it-- that's [chuckles] depends on how deeply you want to look in the study. If you just want to read the-

    9. PAPeter Attia1:47:01

       No, let's go deep

    10. BHBill Harris1:47:01

        ... primary endpoint.

    11. PAPeter Attia1:47:03

        Yeah. Well, my take on that... Well, who cares what my take is? Like, tell us your take, but starting with the dose.

    12. BHBill Harris1:47:08

        You're not a standard doctor, but the typical doctor, his take on it is it didn't work, because that's what the press said. That's what the abstract said. Because they were looking for an effect of less than one gram a day of EPA and DHA, and they were looking at a composite endpoint of four or five different elements of cardiovascular disease, stroke, non-fatal stroke, stroke, non-fatal heart disease. A composite endpoint, which three of the elements maybe w- were not affected, but one affect-- one was affected tremendously, and it was heart attacks were significantly... You know, twenty percent reduction in heart attacks and twenty percent reduction in fatal heart attacks were one of the findings. I mean, that's impressive for eight hundred and fifty milligrams a day. [chuckles] It's amazing to me that you can even do that now.

    13. PAPeter Attia1:47:56

        Mm.

    14. BHBill Harris1:47:57

        And they found that in p- if you look at people who report eating less than one point five fish meals a week, there was a significant benefit on the primary endpoint of cardiovascular disease by taking just one capsule of Lovaza. There was some really positive stuff in this study, but it was buried in the press headlines as fish oils don't work without any caveats.

    15. PAPeter Attia1:48:22

        If you exclude the composite metric and you just look at the CHD metric, how did the magnitude, both in absolute and relative risk, compare to REDUCE-IT? This is one of the things I like doing to sense check studies, which is kind of do my own analysis of them and say, well... Like the, again, an example would be comparing ODYSSEY and FOURIER and saying, "Well, based on the fact that one came in heavily statinized, the other was not heavily statinized, durations are about the same, where would we be fooled versus not fooled on this?" Can you do that sort of analysis between these two studies as well and say, did they at least have a dose response with respect to the reduction in MI, for example?

    16. BHBill Harris1:49:08

        Yeah, that's a good question. I never looked at it that way. I've never broken it down, done the math that way. I, I know that there was a nine or ten percent reduction in... Maybe it was twenty percent, I can't remember at the moment, of risk for heart disease. But again, these were not people at high risk, so your absolute risk reduction was pretty small.

    17. PAPeter Attia1:49:27

        Mm.

    18. BHBill Harris1:49:27

        Relative was pretty big, but also the dose was very low.

    19. PAPeter Attia1:49:31

        Yeah. So you had normal triglyceride, low-risk people on one-fifth of the dose, so it's very hard to compare those two studies. Do you have a sense of what they were really trying to find out? Was the goal of that study, does a low dose of a easily accessible supplement matter in people who are healthy? I mean, I assume that's, at the most basic level, that was the question.

    20. BHBill Harris1:49:55

        First primary prevention study, really, that's been done. So they, they wanted to use a... You know, it was planned ten years ago, and at that time, one gram of Lovaza. So they didn't use a supplement, okay? They used Lovaza, a pharmaceutical, but they just used one d- one gram instead of the four grams indicated by the FDA. And they f-- Yeah, they were looking at cardiovascular disease and cancer. I mean, it was a huge thing in primary prevention. So they've got-- they found no effect on cancer, and they found in their composite endpoint no statistically signi-- it was reduced, but it wasn't significant. But if you look at certain elements of the composite, they were strongly benefited, twenty percent. I'm trying to think if there's a twenty percent reduction in, in MI. That's what sticks in my mind.

    21. PAPeter Attia1:50:41

        Do you think the most important takeaway from that is if you believe that the study had a methodologic issue that prevented it from reaching the clinical and statistical significance one would want to move forward, is the bigger knock on that study the dose, the patient population that was studied, or the composite endpoint?

    22. BHBill Harris1:51:03

        All of those together can conspire to have a, a neutral study when you-- there really are some good effects that are overlooked. I mean, what people don't balance is the f- the extreme safety of these products and cheapness. We're looking at something, even one capsule of Vaser. It's cheap, it's completely safe, it doesn't interact with anything, and if it-- there's even a hint of benefit, why wouldn't you promote it?

    23. PAPeter Attia1:51:29

        Mm-hmm. Do you think that if a person's listening to this and they're deciding, "Hey, this has got me over the goal line as far as I should be using EPA and/or DHA," is there an advantage to using the pharma-grade product versus a reputable supplement company like a... Again, I'll u- the two that I like are-- and I have no financial ties to any of these companies, just sort of like them through reputation and having read analyses of their product. But like Carlson's or Nordic Naturals, for example.

    24. BHBill Harris1:51:59

        I don't think there's a substantial difference at all in quality. There's a lot of omega-3 supplement companies that make very high quality stuff that they just aren't going to the trouble of, of going through an FDA approval to get it treated, uh, developed as a drug. But it's the same chemistry.

    25. PAPeter Attia1:52:16

        And sometimes, I mean, if you get the EPA covered, it might actually be cheaper than the supplement. The supplements are actually not that cheap. They're, they're actually on the spectrum of supplements that I take, you know, when you compare, you know, something like magnesium oxide versus fish oil. I mean, these fish oils are pretty darn expensive supplements.

    26. BHBill Harris1:52:34

        It's a lot of work to get them to be that pure. One thing I'd say about Reduce-It, and back to that one again, you can't buy a pure EPA dietary supplement as far as I know.

    27. PAPeter Attia1:52:44

        No, I think the best we can do, Carlson's does make something called EPA Gems, and it's... I'm gonna get it wrong, but the, the gist of it is it's, it's sort of probably seventy-five to eighty percent EPA to DHA. So it's heavily skewed in a direction that's concentrating EPA, which is not the way it normally occurs, of course, but that's the closest you can get. And is there anything that we haven't talked about, Bill, on this topic that you would like to add? Is there any other trial that you think it's just really important that we, we get to?

16. 1:53:16 – 1:57:25

    Measuring omega-3 status, OmegaQuant, and test options

    1. BHBill Harris1:53:16

       Well, I don't think there's necessarily a trial, but I-- if I can just get into what I, I do now over the last ten years is I think measuring blood omega-3 levels are really important. And whether it's the test we do with the omega-3 index, which is red cell EPA, DHA, or a plasma test or a plasma phospholipid test or a whole blood test, whatever, I just think we need to see more doctors measuring omega-3 status because it means a lot. Low omega-3 means something. You kn- and you know this. Uh, but I, I really want to encourage people to make the assessment of omega-3 status in their patients a-- as important as measuring cholesterol.

    2. PAPeter Attia1:53:56

       Your company is called OmegaQuant, correct?

    3. BHBill Harris1:53:59

       Right. Right.

    4. PAPeter Attia1:53:59

       And you've been at the helm of that for about a decade, right?

    5. BHBill Harris1:54:03

       Yeah. This is our tenth year, right.

    6. PAPeter Attia1:54:05

       Yeah.

    7. BHBill Harris1:54:05

       Ten years.

    8. PAPeter Attia1:54:05

       That, that, that tells me how much time has flown because I remember when you had just sort of started that. That's a tough business to be in, right? Because just laboratory specialty labs, anything that's not sort of garden variety off the shelf tends to be sort of misunderstood by the payer environment, and this, this tends to be a tough place, isn't it?

    9. BHBill Harris1:54:24

       Yeah, but we're not in the payer environment. We are all cash pay.

    10. PAPeter Attia1:54:26

        Are you? Okay. Got it.

    11. BHBill Harris1:54:28

        That's where the, the quests and the, the LabCorps and the, and the Clevelands and the Bostons are... And it used to be Health Diagnostic Labs, of course, back in those days.

    12. PAPeter Attia1:54:38

        So can patients come directly to you or do your tests have to be ordered by physicians?

    13. BHBill Harris1:54:43

        People can come directly to our website and order the tests. It's fifty dollars.

    14. PAPeter Attia1:54:47

        So for fifty dollars, a patient can basically receive a kit from you that they take into... I assume it's a blood test, not a saliva test or something.

    15. BHBill Harris1:54:55

        It's a finger stick test.

    16. PAPeter Attia1:54:57

        I got it. So they don't even need to go into a lab.

    17. BHBill Harris1:54:59

        No, no. They just do it at home and s-send it to us.

    18. PAPeter Attia1:55:02

        That's the same test that I'm getting embedded within my much broader panels, I assume, where I'm seeing the percent of EPA, DHA, or is that a different company?

    19. BHBill Harris1:55:10

        What lab is doing it?

    20. PAPeter Attia1:55:11

        Well, for example, what was True Health Diagnostics using?

    21. BHBill Harris1:55:14

        Okay. True Health. So that-- Yeah. True Health took over from Health Diagnostic Lab, and Health Diagnostic Lab took my test. So you-- they're using my test.

    22. PAPeter Attia1:55:23

        I see. Okay. Do you think there are other tests out there that are directionally comparable or... I mean, I get it's a... You're a bit conflicted to say that there's other... Yeah, it's, it's a loaded question.

    23. BHBill Harris1:55:33

        Yeah, they're certainly directionally comparable. It's just the number. Don't do a plasma omega-3 test and expect to get an eight to twelve percent EPA, DHA. Plasma doesn't go that high, or it's very hard to get that high. So plasma levels are lower numbers. They correlate pretty well by and large with red cells, but red cells are much more stable long-term marker of omega-3 status than plasma is. So I, I like the red cell test for that purpose. So that's pretty much what we use in our research studies is, is red cell. I'd rather see a doctor measure a plasma omega-3 than not measure anything.

    24. PAPeter Attia1:56:07

        That's something that people can also get through LabCorp, Quest, and all of the sort of more generic labs, I assume.

    25. BHBill Harris1:56:12

        Yeah. I'm not even sure they can get it at LabCorp, but Quest has a plasma phospholipid assay they do.

    26. PAPeter Attia1:56:16

        What does Boston Heart do? Do you know?

    27. BHBill Harris1:56:19

        I think they do whole plasma.

    28. PAPeter Attia1:56:21

        I see. Okay. So going forward, if we're not using THD, we'll be-- we'll have to figure out a way to come to you directly.

    29. BHBill Harris1:56:28

        That'd be great. Love to do it. We got a lot of doctors who do, but, um, you know, I mean, I don't know what, what kind of, uh, reimbursement is being paid for these tests in the insurance world. I think it's not much.

    30. PAPeter Attia1:56:40

        I, I was about to say, I'm, I'm gonna go with the not much box on that one.
17. 1:57:25 – 2:02:25

    Upcoming STRENGTH trial, free fatty acids, and absorption

    1. BHBill Harris1:57:25

       Golly, I think we ran down the omega-6 stuff. We talked about EPA and DHA alone. We-- There is a big study that's gonna come out, it should finish a year from now, called STRENGTH, that is bigger than REDUCE-IT and using the same dose as REDUCE-IT, but it's EPA plus DHA.

    2. PAPeter Attia1:57:43

       What dose approximately? So that would be four grams total?

    3. BHBill Harris1:57:46

       The drug is called Epanova or Epanova. It's from, um, AstraZeneca. It's a 13,000-patient trial, virtually the same inclusion criteria as REDUCE-IT. It'll be about a five-year follow-up, the same as REDUCE-IT, and they are gonna-- I, I'm pretty sure they're gonna get much higher omega-3 index levels than REDUCE-IT did.

    4. PAPeter Attia1:58:05

       And again, their drug is four grams EPA plus some amount of DHA, or four grams total?

    5. BHBill Harris1:58:11

       It's very much like Lovaza, EPA plus DHA at around about 85%, but it's fr- the-- they're not ethyl esters. They're free fatty acids. They're un- unesterified of anything.

    6. PAPeter Attia1:58:24

       And do you think that actually makes any difference?

    7. BHBill Harris1:58:26

       Well, they're m- much more readily absorbed.

    8. PAPeter Attia1:58:29

       Oh. Because the esterified ones presumably... Is it like cholesterol, where esterified variants are much harder to absorb, and you risk actually not absorbing them at all?

    9. BHBill Harris1:58:41

       Well, yeah, that's the, the problem. It's been shown pretty clearly that if you take an ethyl ester of omega-3 on an empty stomach, the absorption's quite low, almost none, as opposed to taking it with food, which improves the absorption quite a bit. But a triglyceride-based oil or a free fatty acid, more to the point, free fatty acid doesn't require any enzymatic conversion to get absorbed at all. The triglyceride has to have-- a- and the ethyl ester both have to have enzymatic conversion in the gut.

    10. PAPeter Attia1:59:09

        Well, that's actually really interesting, and I'm glad you brought that up because, as you know, a lot of people these days are fasting more and more or time restricting their feeding, and it does pose a little bit of a problem. The way I've always got around it if I don't eat breakfast, which I don't a lot of the time, is I sort of take my fish oil at night as close to dinner as possible, but it's easier to forget that way. But you're saying another way around it is if you really just want to take these things in the morning and be done with them, you basically have to take one of the pharma grade versions because they're the ones that come as free fatty acids?

    11. BHBill Harris1:59:40

        Right. It's only experimental. I mean, it's not experimental. It's approved by the FDA, but it's not being marketed. It's the only one that's a free fatty acid right now is this Epanova. The Vascepa and Lovaza are ethyl esters.

    12. PAPeter Attia1:59:53

        Ah. So basically, it'll be about a year before we even have the option to get a free fatty acid version.

    13. BHBill Harris1:59:59

        That's when their study will finish, and I think it'll be as or more successful than, than REDUCE-IT. That's my guess.

    14. PAPeter Attia2:00:07

        And that will be released at the American Heart in 2020?

    15. BHBill Harris2:00:11

        On their clinicaltrials.gov website, it says the studies w- will finish in October of next year. So whether they'll be able to report results-

    16. PAPeter Attia2:00:18

        Scramble an abstract, we'll see. Yeah.

    17. BHBill Harris2:00:21

        Yeah, yeah. Whether-- I don't know.

    18. PAPeter Attia2:00:22

        Well, maybe when that study, uh, comes out, Bill, we'll have to sit down in early '21 and discuss it.

    19. BHBill Harris2:00:28

        Love to.

    20. PAPeter Attia2:00:29

        Well, Bill, thanks again. This was really interesting. For me personally, I learn a lot talking with you about this kind of stuff. I just know that this episode will be one of those episodes that a lot of people end up coming back to over and over again because it is so confusing. So thank you for the historical context, the overview, and perhaps most importantly, just the sort of nitty-gritty details on the health benefits of these things.

    21. BHBill Harris2:00:52

        Oh, yeah. My pleasure. Thank you very much for inviting me. I've really enjoyed it. [upbeat music]

    22. PAPeter Attia2:00:58

        You can find all of this information and more at peterattiamd.com/podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peterattiamd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once-a-week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID peterattiamd. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and/or advise, please visit peterattiamd.com/about. [upbeat music]

Episode duration: 2:02:25