The Peter Attia Drive - #83 - Bill Harris, Ph.D.： Omega-3 fatty acids

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00:03:54.980 supporting us directly by signing up for a monthly subscription. My guest this week is Dr. Bill

00:04:00.340 Harris. Bill is an internationally recognized expert on omega-3 fatty acids and how they can

00:04:05.240 benefit patients across a broad range of medical conditions, particularly with attention to heart

00:04:10.940 disease. He's a professor in the Department of Medicine at the Sanford School of Medicine in the

00:04:15.560 University of South Dakota. He's also the president and CEO of Omega Quant, which is a company he started

00:04:19.920 about 10 years ago that we spent a little bit of time at the very end talking about. And again,

00:04:24.120 the caveat being, of course, he does have a vested interest and therefore a conflict with respect to

00:04:29.500 involvement of his company. But I can say I've known Bill for 10 years and I know people who

00:04:34.600 have known Bill for much longer than that. And his reputation amongst his peers is really someone who

00:04:40.720 is a very honest broker of the science. He's been the recipient of five NIH grants for the study of

00:04:47.460 the effect of omega-3 fatty acids, particularly EPA, DHA, on human health. He's published over 300 papers

00:04:53.960 on the topic. And we discussed just a couple of those here, some of the really interesting ones.

00:04:59.080 And he was also the author on two of the American Heart Association scientific statements on fatty

00:05:03.660 acids. He earned his PhD in human nutrition from the University of Minnesota and did a postdoc in

00:05:08.960 clinical nutrition and lipid metabolism with Bill O'Connor at Oregon Health Sciences. I was introduced

00:05:14.480 to Bill, like I said, probably nine years ago from Tom Dayspring. And this was around the time that I was

00:05:20.800 really searching for insight around the polyunsaturated fats and in particular EPA and

00:05:26.220 DHA. And since that time, Bill has been a very generous, generous mentor to me with respect to

00:05:33.000 just one of those guys, you send him an email with a simple question and he responds with a very

00:05:37.920 thoughtful, you know, 600 word response that contains more insight than anything I could have

00:05:43.620 drummed up. We talk about mostly the landscape of polyunsaturated fats here, but this is a great

00:05:50.120 episode. You don't have to know anything going into this episode when it comes to fats. We're

00:05:53.580 going to explain what saturated fats are, monounsaturated fats, polyunsaturated fats,

00:05:58.260 omega-3s, omega-6s. You're going to come out of this and have a better understanding of this topic

00:06:02.460 than if you went to med school and took a course in this subject matter. I think I'm just going to

00:06:06.760 leave it at that. The show notes will be very helpful for this episode because some of this stuff,

00:06:10.620 it really makes sense to be able to look at a diagram as we go through it. And then of course,

00:06:15.240 as usual for subject matter like this, we're going to go heavily into studies. So you'll want to be

00:06:19.560 able to reference those studies and see that. So without further delay, please enjoy my conversation

00:06:24.240 with Bill Harris. Bill, thank you so much for making the time to talk about a subject matter

00:06:33.800 that I think is incredibly confusing and incredibly important. That intersection of things that are

00:06:39.860 confusing and things that are important tends to be a very important and sometimes overlooked

00:06:44.680 intersection in medicine. So with that, I want to thank you for making the time.

00:06:49.560 Yeah, my pleasure.

00:06:51.340 How long have you been the guru of this? I mean, for the listener in the background,

00:06:55.060 I give a little bit of your background, but I was introduced to you in I think 2011 from Tom

00:06:59.640 Dayspring, who basically said anytime I had a question that had to do with anything around fatty

00:07:04.640 acids, you were the guy to ask. And over the past eight years, you've steadfastly answered more

00:07:11.020 questions than I can count. Tell me a little bit about how you got to be the guy that knows so much

00:07:16.900 about this. Just hanging around a long time. So I got my PhD in nutrition in 1978 and I went to work

00:07:24.840 with Bill Connor in Portland, Oregon for my postdoc. His first assignment for me was to study the

00:07:33.020 question of what does the effect of salmon oil on cholesterol levels? Because we were very familiar

00:07:40.620 with the effects of vegetable oil on cholesterol and animal fat, saturated fat, but we really didn't

00:07:45.580 know what a fish oil would do to cholesterol. So my first really metabolic ward study, I organized

00:07:52.920 recruited subjects, did the protocol, and we fed people huge amounts of salmon oil, basically all of

00:08:01.300 the fat in the diet. So people were eating salmon steaks twice a day. And this was a 28-day inpatient

00:08:08.400 feeding. Well, excuse me, outpatient feeding, but metabolic ward. And beyond the salmon steaks,

00:08:14.020 they were drinking about 100 milliliters a day of salmon oil, just drinking it straight.

00:08:21.220 And so it was a huge load, 25 grams of EPA, DHA per day. And we found that the omega-3s lowered,

00:08:29.480 well, actually salmon oil did lower cholesterol relative to the saturated fat diet. And it was about

00:08:35.120 the same lowering as we saw with the vegetable oil diet. But the thing that was unique about salmon

00:08:40.100 oil was that it lowered triglyceride levels. And nobody had known that at that time. So we published

00:08:46.400 our first paper on that in 1980. That's really coincident with the time that the Greenland Eskimo

00:08:52.220 studies were finally becoming well-known from Dyerberg and Bang. And the omega-3s had been sort of

00:08:58.980 discovered in a sense at that time. And so we started chasing omega-3 effects on lipids and

00:09:04.840 platelet function and all kinds of other things. And so I've just been able to stay with it. I've had

00:09:10.340 five grants from the NIH to study omega-3 related questions. And so just again, it's been a field

00:09:17.300 that's continued to be fascinating and ups and downs, but enriching. And as you said, it's confusing right

00:09:23.140 now. It's been confusing for most of its history. That's kind of an amazing story. And I want to

00:09:29.100 come back to that study because it's possible that the listener right now doesn't understand

00:09:33.140 the context of what 25 grams of EPA would mean. But that's, I mean, that's a dose of a type of fat

00:09:40.880 we're going to talk about when we get into the nomenclature that is almost unprecedented. And I already

00:09:46.160 have a dozen questions for you about that exact study. And were there any side effects such as

00:09:50.680 bleeding noses and anti-anabolic effects and all these things, but I'll refrain from going down that

00:09:55.980 path to instead make sure we can get everybody on the same playing field. So I'm going to start and

00:10:03.060 give a little bit of a framework, but I'm going to very quickly hand the baton over to you to get into

00:10:07.800 the weeds on this a little bit. So obviously fat is one of the four or five, depending on how you look

00:10:13.740 at it, macronutrients, right? So fats, proteins, carbohydrates, ketones, alcohol. And I think most people

00:10:19.460 know that fats come in different chemical families. So you've already alluded to one of them called a

00:10:25.980 saturated fat. And then everybody's probably heard of a monounsaturated fat. And then there are these

00:10:31.820 things called polyunsaturated fats, which then get further divided into these omega threes and sixes

00:10:38.080 typically, but there are others. Do you want to say a few words about what separates a saturated fat

00:10:43.500 from a monounsaturated fat from a polyunsaturated fat, and then how we further subdivide those

00:10:49.760 polyunsaturated into the omega threes and sixes? And I guess if you can answer the question, Bill,

00:10:54.860 not just through the chemical explanation, though, I'd like you to provide that, but also through some

00:10:59.180 of the examples and characteristics of each of them so that folks have a sense of what we're talking

00:11:03.220 about. From a chemical structure point of view, a saturated fatty acid is a long single chain of

00:11:10.440 carbon atoms all hooked together. And there are what we call single bonds between each carbon atom.

00:11:17.780 In chemistry, you can have single bonds, you can have double bonds, you can have triple bonds,

00:11:22.420 but in a saturated fatty acid and a saturated fat like lard or butter, any of those saturated fats

00:11:30.980 have the vast majority of fatty acids that make up those fats are saturated, meaning they have long

00:11:37.480 single chain. And they're solid at room temperature. I think that's the most common characteristics.

00:11:42.460 The simplest way to detect a saturated fat is at normal room temperature, they're solid.

00:11:49.320 Monounsaturated fats, fatty acids are the next class, and these have the same long carbon chain.

00:11:57.200 It can be 12, 14, 16, 18 carbons long. And there's one double bond in a monounsaturated fatty acid.

00:12:06.240 So when there's a double bond in a molecule, it now has a point of unsaturation.

00:12:12.200 And why they pick that nomenclature is not worth talking about at the moment, but that's what that

00:12:16.420 means. The classic oil that is rich in monounsaturated fatty acids would be olive oil and canola oil now

00:12:24.780 too. Those are both very rich in monounsaturated fatty acids. They are liquid at room temperature,

00:12:30.620 but you put them in the refrigerator and they'll get hard. That's kind of a way of telling a monounsaturated

00:12:36.900 rich oil. If it's out at room temperature, it'll be liquid in the fridge overnight. It'll get

00:12:41.600 solid or certainly get very cloudy. The polyunsaturated is the next group. It's really instead of one

00:12:47.740 double bond, now we have two or more double bonds, and that's the poly. So again, the same long carbon

00:12:54.420 chain with now two or three typically. Actually in foods, all you really find is two double bonds.

00:13:01.640 The oils that contain polyunsaturated fatty acids are liquid at room temperature, and they're

00:13:07.200 typically liquid in the refrigerator too. You have to put them in a freezer to get them to get solid

00:13:13.420 or to get cloudy. Even some fish oils will not get solid even in a freezer. The polyunsaturated fatty

00:13:20.920 acids are, again, they are what you find in oils. We say fats and oils. When we say fats, we're usually

00:13:26.600 talking about things that are solid at room temperature. Oils, we're talking about things

00:13:30.980 that are liquid at room temperature. And again, the oils are going to be mono or polyunsaturated rich,

00:13:36.820 and the fats will be saturated fat rich. Again, in the polyunsaturated fat world, we have two

00:13:43.400 families, two major families. It's called omega-6 and omega-3. And they're called omega because

00:13:49.780 when chemists first started naming chemicals, naming fatty acids when they were discovering

00:13:56.640 the structure of them, there was the beginning and the end of the molecule. And the way they

00:14:02.160 designated what was the beginning of the molecule, they called that was the alpha carbon, the first

00:14:06.940 carbon. And the last carbon in the molecule was always the omega carbon, taking from the Greek

00:14:12.700 alphabet, the alpha and the omega, the beginning and the end. So the omega carbon was at the end.

00:14:18.060 If you have an omega-6 fatty acid, it's actually said omega minus six, means that if you count back

00:14:27.180 six positions from the omega or final carbon, you get the first double bond in the molecule.

00:14:32.780 And that's specific for all the fatty acids that are omega-6 family, they all have that

00:14:37.060 characteristic. First double bond, six counting back from the omega or final carbon. And the omega-3

00:14:43.060 fatty acids all have the first double bond in the third position.

00:14:46.100 And that sounds like it really shouldn't, you know, so what? But actually, chemically,

00:14:50.480 it makes quite a bit of difference in the physical properties of the oils, as well as the other

00:14:55.200 molecules or metabolites that these fatty acids are converted into by enzymes in the body.

00:15:02.360 So that's the omega-6, omega-3 family. Fish oils are the ones that contain omega-3,

00:15:07.720 predominantly vegetable oils, safflower oil, corn oil, sunflower oil are rich in the omega-6 fatty acids.

00:15:15.060 It would have taken me an hour to have tried to explain that, Bill, and it would have been half

00:15:18.820 as clear. So thank you for that. The thing that's always amazed me is how many different pieces of

00:15:24.280 information can be conveyed in the nomenclature of fatty acids, because you're dealing with the

00:15:30.300 extent or degree of saturation, anywhere from fully saturated to not as mono and poly. You then have the

00:15:36.860 actual number of carbons in the molecule. And then you have the position of that first double bond,

00:15:44.080 in the case of the monos and the polys. So even for someone who's taken a course in organic chemistry,

00:15:50.480 like it still requires a little bit of thought when you're looking at detailed chemical drawings

00:15:55.700 of these things. And I suspect that represents at least some fraction of the challenge that people

00:16:02.000 have when talking about this, as we tend to distance ourself from what we're talking about

00:16:05.260 because of the confusion. But as you point out, it sounds like it shouldn't make that much of a

00:16:10.120 difference, right? The difference between coconut oil and olive oil is one double bond, and yet their

00:16:16.720 properties are almost entirely different. I don't know if you have insight into this, but

00:16:21.920 from a nutrition standpoint, does the specificity of enzymes for these fatty acids, is that kind of

00:16:29.180 unique in terms of just how much difference you can see in the output relative to the starting

00:16:34.900 structure? Or do you see that to be relatively conserved across all of nutrition, outside of

00:16:40.340 fats, that is?

00:16:41.740 No, I think it's probably a truism that every molecule is unique. Every molecule is special

00:16:48.960 in our foods, in our bodies, from water, which is probably the most special molecule in the world

00:16:55.140 or in the universe, which makes up, what, 70% of our bodies, to down to the fats and fatty acids.

00:17:01.660 And of course, carbohydrates and proteins are all very unique molecules. I appreciate you

00:17:06.280 mentioning the number. I should mention how they are numbered in case people ever see them written

00:17:11.520 out in the number format, because any saturated fatty acid, let's take a fatty acid that has 16

00:17:17.600 carbons, and it's a saturated fatty acid. Its common name is called palmitic acid. It comes from

00:17:23.900 primarily from palm trees, palm oil. So it's called palmitic acid. Its designation is 16,

00:17:30.540 colon zero. 16 means how many carbons are in the molecule, the colon. What follows the colon is the

00:17:37.460 number of double bonds in the molecule. So all saturated fats is just a number, colon, and then

00:17:43.220 a zero. When you get into monounsaturated fats, again, it's the carbon number first, like the most

00:17:49.420 common one is 18 carbon fatty acid, 18, colon one. And the one tells you there's one double bond.

00:17:56.880 That fatty acid is called oleic acid. We get oleo from that word oleomargarine. Once you start putting

00:18:05.420 a double bond in a molecule, now you have to tell the reader where it is in the molecule. And to your

00:18:11.060 point, when you have an 18, colon one, you got to know where is that thing. And in this case, it's at

00:18:16.660 position number omega nine. It's the ninth position back from the end. So that'd be 18, one, colon,

00:18:23.680 N. Oh yeah, here we go. Here's the other confusing part of it. We say omega. We like to say omega-3,

00:18:30.040 omega-6, omega-9. But chemists like to talk about them using the term N, like the letter N.

00:18:36.820 It's the final carbon in the molecules, the nth carbon. It's the last one. It's just the nth one.

00:18:43.260 You know, exactly where that came from. I don't know. Sometimes you'll see an omega-3 fatty acid,

00:18:47.960 called an N minus three fatty acid, N-3 fatty acid. Same thing. We're talking about the same

00:18:53.400 molecule. I think there's mathematicians that have snuck in there so that the nth terminus

00:18:57.360 is where that N must have come from in a geometric series or sequence.

00:19:02.420 Yes. We're going to include a lot of figures in the show notes that go through what these

00:19:07.240 pathways look like. Because at least for me, I don't find I can wrap my head around these things

00:19:12.700 without actually looking at the chemical structures. And I still remember probably a figure you sent me

00:19:17.940 eight years ago that really walked through the pathway from linoleic acid and alpha linoleic acid

00:19:26.220 all the way down through the desaturases, elongases, all of these enzymes.

00:19:33.060 And I think I just had to decide like, look, I'm going to sit here and I'm going to learn this.

00:19:37.080 And I remember printing it out, laminating it, carrying it around with me and just going through

00:19:41.880 it. It's like, okay, well, it's a desaturase. Okay. That makes sense. It's an elongase. It's going to

00:19:45.980 elongate here. One that, that, that, that, that, that. And at least for me, that was just sort of

00:19:49.520 the way to do it, which was just, I'm not going to be intimidated by all of these names that by

00:19:53.120 themselves don't mean much to me. But if I can look at them in the context of what you just said,

00:19:57.400 which is they're simply referring to positions of double bonds and things that it makes it a

00:20:02.120 little easier. Now, of course, I think most people listening to this are going to be like, okay,

00:20:04.900 guys, why are you going so far into this? And I think the answer is these fatty acids basically make up

00:20:12.440 the most important parts of our body, right? I mean, every membrane of every cell is formulated

00:20:19.080 with these and it seems that they have a profound impact on our health.

00:20:23.040 They do. And we're finding, we're just discovering that more and more.

00:20:26.280 And there seem to be quite differences. I mean, on the one hand, I'm struck by

00:20:29.480 the relative convergence that you can see across people consuming vastly different things. So there's

00:20:35.920 sort of a dampening effect, if you will, that the body can do where it kind of converges

00:20:40.680 all sorts of inputs to modestly banded outputs. But at the same time, I'm struck by the differences.

00:20:46.720 So I'll give you one example, which is in the weeds clinically, but it's hopefully for the

00:20:52.040 listener gives them a sense of why we want to understand this. So when we do blood tests on

00:20:56.340 patients, one of the things we always like to do is look at the EPA, DHA, AA levels in their red blood

00:21:05.140 cell membranes. And the laboratory will spit out what percentage is EPA, DHA, total saturates, total

00:21:13.700 monounsaturates, et cetera, et cetera. The ranges on those are not that big. And most people tend to

00:21:19.940 fall within them no matter how much they're eating, but they can be at really different ends of those

00:21:23.940 ranges. So you don't have people that differ by two and three fold, but people can definitely differ

00:21:29.600 by 20 or 30%. Is that, that's my observation. Is that fair? That's true. That's true. And because

00:21:34.880 when you're talking about a blood test and specifically, you're talking about a red blood

00:21:39.160 cell, which is the test we like to do and measure the fatty acid composition of the membrane, every,

00:21:46.800 as you alluded to, every membrane of every cell is made up of fatty acids. And I would venture to

00:21:54.560 say that there is a unique suite of fatty acids, a unique pattern of fatty acid for every type of

00:22:01.000 tissue in every cell. It's not the same anywhere. They're all a little bit different. And that's

00:22:06.620 because the body and the way that the wisdom of synthesizing cells, each cell has its own role to

00:22:12.780 play in metabolism. The membrane has to have certain physical characteristics being real loose and floppy or

00:22:20.800 being real stiff depending on the need of that cell. And the fatty acid composition is unique to afford

00:22:29.260 a certain kind of chemical flexibility. It's an amazing thing. There is certainly much wider variation

00:22:36.620 in the fatty acids we eat than when we see in our blood. That's because the body is making the membranes

00:22:42.300 from the raw materials we eat and it picks what it wants. And it puts the fatty acids largely where

00:22:48.940 it wants them to be. When you're making a red blood cell in the bone marrow, the fatty acids that are

00:22:55.040 selected and put into that membrane are taken out of the blood and the bone marrow takes what it wants.

00:23:01.380 You can influence it a little bit, but you can't influence it like two and threefold different for

00:23:06.500 most fatty acids. To give you one real example that is just a great illustration of this, if you take

00:23:12.880 somebody who is on the lowest fat diet in the world or specifically someone who, for example,

00:23:17.820 goes out of their way to avoid saturated fat, someone who's consuming in the neighborhood of 10 grams per

00:23:24.740 day or less of saturated fat, and you counter that with someone who's on a super high fat diet that's

00:23:32.180 eating 75 grams a day of saturated fat or more, you might see a 20% difference or a 10% difference

00:23:40.880 in the amount of saturated fat within their cell membranes. As you said, the body tends to be a heck

00:23:46.860 of a lot smarter at putting things together than just doing it based on what's available in the

00:23:52.560 diet. Yeah, thank God. That's true. Let's talk about why this stuff matters and let's maybe take

00:23:57.840 a step back and go back to 1980. You do this experiment where, and I guess just to set the

00:24:04.840 context for listeners, in 1980 is really we're witnessing the height or I would say the wave is about to

00:24:12.460 crest in the major fat phobia 15, 20 year run that's about to sweep over America. In 1977, George

00:24:22.500 McGovern presiding over the Senate Select Committee on Health basically comes to the conclusion that

00:24:28.580 even though the evidence against or implicating saturated fat and heart disease, even though that

00:24:33.020 evidence is not great, it's good enough and they have to make a decision. And the decision that's put

00:24:38.580 forth at that time is that Americans should greatly reduce their intake of saturated fat. I suspect that

00:24:45.860 it's that decision that largely triggers an enormous interest in the type of work that you carried out

00:24:53.420 as that first paper, that first major experiment you led as a freshly minted PhD student, which was,

00:24:59.680 well, gosh, if saturated fat is going to do this, does polyunsaturated fat do the reverse? And at that

00:25:06.100 point in time, Bill, if I'm not mistaken, there had already been a number of studies that had suggested

00:25:10.040 that broadly speaking, polyunsaturated fats, mostly omega-6s actually showed a reduction in total

00:25:17.480 cholesterol. Is that correct? That's correct. In fact, in those days, even starting back in the

00:25:22.740 seventies, people were taking tablespoons of vegetable oil to lower their cholesterol. It was taken as a

00:25:28.100 medicine. What is the mechanism by which taking tablespoons and tablespoons of sunflower oil or corn oil

00:25:35.520 would lower a person's cholesterol? It's complicated. It's been fairly well worked out

00:25:41.560 since. But what that does, again, we mentioned what you eat is not directly reflected in your

00:25:47.240 cell membranes. But when you're taking the omega-6s or the omega-9s, the monounsaturates,

00:25:53.880 you're replacing some saturated fatty acids in the membranes. If you're reducing your saturated fat

00:25:59.900 intake, like McGovern et al. suggested or said we should do, you're reducing the amount of saturated

00:26:06.940 fat to an extent in your membranes. And that has an effect on the physical chemical fluidity of the

00:26:14.180 membrane. And there is buried within all of our cell membranes, hundreds and thousands of these

00:26:22.080 receptors, proteins that are sitting right in the middle of membranes. One of these is called the LDL

00:26:29.760 receptor, low-density lipoprotein, which is the primary lipid particle that carries cholesterol in

00:26:36.580 our blood. And that receptor is sitting there in the liver membrane. And if you remove saturated fat

00:26:43.800 or lower the amount of saturated fat in that membrane, it changes the properties of the membrane

00:26:47.900 so that that LDL receptor is more efficient at removing and binding to and removing LDL particles

00:26:56.920 from the blood. That essentially lowers your cholesterol level.

00:27:01.760 So the cholesterol lowering comes through more lowering of the LDL than the HDL?

00:27:08.000 Correct. It's the LDL that's affected primarily by the saturation of fats. There's some effect on HDL

00:27:14.180 cholesterol, but most of it is LDL. On the surface, that would sound like a very positive thing. So as

00:27:19.460 tempting as it is to sort of look back at the low-fat mania that swept across America 30 years ago or 40

00:27:26.960 years ago and just sort of dismiss it as buffoonery for a handful of reasons, especially with the sort

00:27:32.200 of substitution of what became the go-to default, based on just the mechanisms and the studies of

00:27:39.680 the day, it was not an entirely unreasonable thing to suggest.

00:27:43.200 No, particularly, as you said, McGovern's committee said saturated fat should be reduced. Didn't say

00:27:49.740 all fat. And I think that's where the message got mixed. Because if Americans had just reduced

00:27:56.200 saturated fat and replaced it with mono and polyunsaturated fats, we wouldn't have had this

00:28:01.360 problem.

00:28:01.980 It seemed to get replaced by sugar was one of the big things that got...

00:28:05.700 Right. It was take all the fat out. And that was the mistake.

00:28:08.720 So the question you were trying to ask when you did that study where patients were consuming

00:28:15.680 in the end, I think you said 25 grams of EPA. And I guess I should, before you answer this,

00:28:21.680 maybe let's go back and explain what EPA, DHA, and all these other things are. And again,

00:28:26.560 assume for a moment, Bill, that there will be a large figure, multiple figures, in fact,

00:28:31.520 will be in the show notes. We'll have the really detailed chemical ones, but we'll also sort

00:28:34.960 of have the cartoony ones. So let's assume that someone's looking at the cartoony figure

00:28:39.280 that takes linoleic acid down to arachidonic acid, and then the one that takes alpha linoleic acid down

00:28:45.460 to EPA and then down to DHA. Can you explain what's happening there? And let's start with the

00:28:50.080 omega-6 one, I suppose.

00:28:51.540 Sure. The left-hand side of the slide that I have in my mind, and I think you have in your mind.

00:28:56.220 I'm probably having in my mind a slide you've shared with me, but we will make sure we use

00:28:59.540 exactly whatever you're speaking from in memory now.

00:29:02.700 It's always done this way for some reason. The left-hand is always the omega-6. So it starts

00:29:07.880 with linoleic acid, which is an omega-6 fatty acid. It's the principal omega-6 fatty acid in our

00:29:13.800 diet. It is an essential fatty acid with a capital E, essential, meaning we cannot make it. It's very

00:29:20.780 much like a vitamin. It can't be made from scratch, and it is important for metabolism. So it is an

00:29:27.920 essential fatty acid. Hey, we have to eat some omega-6.

00:29:30.800 And what are the dominant sources of that, Bill?

00:29:34.240 Vegetable oils. Soybean oil is probably, what, 80% of where we get our linoleic acid in our diet.

00:29:41.140 So sunflower, corn, soybean, cottonseed would be the big four, right, as my recollection?

00:29:47.580 Yeah, actually, sunflower and safflower nowadays are not. Linoleic has been pretty much stripped out

00:29:52.980 of those oils. Now they're what's called hyolaic sunflower, hyolaic safflower. It doesn't say it

00:29:59.560 on the label, but what's in the bottle has vastly changed from the natural fatty acid pattern.

00:30:07.340 But corn and soybean are still high omega-6, meaning 50%, 60% of the fatty acids in that oil

00:30:14.160 are linoleic acid. And linoleic is 18, so 18 carbons, so it's 18 colon 2, two double bonds,

00:30:22.360 omega-6 position. So what happens is you eat that, and a portion of it is glommed onto by certain

00:30:30.580 enzymes in the liver that want to make a longer fatty acid. And so they add two carbons, and they

00:30:37.060 get a 20-carbon fatty acid now. And then they add, the liver has enzymes that will add, instead of

00:30:42.600 having two double bonds, it'll now have four double bonds. It goes through a three-double bond molecule,

00:30:47.720 and now we're at a four-double bond. When you get to this molecule, it's an omega-6 family,

00:30:52.900 20 carbons, four double bonds. That's called arachidonic acid. And that is an extremely important

00:30:59.560 fatty acid in metabolism. If your listeners have ever heard of prostaglandins, this is the stuff of

00:31:06.080 which all prostaglandins, well, most prostaglandins are made. It's the substrate. It's the beginning,

00:31:11.800 and it's terribly important throughout the body. The liver can even take that molecule and make it

00:31:18.600 even longer, 22 carbons, and add more double bonds, up to five double bonds. But there's not

00:31:23.620 much of that around, and we really don't know what it does. I think the most important end point of

00:31:28.780 omega-6 metabolism is to produce arachidonic acid, 20-carbon, four double bond.

00:31:35.180 The way you explain it, like I think going back to the biochem, anyone who's listening to this who's a

00:31:38.860 college student or a med student or something, I mean, that's not rocket science, right? You

00:31:42.660 elongate it with the elongase enzyme, and then you further desaturate it, take two of the saturations

00:31:49.380 out, and there you go. So you go from 18.2 to 24. Now, arachidonic acid has a real bad rap, doesn't it?

00:31:56.240 It is. Yes.

00:31:58.380 We'll get into it in detail, but just is it safe to say that that's a bit misunderstood and that the

00:32:04.860 binary view of arachidonic acid might not be the whole story?

00:32:08.820 That's safe to say.

00:32:10.060 All right.

00:32:10.640 I would agree with that. We'll get into that later.

00:32:12.120 So we'll come back to the demonization of arachidonic acid. Let's go over to the right-hand

00:32:18.540 side of the picture we both have in our mind that is hopefully about the same picture.

00:32:22.720 It is, right? Now we have at the top, instead of linoleic acid, we have linoleic acid. Just add

00:32:29.020 one N to the name, and you get linseed oil. Most people are familiar with linseed oil.

00:32:34.860 That is rich in this particular fatty acid. Flaxseed oil is similar. Chia seed oil are all

00:32:41.420 sources of this linoleic acid. It's in carbons, again, same length as the omega-6 cousin. It has

00:32:48.720 three double bonds instead of two, and the first double bond is in the omega-3 position. So it's

00:32:54.540 an 18 colon 3 N minus 3 fatty acid. It also is essential in the same sense that the omega-6

00:33:03.580 cousin linoleic is essential in the diet. Alpha, it's just called alpha-linolenic acid is also

00:33:09.620 essential. We can't make it, and it's important for metabolism and health. And so the same game

00:33:15.900 happens. This 18 to alpha-linolenic acids, we call it ALA, thank God. ALA is consumed,

00:33:23.060 and then again goes to the liver and is elongated. In other words, two more carbons are added,

00:33:28.480 and more double bonds are added to the molecule. So it goes from three to four to five double bonds.

00:33:34.260 And now you have 20 carbon, five double bond, omega-3 fatty acid, and that's called EPA.

00:33:41.400 The EPA stands for icosa, E-I-C-O-S-A, which is 20 in Greek. Penta is five, which is 20 carbons,

00:33:50.480 five double bonds. And then we say enoic acid means it's a fatty acid. So it's a 20 carbon,

00:33:56.280 five double bond molecule. And that's EPA, one of the two most important of the, quote,

00:34:02.220 omega-3 fatty acids. That fatty acid then, EPA, can then be further converted to two more carbons.

00:34:08.940 Again, elongates the chain and desaturates, replaces single bonds with double bonds. So you

00:34:15.060 end up with a 22 carbon, six double bond molecule. And that's called DHA, which stands for

00:34:21.600 docosa, 22, hexa, six enoic acid. So it's a 22 carbon, six double bond. So EPA and DHA are the

00:34:30.600 two. When people talk about omega-3s, that's what they mean. Those two fatty acids are the principal

00:34:35.360 ones. Going forward, just to make everybody's life easy, we're going to talk about ALA,

00:34:41.880 alpha-linolenic acid as the omega-3 that you get mostly out of flax seed and chia seed, I think.

00:34:50.760 Are there any other sources of high, high dose of ALA? Well, no, not a high, high dose. But if you

00:34:56.440 look at what's the principal source in the American diet, it's soybean oil. Soybean and maybe canola to

00:35:02.460 some extent has a little bit. To some extent, to some extent, yeah. Soybean is such a, it's the gorilla

00:35:07.820 in the room when it comes to vegetable oils in America. And it's about 7% of the fatty acids in

00:35:13.460 soybean oil or ALA. ALA goes through a number of steps, adds a couple carbons, desaturates a couple

00:35:21.120 bonds, and you have EPA. Though I don't think you've stated this, I do believe there's an

00:35:26.040 equilibrium. EPA and DHA can go back and forth between each other, or is that mostly a one-way

00:35:30.900 street? We thought they kind of went back and forth, but now I think we know, based on a paper that was

00:35:35.760 published a couple months ago, it looks like EPA goes to DHA. DHA does not, what they used to call

00:35:42.480 it is, gets retro-converted. In other words, goes from a 22-carbon, six-molecule to a 20-carbon,

00:35:49.000 five-double-bond molecule. That's retro-conversion going backwards. We thought it happened. We don't

00:35:54.520 think it happens anymore.

00:35:55.760 It's more straightforward than what I used to.

00:35:57.900 Yes.

00:35:58.180 My laminated sheet's got to be updated. So it's basically ALA to EPA to DHA on the right-hand side

00:36:06.320 of the page. That's your omega-3 family. And then for the sake of simplicity, we're basically going

00:36:11.840 from LA linoleic, not linoleic, linoleic acid down to arachidonic acid AA. So LA to AA is your big omega-6

00:36:20.380 pathway. We'll pause there for a moment. With all of that said, what was your state of understanding

00:36:27.280 circa 1978-ish, whenever you probably started this study, about EPA and DHA, which today we know a lot

00:36:36.300 about and we'll talk about it, but what did you know then?

00:36:39.100 I didn't know anything about them. All I knew was we were using salmon oil. And I don't remember,

00:36:45.480 at the beginning of our experiments to see what the effect of salmon oil was on cholesterol.

00:36:51.340 I'm not sure I even knew EPA and DHA existed. In a very simple-minded way, we were asking the

00:36:58.920 question, we know animal fats that are solid at room temperature raise cholesterol levels. And we

00:37:04.660 know that vegetable oils, plant fats, basically, plant oils lower cholesterol and they're liquid at

00:37:12.320 room temperature. So we have animal and solid and we have vegetable, plant and liquid. So is it the

00:37:20.360 liquidness that's important or is it the animalness, animal versus plantness that's important in

00:37:26.700 controlling cholesterol levels? And so the uniqueness of fish oil is it comes from an animal, but it's a

00:37:33.560 liquid.

00:37:34.220 That's really a funny and cute way, yet an elegant way to think about it, right? It's a two by two of

00:37:38.500 solid versus liquid, animal versus plant derived. And the fish oils sit in a unique part of that

00:37:46.620 two by two, as you said, liquid, but animal derived. Okay. So that makes sense.

00:37:50.400 That was the question. So is it the animalness or the liquidness of the oil that lowered cholesterol?

00:37:55.280 It turns out that fish oil lowered cholesterol and it's an animal fat. So it's the liquidness that

00:38:01.760 was important, not the source, not whether it's a plant or an animal, it's the physical property of

00:38:06.320 the oil. That's the important thing. But EPA and DHA, we really, I mean, I don't remember knowing

00:38:11.580 anything about them until well into our study. And I started reading the papers from the Greenland

00:38:16.200 Eskimo studies. And that's when I said, oh, these things have EPA and DHA in them. How about that?

00:38:21.780 Now, the average American today who is not supplementing with fish oil will get approximately

00:38:31.940 how many grams of EPA and DHA in their diet? Well, let's talk about milligrams because it's about

00:38:40.060 roughly a hundred, 150 milligrams, 0.15 grams per day is about the average EPA plus DHA.

00:38:49.040 You mean 150 milligrams combined EPA and DHA?

00:38:54.020 Yeah, right. It's about how much arachidonic we eat too. As a matter of fact, it's about the same

00:38:58.640 scale. That's kind of mind boggling when you think about how much fat the average person eats,

00:39:03.820 right? Oh, yeah. Yeah. Out of 80 to 100 grams a day, that 0.15 grams might be EPA and DHA. That's

00:39:11.500 too bad. Historically, was there a day when we consumed more of that or where is that in line

00:39:17.920 with history? Certainly any culture that lived off seafood was eating more EPA and DHA.

00:39:23.900 So let's use the Okinawa as an example, not including this generation, which I've read

00:39:30.540 have sort of fallen off the rails. But if you go back a generation and beyond of the Okinawa,

00:39:35.900 who obviously would have been consuming seafood daily, how much EPA and DHA would they have

00:39:40.040 consumed? They were probably in the neighborhood of one and a half, maybe two grams a day, 2,000

00:39:45.480 milligrams maybe. I mean, the Eskimos, when they were discovered by Dyerberg and Bang in the 1970s,

00:39:52.240 documented six to seven grams a day of EPA and DHA. As impressive as that is, let's come back to

00:39:59.920 your study. You were giving 25 grams of EPA and DHA to these subjects. So this was, there had

00:40:06.820 probably been no, I mean, I assume that your rationale for doing this was, if this doesn't

00:40:12.440 show an effect, we never need to study this again. That's exactly the rationale. Do it once.

00:40:19.420 What was the magnitude of the reduction in total cholesterol, LDL cholesterol and triglyceride

00:40:24.640 that you saw in that study? Not to put you on the spot with something you did a hundred years ago,

00:40:28.120 but directionally, was it significant? Not just statistically, but clinically.

00:40:32.500 Oh no, it wasn't marked. Like cholesterol might've gone from 250 to 230.

00:40:40.240 Okay. What about triglycerides?

00:40:41.700 Triglycerides went from about 100 to 75.

00:40:43.980 Okay. So that's a pretty big reduction in triglycerides. It's a, you know.

00:40:47.840 That's a percent it is.

00:40:49.140 Yeah. Yeah. Any other phenotypic changes you observed in those subjects or was that,

00:40:54.720 those were your primary endpoints? That's all you had the budget to study.

00:40:57.660 You alluded to it earlier. Platelet function bleeding was something we looked at because that,

00:41:02.840 by that time, Jorn Dyerberg had published a paper in Lancet 1978,

00:41:06.980 1878, proposing that EPA was an antiplatelet or like a blood thinning fatty acid. And that is why

00:41:16.580 it prevented blood clots. And that is why Eskimos didn't have heart attacks. That was the proposal.

00:41:23.040 And EPA had been shown by that time to be antiplatelet. So we were very interested in the

00:41:29.560 effect on bleeding. And we saw a significant prolongation of an old fashioned test called the

00:41:35.200 bleeding time test, where we actually cut the skin and count how many seconds it takes to stop

00:41:40.580 bleeding. It didn't prolong it any longer than aspirin did. So not outrageous, except in one

00:41:48.180 patient. It wasn't a patient. It was a college student. But he had a marked drop in his platelet

00:41:54.620 count. We wrote a whole paper on this guy. He had a marked drop in his platelet count, a really

00:41:59.580 prolonged bleeding time. And we stopped him on the omega-3 diet because of that. But

00:42:04.740 everybody else had just kind of a mild prolongation of bleeding, which was an inhibitor. So the

00:42:10.300 platelets were less reactive, less likely to clot, which is a good thing. So that fit with the idea

00:42:16.380 that these are protective against heart attacks. Now, if I did the math somewhat correctly on your

00:42:22.360 salmon burger versus salmon oil distinction, is it safe to say they were getting about two-thirds of

00:42:28.020 their EPA and DHA through consumption of salmon and about a third of it then through actual

00:42:34.240 concentrate oil?

00:42:35.580 It'd probably be the reverse because let's say they were getting two four-ounce servings a day of

00:42:41.700 salmon. And let's just ballpark that at two grams. Let's be generous. Each one of those has two grams

00:42:47.980 of EPA and DHA. So there's four grams. And then they were getting 20 grams from the liquid oil they

00:42:54.200 drank. Oh, okay. I don't know why I thought it was only 10. Okay. So that was the reverse. So

00:42:58.160 they're getting most of it in concentrate. They're getting maybe a quarter of it or even less

00:43:03.520 potentially through consumption of salmon. Going back to the Eskimo for a second, do you have a

00:43:08.800 sense from those studies what percentage of their total calories were fat and then how much of that

00:43:14.180 was saturated versus poly? And I'm guessing mono was not a very abundant source in the North Pole.

00:43:20.000 Very high fat diets. Again, I'd have to look it up, but their diet was largely seafood. And we're

00:43:27.160 talking about seal, blubber, and whale meat, and some fish. This is pretty much what they ate.

00:43:35.920 You know, Greenland, you don't grow anything, at least not until global warming comes along. But for

00:43:39.880 now, they didn't grow anything. So fruits and vegetables and grains were, you could get them at

00:43:45.560 an occasional store. But fundamentally, they were living a traditional lifestyle in eating what they

00:43:51.720 killed out of the sea. So they were probably 80% of their calories were fat.

00:43:56.360 And of that, do you have a sense of how much was polyunsaturated versus saturated?

00:44:01.420 Probably about maybe six or seven grams a day out of, let's say, let's say they ate 100 grams of fat a

00:44:07.000 day. So six or 7% of it might've been the omega-3, the polys, polyunsaturates, very little omega-6.

00:44:13.980 And probably 70% of the fat was saturated. Huge amount. I mean, this is what was so amazing about

00:44:23.620 the Eskimo studies, because we had this paradigm that high fat, high saturated fat, high cholesterol,

00:44:29.900 of course, eating very high cholesterol diet, because everything was from animals.

00:44:33.940 Those are bad diets. And yet the evidence, which has been challenged nowadays, but at the time,

00:44:40.000 the evidence was these Eskimos were all virtually free of acute myocardial infarction of heart

00:44:45.460 attacks. It just didn't make any sense, which is why the couple of Danish investigators went over

00:44:52.000 there and started studying them, measured their plasma, their food, and they kind of discovered

00:44:56.900 omega-3 fatty acids. So was your conclusion from the study in 1980 that the high amounts of EPA and DHA

00:45:05.520 and their diet were offsetting or protective to the high amounts of saturated fat? Or was your

00:45:12.160 conclusion that maybe the saturated fat, because it came from fish, was somehow different from,

00:45:20.320 say, dairy or land animals? I mean, how did you reconcile your experiment with this broader volume

00:45:29.120 of data, though they're obviously asking very different questions and looking at very different

00:45:33.360 things? I mean, how did you begin to square those things? For one thing, again, we didn't feed any

00:45:38.160 blubber or any whale meat or seal meat, any of that really high. We were feeding salmon oil.

00:45:45.320 Your subjects didn't really have a significant increase or change in macros, really. They were

00:45:50.260 just basically getting an extra 25 grams of fat that happened to be polyunsaturated omega-3, but they

00:45:56.440 weren't- Largely true. Largely true.

00:45:59.060 So where do you go next, Bill? So obviously, well, you've never stopped looking at polyunsaturated,

00:46:03.000 unsaturated fat since. So tell me how that study basically piqued your curiosity.

00:46:08.220 I think the interesting thing, the way that played out is actually 1985 was a turning point

00:46:13.560 year for omega-3. In that year, in May of that year, the New England Journal published three back-to-back

00:46:24.460 omega-3 studies. One was our study in giving very high doses of omega-3 and looking at

00:46:32.760 effects on lipids. We showed huge drops in triglycerides. We were studying people. The

00:46:40.440 study I did was with the normal volunteers. We later did studies with people who had lipid

00:46:46.020 disorders, had very high triglyceride levels, for example. We found that giving them fish

00:46:50.960 oil just knocked the socks out of their triglycerides. Instead of their triglycerides being 2,000, they

00:46:56.180 were down to 250. It was a huge effect.

00:46:59.980 And how much EPA and DHA did you have to give them?

00:47:02.680 That was the 18 to 20 gram. We're still doing play in the same game. We were still giving

00:47:07.880 high doses of salmon oil. So New England Journal publishes our paper. It publishes a paper on kind

00:47:14.060 of arthritis or inflammatory disease. And it publishes a paper on kind of molecular biology,

00:47:19.240 sell the effects of EPA on what's called leukotrienes in inflammatory molecules. It was a basic science

00:47:26.640 paper. But it was bang, bang, bang, three papers in a row, literally in the magazine in a row,

00:47:33.360 in May of 1985, that just put omega-3s in lights on the map. And people got very excited about them.

00:47:40.820 What we did subsequent to that, instead of patients completely controlling their diet,

00:47:47.960 by that time, we were able to, because omega-3 supplements, concentrated pills were now becoming

00:47:53.420 available. And so we did some studies just giving 18 capsules. So we were giving six grams a day of

00:48:00.560 EPA and DHA in capsule form without changing anybody's diet. What happened in that setting was

00:48:07.740 very different. In that setting, where we didn't change their background fat intake,

00:48:12.840 just added omega-3s, triglycerides still came down very nicely. But the conundrum was LDL cholesterol,

00:48:20.320 the bad cholesterol started to go up. That was one of the downsides of the omega-3 story. Because all

00:48:26.360 of a sudden, we published this, it gets a lot of press, American Heart Association, and these fish oil

00:48:32.960 companies that were just starting to advertise their product as cholesterol lowering, based on our

00:48:39.780 earlier studies, and others, it's not just us. Fish oil folks were marketing their fish oils as

00:48:45.340 cholesterol lowering products. And then we show, when we directly test them, that they don't lower

00:48:51.320 cholesterol. In fact, in some people, at high dose, they will raise cholesterol. So FDA sends out all

00:48:58.840 these letters to these companies and say, you can't, you're false advertising. You can't say this

00:49:03.060 anymore. So that was what they call a gut punch to the industry at that point.

00:49:08.400 At the time, was it clear whether LDL cholesterol alone was going up? Was ApoB going up as well? What

00:49:15.940 other parameters of the lipoproteins were changing?

00:49:20.140 LDL cholesterol and ApoB. There were more particles.

00:49:23.480 How much were they going up based on just this six grams of additional EPA and DHA?

00:49:28.580 They might've gone from an LDL of 120 to 140 or 150.

00:49:34.040 That's amazing. I mean, we're talking about six additional grams of a very specific type of fat

00:49:38.720 having that much of an impact on LDL cholesterol and presumably, as you said, the particle number

00:49:44.500 ApoB. So mechanistically, what do you think was happening there?

00:49:49.400 That's been hard to figure out, but more recent studies have suggested that there's actually an effect

00:49:54.940 primarily of the DHA component on LDL receptor activity. It actually can slow down the action of

00:50:03.140 LDL receptors. So the LDL receptors are not removing LDL particles from the blood

00:50:09.300 as fast as they used to be. So the blood levels go up.

00:50:13.380 So it's an effect on clearance, not an effect. It's not an effect on production.

00:50:17.760 In the previous example, were you saying that the part of the saturated fat issue on clearance,

00:50:21.400 because there's obviously a big effect of saturated fat on production, but you're saying

00:50:25.220 that saturated fat on clearance was altering membrane permeability and the LDL receptor was

00:50:30.540 therefore losing efficacy.

00:50:33.020 Yeah, right. That's, I think, our current understanding of why saturated fats raise cholesterol,

00:50:38.620 raise LDL. Now here, several years later, we kind of begin to see evidence that,

00:50:43.380 fish oil, and again, I want to emphasize, this is in people that have high triglyceride levels.

00:50:48.320 This is not just a normal people taking one fish oil pill. This is completely out of that realm.

00:50:52.780 We're six grams a day of EPA and DHA in people with elevated triglycerides. In that setting,

00:50:58.220 the LDL and ApoB went up.

00:51:00.500 Now there's another little wrinkle here, Bill, which is if you're going to take people that have

00:51:05.220 triglycerides that are that high, how many of them are insulin resistant or have metabolic syndrome

00:51:12.380 as the underlying disease state versus how many of them are metabolically very healthy,

00:51:18.500 but have a hypertriglyceridemia, a familial, I think that's a Friedrichson-Levy-Lease type 3,

00:51:24.580 but I'm probably wrong on that. But how many of them are genetically seeing this high triglyceride

00:51:30.480 in the context of perfect metabolic health versus metabolically ill?

00:51:35.300 Well, yeah, that's a good question. And I'd have to look back. I mean, you're right about

00:51:40.500 Fredrickson types. It's not type 3, it's type 4, which is the isolated hypertriglyceridemic

00:51:46.280 person. And there's type 2B, which is high triglycerides. In both of those settings,

00:51:52.460 the LDL cholesterol went up. We had never heard of metabolic syndrome in the mid-80s.

00:51:58.040 We'd have to look back, you know, what was their glucose level? I'm not even sure we measured it.

00:52:01.380 I'm sure we measured their blood pressure and their body weight, but other metrics of the

00:52:06.560 metabolic syndrome weren't even crossing our minds in those days. So it's hard to say.

00:52:11.620 That's interesting. But today, the largest dose of EPA that is given pharmacologically is about

00:52:18.060 4 grams. Is that correct?

00:52:19.620 4 grams.

00:52:20.640 Isn't that indicated primarily for people with elevated triglycerides?

00:52:24.940 It's indicated for people with very high triglycerides. So we've got two levels of high

00:52:29.160 triglycerides. You've got garden variety, high triglycerides, which is maybe 200.

00:52:34.160 So a normal triglyceride may be 100, 150. I mean, maybe that's not optimal, but that's kind of normal.

00:52:40.360 200 to 500 is what we call hypertriglyceridemia. And over 500 is now very high triglycerides.

00:52:48.840 And there's kind of a bright white line. The FDA indicated when the first omega-3 drug was approved,

00:52:56.780 it was Lovesa or Omicor. And it was approved by the FDA for treating triglycerides over 500,

00:53:03.980 not under 500, over 500. And it was approved at this dose of 4 grams a day because that's the dose that the

00:53:11.340 company did the studies at.

00:53:13.840 They could get better triglyceride lowering with higher doses, but now you're talking six or eight

00:53:18.700 pills a day and it becomes totally impractical. So it was a compromise. Let's make the dose 4

00:53:24.620 grams a day. It does lower triglycerides and it works to some extent. And so that's what the FDA

00:53:31.500 approved. And so FDA has now set 4 grams as the standard dose.

00:53:36.940 Their product, is it any different from what one buys over the counter?

00:53:43.840 That product that I was just talking about, what's called Lovesa, and it's now Lovesa,

00:53:49.760 that's about 85% EPA plus DHA. It's ethyl esters. You can buy over the counter or dietary supplement

00:53:59.300 essentially, more accurately. Dietary supplements that have that much EPA and DHA as ethyl esters

00:54:06.260 in one pill. Typically you have to buy, the pill is not a one gram pill. So maybe we're going to get

00:54:13.740 into this, the confusion about 1,000 milligrams of fish oil. But the standard drug, the Lovesa drug

00:54:20.880 is 1,000 milligram capsule of which 850 or 85% is EPA and DHA.

00:54:28.500 Oh yeah, no, we should definitely cover that now. So if you go on Amazon, I mean, I'll just share my

00:54:33.560 bias. I've talked about it before. The two brands I typically recommend to patients are

00:54:37.720 Carlson's and Nordic Naturals. And I'm sure there are several brands out there that are quite

00:54:43.400 reputable. Anahad O'Connor at the New York Times wrote a story on this probably four or five years

00:54:47.820 ago, looking at lots of different brands of fish oil. And it was looking to basically see how many of

00:54:54.920 these were made at GMP standard, how many of them actually had in them what they said they contained

00:55:00.440 from a content perspective, what was the level of contaminant, all sorts of variables. But for

00:55:05.800 whatever reason, again, those two brands I've just gotten to know and I've gotten to trust.

00:55:09.700 But you still have to read the label very carefully because one, these are very large capsules. Two,

00:55:16.160 the entirety of the capsule is not EPA and DHA. So we tend to think about how much EPA and DHA we want,

00:55:23.500 and we then have to sort of reverse engineer it out of the capsules. If you're taking 2,000 milligrams

00:55:29.300 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

00:55:37.640 finding. What's the other 400 milligrams? It would be a mixture of some monounsaturates and some

00:55:43.920 polyunsaturates. Just a kind of general standard fatty acid you'd find in most foods is just a very

00:55:50.860 small fraction of what's in the fish oil, particularly a fish oil concentrate.

00:55:54.980 Now, am I being paranoid about this stuff or do you think that most of these things that are sold

00:55:59.320 as dietary supplements are reasonably safe or what is your view on that?

00:56:04.320 I don't have a problem with dietary supplements. I think that the vast majority of them,

00:56:08.820 when they've done consumer reports, testing, they've done it twice in my memory. Their final

00:56:13.940 conclusion is generally, the products have pretty much as much EPA and DHA as they say,

00:56:20.280 with some variation, and they're free of toxins and any meaningful levels of environmental pollutants.

00:56:27.460 So, I don't have a problem with it. The challenge is, if you're going to try and get four grams a day

00:56:33.240 of EPA and DHA, which, or three and a half grams is really what four capsules of LaVesa would give you,

00:56:39.140 because it's, again, 85%. So, you're going to be taking a whole lot of dietary supplements,

00:56:45.540 a lot of pills, because most pills are not that concentrated, typically. Nowadays, you can find

00:56:50.240 very highly concentrated products, and the line between a drug and a dietary supplement is getting

00:56:56.360 a little bit fuzzy, which is something some of the drug manufacturers are pointing out more and more

00:57:02.320 loudly, that there's a lot of products that are being sold as dietary supplements that fundamentally

00:57:07.560 have the same chemical composition as FDA-approved drugs. There's going to be a fight about this

00:57:14.020 coming on. But the processing of omega-3 rich oils has advanced tremendously over the last 20,

00:57:21.140 30 years, and they can really concentrate these, take a raw fish oil, which might have 30%

00:57:26.780 of its fatty acids, EPA and DHA, and you do lots of processing to get rid of all the other fatty

00:57:34.040 acids, and all you have left is EPA, DHA, and you're really highly concentrated. And that's

00:57:38.460 not all that different than the composition of some of these drugs. It's going to be confusing,

00:57:43.180 I think, to the consumer. Bill, what is our current understanding

00:57:47.500 of the health benefits of EPA specifically? I want to actually talk about this and then do the same

00:57:54.500 thing on DHA and then do the same thing on arachidonic acid. So cover these three end products of the

00:58:01.560 omega-3 and omega-6 pathways. But let's come back to EPA, because that's sort of where we got off on

00:58:08.980 this little side tangent. Today, is the consensus view that EPA is a quote-unquote heart-healthy oil?

00:58:15.880 Yes. And you could say the same for DHA, in my view. But yeah, EPA is heart-healthy. Its mechanisms by

00:58:24.260 which it is heart-healthy are multiple, and they include being converted into, again, some metabolites,

00:58:32.720 some prostaglandin-type molecules that make the platelets, the blood platelets, less likely to get

00:58:37.480 sticky. And so there's a reduced, it's kind of like taking aspirin without some of the side effects

00:58:42.920 of aspirin. So that's one of the arms of the benefit. The EPA is also able to produce a whole

00:58:50.840 series of molecules that we call resolvins, because they resolve inflammation. So they're kind of

00:58:57.920 anti-inflammatory in that sense. They also, when EPA becomes incorporated into cell membranes, it changes

00:59:06.360 the flexibility, the fluidity of the membrane, just because of its own physical properties. And that

00:59:12.120 changes the way the enzymes that live in the membranes work in such ways that makes cellular

00:59:18.900 metabolism run more smoothly. I mean, to try to simplify this. Those are really primary ways that

00:59:25.520 EPA, I think, is heart-healthy. We've only had one big study with EPA only, free of DHA.

00:59:34.820 Okay. Let's talk about that one now. And then I want to come into potential risks of EPA. And then

00:59:40.680 I want to circle back to DHA. But let's talk about the EPA only study. What was the patient population?

00:59:47.240 What was the dose? And what was the objective of the study?

00:59:50.440 The study was called Reduce It, which was an acronym, as they all are for something. Reduce It

00:59:56.820 was the name of the study. The product was called Vasepa, like vascular EPA, V-A-S-C EPA,

01:00:03.880 a company that makes the drugs called Amarin. And the way the study was done, they gave four grams a

01:00:10.300 day of this EPA. It's EPA ethyl ester. So it's a very purified EPA that has a ethyl ester, which is

01:00:18.080 the typical way that they use. They concentrate omega-3s nowadays. Four grams a day versus the four

01:00:24.960 grams of a mineral oil placebo, which has had some controversy as to whether that's a real

01:00:29.740 placebo or not. Roughly 8,000 patients who all were on statin drugs to control their cholesterol

01:00:35.860 levels. And they all still had triglycerides between 2 and 500, roughly, 150 to 500. So

01:00:43.980 triglycerides were still elevated even though they were on a statin. LDL cholesterol was roughly in the

01:00:49.800 70s. So there was low or healthy levels of LDL. And they also had to have either a history of heart

01:00:56.560 disease or some other risk factors like having diabetes, for example, was another way you could

01:01:02.480 get in. So if you met that criteria, that kind of patient, you were given either four grams of

01:01:06.740 placebo or four grams of Vasepa. Do we know what fraction of those patients were metabolically ill?

01:01:14.800 I assume most of them were. And I know this study is only about a year and a half old,

01:01:18.580 right? I mean, I remember this when this came out. Well, it was reported in November. So six

01:01:22.760 months ago. So almost a year, but okay. I've lost track of time. Time flies. Right. Exactly.

01:01:30.020 But how many of these people were sort of metabolically super healthy, but just happened

01:01:33.400 to have these genetic triglyceride elevations? Nobody checked in the study what any kind of,

01:01:39.220 they may be someday. They probably have blood for them and they'll check things later. But

01:01:42.640 as a recruitment strategy, they just took people who met those criteria. You're on a statin,

01:01:48.300 you have triglycerides between 150 and 500, and you've got some other risk factors for heart

01:01:53.840 disease. And that's it. And you're in. What did the study show? Because it sure made a lot of

01:01:59.200 headlines. It should have. And it did. It showed a 25% reduction in risk for overall cardiovascular

01:02:05.900 events over about a four or five year period, which is not that long. And it was effective across,

01:02:13.980 you know, myocardial infarction, need for angioplasty, a variety of different cardiovascular

01:02:18.660 unfortunate outcomes. So it was a big hit. It was really, for the last 15 years, we've been

01:02:25.980 searching for other lipid lowering drugs that, or other drugs that will improve the outcomes over

01:02:34.040 statins. The statins have been established in the 80s and 90s and 2000s as very, very effective in

01:02:40.740 reducing risk for heart disease. But there's still people, even on a statin, that still have

01:02:45.860 events, cardiac events. So that's called residual risk. We have leftover risk. So what do we do for

01:02:51.380 that? And there have probably been 10 or 15 drugs that have been tested to try to improve upon a

01:02:57.940 statin. Really, none of them have worked without going into all the details. But this one, pure EPA,

01:03:04.320 worked. And it worked great. And it worked with virtually no side effects. And you can take it

01:03:11.220 with any other medications. It doesn't have any drug-drug interactions. I think it was a big hit

01:03:16.920 and well-deserved. I should mention the name, the trade name of the drug is Vasepa. The generic name

01:03:24.480 is called eicosapent ethyl, two words. And it starts with an I, I-C-O-S-A, eicosapent. It's

01:03:34.680 really just a flipping around of the spelling of eicosapentaenoic acid or EPA.

01:03:40.120 Now, Bill, one of the issues with this study, of course, is the inclusion criteria

01:03:43.840 assumes that the patients have very high triglycerides. I must have received 12 emails

01:03:48.920 in the span of a day from patients of mine saying, hey, should I be taking this? To which

01:03:54.440 my answer was, well, your triglycerides are 86. So I'm going to go with no on that because

01:04:00.540 I can't infer that the mechanism by which this worked in these patients is going to have a benefit

01:04:07.520 in you. Do you know if there's any plans to repeat that study or a study like it in a normal

01:04:15.420 triglyceride population? I don't. I know that what's fundamentally being reproduced

01:04:20.760 is the same type of patient, but with a EPA plus DHA product.

01:04:26.880 Why was that study done with only an EPA versus a combined?

01:04:31.740 Well, in the late 80s, a EPA only drug was approved in Japan called Epidil, which is essentially

01:04:41.780 it's exactly the same thing as Vasebo. In the Japanese, back in the 1980s, believed that it was

01:04:48.840 EPA that was the active agent in fish oils. So a drug company called Mochita developed an EPA drug

01:04:57.380 and they got it approved and they've been using that EPA drug for years and years. And the JELUS trial,

01:05:04.940 which was published in 2007, which was a Japanese omega-3 trial, used this product. It's called

01:05:12.040 Epidil. We would call it Vasepa. And it was successful. This company in Ireland, Amarin,

01:05:19.060 has the same molecule, essentially. I think they're trying to carve out a unique niche in the omega-3

01:05:24.960 world that they can get an approved drug. EPA plus DHA is already approved. That's Lovasa,

01:05:31.860 Omicor. They say, well, let's just try the EPA part and see what that does. And it works well.

01:05:38.660 What nobody's ever done and nobody is doing yet is the counter part, a DHA only study.

01:05:45.100 What is your take on this from two standpoints? The first is, if you can speculate for a moment,

01:05:51.200 do you believe that EPA and DHA from a cardiovascular standpoint are as beneficial

01:05:57.820 or have benefit in people with normal triglycerides?

01:06:02.840 Yes. I don't think the benefit, the cardiovascular benefit comes from lowering triglycerides.

01:06:10.660 In fact, in this study, the reduce it study I just talked about with EPA, triglycerides were

01:06:15.960 lowered 15% maybe. It was not a huge drop in triglycerides by any means.

01:06:22.820 What was the reduction in LDL-C and ApoB? I don't recall.

01:06:26.120 Virtually no change. Unlike PCSK9 inhibitors, which really have had the biggest impact on

01:06:33.300 residual risk in cardiovascular disease over the past five years, very similar population to what

01:06:38.880 you've described in Fourier, more so than Odyssey, where they started with patients already maximally

01:06:45.780 statinized. These patients, it was independent of their triglyceride level, but they had to be

01:06:49.860 maximally statinized. I think they came in with an average LDL cholesterol of 74 milligrams per

01:06:54.700 deciliter. And in a very short period of time, something to the neighborhood of two and a half

01:06:59.940 years saw an amazing event risk reduction. But the event risk reduction in reduce it was greater

01:07:06.620 than the PCSK9 studies.

01:07:09.340 Yeah. It was a longer study. Wasn't it about five years in reduce it?

01:07:12.380 Yeah. Right, right.

01:07:13.040 Yeah. And Fourier was like 2.2 and Odyssey was about 2.4, which again, I think all of those

01:07:18.980 are amazing. I'm not saying that to be one up on reduce it or one down. I actually just,

01:07:24.400 I think most people don't understand the time course of cardiovascular disease well enough

01:07:29.280 to appreciate the fact that you can take a disease that is a time course disease that starts at birth

01:07:36.300 and in somewhere between two years and five years actually reduce events. It shouldn't happen. And

01:07:42.860 in fact, I remember, I don't know if I actually said it out loud. It would be great if I did,

01:07:48.340 because I could go back and, you know, maybe someone would remember, but, but I certainly

01:07:51.620 remember thinking Fourier is going to fail because not that I didn't have faith in the mechanism of

01:07:58.100 PCSK9 inhibition, but because I simply didn't think you could bend the arc of a disease like

01:08:03.600 cardiovascular disease in two years on a group of patients who had an LDL cholesterol in the 70s.

01:08:09.500 That just struck me as impossible. It is really quite amazing that all of these things work. And

01:08:14.560 in some ways it's even more amazing, frankly, that just pure EPA could have this effect,

01:08:19.100 which again, I'm bringing you back to the question that I keep interrupting you when you start to

01:08:24.900 answer. I apologize. Why in the world would four grams of EPA reduce events, especially as you said,

01:08:32.880 when it's not the obvious mechanism of, Hey, we're going to drop triglycerides, which all things

01:08:38.360 equal should drop ApoB. And by the way, you're seeing a greater magnitude of event reduction than

01:08:42.960 you're seeing with aspirin. So the pure antiplatelet effect also seems a bit counterintuitive. What

01:08:50.420 else do you think is going on here? Right, right. It's not enough. Whatever role inflammation,

01:08:55.400 and it's such a slippery word that's thrown around so much, but EPA definitely gives rise to molecules

01:09:02.880 that are pro-resolution of inflammation. So inflammation starts, the EPA will shut it down.

01:09:11.640 To whatever extent a cardiovascular event is precipitated by an inflammatory event,

01:09:18.420 the omega-3 EPA could participate in that. It could stop it. The omega EPA could also play a role in

01:09:26.280 even the control of the heart rate. The heart rate variability can be reduced. I'm not sure in

01:09:32.560 this study they measured it, but we've done studies with omega-3 showing heart rate variability,

01:09:37.360 which is a marker of autonomic nervous system control of the heart, is improved. So that's

01:09:43.440 another piece of the puzzle. It could just be several different things that each one in and

01:09:48.300 of itself. They add up and they multiply. And you said heart rate variability improved. Before that,

01:09:53.480 you said reduced, but I think you mean improved or increased, right? Is that what I would say?

01:09:56.980 Correct. Yeah, correct. Do you recall if in reduce it, they measured other cytokines,

01:10:02.400 inflammatory cytokines beyond the usual suspects? Did they look at all of the suite of interleukins and

01:10:08.340 things like that? Was that published in the original study? So presumably, as you said,

01:10:12.180 they've got a biobank that may be able to look at other markers of what was the signature of this

01:10:18.980 event reduction. Going down this path you just described, it'd be great to see what happened to

01:10:24.220 IL-1, IL-6, TNF. If you look at all of these other things that could be playing a role in the

01:10:31.500 inflammatory component of atherosclerosis, that would be interesting to see, right? Because then it

01:10:36.600 would give you more confidence that this has broader applicability than just people with

01:10:42.080 sky-high triglycerides. Back again to the inclusion criteria, these are not sky-high

01:10:46.500 triglycerides. And this is not triglycerides over 500. These are not people at risk for pancreatitis.

01:10:52.000 This is much more garden variety hypertriglyceridemia. I don't know. In my practice,

01:10:55.880 Bill, 150 to 500 is sky-high. Okay. Well, I guess I'm used to hearing type 500,000, 2,000.

01:11:04.980 And, you know, people have that. But that's the place the omega-3s first got their approval in that

01:11:11.000 very high triglyceride world. And so when we bump it down to under 500, to me, it seems like kind of

01:11:15.900 garden variety. But you're right. Well, but that's a fair point. I mean,

01:11:19.580 it's certainly representative of the U.S. population. Did that study, did it look at how

01:11:23.760 much of that EPA converted to DHA? In other words, one of the advantages, presumably, of giving megadose of

01:11:29.720 EPA versus megadose of DHA is you're higher up the food chain. So presumably, you're covering

01:11:37.040 any benefit that's unique to EPA, if you believe there may be one, and then you're also transmitting

01:11:43.040 into DHA and getting that. Or do you believe that all of the benefits of EPA are transmitted through

01:11:49.480 DHA? I think it's probably all the benefits of EPA are transmitted through EPA, not through conversion

01:11:56.460 to DHA. Not through the conversion to DHA. No, no. In fact, when you look at a couple of papers

01:12:02.920 looked at the effects of giving pure EPA programs on red blood cell DHA levels, for example. And

01:12:12.400 DHA levels actually go down a little bit. EPA goes up. Of course, you're feeding EPA. But the DHA

01:12:20.600 component in the red cell membrane goes down. Or in other studies, stays the same, but doesn't

01:12:26.440 grow up. You're not increasing DHA tissue levels. That's really interesting. So in other words,

01:12:31.820 if EPA is being converted to DHA, which I assume we still think it is, it's not necessarily, I mean,

01:12:38.000 it's just increasing the substrate pool of DHA, but not necessarily the incorporation into cell

01:12:42.280 membranes. Right, right. That's interesting. And that actually explains, I think, some of what I

01:12:47.620 guess I would see when I look at people's laboratory values. While we're on this topic, if I consumed

01:12:53.580 staggering amounts of flaxseed oil, by the way, a friend of mine once gave me a recipe to make flaxseed

01:13:00.540 tea. And I, A, it tasted really good when I had it at her place. So part of it is just,

01:13:07.780 it was really amazing. And part of it is the recipe was so complicated that I took pride in

01:13:12.820 like taking two days to make a vat of flaxseed tea that could feed a small village. I was never able

01:13:19.240 to get it quite right, but let's assume I could get it right and I could consume a near infinite

01:13:25.160 amount of flaxseed oil. Could that amount of ALA ever give me sufficient enough substrate EPA and DHA

01:13:33.780 to rival what we're talking about in these supplemental doses of four grams?

01:13:39.860 No, it's never. When people have tried giving 12 grams of ALA, or not just flaxseed oil, ALA.

01:13:48.300 Just straight ALA.

01:13:49.360 Yeah, you don't even get. You might take an EPA level of 1% in a red cell and maybe drive it to 2%.

01:13:56.420 There's two questions I have, and I hope I'm going to remember the second one.

01:14:00.540 Is there a risk that looking at the red blood cell, which of course is the most obvious and easy cell for

01:14:05.960 us to access the membrane in? Is there a risk we're missing something that's not occurring in

01:14:11.740 cells that we can't access like as easily? We can't look at the membrane of adipose cells or muscle

01:14:17.480 cells. And we typically, even though it would be just as easy to look at leukocytes, I assume we don't

01:14:22.300 look at them at least clinically or commercially. Do we run the risk of just looking at one pony here?

01:14:28.760 Right. Everything's a compromise. So the red cell is the easiest cell type to get at.

01:14:33.300 Leukocytes are not that easy to get at.

01:14:35.020 Right. You need some apheresis or something like that.

01:14:37.960 Clinical lab. Right, right. And just a clinical lab setting is very difficult. Red cells are

01:14:42.800 thrown away by the gallon day by day just because all you really wanted was the plasma, right? So

01:14:48.040 the red cells go to the bottom and you take the plasma off and you throw them away. Red cells are,

01:14:52.800 we've shown red cells correlate with quite a few other tissues in terms of the omega-3 levels.

01:14:58.260 So they are a good reflection of other tissues. Probably the only one that's the least reflective of

01:15:02.640 is the brain, at least in the adult. It's hard to get the acid composition of the brain.

01:15:07.920 Yeah. I don't think anyone's going to sign up for the brain biopsy. So what are some of the

01:15:11.260 tissues that you've seen high correlation with with RBC?

01:15:13.920 Well, we did it originally with the heart using heart transplant patients who were being followed

01:15:20.100 up every six months with a heart biopsy to see how their heart was doing, of course. And we were

01:15:24.980 able to get their red cells and the heart biopsy and measure the omega-3 content and show the nice

01:15:30.160 correlation. The higher the omega-3 in the red cell, the higher the omega-3 in the heart. Other

01:15:34.640 people have done this too. And you can do it in animals, of course. Yeah. Lots of tissues.

01:15:38.100 Is there a high correlation with liver as well as myocyte, skeletal myocyte?

01:15:42.720 Right. Muscle and liver and yes, it's small intestine, large intestine.

01:15:46.880 Wow. Okay. We'll make sure we include all these papers, Bill, as well in the show notes because

01:15:50.880 this is, that's actually something I've just been too lazy to personally go back and check. It's on my

01:15:55.360 list of 2,000 things I want to go and check. And that's one of them is I always wanted to go back

01:16:00.180 and look at what the association between RBC membrane level was and other tissues. The other question I had

01:16:06.120 was what are the, we've kind of glossed over it because it's a little bit of the stepchild, but

01:16:10.260 what are some of the direct benefits, if any, of ALA by itself? Because you just noted that

01:16:15.560 it's not that having all the ALA in the world is not really meaningful to conversion to EPA. So if

01:16:21.620 there's benefit to ALA, it needs to be through ALA, right? We don't really know. There's certainly some

01:16:27.000 hints in some of the population epidemiologic studies that higher ALA intakes, presumably independent

01:16:34.540 of EPA and DHA intake, is associated with reduced risk for disease. So that's a good thing. I have

01:16:41.580 no problem with ALA. I just have a problem with it being a substitute for fish oils, for omega-3,

01:16:48.000 long chain omega-3s, because it doesn't. But ALA itself, I mean, I don't think it's a bad idea to

01:16:53.620 take ALA products, rich oils, as well as take fish oils. But we don't really know the mechanism,

01:17:00.060 but I think there's probably going to be some metabolites of ALA itself, in the same sense that

01:17:06.200 there are prostaglandins, leukotrienes, and other metabolites from EPA and DHA. There probably are

01:17:12.540 from ALA too, that are doing things we don't know about. It's all dark on the inside, so we don't

01:17:18.840 really quite know what's going on. I think there's going to be benefit, but it's not because it's

01:17:23.500 converted to EPA and DHA, as far as we know.

01:17:25.620 Wow. And speaking of which now, let's go down the bottom of that chain. We've talked about EPA.

01:17:31.200 Let's talk about DHA. As you said, we haven't had the study that takes four grams of DHA,

01:17:37.540 administers it in either a high, low, or normal triglyceride population. But based on studies

01:17:44.220 that have looked at high doses combined, and maybe trying to contrast with high dose EPA studies,

01:17:51.020 plus looking at all the animal and mechanistic studies, what is your best guess as to what a

01:17:56.220 high dose of DHA is doing?

01:17:58.740 In a sense, much the same thing as EPA. There are parallel mirror image molecules being made.

01:18:05.060 What DHAs are called, instead of resolvins, are called protectins. These are the metabolites that

01:18:11.060 are very active in anti-inflammatory processes. DHA will improve platelet function, make platelets

01:18:17.200 less sticky, the same way that EPA does. Different mechanism, but the same outcome.

01:18:23.420 DHA is probably better at actually lowering triglycerides and raising HDL than EPA is.

01:18:30.560 So there could be actually a lipoprotein benefit there. Although DHA does raise,

01:18:36.840 particularly in people who are hypertriglyceridemic, taking fairly high doses of DHA,

01:18:41.740 there will be an LDL raising effect. Whether that's a bad thing or not, nobody knows. But it's

01:18:47.740 been observed. And that's one of the differences between an EPA only product and a EPA plus DHA is

01:18:55.160 there have been folks who've been trying to say that the EPA plus DHA products are not good for you

01:19:00.420 because they have DHA, which can raise LDL. But I think that's a big stretch. And this is a lot of

01:19:06.420 caveats. But nevertheless, that's part of some marketing programs now, which I find unfortunate.

01:19:12.300 DHA is certainly, if you look at biology at the membranes of any of our membranes, red cells or

01:19:18.260 heart, DHA is by far the most common, much higher levels of DHA. Like the red cell, 85% and 15%. If you

01:19:28.100 look at the total of EPA plus DHA. Yeah. I usually think of it in terms of absolute. So I know I was

01:19:33.780 looking at my labs from, I draw my labs every once in a while. I think the last check was a few weeks ago

01:19:39.680 and my red blood cell EPA level was about 2.2% and DHA level was about 8%. So it's a comparable to

01:19:50.940 what you're saying for a total of about, you know, a little over 10%, 10 to 11%. At what point do you

01:19:56.820 worry? Is it too high? We really haven't seen any adverse effects in higher doses. And there are

01:20:01.980 major international bodies that are saying up to five or six grams a day of EPA, DHA is no problem.

01:20:07.960 And five or six grams of EPA would give you what level in the RBC? The highest level I've ever seen

01:20:13.060 in RBC is about, I've had a patient who was just taking this stuff by the truckload and which means

01:20:18.140 he was probably taking about three grams a day, maybe four, I'm not sure, but you know, was sitting

01:20:22.500 there at about 16% EPA plus DHA in the red blood cell. Is that complex? We have seen higher, but that is

01:20:29.820 very, that guy's probably 99.9% percentile. We've seen people over 20 who are not taking fish oil,

01:20:38.560 which is pretty, so there's some interesting biology. What do you think's going on in there?

01:20:42.460 How is that happening? Are they just eating a lot of fish or? This particular lady I'm thinking of

01:20:47.240 was when we interviewed her, said, yeah, she eats baby fish once a week, you know, some salmon,

01:20:52.580 but it's not like she's not doing anything Eskimo and she wasn't taking a supplement. She was a

01:20:58.840 woman of Indian, East Indian extraction and drank a lot of, the thing that really stuck out, she drank

01:21:03.820 a lot of kefir, liquid yogurt, but what in the world that would have to do with omega-3? I have

01:21:09.460 no idea. So we don't know what happened to her, why she's that way. And there's other people that

01:21:14.220 have been up that level that I think it's just genetic. I mean, that's, that's a cop-out word.

01:21:19.400 I know. I know it is funny, but I was just about to say the ubiquitous cop-out of genetic, but

01:21:24.340 I've absolutely seen patients who eat one serving of fish a week and need four mega EPA DHA and it's

01:21:33.760 the same brand. So it's not a brand issue. They'll take a, you know, mega dose, four capsules a night

01:21:39.200 of the big stuff, and you might get them up to 7%. And then I've seen other people who eat fish

01:21:44.780 twice a week and they walk around at 9%. You're seeing this as well and you're equally stumped by it.

01:21:51.860 Yeah, right. We published a paper recently looking at in something like 3,500 people that have

01:21:59.040 submitted blood to us and have told us how much oily fish they eat and whether they take a supplement

01:22:04.760 or not. Then that's all we asked. And we found out that the group that has the 50-50 chance of an

01:22:11.940 8% omega-3 index, we're eating three, reported eating three oily fish meals a week and taking a

01:22:19.000 supplement. But below that, the chances of having 8% are diminished, diminished. But there's even

01:22:26.120 within the category of people that were not taking any supplements and eating maybe one fish meal a

01:22:31.280 week, there were some people that had 8%. It's just, they're real outliers. There's a tremendous

01:22:36.760 variability in the level in the blood compared to what's in the diet.

01:22:41.140 Bill, just based on your knowledge around this, and we haven't fully finished the DHA stuff. So

01:22:46.120 with that caveat, do you have a recommendation for physicians or patients who are monitoring EPA

01:22:53.280 and DHA levels in red blood cells for a target? I mean, the lab that I use,

01:22:57.860 I think gives a range of 8% to 10% is ideal. Do you have a view on this?

01:23:03.040 We think in what we call the omega-3 index, which is EPA plus DHA in red cell membranes,

01:23:09.860 our target is 8% to 12%. That's a range we think is the healthy range. Average American is around 5%,

01:23:17.760 maybe 4% or 5%, twice as high as normal. I've seen people at 2%, which are obviously people who

01:23:25.680 don't supplement and don't eat fish. But I've also seen people who don't supplement, don't eat fish,

01:23:29.700 and they're at 5% to 6%, which again, comes back to this sort of question of the role of genetics in

01:23:35.860 driving this. So let's come back to DHA for a moment. A few years ago, there was certainly a

01:23:40.820 little bit of hoopla around the neuroprotective benefits of DHA. What is the state of the art

01:23:48.360 and science around that particular question? So it begins with the observation that the brain

01:23:53.300 and the retina, which is really just an extension of the brain, are very rich in DHA.

01:23:58.640 Virtually no EPA in the brain. Beginning with that, the logical conclusion is DHA is important

01:24:06.980 in the brain and the eye because they're there. People have then tried to jump to the conclusion

01:24:13.940 that therefore, if you give more DHA, you're going to get better brain health and better eye health.

01:24:18.740 Well, that's not necessarily panned out, particularly like in depression studies. That's the most clear

01:24:24.640 area at the moment where folks have tried to give high DHA products to try to affect depressive

01:24:30.760 symptoms and they don't really work. The products that seem to work to actually have an effect on

01:24:37.720 depressive symptoms are ones that are richer in EPA than DHA. And, you know, when, so you look at a

01:24:44.580 meta-analysis, a compilation of lots of different studies, the positive ones are the ones that are

01:24:49.280 richer in EPA, but there's no EPA in the brain. The logic was that if the meat of the brain has

01:24:55.840 got DHA in it, the actual physical flesh of the brain is DHA, then DHA should be given and it would

01:25:02.180 be beneficial, but that's not a logical assumption. I think what's happening is EPA is probably providing

01:25:08.120 some unique anti-inflammatory effects in the brain circulation that's affecting, because we don't

01:25:15.320 understand depression at all, but it's somehow affecting the expression of depressive symptoms

01:25:20.980 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

01:25:28.180 think that's true. I don't think we can at this point say one of them is better than the other

01:25:33.460 for any given system. They come together in nature in all fish that provide, that contain EPA and DHA

01:25:41.600 has both of them. It's not 50-50, it's usually 60-40 or 40-60 in terms of ratio, EPA and DHA.

01:25:49.640 So I think that's the best thing to do is to get both of them at this point for any condition,

01:25:55.020 all conditions. Because you've done a PhD in nutrition, I'm going to ask you a nutrition

01:25:59.420 question. If you recommend fish for people to eat, if someone says, look, I want to get as much of the EPA

01:26:06.480 DHA as I can through my food intake as opposed to supplement intake, and then being mindful of

01:26:12.400 fish that contain toxins, particularly mercury, what's the best yield for safety and then high

01:26:18.840 quantity of EPA DHA? I mean, salmon seems to be at the top of that intersection, right? Is there

01:26:23.860 other fish you'd put there? Sardines, herring, mackerel, almost all the oily fish are going to have

01:26:32.060 high EPA levels just simply because they have high oil, because they have fat in their flesh and their

01:26:37.620 tissues. There's really only about four or five fish that are, because of the mercury, have a mercury

01:26:43.220 concern, and they're fish that are really very rarely eaten. Tile fish, swordfish, king mackerel,

01:26:49.780 and shark. So those are the ones that everybody agrees that pregnant women, lactating women should

01:26:56.980 not eat because they affect neurodevelopment of the brain. There's anecdotal stories of people eating

01:27:02.040 vast amounts of tuna and getting high levels of mercury, and sure, I'm sure that can happen.

01:27:09.340 But by and large, albacore tuna, for example, is twice as much EPA and DHA as chunk light tuna.

01:27:16.960 It's more expensive. So it's a great source of EPA and DHA, but it has more mercury than chunk light

01:27:22.160 tuna has. I think people get that balance way out of whack. They're far more concerned about minuscule

01:27:29.620 amounts of mercury, and they will forego the good benefits of EPA and DHA in a food like

01:27:37.300 albacore tuna, white tuna, because they're afraid of the small amount of a toxin. The benefits of

01:27:43.940 eating fish, even if there's some mercury in it, far outweigh the downside of the mercury.

01:27:51.040 Yeah, I probably need to go a little further down this rabbit hole, but again, this is another example

01:27:55.020 where I've seen amazing individual variability. I've seen people who eat three servings of tuna

01:28:00.820 a week who have a mercury level below 10 on a laboratory assay like LabCorp, where the upper

01:28:07.020 limit of normal is 15, and there are people that walk around at 10, so they're perfectly fine,

01:28:12.020 and they're eating tuna three times a week. And then I've seen people who consume tuna twice a month,

01:28:17.960 and they're right at the upper limits. There's a lab called Quicksilver that we use

01:28:22.100 to further scratch at that a little bit and look at the inorganic and the organic. But one of the

01:28:27.800 things we've learned through that is clearance matters a lot. In fact, clearance seems to matter

01:28:32.160 at least as much, and maybe not surprisingly, as intake. So the Quicksilver test looks at the

01:28:38.980 hair, urine, blood. It basically quantifies how they're clearing inorganic and organic,

01:28:47.220 and then you get a sense, and then you're measuring organic and inorganic. So you're getting a sense of

01:28:51.420 is this coming in through food? Is this coming in through the environment? But yeah, it's another

01:28:56.900 one of those things that's complicated. I mean, my general rule and advice to patients is sort of

01:29:01.880 salmon and small bait fish is sort of open field running. And if you're going to go haywire on tuna,

01:29:10.040 which I could do, I could eat tuna every day. I love it so much. I don't. You're probably best to at

01:29:14.480 least measure your levels. But to your point, maybe we don't know exactly what the toxicity

01:29:19.220 curve looks like. It's worth exploring. I do want to come back to something else on the omega-3

01:29:24.380 broad front, which is there are a handful of studies. I've seen one of them, but I believe

01:29:29.160 there are others. I think one of them was the Honolulu Heart Study or something about, this has

01:29:33.380 got to be over 20 years old now, that actually looked at a reduced amount of lung cancer in smokers

01:29:42.260 who had high omega-3 levels. Am I getting that right? I've not seen that. I'd like to see that,

01:29:48.280 but I've seen papers recently that looking at smokers, some of the adverse effects of smoking

01:29:54.800 seem to be mitigated by a high omega-3 intake. Sort of the same idea.

01:30:00.260 It's the same idea. Yeah. And maybe I'm just not remembering the study correctly, but it sort of

01:30:05.000 goes down this theme of there was a protective benefit of high amounts of EPA and DHA.

01:30:09.860 Let's pivot back over now to the other side of the axis. We talked about linoleic acid or LA as an

01:30:19.060 essential fatty acid. I believe you said we get the lion's share of it from soybean and corn oil,

01:30:24.760 correct? Right.

01:30:26.320 Linoleic acid, you described through the process of elongation, desaturation, ultimately becomes

01:30:33.440 arachidonic acid. How did arachidonic acid get such a bad name? Is that all Barry Sears that we have to

01:30:39.380 thank for that? Partly Barry, partly Bill Lanz, partly Artemis Simopoulos. The way I look at it

01:30:46.440 is if we think back to the 1960s and 70s, we had this thing called the P to S ratio in oils. Do you

01:30:52.600 remember that? Polydesaturates, right? For heart health, you want to eat high P to S ratio foods,

01:31:00.260 oils. The ratio mentality, that was the idea. And that made sense. We want less saturated fat,

01:31:07.080 more polyunsaturated fat was good for your health, good for your heart. We move a couple decades in

01:31:13.360 now. Now we have the omega-6s and the omega-3s. And we know that they eat the linoleic and ALA

01:31:19.460 on the omega-3 side compete with each other for enzymes to metabolize up to other EPAs and

01:31:26.300 arachidonates. And so there's a competition there. So people like ratios, black and white,

01:31:31.620 you know, black hat, white hat, arachidonic acid does give rise to several or many pro-inflammatory

01:31:38.440 compounds. No question. It's a good thing. It's what it's supposed to do. The concern is,

01:31:43.920 does that get out of whack? And does it go on and on and on and never get resolved?

01:31:48.300 So arachidonic got this black hat idea. It's the pro-inflammatory one and then EPA and DHA are the

01:31:54.500 anti-inflammatory ones. So let's just do an omega-6, omega-3 ratio. I have a lot of problems with that

01:32:00.660 ratio. I think it doesn't make any sense, partly because it presumes that the omega-6s actually are

01:32:05.500 bad and they really aren't. The evidence now coming out from large meta-analyses where people are,

01:32:11.880 and we were part of this study, where they looked at plasma linoleic acid levels or blood linoleic

01:32:18.440 acid levels. So omega-6 levels in the blood and arachidonic levels in the blood. And they measured

01:32:24.120 it in thousands and thousands of people and they followed them for the development of heart disease

01:32:29.480 and diabetes over between five and 30 years. And a very clear signal that the higher the level of

01:32:36.840 linoleic acid, meaning the more you eat, that's the only way you can raise it, is by eating more.

01:32:42.380 The higher the level of linoleic acid in the blood, the lower the risk of heart disease,

01:32:47.100 the lower the risk of myocardial infarction, the lower the risk of diabetes.

01:32:50.460 And arachidonic acid levels were unrelated to either of those outcomes. It was neutral.

01:32:57.780 It wasn't higher or lower. It didn't make any difference.

01:33:00.300 So what's the correlation between arachidonic acid level and linoleic acid level? And what's

01:33:06.080 the correlation between arachidonic acid level and ingested linoleic acid?

01:33:10.840 Virtually none. Even though we know arachidonic can be made from linoleic acid,

01:33:15.060 it's only less than 1% of the linoleic we eat gets made into arachidonic. Very little of it's

01:33:21.660 made it. And you may have already said this, and I was too busy trying to think about something you

01:33:26.240 previously said, but just as ALA conversion to EPA is virtually irrelevant, is that a similar

01:33:34.380 statement for LA conversion to AA? The same idea. When the people have given radioactive tracers

01:33:41.040 and measured how much actually goes from LA to AA, very, less than a percent. Very little.

01:33:50.580 So, and people have also looked at, you know, if you give a huge dose of LA in the diet,

01:33:56.680 and then you measure the effect on a plasma arachidonic, no effect. If you completely strip

01:34:02.620 the diet for, you know, weeks and weeks of LA, arachidonic levels don't go down. It just doesn't

01:34:08.960 respond. So, arachidonic is very tightly controlled. And it's not driven by a linoleic acid.

01:34:15.560 While we're on the subject of ratios, Bill, one of the other ratios that people like to talk about

01:34:21.200 is the ratio of AA to EPA and AA to DHA. Do you put that in the same category of helpfulness as

01:34:30.600 total omega-3 to total omega-6 or?

01:34:34.520 It's a little bit better. One of the problems with the total omega-6 to omega-3 is it doesn't

01:34:39.320 define what the fatty acids are.

01:34:42.000 Right. Because the omega-3 can be dominated by ALA, which is what it is. That number could

01:34:47.940 be dwarfed by how much is EPA and DHA.

01:34:51.460 Correct. Right. And the same on the omega-6 side. There's seven different omega-6 fatty acids you

01:34:56.720 throw into that recipe. Which one are we talking about? And so that's a problem. The fact that you can

01:35:03.240 have the same ratio of EPA or of omega-6 to omega-3 with very high levels of omega-6 and omega-3 or

01:35:11.480 very low levels of omega-6 and omega-3, same ratio, doesn't make any sense. And it's very hard to.

01:35:18.860 The other problem is it presumes that the omega-6 is bad and the omega-3 is good. I love a quote

01:35:24.400 I read somewhere that the guy said, what's the point of the omega-6 to omega-3 ratio? It's good

01:35:29.800 versus good. So why are we doing this? AA EPA ratio is better because it at least defines which fatty

01:35:38.380 acids you're talking about. That's good. I don't think it's any more informative. It leaves out DHA

01:35:44.260 completely, which I think is unfortunate. Again, it's a ratio that presumes arachidonate's bad.

01:35:51.040 And I don't think we can presume that because arachidonate is not only made into pro-inflammatory,

01:35:57.440 it's made into anti-inflammatory molecules too. What drives that balance? First of all,

01:36:02.320 what are the top two or three things that drive the pool of arachidonic acid? And then secondly,

01:36:08.380 what are the top two or three things that drive its destination, either pro or anti-inflammatory?

01:36:15.300 That's tough to say. I don't know what controls arachidonate levels, substrate levels to begin

01:36:21.320 with. That's kind of amazing, right? Some that you make, the tissues get incorporated with a certain

01:36:28.280 amount of arachidonate and the body likes a certain level. And it's released from membranes when you have

01:36:34.900 a stressor of some kind and you make prostaglandins. But there are like a hundred different metabolites

01:36:40.720 you get made from these molecules. And it's almost virtually impossible to study all of them

01:36:46.760 in vivo together. You can take one particular metabolite and sprinkle it on a cell in a test

01:36:53.900 tube and see what it does and then write a paper on it. But it may have nothing to do with reality

01:36:59.800 because in reality, you've got a hundred different molecules all banging on the door,

01:37:04.440 fighting with each other, one balancing the other. It's an incredible dance that you can't replicate

01:37:11.840 outside of the body. And people draw these conclusions about this fatty acid's bad and

01:37:18.080 that fatty acid's good based on really naive views, I think, of the complexity of the biology.

01:37:24.960 What's most compelling is let's look at blood levels of fatty acids and who's actually having

01:37:30.540 diseases? Who's getting sick? I mean, I don't care about looking at metabolic charts and what

01:37:36.700 pathway intersects with what pathway or competes. That's swell. But at the end of the day, if omega-6

01:37:43.520 levels are high and that's associated with reduced risk for diabetes and heart disease, that's a very

01:37:49.080 powerful testimony to me that the omega-6s are good. When you say omega-6 in that situation,

01:37:56.460 is the bulk of it made up through LA or is it a proxy metric of LA plus AA?

01:38:02.320 LA. Because that's what we eat. Again, on average, we eat maybe 15 grams a day of LA and we eat about

01:38:10.300 a tenth of a gram a day of arachidonic. You have a bit of a contrarian view of the sort of plant oils,

01:38:18.080 the canolas, the safflowers and the sunflowers, et cetera. Many people view these as sort of unhealthy

01:38:24.900 oils. Do you view any of those oils when consumed in the quantities that Americans consume them as

01:38:30.800 unhealthy? I thought you were going to say people, when you're talking about canola and olive oil,

01:38:36.020 people think those are great because they're mono. They're mono-rich oils.

01:38:39.840 Well, yeah, that's actually funny. The canola and the safflower, at least in its original form,

01:38:44.400 and olive oil are virtually indistinguishable by fatty acid composition.

01:38:49.220 Well, canola and olive, yeah. But the safflower was like 77% linoleic acid originally. And now

01:38:56.900 it's down to like 15%.

01:38:58.840 Right. And isn't it largely boosted in omega monounsaturated now, omega-9?

01:39:04.340 Monounsaturated, right. They call them high mono, high mono saff and high mono sunflower.

01:39:09.980 I think those are a problem. I'm sorry to see that happening. I know what's happening because,

01:39:13.940 partly because omega-6 fatty acids are unstable or are more likely to go rancid. So they'd like to

01:39:20.180 get rid of them, which led to the whole trans fatty acid thing, but we're not going to go there

01:39:24.120 today. So we're reducing omega-6 levels in our oils, which is going to reduce them in our blood,

01:39:30.900 which if the evidence is pointing in the right direction, that's going to lead to an increased

01:39:36.260 risk for these major diseases. Wasn't there a day when we really didn't have much omega-6 in our

01:39:42.880 diet? Sure.

01:39:44.600 Isn't it a relatively recent thing? Like more than a few hundred years ago, wouldn't we have only been

01:39:50.360 consuming saturated and monounsaturated fats primarily in addition to EPAs and DHA?

01:39:57.280 Right, right. We didn't live very long either.

01:40:00.320 Well, is that really true though? I mean, the mortality curve had more to do with infectious

01:40:04.040 diseases, infant mortality and things like that, but we certainly weren't dying of chronic diseases

01:40:08.140 either. Are you suggesting that the addition of plant seed oils is protective against the things

01:40:15.840 that were killing us or are we surviving despite them? I don't know what the case is. I know that

01:40:21.500 people have shown huge increases in linoleic acid intake over the 20th century. They do that with

01:40:28.980 the intent of scaring people. Look at how unnatural this is, but then you look at death rates from heart

01:40:35.280 disease, heart disease rates as the levels of LA go up, they seem to go down.

01:40:42.180 Although it's so hard to look at, I mean, the problem with that type of data is that, you know,

01:40:46.000 we superimpose the use of statins and advanced cardiac life support and defibrillators and smoking.

01:40:53.920 Yeah. So I think it's very difficult to do that. But if we look at the literature as far as what we can

01:41:00.840 say, I mean, it seems that we're on more stable ground saying that EPA and DHA are probably

01:41:06.440 protective. I'm still at a bit of a loss as to what to say about omega-6. I mean, on a personal

01:41:13.520 level, I just find them kind of disgusting. If I'm going to be brutally honest, like I just think

01:41:17.780 they're disgusting oils. Like I think they taste like crap. Oh, but that's just my taste, right?

01:41:23.720 Like I just, I think canola, safflower, sunflower, corn oil, they just taste gross to me. But I think

01:41:29.840 that's because I've just acquired a taste for saturated fat and monounsaturated fat over time.

01:41:35.780 Oh, well, yeah, that could be. And most people don't eat it as oil. It's incorporated in salad

01:41:40.680 dressings. Well, but that's my point. Like even like, I don't know the last time I had a salad

01:41:44.360 dressing out of a bottle because it just tastes disgusting relative to being able to put real

01:41:51.260 olive oil on. And by the way, we should actually say most of the time when you buy olive oil,

01:41:57.040 you're not really getting olive oil, right? I mean, it's a very, very diluted olive oil.

01:42:01.760 So, but assuming you're getting real olive oil, which actually has kind of a strong taste to it,

01:42:05.940 away you go. I don't like to get too far down the omega-6 pathway other than to say,

01:42:10.380 I don't think it's the evil that people think it is. And the problem is that we need to get more EPA

01:42:16.120 and DHA in our diet, not necessarily get all hung up on omega-6.

01:42:21.140 Yeah. It seems to me that that's the bigger place to move the needle is if you can increase

01:42:26.360 the EPA and DHA in your diet, the body's ability to buffer high amounts of LA seems impressive. Is

01:42:34.560 that a fair statement? I don't know about the second half. I don't know that it needs to be buffered.

01:42:39.940 Maybe buffer is the wrong word. Again, I think I use this term of like a reducing function or,

01:42:44.960 you know, a capacitor, like in a circuit. It just seems like you can have people, like I consume

01:42:51.400 virtually no, none of those seed oils, like meaning I probably consume one-tenth of what

01:42:58.460 the average person does because I, again, I just don't eat many processed foods and I don't,

01:43:04.100 I don't have any of those oils. Like I don't have salad dressing or any of those oils in my home.

01:43:08.280 So they're going to sneak in a little bit somewhere, but I'm not consuming them in high amounts.

01:43:13.100 Beats, animal products.

01:43:14.600 Sure. Exactly. So you're going to, you're going to get them, you know, through those things.

01:43:18.860 But if you look at my blood levels, my RBC levels and compare them to someone who's eating

01:43:25.620 literally 10 times the amount I'm eating, we might only differ by 10 or 20%. That's what I mean by

01:43:31.660 there's sort of this huge buffer capacitance function to it. Whereas on the EPA, DHA level,

01:43:38.820 it seems that what you eat matters a heck of a lot more in the output. Is that, is that a fair

01:43:44.500 assessment? Absolutely true. Your cells respond to EPA and DHA much more strongly than they do to

01:43:49.980 changes in LA intake. Do you think there's clinically a role for looking at the AA to EPA

01:43:57.660 and AA to DHA levels? Can we infer anything from that? I prefer the omega-3 index.

01:44:04.180 Yeah. Just look at the EPA, DHA total. To me, that's the problem. The problem is the

01:44:09.860 lack of EPA and DHA. If you get those up, your arachidonate levels will go down. That's the best

01:44:15.920 way to lower. If you want to lower arachidonate is to take fish oil. And so you'll, your ratios will

01:44:21.800 change. You can change ratios all day long by just changing the denominator. And what I don't like

01:44:27.960 about AA EPA ratio or omega-6 to omega-3 is it distracts people from the real problem, which is

01:44:33.640 the lack of EPA and DHA. It lets them run and say, okay, well, I can, I can fix my ratio by eating

01:44:41.100 less omega-6 and not eating more omega-3. That doesn't help. Whereas if you just look at the

01:44:46.680 omega-3 index, EPA, DHA, that's your focus. It's too low. Fix it. Raise it up. Everything else will

01:44:53.120 settle out. What do you think is the best case for and against the notion that, I mean,

01:45:02.020 the reduce it study, in addition to at least one or two other studies, makes a pretty compelling case

01:45:08.120 that you don't have to eat fish to get these benefits. You can get the supplements. I know

01:45:14.080 that prior to a year ago when reduce it came out, there was still a piece of me that wondered,

01:45:20.540 did you have to actually eat the fish? And is the consumption of fish itself and the EPA, DHA level

01:45:28.320 that rises with it more of a proxy for some subtler thing that we're not measuring?

01:45:34.280 Is the omega-3 content of fish and hence of your blood levels really just a marker of fish intake?

01:45:40.080 And there's something really beneficial in fish other than omega-3 that's really doing the good

01:45:44.900 work. Or even complements it. Yeah. So even if you posit that the EPA and the DHA are part of the

01:45:51.080 benefit from eating fish, is there something else in the fish or other things that one would eat with

01:45:56.220 it that augment or transduce that benefit that you could be missed? And again, reduce it now makes

01:46:01.920 that question much less likely or makes the answer to that question being yes, much less likely. But

01:46:07.460 I want to round that out and make sure that you haven't forgotten anything you wanted to talk about

01:46:11.340 there. I agree with you. I think it can be done with, we prefer to do it with fish if possible,

01:46:15.700 but there's a lot of challenges with that. Not only just personal taste and cost and, but ecological

01:46:21.060 issues. So yeah, you can do it from EPA and I think you can do it from EPA plus DHA supplements.

01:46:27.320 I think we need to talk about the other study though, the vital study, which was reported out at the same

01:46:32.840 meeting as reduce it. And it was widely reported. It was not done in people who have high triglycerides.

01:46:39.460 It was done in normal, relatively healthy Americans in about 20,000, 25,000 of them.

01:46:46.160 What was the dose that was used?

01:46:48.380 It was one low vasocapsule. So 850 milligrams of EPA DHA.

01:46:52.700 Yeah. And that study didn't find a difference, did it?

01:46:56.020 Well, that depends on how deeply you want to look in the study. If you just want to read the

01:47:01.240 primary endpoint.

01:47:03.200 Yeah. Well, my take on that, well, who cares what my take is? Tell us your take, but starting with the

01:47:08.040 dose. You're not a standard doctor, but the typical doctor, his take on it is it didn't work

01:47:13.240 because that's what the press said. And that's what the abstract said because they were looking

01:47:18.520 for an effect of less than one gram a day of EPA and DHA. And they were looking at a composite

01:47:24.960 endpoint of four or five different elements of cardiovascular disease, stroke, non-fatal stroke,

01:47:30.680 stroke, non-fatal heart disease, a composite endpoint, which three of the elements maybe

01:47:37.080 were not affected, but one effect, one was affected tremendously. And it was heart attacks

01:47:41.680 were significantly, you know, 20% reduction in heart attacks and 20% reduction in fatal heart

01:47:46.900 attacks were one of the findings. I mean, that's impressive for 850 milligrams a day. It's amazing

01:47:54.540 to me that you can even do that now. And they found that if you look at people who report eating

01:48:00.860 less than 1.5 fish meals a week, there was a significant benefit on the primary endpoint

01:48:08.680 of cardiovascular disease by taking just one capsule of Levasin. There was some really positive stuff in

01:48:15.360 this study, but it was buried in the press headlines says fish oils don't work without any caveats.

01:48:22.180 If you exclude the composite metric and you just look at the CHD metric, how did the magnitude both

01:48:29.940 in absolute and relative risk compare to reduce it? This is one of the things I like doing to sense

01:48:36.040 check studies, which is kind of do my own analysis of them and say, well, like that again, an example

01:48:42.920 would be comparing Odyssey and Fourier and saying, well, based on the fact that one came in heavily

01:48:50.540 statinized, the other was not heavily statinized, durations are about the same, where would we be

01:48:55.960 fooled versus not fooled on this? Can you do that sort of analysis between these two studies as well

01:49:01.000 and say, did they at least have a dose response with respect to the reduction in MI, for example?

01:49:08.000 Yeah, that's a good question. I've never looked at it that way. I've never broken it down,

01:49:11.500 done the math that way. I know that there was a nine or 10% reduction in, maybe it was 20%,

01:49:18.940 I can't remember at the moment, of risk for heart disease. But again, these were not people at high

01:49:24.100 risk. So your absolute risk reduction was pretty small. Relative was pretty big, but also the dose

01:49:29.940 was very low. Yeah. So you had normal triglyceride low risk people on one fifth of the dose. So it's

01:49:37.280 very hard to compare those two studies. Do you have a sense of what they were really trying to find

01:49:43.580 out? Was the goal of that study, does a low dose of a easily accessible supplement matter in people

01:49:52.280 who are healthy? I mean, I assume that's at the most basic level, that was the question.

01:49:55.780 First primary prevention study, really, that's been done. So they wanted to use it. It was planned 10

01:50:02.300 years ago. And at that time, one gram of Lovesa. So they didn't use a supplement. They used Lovesa,

01:50:08.660 a pharmaceutical, but they just used one gram instead of the four grams indicated by the FDA.

01:50:14.420 And they, yeah, they were looking at cardiovascular disease and cancer. I mean, it was a huge thing in

01:50:20.140 primary prevention. So they've got, they found no effect on cancer and they found in their composite

01:50:26.280 endpoint, no statistically significant, it was reduced, but it wasn't significant. But if you look

01:50:31.220 at certain elements of the composite, they were strongly benefited. 20%, I'm trying to think if there's a

01:50:37.720 20% reduction in MI, that's what sticks in my mind. Do you think the most important takeaway from that

01:50:43.620 is if you believe that the study had a methodologic issue that prevented it from reaching the clinical

01:50:50.300 and statistical significance, one would want to move forward. Is the bigger knock on that study,

01:50:56.460 the dose, the patient population that was studied, or the composite endpoint?

01:51:02.800 All of those together can conspire to have a neutral study when there really are some good

01:51:09.280 effects that are overlooked. I mean, what people don't balance is the extreme safety of these

01:51:15.640 products and cheapness. We're looking at something, even one capsule Lovesa, it's cheap, it's completely

01:51:21.960 safe. It doesn't interact with anything. And if there's even a hint of benefit, why wouldn't you

01:51:28.420 promote it? Do you think that if a person's listening to this and they're deciding, hey,

01:51:34.480 this has got me over the goal line as far as I should be using EPA and or DHA, is there an advantage

01:51:41.860 to using the pharma grade product versus a reputable supplement company? Again, the two that I like are,

01:51:50.020 and I have no financial ties to any of these companies, just sort of like them through reputation

01:51:53.940 and having read analyses of their product, but like Carlson's or Nordic Naturals, for example.

01:51:59.260 I don't think there's a substantial difference at all in quality. There's a lot of omega-3 supplement

01:52:05.140 companies that make very high quality stuff that they just aren't going to the trouble of going

01:52:11.380 through an FDA approval to get it treated and developed as a drug. But it's the same chemistry.

01:52:16.420 And sometimes, I mean, if you get the EPA covered, it might actually be cheaper than the supplement.

01:52:20.860 The supplements are actually not that cheap. They're actually on the spectrum of supplements

01:52:25.020 that I take when you compare something like magnesium oxide versus fish oil. I mean,

01:52:31.320 these fish oils are pretty darn expensive supplements. It's a lot of work to get them

01:52:35.220 to be that pure. One thing I'd say about Reduce It, and back to that one again, you can't buy a pure

01:52:40.740 EPA dietary supplement as far as I know. No, I think the best we can do, Carlson's does make

01:52:46.740 something called EPA GEMS. And it's, I'm going to get it wrong, but the gist of it is it's sort of

01:52:53.900 probably 75% to 80% EPA to DHA. So it's heavily skewed in a direction that's concentrating EPA,

01:53:02.440 which is not the way it normally occurs, of course, but that's the closest you can get.

01:53:06.300 And is there anything that we haven't talked about, Bill, on this topic that you would like to add?

01:53:11.540 Is there any other trial that you think it's just really important that we get to?

01:53:16.400 Well, I don't think there's necessarily a trial, but if I can just get into what I do now over the

01:53:21.780 last 10 years is I think measuring blood omega-3 levels are really important. And whether it's the

01:53:28.420 test we do with the omega-3 index, which is red cell EPA DHA or a plasma test or a plasma phospholipid

01:53:34.700 test or a whole blood test, whatever, I just think we need to see more doctors measuring omega-3

01:53:40.960 status because it means a lot. Low omega-3 means something, and you know this. But I really

01:53:47.620 want to encourage people to make the assessment of omega-3 status in their patients as important

01:53:54.460 as measuring cholesterol.

01:53:56.500 Your company is called OmegaQuant, correct?

01:53:59.040 Right, right.

01:53:59.740 And you've been at the helm of that for about a decade, right?

01:54:03.420 Yeah, this is our 10th year, right?

01:54:05.060 Yeah, that tells me how much time has flown because I remember when you had just sort of started

01:54:10.080 that, that's a tough business to be in, right? Because just laboratory, specialty labs, anything

01:54:15.280 that's not sort of garden variety off the shelf tends to be sort of misunderstood by the payer

01:54:20.680 environment. And this tends to be a tough place, isn't it?

01:54:23.900 Yeah, but we're not in the payer environment. We're all cash pay.

01:54:26.700 Are you? Okay, got it.

01:54:28.640 That's where the quests and the lab cores and the Clevelands and the Bostons are. And it used

01:54:35.580 to be health diagnostic labs, of course, back in those days.

01:54:38.260 So can patients come directly to you or do your tests have to be ordered by physicians?

01:54:42.980 People can come directly to our website and order the tests. It's $50.

01:54:46.680 So for $50, a patient can basically receive a kit from you that they take into it. I assume

01:54:53.320 it's a blood test, not a saliva test or something.

01:54:55.760 It's a finger stick test.

01:54:57.220 I got it. So they don't even need to go into a lab.

01:54:59.380 No, no. They just do it at home and send it to us.

01:55:01.940 That's the same test that I'm getting embedded within my much broader panels, I assume, where

01:55:06.640 I'm seeing the percent of EPA, DHA, or is that a different company?

01:55:10.260 What lab is doing it?

01:55:11.700 Well, for example, what was True Health Diagnostics using?

01:55:14.280 Okay. True Health. So that, yeah. True Health took over from Health Diagnostic Lab and Health

01:55:18.900 Diagnostic Lab took my test. So they're using my test.

01:55:23.040 I see. Okay. Do you think there are other tests out there that are directionally comparable or,

01:55:28.420 I mean, I guess you're a bit conflicted to say that there's other, yeah, it's a loaded question.

01:55:32.780 Yeah. They're certainly directionally comparable. It's just the number. Don't do a plasma omega-3

01:55:37.940 test and expect to get an eight to 12% EPA, DHA. Plasma doesn't go that high or it's very hard

01:55:43.420 to get that high. So plasma levels are lower numbers. They correlate pretty well by and large

01:55:49.280 with red cells, but red cells are much more stable, long-term marker of omega-3 status than plasma is.

01:55:56.060 So I like the red cell test for that purpose. So that's pretty much what we use in our research

01:56:01.460 studies is red cell. I'd rather see a doctor measure a plasma omega-3 than not measure anything.

01:56:07.400 That's something that people can also get through LabCorp, Quest, and all of the sort of more

01:56:10.620 generic labs, I assume? Yeah. I'm not even sure they can get it at LabCorp, but Quest has a

01:56:14.620 plasma phospholythic assay they do. What does Boston Heart do? Do you know?

01:56:19.060 I think they do a whole plasma. I see. Okay. So going forward, if we're not using THD,

01:56:25.820 we'll have to figure out a way to come to you directly.

01:56:28.680 That'd be great. I'd love to do it. We've got a lot of doctors who do, but I don't know what

01:56:33.940 kind of reimbursement is being paid for these tests in the insurance world. I think it's not much.

01:56:40.520 I was about to say, I'm going to go with the not much box on that one.

01:56:45.160 Yeah. Yeah. So.

01:56:47.020 But again, these aren't tests you have to get every two weeks, right? I mean, this is the type of test

01:56:51.100 where you get it maybe once a year and you make a change and you look and see, hey, am I taking

01:56:56.220 enough of this supplement or am I eating enough fish? And.

01:56:58.740 Yeah. Usually about every four months. It takes about four months after you make a change in your

01:57:02.540 omega-3 intake to see a new steady state.

01:57:04.860 Oh, okay. Well, actually that's very interesting. I'm glad you brought that up. I wasn't aware it was that

01:57:08.660 long, actually. I thought you could see a change quicker, but it's the life of the red blood cell,

01:57:13.300 I guess, to fully turn them over.

01:57:14.660 Red cell, exactly.

01:57:15.040 Yeah. Yeah. Okay. Well, that makes sense. Bill, is there anything else that we didn't discuss on

01:57:20.220 this particular nuanced and super enjoyable topic?

01:57:25.640 Golly, I think we ran down the omega-6 stuff. We talked about EPA and DHA alone. There is a big

01:57:31.700 study that's going to come out. It should finish a year from now called strength that is bigger than

01:57:38.400 reduce it. And using the same dose as reduce it, but it's EPA plus DHA.

01:57:42.920 What dose approximately? So that would be four grams total?

01:57:46.060 The drug is called Epinova or Epinova. It's from AstraZeneca. It's a 13,000 patient trial,

01:57:53.540 virtually the same inclusion criteria as reduce it. That'll be about a five-year follow-up,

01:57:59.040 the same as reduce it. And they are going to, I'm pretty sure they're going to get much higher

01:58:03.140 omega-3 index levels than reduce it did.

01:58:05.220 And again, their drug is four grams EPA plus some amount of DHA or four grams total?

01:58:11.360 It's very much like Lovasa. EPA plus DHA at around about 85%, but they're not ethyl esters. They're

01:58:20.060 free fatty acids. They're unesterified.

01:58:23.720 And do you think that actually makes any difference?

01:58:25.920 Well, they're much more readily absorbed.

01:58:30.260 Because the esterified ones presumably, is it like cholesterol where esterified variants are

01:58:36.620 much harder to absorb and you risk actually not absorbing them at all?

01:58:40.960 Well, yeah, that's the problem. It's been shown pretty clearly that if you take an

01:58:44.320 ethyl ester of omega-3 on an empty stomach, the absorption is quite low, almost none, as opposed

01:58:51.880 to taking it with food, which improves the absorption quite a bit. But a triglyceride-based

01:58:56.440 oil or a free fatty acid, more to the point, free fatty acid doesn't require any enzymatic

01:59:01.340 conversion to get absorbed at all. The triglyceride has to have, and the ethyl ester both have to

01:59:06.940 have enzymatic conversion in the gut.

01:59:09.220 Well, that's actually really interesting. And I'm glad you brought that up because

01:59:12.020 as you know, a lot of people these days are fasting more and more or time restricting their

01:59:17.140 feeding. And it does pose a little bit of a problem the way I've always got around it if I

01:59:22.260 don't eat breakfast, which I don't a lot of the time, is I sort of take my fish oil at night as

01:59:26.580 close to dinner as possible. But it's easier to forget that way. But you're saying another way

01:59:31.100 around it is if you really just want to take these things in the morning and be done with them,

01:59:34.580 you basically have to take one of the pharma-grade versions because they're the ones that come as

01:59:38.400 free fatty acids?

01:59:39.860 Right. It's only experimental. I mean, it's not experimental. It's approved by the FDA, but it's

01:59:43.680 not being marketed. It's the only one that's a free fatty acid right now is this Epinova. The

01:59:48.800 Vasepa and Lovasa are ethyl esters.

01:59:52.880 Ah, so basically it'll be about a year before we even have the option to get a free fatty acid version.

01:59:59.300 That's when their study will finish. And I think it'll be as or more successful than reduce it.

02:00:05.460 That's my guess.

02:00:06.440 And that will be released at the American Heart in 2020?

02:00:10.360 On their clinicaltrials.gov website, it says the studies will finish in October of next year.

02:00:16.960 So whether they'll be able to report the results.

02:00:18.620 Scramble and abstract, we'll see.

02:00:20.920 Yeah, yeah. I don't know.

02:00:22.660 Well, maybe when that study comes out, Bill, we'll have to sit down in early 21 and discuss it.

02:00:28.360 Love to.

02:00:29.180 Well, Bill, thanks again. This was really interesting. For me personally,

02:00:32.420 I learned a lot talking with you about this kind of stuff. I just know that this episode will be one

02:00:37.420 of those episodes that a lot of people end up coming back to over and over again because it is

02:00:40.940 so confusing. So thank you for the historical context, the overview, and perhaps most importantly,

02:00:47.320 just the sort of nitty gritty details on the health benefits of these things.

02:00:52.500 Oh, yeah. My pleasure. Thank you very much for inviting me. I've really enjoyed it.

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The Peter Attia Drive - December 09, 2019

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

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