#380 ‒ The seed oil debate: are they uniquely harmful relative to other dietary fats? | Layne Norton, Ph.D.

Layne Norton is a nutrition scientist and accomplished power athlete,who returns to The Drive for a conversation that departs from the show’s usual format. In this episode, Layne presents the evidence-based case that seed oils are not uniquely harmful under isocaloric conditions, while Peter steelmans the strongest versions of the opposing argument that seed oils are inherently harmful. They examine how scientific bias and evidence are evaluated, revisit the historical randomized controlled trials that shaped the seed oil controversy, and explore the mechanistic biology underlying LDL oxidation and atherosclerosis. Along the way, Layne unpacks the chemistry and processing of modern seed oils, assesses evolutionary and ancestral nutrition arguments, clarifies the relationship between seed oils, ultra-processed foods, and contemporary dietary patterns, and situates these questions within the larger context of lifestyle factors that drive cardiometabolic health. Layne concludes by offering practical considerations around dietary fats, cooking oils, and real-world food choices.

Subscribe on: APPLE PODCASTS | SPOTIFY | RSS | OVERCAST

We discuss:

Timestamps : There are two sets of timestamps associated with the topic list below. The first is audio (A), and the second is video (V). If you are listening to this podcast with the audio player on this page or in your favorite podcast player, please refer to the audio timestamps. If you are watching the video version on this page or YouTube, please refer to the video timestamps.

• The idea behind this episode, biases, and evidence-based thinking [A: 5:15, V: 0:11];
• The four core arguments behind claims that seed oils are harmful [A: 12:30, V: 8:49];
• The Minnesota Coronary Experiment (MCE) [A: 14:30, V: 11:00];
• The differences among saturated, monounsaturated, polyunsaturated, and trans fats, and why those differences matter for cardiovascular disease [A: 18:30, V: 15:45];
• Missing trans fat data as a confounder in the Minnesota Coronary Experiment, other limitations of that study, and the challenge detecting meaningful differences in hard outcomes through nutrition research [A: 24:00, V: 22:01];
• The Sydney Diet Heart Study (SDHS): an attempt to address the “duration problem” by enrolling a much higher-risk population [A: 28:30, V: 26:53];
• Debating whether evidence from randomized trials supports the idea that seed oils are uniquely harmful once major confounders are removed [A: 34:00, V: 33:38];
• The Rose Corn Oil trial: an often-cited study used to argue against polyunsaturated fats [A: 36:30, V: 36:44];
• Three studies where replacing saturated fat with polyunsaturated fat produced different results than earlier trials [A: 41:30, V: 42:37];
• Layne’s explanation for why the evidence is pointing towards cardiovascular risk reduction when substituting polyunsaturated fat for saturated fat [A: 47:30, V: 49:39];
• What Mendelian randomization says about the causal role of LDL cholesterol in ASCVD [A: 56:45, V: 1:00:34];
• The compounding effects of life-long exposure to high LDL cholesterol [A: 1:06:45, V: 1:12:09];
• Does the linoleic acid (omega-6) content of seed oils cause inflammation? [A: 1:13:45, V: 1:20:49];
• Does the linoleic acid (omega-6) content of seed oils increase oxidized LDL? [A: 1:19:30, V: 1:27:50];
• Layne’s analogy to explain why lower LDL particle number outweighs higher per-particle oxidation risk when comparing polyunsaturated fats to saturated fats [A: 1:26:15, V: 1:36:05];
• The role of oxidized LDL in CVD: exploring differences in a diet high in polyunsaturated fat (seed oils) versus high in saturated fat [A: 1:28:00, V: 1:38:22];
• Examining whether industrial processing and solvent extraction of seed oils—especially residual hexane—could plausibly cause long-term harm [A: 1:34:00, V: 1:45:37];
• The evolutionary and “ancestral diet” argument against seed oils [A: 1:40:45, V: 1:53:55];
• Weighing concerns about industrial processing of seed oils against the totality of metabolic and cardiovascular evidence [A: 1:47:30, V: 2:02:15];
• Practical considerations around dietary fats, cooking oils, and real-world food choices [A: 1:50:00, V: 2:05:17];
• Comparing the health impact of seed oils with that of caloric intake and activity levels, and how to prioritize interventions [A: 2:00:15, V: 2:18:26];
• More.

Show Notes

• Notes from intro :

• Layne Norton is a nutrition scientist and accomplished power athlete

• He is a very evidence-based thinker in the space of diet and metabolic health
• While Layne has been on the podcast many times, today’s episode is a little bit different Originally this was supposed to be our first in a series we’ve been toying with, which is a debate episode
• Peter wanted to do a debate that was going to be incredibly rigorous In fairness, he’s never seen a podcast debate that was anything other than nonsense (to be blunt) The reason is, the format is basically impossible because people can make up anything they want, they can cite anything out of context And no human has the capacity to know the entire body of literature up front, and therefore it’s very difficult to counter claims Regardless of the topic of discussion, Peter has never found this appealing
• Over the past year, we’ve been noodling this idea of: What if we ran a debate like a court case? In a court case, everybody has to present their evidence up front during a process called discovery That allows both sides to view the evidence of the opposing arguments along with their own arguments in equal time That way there’s no ambiguity about what’s being presented
• We came up with the idea to start with this first topic: the seed oil debate
• The idea was to take 2 very thoughtful individuals who have opposing views
• Layne was on the side of the argument which was that seed oils are not harmful
• We had an individual who took the opposite point of view
• The idea was that Layne and this other individual would share all of the information that they planned to present with Peter’s team and with each other, and Peter would serve as a moderator of this discussion Peter’s research team would serve as the fact checkers The public would serve as the jury
• However, the individual on the other side of this argument, for reasons unclear, decided they didn’t want to do this
• Peter felt that it was still a worthwhile topic to explore

• While the format of today’s podcast is not as potentially interesting as it would have been, we still think that it brought a lot of value

• Originally this was supposed to be our first in a series we’ve been toying with, which is a debate episode

• In fairness, he’s never seen a podcast debate that was anything other than nonsense (to be blunt)

• The reason is, the format is basically impossible because people can make up anything they want, they can cite anything out of context
• And no human has the capacity to know the entire body of literature up front, and therefore it’s very difficult to counter claims

• Regardless of the topic of discussion, Peter has never found this appealing

• In a court case, everybody has to present their evidence up front during a process called discovery

• That allows both sides to view the evidence of the opposing arguments along with their own arguments in equal time

• That way there’s no ambiguity about what’s being presented

• Peter’s research team would serve as the fact checkers

• The public would serve as the jury

Peter attempted to steelman the argument against seed oils and therefore allow Layne to represent the pro-seed oil position for why seed oils may or may not be harmful when consumed in isocaloric quantities relative to other fatty acids

• Peter doesn’t think anybody would dispute that consuming excess anything is harmful So consuming excess calories in the form of seed oils versus monounsaturated fats versus polyunsaturated fats versus carbohydrates (probably not many people are going to debate the downside of that)

• So consuming excess calories in the form of seed oils versus monounsaturated fats versus polyunsaturated fats versus carbohydrates (probably not many people are going to debate the downside of that)

What we were trying to understand: Is there something that even under isocaloric conditions would make seed oils particularly metabolically harmful?

In this episode, we discuss:

• The role of bias
• Evidence evaluation in scientific interpretation
• As a lead-in to this, we’re going to discuss the historical randomized controlled trials that shape the seed oil conversation
• The mechanistic biology of LDL oxidation and atherosclerosis (which is central to one of these arguments)
• Methods of oil processing and the chemistry behind modern seed oils
• How evolutionary and ancestral arguments fit into these nutritional debates
• The relationship between seed oils, ultra-processed foods, and modern dietary patterns
• The broader lifestyle factors that influence cardiometabolic health
• And ultimately, practical considerations around dietary fats, cooking oils, and real-world food choices
• In the end, Peter thinks we salvaged a lot of hard work that had gone into the preparation for the debate (over the course of a year)
• Peter thinks you’re going to find a lot of value in this episode

The idea behind this episode, biases, and evidence-based thinking [A: 5:15, V: 0:11]

• This is a different type of episode
• Originally we were planning to do this as our inaugural debate series People have heard Peter talk a little bit about how he desired to do a debate series, which was to have two people on who had opposing views on a topic
• But he’s been very vocal of his criticism of debates on podcasts in that he could charitably call them useless Which is to say anybody can sort of say anything And in real time, it’s almost impossible to verify what people are saying It’s not to say that people are necessarily lying It’s that people are maybe taking liberal interpretations or not interpreting things the same way, and it would be much more valuable if everybody could be looking at the same thing
• The idea was we were going to have 2 people that were going to pre-submit all of their evidence to Peter and the entire research team, and everybody was going to agree upfront what the papers were What the questions were that we were asking, what the data were And during the process of the debate, people could only reference things that were pre-submitted In other words, we’re going to make it feel a lot like a courtroom Peter says that through the lens of, we have a process in court where you have discovery and the opposing lawyers have to submit everything Peter’s role was really to play judge, not jury The public, the people listening to this would be the jury ‒ they would ultimately be the ones that would decide
• And the first topic we were going to focus on was the one we are going to talk about today: seed oils
• How long did we spend on this? About 9 months, over a year maybe
• Layne was identified as the person who would speak to the argument that seed oils are not uniquely harmful
• We identified another individual who seemed incredibly qualified to speak to the other side of this debate, which is to say that seed oils do pose a unique nutritional risk And for reasons Peter honestly doesn’t even remember, that individual at some point just decided they didn’t want to do it There was some concern that Peter’s personal view leaned more towards the side that seed oils are probably not that harmful Peter is always pretty vocal about his biases and was very vocal about stating, “ I don’t really see something here guys. ” But he was also clear to point out that he’s simply the judge and not the jury, and ultimately the jury decides, and they’re going to also decide if he can be a fair judge
• This is still a topic we care about, so we thought we would do it anyway

• However, we are going to do this a little differently than a normal podcast Instead of just a regular interview, Peter is actually going to make his best attempt to steelman the case for the other guest who is not here In the process of the year spent together, Peter did come to better understand the arguments for why a person would think seed oils are uniquely harmful as a class of fatty acids

• People have heard Peter talk a little bit about how he desired to do a debate series, which was to have two people on who had opposing views on a topic

• Which is to say anybody can sort of say anything

• And in real time, it’s almost impossible to verify what people are saying
• It’s not to say that people are necessarily lying

• It’s that people are maybe taking liberal interpretations or not interpreting things the same way, and it would be much more valuable if everybody could be looking at the same thing

• What the questions were that we were asking, what the data were

• And during the process of the debate, people could only reference things that were pre-submitted
• In other words, we’re going to make it feel a lot like a courtroom
• Peter says that through the lens of, we have a process in court where you have discovery and the opposing lawyers have to submit everything
• Peter’s role was really to play judge, not jury

• The public, the people listening to this would be the jury ‒ they would ultimately be the ones that would decide

• And for reasons Peter honestly doesn’t even remember, that individual at some point just decided they didn’t want to do it

• There was some concern that Peter’s personal view leaned more towards the side that seed oils are probably not that harmful
• Peter is always pretty vocal about his biases and was very vocal about stating, “ I don’t really see something here guys. ”

• But he was also clear to point out that he’s simply the judge and not the jury, and ultimately the jury decides, and they’re going to also decide if he can be a fair judge

• Instead of just a regular interview, Peter is actually going to make his best attempt to steelman the case for the other guest who is not here

• In the process of the year spent together, Peter did come to better understand the arguments for why a person would think seed oils are uniquely harmful as a class of fatty acids

With all of that said, would you like to add anything before we jump into this?

Layne points out, “ When speaking to bias, I think it’s important to point out that everyone has bias. ”

• Everyone has personal beliefs they developed, and that is just a human characteristic There’s no way to get rid of that Layne has his own personal beliefs
• But Layne is very upfront about his biases If we’re on a topic where he has a different opinion than perhaps the consensus of the literature or some other experts who he considers to be good evidence-based experts, he will say, “ Hey, look, this could be my bias showing here, ” or, “ I have a bias towards this. I understand what this literature says. Here’s why I think that maybe it doesn’t capture it all right now. ” And I think that that’s about as best as you can do

• One of the things Layne told a friend the other day was, “ People think that funding or money is by far the biggest driver of people essentially not sticking with the evidence. ” In some cases that’s true

• There’s no way to get rid of that

• Layne has his own personal beliefs

• If we’re on a topic where he has a different opinion than perhaps the consensus of the literature or some other experts who he considers to be good evidence-based experts, he will say, “ Hey, look, this could be my bias showing here, ” or, “ I have a bias towards this. I understand what this literature says. Here’s why I think that maybe it doesn’t capture it all right now. ”

• And I think that that’s about as best as you can do

• In some cases that’s true

Layne thinks that personal beliefs are actually just as powerful, if not a more powerful reason why people stray from the evidence

• Look at how many people spend hours online arguing over politics that get zero money from arguing about politics

In the current day and age with social media, with clickbait, things are very information siloed and there can be a lot of talking past each other

Layne shares his goal, “ I hope today what we can do is present this evidence, and I will acknowledge where I think that there is something really there and then I will also explain why I think overall my view is accurate and in line with the best data available. ”

• To be clear, if anybody has a bias against seed oils, it probably should be Layne
• He came from a lab that was very much in line with the lower carb way of thinking of: Maybe saturated fat isn’t as bad as we thought Maybe LDL doesn’t matter

• When he got into graduate school in 2004, that was a pretty popular idea Maybe it’s not just saturated fat, LDL, maybe it’s the particle size, the oxidation status, the LDL to HDL ratio

• Maybe saturated fat isn’t as bad as we thought

• Maybe LDL doesn’t matter

• Maybe it’s not just saturated fat, LDL, maybe it’s the particle size, the oxidation status, the LDL to HDL ratio

Layne admits, “ I said those things for a long time and eventually changed my mind with the evidence .”

Layne discloses his research funding

• He got money from the National Dairy Council, the National Cattlemen’s Beef Association and the Egg Board
• He’s painting with a broad brush, but he would say most of the very, very rigorous anti-seed oil people tend to err on the side of either low-carb, animal-based, or carnivore

And if anybody has a bias towards high quality animal protein, it’s Layne

• He thinks a lot of people, when the research conflicts with whatever their viewpoint is, they immediately jump to funding source or think that there’s something nefarious going on

“ What I will say is, the scientific method is perfect. It is a perfect method, but it is done by people who are not. ”‒ Layne Norton

Judging the strength of evidence

• The scientific method is a perfect method, but it is done by people who are not [perfect]

• That is why it is so important to look at the overall consensus of the evidence and looking at the different converging lines of evidence Which is something Layne will talk about a lot today

• Which is something Layne will talk about a lot today

There are a lot of converging lines of evidence here, and that can give us a relatively strong or weak amount of confidence in how accurate something is or a statement is

• Layne also points out that when you’re looking through scientific research or you’re scrolling social media, if you have a bias towards something, you can always find a study or phrase something in a way that supports whatever you wish to be true
• That is why it’s important that people (like Peter and himself) try to cut through that noise for other people who aren’t equipped to read research

The four core arguments behind claims that seed oils are harmful [A: 12:30, V: 8:49]

The 4 main arguments Peter has heard for why seed oils should be viewed as potentially harmful

• We’re going to talk through these, not necessarily in the order that Peter is going to introduce them here
• 1 – Mortality literature on some of the large RCTs (2 in particular) In other words, when we go back and look at the literature, particularly in the era when people began to appreciate that saturated fat raised cholesterol At the time it was total cholesterol, eventually when it got fractionated, it became another subset of that called LDL cholesterol We saw the association between LDL cholesterol and ASCVD The question became, “ Hey, can we substitute something else for saturated fat (think margarine versus butter) to lower cholesterol? ” So a couple of these studies were done and these studies, while lowering cholesterol, did not lower mortality (we’re going to talk about that)
• 2 – We’re then going to get into some really mechanistic stuff and talk about LDL through the lens of oxidation Layne alluded to this a little bit with his change in thinking around LDL particle size, but this goes kind of a step further than just particle size And we get into the really granular biochemistry of what is happening to an LDL particle that renders it pathologic versus maybe not so much
• 3 – We’re then going to talk a little bit about not just the seed oil per se, but the industrialization of how a seed oil is refined In other words, is there something about the process of making a seed oil commercially that introduces something that’s harmful as a byproduct?

• 4 – Then finally we’re going to talk about this from maybe an evolutionary or first principles perspective Which is, look, if we were having this discussion 100 years ago, there were no seed oils and people were a lot healthier, so maybe the introduction of seed oils should be viewed as potentially problematic

• In other words, when we go back and look at the literature, particularly in the era when people began to appreciate that saturated fat raised cholesterol At the time it was total cholesterol, eventually when it got fractionated, it became another subset of that called LDL cholesterol We saw the association between LDL cholesterol and ASCVD

• The question became, “ Hey, can we substitute something else for saturated fat (think margarine versus butter) to lower cholesterol? ”

• So a couple of these studies were done and these studies, while lowering cholesterol, did not lower mortality (we’re going to talk about that)

• At the time it was total cholesterol, eventually when it got fractionated, it became another subset of that called LDL cholesterol

• We saw the association between LDL cholesterol and ASCVD

• Layne alluded to this a little bit with his change in thinking around LDL particle size, but this goes kind of a step further than just particle size

• And we get into the really granular biochemistry of what is happening to an LDL particle that renders it pathologic versus maybe not so much

• In other words, is there something about the process of making a seed oil commercially that introduces something that’s harmful as a byproduct?

• Which is, look, if we were having this discussion 100 years ago, there were no seed oils and people were a lot healthier, so maybe the introduction of seed oils should be viewed as potentially problematic

The Minnesota Coronary Experiment (MCE) [A: 14:30, V: 11:00]

Let’s start with the Minnesota Heart Study

• Peter has talked about the Minnesota Heart Study before [Aka the Minnesota Coronary Experiment (MCE) ] [They spoke about it the last time Layne was on the podcast, episode #235 after [2:05:00]]
• This is a study that took place in the 1960s
• It’s notable because it was carried out in an environment that would be very difficult to do today It’s very difficult to do long-term nutritional studies with complete control over what your subjects eat, and yet that is essentially what this study was able to do because it was carried out in institutionalized patients
• These were mentally institutionalized patients (inpatients in a hospital)
• The experimental design was quite elegant The subjects were divided into 2 groups One group was given a diet that was higher in saturated fat The other group was given a diet that was lower in saturated fat, but had an isocaloric substitution of polyunsaturated fat It was mostly linoleic acid that made the substitution So in other words, you can think of this as substituting saturated fat like butter, lard, meat for other sources, but the oils would be the canolas, the safflowers, sunflowers, things like that Layne thinks it was mostly corn oil and margarine

• The study was completed around 1973 It ran from ‘66 to ‘73 [it was a little bit shorter, running from ‘68-’73]

• [Aka the Minnesota Coronary Experiment (MCE) ]

• [They spoke about it the last time Layne was on the podcast, episode #235 after [2:05:00]]

• It’s very difficult to do long-term nutritional studies with complete control over what your subjects eat, and yet that is essentially what this study was able to do because it was carried out in institutionalized patients

• The subjects were divided into 2 groups

• One group was given a diet that was higher in saturated fat
• The other group was given a diet that was lower in saturated fat, but had an isocaloric substitution of polyunsaturated fat It was mostly linoleic acid that made the substitution
• So in other words, you can think of this as substituting saturated fat like butter, lard, meat for other sources, but the oils would be the canolas, the safflowers, sunflowers, things like that

• Layne thinks it was mostly corn oil and margarine

• It was mostly linoleic acid that made the substitution

• It ran from ‘66 to ‘73 [it was a little bit shorter, running from ‘68-’73]

The study found that indeed the total cholesterol of the patients on the higher polyunsaturated fat diet was significantly reduced (again, this was isocaloric and a low saturated fat diet)

• It wasn’t like we were playing tricks with calories. No, no, no. They were getting the same amounts of calories from the macros even They were just substituting saturated fat for polyunsaturated fat

• At the time, that was the only tool you had at your disposal [to measure total cholesterol] You didn’t even have LDL cholesterol, let alone apoB or particle size or any of that stuff But you saw that total cholesterol went down

• They were getting the same amounts of calories from the macros even

• They were just substituting saturated fat for polyunsaturated fat

• You didn’t even have LDL cholesterol, let alone apoB or particle size or any of that stuff

• But you saw that total cholesterol went down

Interestingly, and much to the surprise of the investigators, mortality did not

• This was such a surprise to the experimenters that they chose not to publish the results of this study for another 13 years [ published in 1989 ]

But as someone trying to make the case that there’s got to be something wrong with polyunsaturated fats, how could we otherwise explain that there was no improvement in mortality despite the fact that total cholesterol went down?

• And total cholesterol went down quite a bit [shown in the figure below]

Figure 1. Total cholesterol for patients on the control diet and treatment diet (low saturated fat, high polyunsaturated fat) in the MCE . Image credit: Arteriosclerosis 1989

• We don’t have the data to say if it was atherogenic particles that went down
• But given the magnitude by which it went down, you have to assume at least the fraction of LDL cholesterol went down with it, even if HDL cholesterol went down with it as well

Doesn’t that study at least suggest that there could be something nefarious about the substitution of lards to those polyunsaturated fats?

• This is probably the single most popular study that gets cited by people who are making the case that polyunsaturated fats are actually bad for you compared to saturated fat

• Layne wants to be really clear upfront by saying, “ When I make any criticisms of this study, I think it was a very well-designed study for the tools they had at the time and what they knew at the time. ” It’s always easy to Monday morning quarterback these things, but it was a very well-designed study

• It’s always easy to Monday morning quarterback these things, but it was a very well-designed study

The big takeaway : for every 30 mg/dL decrease in total cholesterol there was a 22% increase in mortality [ 22% higher risk of death ]

Right off the bat, the biggest things that really confounds all these outcomes is the inclusion of trans fats

• The polyunsaturated fat group, they were getting quite a bit of their polyunsaturated fats from margarine
• Margarine at the time was around 25-40 % trans fats

⇒ We know that trans fats are absolutely atherogenic

The differences among saturated, monounsaturated, polyunsaturated, and trans fats, and why those differences matter for cardiovascular disease [A: 18:30, V: 15:45]

We should probably tell people the difference between a saturated fat, a monounsaturated fat, a polyunsaturated fat, and a trans fat as a subset of polyunsaturated fats

• A saturated fat is a hydrocarbon where every bond is saturated [Shown in the first row of the figure below] That means there are no double bonds So every carbon is attached to another carbon, but it has two hydrogens on it The hydrogens can swiggle around and that gives it unique properties

• [Shown in the first row of the figure below]

• That means there are no double bonds
• So every carbon is attached to another carbon, but it has two hydrogens on it
• The hydrogens can swiggle around and that gives it unique properties

Figure 2. Summary of types of dietary fats . Image credit: Centre for Food Safety, Hong Kong

• One of the properties of a saturated fat is it is more likely to be solid at room temperature There are a whole bunch of reasons that are going to come up later when we talk about why saturated fat plays a role in cardiovascular disease through its impact on LDL receptors and cholesterol synthesis
• A monounsaturated fat means there is one double bond in the fatty acid chain
• Important to point out when it comes to these double bonds and why this probably makes a difference, is it changes the fluidity of these membranes

• Because fatty acids and lipoproteins in particular, they’re not just like individual fats, they’re arranged into what are called micelles [shown below], which basically the polar head of the fatty acid is on the outside, and on the inside you have all the fatty acid tails And the reason for that is: if it wasn’t that way, they could never travel around our body Because to travel through the medium of our blood, you have to be able to be repelling water on the inside, hydrophobic, while being attracted to water, hydrophilic, on the outside So you have all these tails kind of pointing towards the center

• There are a whole bunch of reasons that are going to come up later when we talk about why saturated fat plays a role in cardiovascular disease through its impact on LDL receptors and cholesterol synthesis

• And the reason for that is: if it wasn’t that way, they could never travel around our body

• Because to travel through the medium of our blood, you have to be able to be repelling water on the inside, hydrophobic, while being attracted to water, hydrophilic, on the outside
• So you have all these tails kind of pointing towards the center

Figure 3. Structures formed by phospholipids in an aqueous solution, the fatty acid tails are shown as orange lines and the polar head groups as white balls . Image credit: Wikipedia

• Then if you think about even on cells, the phospholipid bilayer, the tails are pointing towards each other
• For natural unsaturated fats (like monounsaturated fats or polyunsaturated fats ) most of those double bonds are what are called cis double bonds Essentially if you have a cis double bond, it puts a kink in the fatty acid tail
• If you have a trans double bond [present in trans fats ], it doesn’t change it It still essentially looks like a saturated fat in terms of structure besides the double bond [shown in the second row of the earlier figure summarizing fats]

• As we’re going to talk about later when it comes to LDL aggregation and whatnot, the actual membrane fluidity is actually very important when it comes to the progression of cardiovascular disease

• Essentially if you have a cis double bond, it puts a kink in the fatty acid tail

• It still essentially looks like a saturated fat in terms of structure besides the double bond [shown in the second row of the earlier figure summarizing fats]

So the membranes and the fatty acid composition of these lipoproteins actually becomes very important

⇒ But when we’re talking about unsaturated fat, it’s important to point out that trans fats are very unique in terms of the research literature very clearly showing an atherogenic effect

Peter emphasizes, “ And the atherogenic effect of trans fats was so significant that they have effectively been banned by the FDA .”

It’s also important to understand how trans fats came about

• When the belief and realization around saturated fats (which have been probably overdemonized historically) took place, food makers looked for a substitute

Layne brought up an interesting point a moment ago: i f you have a trans fat, you can have something that is not saturated, but behaves as saturated

• So if you think of one of our favorite saturated products, it’s butter Of course, as maybe we will talk about later, there’s no food that is purely one thing It’s not like butter is just saturated fat In fact, it’s probably made up of mono and polyunsaturated fats, if Peter’s memory serves correctly, as is even the fattiest ribeye And it has some natural trans fats in it as well (low, low amounts)
• But what makes butter appealing is that it is solid at room temperature

• So in an effort to create something that looked, felt, tasted, and behaved like butter, and we were going to deprive you of saturated fat, we had to put in something that at least behaved like saturated fat

• Of course, as maybe we will talk about later, there’s no food that is purely one thing

• It’s not like butter is just saturated fat
• In fact, it’s probably made up of mono and polyunsaturated fats, if Peter’s memory serves correctly, as is even the fattiest ribeye
• And it has some natural trans fats in it as well (low, low amounts)

⇒ Margarine is made up of high amounts of trans fats (25%)

• Initially it was thought that was a win because you got the benefit of solid at room temperature
• It was only after a few years we realized, actually, this was creating far more heart disease than we were seeing even with saturated fat
• And part of that is likely because it makes the membrane very rigid because those fatty acid tails can get packed in tighter with saturated fat and trans fat

• Whereas when you have those kinks with mono and polyunsaturated fats, it essentially creates space in the membrane That is actually very critical in terms of particle recognition by the LDL receptor and also aggregation (discussed further later)

• That is actually very critical in terms of particle recognition by the LDL receptor and also aggregation (discussed further later)

Takeaway on trans fats

• So not only do you have trans fats being able to be packed into lipoproteins in a similar way as saturated fat, but now they have a double bond that can be oxidized as well
• So you’re getting kind of the worst of both worlds with trans fats

Missing trans fat data as a confounder in the Minnesota Coronary Experiment, other limitations of that study, and the challenge detecting meaningful differences in hard outcomes through nutrition research [A: 24:00, V: 22:01]

Do we know how much trans fats was consumed by the low saturated fat group in the Minnesota coronary experiment?

• Layne’s understanding is that we don’t have the specific numbers, we just know that it was likely a significant portion of the polyunsaturated fat Based on they essentially got a lot of their polyunsaturated fats from either corn oil or margarine

• Based on they essentially got a lot of their polyunsaturated fats from either corn oil or margarine

Was it Chris Ramsden at the NIH, who did a reevaluation of this? Was he ever able to identify the raw data on that?

• Layne didn’t see it anywhere If people smarter are watching or are familiar with it, he would love to know if they did

• [The publication states, “ Because the trans fatty acid contents of MCE study diets are not available, one could speculate that the lack of benefit in the intervention group was because of increased consumption of trans fat. ”]

• If people smarter are watching or are familiar with it, he would love to know if they did

We just know that it was likely a significant portion of the polyunsaturated fat, based on they essentially got a lot of their polyunsaturated fats from either corn oil or margarine

• We have to remember, as you said, this study started in 1966 Very shortly after, it was identified and accepted that saturated fat raised cholesterol and that that seemed to have a pretty strong association with heart disease So when it came to doing this study, they had no reason to suspect that these trans fats were going to be uniquely deleterious

• Very shortly after, it was identified and accepted that saturated fat raised cholesterol and that that seemed to have a pretty strong association with heart disease

• So when it came to doing this study, they had no reason to suspect that these trans fats were going to be uniquely deleterious

2 other things are important to point out with this study (MCE)

• 1 – During the time that this study was going on, laws changed where people who were in psychiatric wards could just check themselves out So many of the people in this study were not continuous In fact, it kind of threw a wrench in the researcher’s protocol, because they had originally planned that these people were going to be continuously housed in these psychiatric wards for the duration of the study So now you’ve got another confounder where, okay, they’re going in for a period of time and now they’re coming out, and we don’t know what they’re consuming while they’re out

• If Layne were going to make a counterargument to that: this is why randomization is important because if they’re changing what they’re eating while they’re out, it should affect both groups equally (it’s probably equally distributed)

• So many of the people in this study were not continuous

• In fact, it kind of threw a wrench in the researcher’s protocol, because they had originally planned that these people were going to be continuously housed in these psychiatric wards for the duration of the study
• So now you’ve got another confounder where, okay, they’re going in for a period of time and now they’re coming out, and we don’t know what they’re consuming while they’re out

That’s a far less significant criticism compared to the inclusion of trans fats

• 2 – It’s really hard to do very long RCTs in humans

• This is something uniquely difficult when you’re trying to do cardiovascular disease research with hard endpoints Because cardiovascular disease is not something that develops in a couple of years, it develops over the course of decades

• Because cardiovascular disease is not something that develops in a couple of years, it develops over the course of decades

Layne likes to compare it to investing

• If you and I start investing at the same time, and I get into a mutual fund that on average over the course of, let’s say, 40 years, gets me a 9% return, and you invest in something that gets 8.5%
• If we look a couple years out, there’s really not going to be that much difference

But if we look 40 years out, there’s going to be a major difference ‒ that is important to understand as we get into the mechanisms of LDL cholesterol

• This is a total lifetime exposure risk

• When you have people coming in who we don’t know what their baseline LDL was Because now if we were doing this experiment, what would probably happen is you would randomize the groups based on their baseline LDL or based on some other marker, maybe calcium score, whatever it is, so that you can have some degree of confidence that you don’t have differences at baseline But they didn’t know any of this stuff back then; they didn’t have those tools available

• Because now if we were doing this experiment, what would probably happen is you would randomize the groups based on their baseline LDL or based on some other marker, maybe calcium score, whatever it is, so that you can have some degree of confidence that you don’t have differences at baseline

• But they didn’t know any of this stuff back then; they didn’t have those tools available

It’s also important to point out, when you’re looking at these studies where the average follow-up time in this study was about 1-2 years

• That’s a pretty short period of time to actually see any real differences in progression of cardiovascular disease and to try and actually find hard endpoints

• And as we’ll talk about here with some of these other studies, the overall number of deaths are very, very low Even to the point in one trial, like the corn oil trial (the Sydney Heart Study)

• Even to the point in one trial, like the corn oil trial (the Sydney Heart Study)

The Sydney Diet Heart Study (SDHS): an attempt to address the “duration problem” by enrolling a much higher-risk population [A: 28:30, V: 26:53]

The Sydney Diet Heart Study

• Peter was going to get around Layne’s point about duration because the Sydney Heart Study (which Layne just referred to) attempts to solve this
• It was a much smaller study than the Minnesota Coronary Experiment, which had nearly 9,000 subjects This one had a little under 500 subjects, but they were selected to be very high risk Each of these men had just suffered an MI

• So you took a group of men who had just suffered an MI, but they were in the fortunate group at the time who didn’t die Remember, back at the time of the Sydney Heart Study, you were most likely to die from a heart attack So you’re already pre-selected to be pretty lucky, you haven’t died, but your risk is now very, very high

• This one had a little under 500 subjects, but they were selected to be very high risk

• Each of these men had just suffered an MI

• Remember, back at the time of the Sydney Heart Study, you were most likely to die from a heart attack

• So you’re already pre-selected to be pretty lucky, you haven’t died, but your risk is now very, very high

The baseline characteristics of this group were as follows

• Their baseline saturated fat intake was 16% of total calories
• Their PUFA intake (that’s polyunsaturated fat intake) was 6%

The instruction set for the intervention group, they were randomized

• The low saturated fat group was instructed to increase PUFA to 15% and reduce saturated fat to 10% Now that’s not draconian, but of course these people, they were not housed The manner in which they were doing this was basically through safflower oil and safflower margarine

• Now that’s not draconian, but of course these people, they were not housed

• The manner in which they were doing this was basically through safflower oil and safflower margarine

Let’s talk about what happened

In this study, there was a higher mortality in the control group (meaning the group that stayed on the saturated fat) and it was 32% versus 20% at 3 years

• Which again, it’s good in a bad way It’s good that you can see a high mortality in 3 years because you’ve started with such a sick group
• This would at least suggest that that group that lowered saturated fat, raised polyunsaturated fat, they had a higher mortality risk in a short period of time

• It could suggest that there’s something wrong with the safflower oil

• It’s good that you can see a high mortality in 3 years because you’ve started with such a sick group

Layne raises an important point, “ A lot of anti-seed oil people will specifically talk about linoleic acid, and safflower oil is very high in linoleic acid. ”

The strengths of this study

• 1 – It was a longer duration [The SDHS was conducted over nearly 7 years (83 months, with a medium follow-up of 39 months or 3.25 years)] [compared to the the Minnesota Coronary Experiment which had a mean follow-up of 2.9 years (median 3.1 years)]
• 2 – These were people who already had cardiovascular disease So the likelihood that you could see more hard endpoints during the duration of the study was higher

• Now, that also comes with the opposite side of the coin, which is, they already had a cardiovascular disease event

• [The SDHS was conducted over nearly 7 years (83 months, with a medium follow-up of 39 months or 3.25 years)]

• [compared to the the Minnesota Coronary Experiment which had a mean follow-up of 2.9 years (median 3.1 years)]

• So the likelihood that you could see more hard endpoints during the duration of the study was higher

Layne points out, “ They’ve already had a lifetime of accumulation of plaque, so how much difference can you really make on this truck that’s already rolling down the hill? ”

The main criticism of this study

The biggest confounder with these trials is the inclusion of trans fats

⇒ A large portion of what they consumed was safflower-based margarine, which at the time was 25-40% trans fats

1 – It’s really difficult to pick out: Is this a polyunsaturated fat problem or is this specifically a trans fat problem?

• Layne argues that the human randomized control trials that were not confounded by trans fats, were actually probably better designed studies and better powered
• But acknowledges that we’re seeing some of these trials where higher cholesterol in the blood is actually associated with lower mortality

2 – With really sick people, sometimes you can have what’s called reverse causality , especially with cholesterol

• Once you get to a certain age, wasting diseases become a problem
• High cholesterol or low cholesterol, more specifically, low cholesterol, can actually be an indicator of just overall poor health People with really low levels of cholesterol, they’re more prone to wasting It may be more of a downstream effect than it is an upstream effect

• This is where it’s really hard to pick out these sorts of things because it does get confounded by the reverse causality, especially in people who are really sick

• People with really low levels of cholesterol, they’re more prone to wasting

• It may be more of a downstream effect than it is an upstream effect

3 – Even though the Sydney Heart Health Study was a longer study, it was a lower number of people, and even though they’d had a cardiovascular event, the overall number of deaths was still pretty low

• 37 in the treatment group and 28 in the control group

When you’re comparing 28 versus 37, just a few deaths, this is where you can have a sampling error

• Just a few deaths would’ve swung the significance
• If you look at the confidence interval, the confidence interval nearly crossed the 1 [meaning it includes the risk of the control group and therefore is not a statistically significant difference from the control] [Peter discusses this in a newsletter ] [re-evaluation of the data from this study reports, “ [The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64)](https://www.bmj.com/content/346/bmj.e8707#:~:text=The%20intervention%20group%20(n%3D221)%20had%20higher%20rates%20of%20death%20than%20controls%20(n%3D237)%20(all%20cause%2017.6%25%20v%2011.8%25%2C%20hazard%20ratio%201.62%20(95%25%20confidence%20interval%201.00%20to%202.64)) . ”]
• Peter wonders if that was in the original analysis [it wasn’t]

• In the Ramsden reanalysis , the confidence interval was 1.03-2.80

• [re-evaluation of the data from this study reports, “ [The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64)](https://www.bmj.com/content/346/bmj.e8707#:~:text=The%20intervention%20group%20(n%3D221)%20had%20higher%20rates%20of%20death%20than%20controls%20(n%3D237)%20(all%20cause%2017.6%25%20v%2011.8%25%2C%20hazard%20ratio%201.62%20(95%25%20confidence%20interval%201.00%20to%202.64)) . ”]

Layne makes the point that the confidence interval is relatively wide considering the risk it’s showing

• The most powerful thing to pick out is the inclusion of trans fats Which is through no fault of the researchers of their own because when these studies were done, they just didn’t know that trans fats had that effect

• Which is through no fault of the researchers of their own because when these studies were done, they just didn’t know that trans fats had that effect

Debating whether evidence from randomized trials supports the idea that seed oils are uniquely harmful once major confounders are removed [A: 34:00, V: 33:38]

Peter is playing the role of, “ I believe seed oils are bad, ” and explains the biggest contention we would have if we go through the RCTs

• These RCTs were done at a time when trans fats were the substitution fat du jour
• Peter doesn’t know how we’re going to reconcile that

Basically it comes down to: Do I believe that trans fats are less problematic than you believe?

• Because if I believe that trans fats are actually not harmful, then that would take away your argument
• You wouldn’t have an argument

Is there any other argument you’ve got besides trans fats on this?

• The relatively short duration of the trials is another thing
• If we talk about some of the other studies where it wasn’t confounded by trans fats, some of those were longer

• Put a different way: let’s just say we take the trans fats out of it This was in the Ramsden reanalysis as well If we include all the human randomized control trials, looking at substituting polyunsaturated fats for saturated fat, the overall effect is null (there was no effect one way or the other)

• This was in the Ramsden reanalysis as well

• If we include all the human randomized control trials, looking at substituting polyunsaturated fats for saturated fat, the overall effect is null (there was no effect one way or the other)

When you say that, you’re referring to the largest Cochran analyses, there are two, correct?

• Yeah, and Ramsden also did an analysis
• [Cochran analyses by Hooper were published in 2011 and 2020 ]
• Where some of the trials that showed a benefit to PUFA were confounded by the fact that there was omega-3s included in them
• Layne would argue that if you look at the literature on omega-3s, it’s actually not super strong that they decrease hard cardiovascular disease endpoints, but nevertheless, it’s a confounding variable

Ramsden took those out and then showed: when we take out omega-3s, we see an increased risk; but of course, that still includes the trans fats confounders

Layne’s takeaway

• If we just include both and lump them all in together, the net overall effect is that one way or another, reducing saturated fat, raising PUFA, it was equal risk

Layne’s response to the statement: seed oils are uniquely deleterious to human health

• Even if we take the trans fats out of it
• And if you’re going to allow those to be included, you have to have what he calls “logical symmetry” Which is if I’m going to allow this confounding variable to support my point, I also have to allow your confounding variables to support your point

• Otherwise, we just got to find the ones that take both of them out

• Which is if I’m going to allow this confounding variable to support my point, I also have to allow your confounding variables to support your point

And in that case, the net effect of seed oils is still no harm

What’s the other confounding variable, the EPA and DHA [omega-3s]?

• Correct

The Rose Corn Oil trial: an often-cited study used to argue against polyunsaturated fats [A: 36:30, V: 36:44]

Layne points out the other study they cite is the Rose corn oil trial (RCOT)

• Quite frankly, he doesn’t know what to make of it because it was only about 70 people in the entire thing It was 26 people in a control group, 26 people in an olive oil group, and 28 people in a corn oil group [80 people]
• This was a 2 year study in people with significant cardiovascular disease

• There were 3 groups: 1 – Control group: business as usual, 3 of those people died 2 – Olive oil group: 5 people died 3 – Corn oil group: 8 people died (sorry, that was total deaths) [ Table 5 shows sudden death and fatal infarction ‒ total deaths in each group add up to: 1 in the control group 3 in the olive oil group 5 in the corn oil group]

• It was 26 people in a control group, 26 people in an olive oil group, and 28 people in a corn oil group [80 people]

• 1 – Control group: business as usual, 3 of those people died

• 2 – Olive oil group: 5 people died
• 3 – Corn oil group: 8 people died (sorry, that was total deaths)

• [ Table 5 shows sudden death and fatal infarction ‒ total deaths in each group add up to: 1 in the control group 3 in the olive oil group 5 in the corn oil group]

• 1 in the control group

• 3 in the olive oil group
• 5 in the corn oil group]

Peter points out, “ Now, again, the confidence intervals on this were very large because the sample size was very small. ”

• [Peter is referring to Ramsden’s meta-analysis where RCOT is the Rose Corn Oil Trial, results shown below] [abbreviations used in the figure below: MCE=Minnesota Coronary Experiment, SDSH=Sydney Diet Heart Study, RCOT=Rose COrn Oil Trial, LA Vet = Los Angeles Veterans Trial, MRC-Soy=Medical Research Council Soy Oil Trial, DART=Diet and Re-infarction Trial, ODHS=Oslo Diet Heart Study, STARS=St. Thomas Atherosclerosis Regression Study, LA=linoleic acid, SFA=saturated fat, ALA=α linolenic acid]

• [abbreviations used in the figure below: MCE=Minnesota Coronary Experiment, SDSH=Sydney Diet Heart Study, RCOT=Rose COrn Oil Trial, LA Vet = Los Angeles Veterans Trial, MRC-Soy=Medical Research Council Soy Oil Trial, DART=Diet and Re-infarction Trial, ODHS=Oslo Diet Heart Study, STARS=St. Thomas Atherosclerosis Regression Study, LA=linoleic acid, SFA=saturated fat, ALA=α linolenic acid]

Figure 4. Ramsden et al. meta-analysis for mortality from coronary heart disease in trials testing replacement of saturated fat with vegetable oils rich in linoleic acid . Image credit: BMJ 2016 figure 7

• This one is a bit challenging because the participants were given their oils

• You could think of this as kind of an early version of the PREDIMED study where it was a free-living study, but the participants were given olive oil when they were in the olive oil group There were 3 groups in the PREDIMED: 1 – Low fat diet 2 – high MUFA (monounsaturated fat) through olive oil, and you were given a bottle of olive oil every week [Mediterranean diet + olive oil] 3 – high MUFA through nuts, and you were given the nuts every week [Mediterranean diet + nuts]

• There were 3 groups in the PREDIMED:

• 1 – Low fat diet
• 2 – high MUFA (monounsaturated fat) through olive oil, and you were given a bottle of olive oil every week [Mediterranean diet + olive oil]
• 3 – high MUFA through nuts, and you were given the nuts every week [Mediterranean diet + nuts]

⇒ In the Rose corn oil trial they were given corn oil or olive oil

• Other than that, we don’t have dietary recall

Layne points out, “ Now the benefit is not confounded by trans fats… So that would be a positive. ”

• But the number of deaths was low

Those are such small numbers [of deaths] that you’re so prone to sampling errors where if you’d had 10,000 participants, that’s very likely going to get lost in the wash

The olive oil group in the Rose corn oil trial

• Even people who are anti-seed oil typically acknowledge that olive oil is heart healthy

Well, you had 3x the deaths from cardiovascular disease in the olive oil group compared to the control group; and so it doesn’t fit with the evidence we have

• And it’s so small
• The confidence intervals were absolutely massive If we want to talk about a confidence interval being wide of 1.03 to 2.8 as being wide The confidence interval in this, Layne believes it was 0.6 to 37 (not statistically) significant

• Here’s where Layne’s PhD advisor used to say, “ If you torture the data enough, it will confess what you want it to show. ” If you say there was 6x the number of deaths in the polyunsaturated fat group (corn oil), you’re technically correct, but you’re leaving out a really big proportion of the data [Layne is recalling that there was 1 death in the control group and 6 deaths in the corn oil group; table 5 showed 1 death in the control group and 5 deaths in the corn oil group]

• If we want to talk about a confidence interval being wide of 1.03 to 2.8 as being wide

• The confidence interval in this, Layne believes it was 0.6 to 37 (not statistically) significant

• If you say there was 6x the number of deaths in the polyunsaturated fat group (corn oil), you’re technically correct, but you’re leaving out a really big proportion of the data

• [Layne is recalling that there was 1 death in the control group and 6 deaths in the corn oil group; table 5 showed 1 death in the control group and 5 deaths in the corn oil group]

When we plop all these studies into the meta-analysis, don’t take out any confounding variables. What do we see? We see a null effect

Now, if we take out the trans fats: there was a meta-analysis where they put together all the trials

• [There are 2 relevant meta-analyses here: Ramsden re-analysis of the MCE and meta-analysis of trials replacing saturated fat with vegetable oil/PUFA (results shown in the previous figure) The American Heart Association presidential advisory summarizing major RCTs and presenting additional meta-analysis (results shown below) Dayton=Los Angeles Veterans Administration Trial 1968 Oslo+Oslo Diet-Heart Study 1970 MRC=British Medical Research Council (soybean oil) 1969 Finnish=Finnish Mental Hospital Study 1979]
• There were human randomized control trials looking at substitution of polyunsaturated fats for saturated fats, not confounded by trans fat
• This was a very clear benefit to substitution
• Layne thinks it was around 20% reduced mortality risk

• Peter interjects about the reduced mortality risk, “ No, it was even more… I have the luxury of cheating because I’m looking at the actual figure. ” [a RR of 0.71 or 29%% risk reduction is shown below]

• Ramsden re-analysis of the MCE and meta-analysis of trials replacing saturated fat with vegetable oil/PUFA (results shown in the previous figure)

• The American Heart Association presidential advisory summarizing major RCTs and presenting additional meta-analysis (results shown below) Dayton=Los Angeles Veterans Administration Trial 1968 Oslo+Oslo Diet-Heart Study 1970 MRC=British Medical Research Council (soybean oil) 1969 Finnish=Finnish Mental Hospital Study 1979]

• Dayton=Los Angeles Veterans Administration Trial 1968

• Oslo+Oslo Diet-Heart Study 1970
• MRC=British Medical Research Council (soybean oil) 1969
• Finnish=Finnish Mental Hospital Study 1979]

Peter points out, “ The Rose corn oil trial has the largest hazard ratio of any trial ever done, of these trials. It was 4.64. ”

Figure 5. Sacks et al. meta-analysis on the relative risk of coronary heart disease (CHD) death by replacing saturated fat with polyunsaturated fat . Image credit: Circulation 2017

• [Figure 7 from the Ramsden meta-analysis , shown earlier in figure]
• What that means is there was a 364% increase in risk if you took corn oil

But it did not reach anywhere near statistical significance to Layne’s point because the 95% confidence interval was 0.58 to 37.15

• So if we limit ourselves to this body of literature and the one, two, three, four, five studies, we do not achieve statistical significance, though we do have a trend towards risk

That trend is 1.13, meaning a 13% relative risk increase

• This is a bit of a messy analysis because we’re including the MCE , we’re including Sydney , but we’re also including Rose corn oil

We’re just trying to get as many bodies as possible through the engine of the meta-analysis, and we don’t reach significance

In fact, the only study that reaches statistical significance is the Sydney Heart Study

• That had a 74% increase with a confidence interval of 1.04 to 2.91
• Peter expects Layne’s argument is going to be: yes, but they were at 25-50% trans fats

Three studies where replacing saturated fat with polyunsaturated fat produced different results than earlier trials [A: 41:30, V: 42:37]

Peter argues, “ This a tough one to score, Layne, because on the one hand, it looks pretty bad for polyunsaturated fats here. Every time you eat them, it just seems to move you in the wrong direction, except for the linoleic VA study .”

There’s several strengths to the VA study

• [aka The Los Angeles Veterans Administration Trial by Dayton]
• It was in veterans homes, the food intake was controlled
• They provided it to the participants, and there were around 850 participants
• The average follow-up, Layne believes was just under 9 years (that’s actually a pretty long study for this) [1959-1967]
• It is not confounded by trans fats

• They did show around a 20 or 30% reduction in risk (Layne doesn’t have the numbers in front of him) Peter points out that they found an 18% reduction in overall risk , confidence interval 0.56-1.21 [this is from Ramsden’s re-analysis of the MCE where he reported a hazard ratio of 0.82 in figure 7] Though it did not reach statistical significance It didn’t have a wide confidence interval (it was actually quite narrow,) but it crossed unity [the confidence interval crossed 1]

• Peter points out that they found an 18% reduction in overall risk , confidence interval 0.56-1.21 [this is from Ramsden’s re-analysis of the MCE where he reported a hazard ratio of 0.82 in figure 7]

• Though it did not reach statistical significance
• It didn’t have a wide confidence interval (it was actually quite narrow,) but it crossed unity [the confidence interval crossed 1]

Peter points out a potential confounder, “ They included omega-3s , if we believe that. ”

• So the question is, did the omega-3s help or was the study underpowered?
• Is that why it didn’t reach statistical significance or does it just not matter?

Layne makes the point, “ This is why we do meta-analysis because when it comes to single studies sometimes, especially when things are messy like this with hard endpoints, even if 800 people sounds like a lot, when you’re trying to get hard endpoints like mortality and cardiovascular disease events, it’s pretty small. ”

The Oslo Diet-Heart Study

• That was only 400 people, but it showed around a 47% risk reduction [Figure 2 reports fatal myocardial infarction: 11-year survival curves with an estimated survival of people on the diet of 80.5% (standard error 3.2) compared to people on the control diet of 66.1% (standard error 3.8), p = 0.004 In the meta-analysis by Sacks , MI was reduced by 37%]
• Again this is compounded by omega-3s

• [this study evaluated a diet low in saturated fat, low in cholesterol, and high in polyunsaturated fat]

• [Figure 2 reports fatal myocardial infarction: 11-year survival curves with an estimated survival of people on the diet of 80.5% (standard error 3.2) compared to people on the control diet of 66.1% (standard error 3.8), p = 0.004

• In the meta-analysis by Sacks , MI was reduced by 37%]

The Finnish Hospital study

• Layne thinks this is one of the strongest studies
• It is not confounded by trans fats or omega-3s
• People did each diet for 6 years and it was a crossover design

⇒ A crossover design is when you take people and you have them do both treatments

• The downside is the crossover effect where let’s say you have a cardiovascular event on one of the diets, but you did the other diet before that So is it from the diet you’re on now or is it from the previous diet?
• The way researchers attempt to get around that is by essentially making the order in which they do both diets split so that there’s 50% of people did one diet first and then the next diet and then they reverse it Usually you do that by randomizing each individual person

• The weakness of this study : they didn’t randomize individually They had 2 hospitals: one hospital started with one diet and one hospital did the other diet; and then they switched them after 6 years Logistically it makes sense If you were going to try and make the argument that this introduced a lot of bias, the argument you would make is that perhaps there was inherent characteristics about one hospital versus the other that were more prone to people getting cardiovascular disease Layne would say that risk is probably pretty low, but it’s an argument that can be made

• So is it from the diet you’re on now or is it from the previous diet?

• Usually you do that by randomizing each individual person

• They had 2 hospitals: one hospital started with one diet and one hospital did the other diet; and then they switched them after 6 years

• Logistically it makes sense
• If you were going to try and make the argument that this introduced a lot of bias, the argument you would make is that perhaps there was inherent characteristics about one hospital versus the other that were more prone to people getting cardiovascular disease
• Layne would say that risk is probably pretty low, but it’s an argument that can be made

The benefits of this [study design]

• It was 1,200 people, but since they crossed them over, effectively it was like 2,400 people One of the benefits to a crossover experiment is you can up your power

• Peter hopes somebody listening is sharper than he is in statistics It’s been so long… he used to know the answer to this He thinks it’s even more impressive than 1,200 to 2,400 [Gemini says a crossover trial with 1200 people would have a power equivalent to a parallel RCT with 4800 or more people (assuming a correlation of 0.50)]

• One of the benefits to a crossover experiment is you can up your power

• It’s been so long… he used to know the answer to this

• He thinks it’s even more impressive than 1,200 to 2,400
• [Gemini says a crossover trial with 1200 people would have a power equivalent to a parallel RCT with 4800 or more people (assuming a correlation of 0.50)]

⇒ A crossover design is even more powerful statistically because every person get to be their own control

• The largest benefit is the way you do the T-test and statistical comparisons

• Each person is their own control Because when you’re doing a parallel group design, which is where you just have one group on one diet, one group on the other diet, you are assuming that the randomization process randomly distributes the baseline characteristics that may be different between groups to where they’re equally distributed amongst the groups, but you don’t know that for sure But when you cross over, now you’re very confident that inherent baseline characteristics are now no longer a confounding variable And it’s likely that the people’s overall lifestyles are going to be similar throughout the course of the experiment There’s less risk of bias from inherent lifestyle differences as well For example: somebody having more stress versus less stress and those sorts of things.

• Because when you’re doing a parallel group design, which is where you just have one group on one diet, one group on the other diet, you are assuming that the randomization process randomly distributes the baseline characteristics that may be different between groups to where they’re equally distributed amongst the groups, but you don’t know that for sure

• But when you cross over, now you’re very confident that inherent baseline characteristics are now no longer a confounding variable
• And it’s likely that the people’s overall lifestyles are going to be similar throughout the course of the experiment
• There’s less risk of bias from inherent lifestyle differences as well
• For example: somebody having more stress versus less stress and those sorts of things.

Again this study is not confounded by trans fats or omega-3’s, and it’s pretty well-powered for a long duration

• 6 years on each diet, 12 years overall

They saw a pretty significant reduction in the risk of cardiovascular disease events and mortality: a 41% reduction in the treatment group

• 41% reduction in the treatment group [reviewed in Circulation 2017 by Sacks et al. ]

The intervention

• The control arm : high saturated fat diet: 18% saturated fat, 3-4% polyunsaturated fat
• The treatment group : 9% saturated fat, 14% polyunsaturated fat Similar targets to the MCE study

• Layne believes they measured linoleic acid in tissue too [The review by Sacks in 2017 states, “ Adherence was also demonstrated by 3-fold enrichment of linoleic acid in adipose tissue .”]

• Similar targets to the MCE study

• [The review by Sacks in 2017 states, “ Adherence was also demonstrated by 3-fold enrichment of linoleic acid in adipose tissue .”]

Layne’s explanation for why the evidence is pointing towards cardiovascular risk reduction when substituting polyunsaturated fat for saturated fat [A: 47:30, V: 49:39]

What would be your best explanation for this?

The Finnish study showed a 41% relative risk reduction in cardiovascular disease with a low saturated fat, high polyunsaturated fat diet, and the confidence intervals are really tight [see the earlier figure from the Sacks meta-analysis, figure 5]

• This is why we have this situation today where there seems to be a negative effect of polyunsaturated fats in some of these studies

• But Layne is explaining why he thinks that the studies that show a reduction in risk are, on balance, better Again, not making a criticism of the researchers, because as they discussed earlier, they did the best they could at the time with the information they had So this isn’t an indictment on the researchers, whatsoever

• Again, not making a criticism of the researchers, because as they discussed earlier, they did the best they could at the time with the information they had

• So this isn’t an indictment on the researchers, whatsoever

When you look at these studies that showed a reduction in risk, they’re longer, they’re typically better controlled, and they don’t have the inclusion of trans fats

• Layne thinks those things are the most powerful movers

So we think that that is the best explanation for why the Finnish Heart study came up with a different answer

• Yes

• There was a meta-analysis in 2017 of the studies not confounded by trans fats Now they included some of the ones that had fish oil in them or omega-3s rather But they showed overalls around a 29% reduction in risk [shown in the figure below]

• Now they included some of the ones that had fish oil in them or omega-3s rather

• But they showed overalls around a 29% reduction in risk [shown in the figure below]

[The figure below shows analysis of the Los Angeles VA study by Dayton , Oslo Diet-Heart Study, MRC study of soybean oil , and the Finnish Mental Hospital Study ]

Figure 6. Sacks et al. meta-analysis of core trials on replacing saturate with polyunsaturated fat. Relative risk (RR) of the primary FHD outcome of each trial . Image credit: Circulation 2017 figure 2

• If you look at the Ramsden analysis , in their best case for polyunsaturated fats being bad: it’s a smaller increase in risk, and the confidence intervals are very wide [shown in the figure below Using the abbreviations: MCE=Minnesota Coronary Experiment, SDSH=Sydney Diet Heart Study, RCOT=Rose COrn Oil Trial, LA Vet = Los Angeles Veterans Trial, MRC-Soy=Medical Research Council Soy Oil Trial, DART=Diet and Re-infarction Trial, ODHS=Oslo Diet Heart Study, STARS=St. Thomas Atherosclerosis Regression Study, LA=linoleic acid, SFA=saturated fat, ALA=α linolenic acid]

• [shown in the figure below

• Using the abbreviations: MCE=Minnesota Coronary Experiment, SDSH=Sydney Diet Heart Study, RCOT=Rose COrn Oil Trial, LA Vet = Los Angeles Veterans Trial, MRC-Soy=Medical Research Council Soy Oil Trial, DART=Diet and Re-infarction Trial, ODHS=Oslo Diet Heart Study, STARS=St. Thomas Atherosclerosis Regression Study, LA=linoleic acid, SFA=saturated fat, ALA=α linolenic acid]

Figure 7. Meta-analysis for mortality from coronary heart disease in trials testing replacement of saturated fat with vegetable oils rich in linoleic acid . Image credit: BMJ 2016 figure 7

Peter plays devil’s advocate for a moment and asks, “ What if this says more about saturated fats harm than polyunsaturated fats benefit? ”

• This is a situation where you’re doing nutritional studies
• You have to substitute something if it’s going to stay isocaloric

Layne adds, “ I’m not saying that there’s no deleterious effect to seed oils, whatsoever because added oils in the diet are a major source of calories and excess calories are not innocuous. ”

• So we have to compare apples to apples, which is when you are substituting in a one-to-one ratio, what is more beneficial?
• Layne thinks you could take any food or any nutrient and you can find both positive and negative pathways that it activates

The question is NOT whether or not a nutrient or a particular food activates positive or negative pathways

• He says that very broadly because there’s not really such a thing as a positive or negative pathway, but just in general, there could be positive and negative outcomes

What matters is on balance, what is the net effect?

Layne’s financial analogy

• We’re talking about these pathways, we’re talking about mechanisms, which are important
• If an outcome exists, there’s a mechanism or mechanisms to explain it, but those are like single stocks
• An outcome like a cardiovascular disease event, that is like a mutual fund
• And what Layne means by that is he could take a mutual fund that’s doing really well (up 20% year over year), but he could find a few stocks in it where he’s like, “ Oh, you don’t want to invest in this. Look at these. They’re down like 50% .”
• But what matters more? Those individual stocks that are down or the overall mutual fund that’s killing it?

You care about what the overall mutual fund is doing

An example of this: smoking decreases the risk of Parkinson’s disease

“ Smoking decreases the risk of Parkinson’s disease. There’s a very consistent effect in the research literature, but on balance, I don’t think anybody’s going to say smoking is good for you. ”‒ Layne Norton

• Peter points out, “ It appears to be the nicotine that is causing that benefit. ” He doesn’t want anybody with Parkinson’s disease or at risk for Parkinson’s picking up cigarettes If you’re going to do anything, choose non-tobacco nicotine

• He doesn’t want anybody with Parkinson’s disease or at risk for Parkinson’s picking up cigarettes

• If you’re going to do anything, choose non-tobacco nicotine

A better comparison is aspirin

• Aspirin is an anticoagulant overall, but it also activates some procoagulant pathways
• But the overall effect is anticoagulation
• If you were to pick out and say, “ Well, look, it activates these pathways .”
• Not that it doesn’t matter, but on balance, it is a net positive for anticoagulation

When it comes to looking at polyunsaturated fats versus saturated fats

Yes, there are mechanisms that exist that would suggest that polyunsaturated fats can have a negative effect, but on balance, there are more mechanisms that exist that show saturated fat to be a negative

To circle back to Peter’s original question: Is this an effect of polyunsaturated fats being beneficial or saturated fats being a negative?

• Layne thinks it’s almost impossible to disconnect those two questions because when it comes to nutrition research to do it accurately, you’re looking at substitutions
• If you’re going to take saturated fat out, you’ve got to put something in
• If we look at studies where you s ubstitute carbohydrate for saturated fat , not really much changes Layne would say that probably depends on the type of carbohydrate very much If you were doing fibroid end sources of carbohydrate, he’s pretty sure you’d see a reduction in risk
• With monounsaturated fats , there appears to be a reduction in risk of cardiovascular disease It appears to be not quite as powerful (at least in the cohort studies) as polyunsaturated fats

• But again, since we have to substitute something, let’s make it very basic

• Layne would say that probably depends on the type of carbohydrate very much

• If you were doing fibroid end sources of carbohydrate, he’s pretty sure you’d see a reduction in risk

• It appears to be not quite as powerful (at least in the cohort studies) as polyunsaturated fats

Even if polyunsaturated fats didn’t do anything cardioprotective, it’s still cardioprotective in that when you put them in in place of saturated fat, you have improvements in outcomes

• Layne would argue that there are mechanisms in place that explain why polyunsaturated fats are cardioprotective

The point he’s making is that he thinks it’s difficult to disconnect those 2 questions

Do we know if the Cochrane analyses on this question have blended and included the studies across those that contain trans fats and those that don’t?

• Where they look at all the PUFA versus SFA studies
• They specifically excluded ones that were confounded by trans fats Cochrane had no trans fats but they did have omega-3s The Cochrane study including omega-3s showed a slight benefit to PUFA (29 or 31%) [Peter is referring to the meta-analysis : meta-analysis: Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association , figure 2 shows a relative risk of 0.71 (29% risk reduction)]

• Ramsden had one where it included basically all of them [In Ramsden’s re-evaluation of the MCE he also did a meta-analysis (figure 7)] Net effect being null, nothing And when he pulled out the ones that were confounded by omega-3s, they showed a negative effect of polyunsaturated fats (but with trans fats still in) [ Ramsden (in figure 7) reported an overall hazard ratio of 1.13 (CI 0.83 to 1.54)]

• Cochrane had no trans fats but they did have omega-3s

• The Cochrane study including omega-3s showed a slight benefit to PUFA (29 or 31%)

• [Peter is referring to the meta-analysis : meta-analysis: Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association , figure 2 shows a relative risk of 0.71 (29% risk reduction)]

• [In Ramsden’s re-evaluation of the MCE he also did a meta-analysis (figure 7)]

• Net effect being null, nothing

• And when he pulled out the ones that were confounded by omega-3s, they showed a negative effect of polyunsaturated fats (but with trans fats still in) [ Ramsden (in figure 7) reported an overall hazard ratio of 1.13 (CI 0.83 to 1.54)]

• [ Ramsden (in figure 7) reported an overall hazard ratio of 1.13 (CI 0.83 to 1.54)]

There was a pretty decent benefit (29%) with PUFAs

Has anybody done the analysis of excluding omega-3, excluding trans fats?

• You’re down to very few studies (maybe two)

When you say omega-3s , are you talking α-linolenic acid or are you talking EPA-DHA?

• Layne believes they’re specifically talking about the EPA-DHA, but α-linolenic acid is an omega-3 as well (and that was part of it as well)
• α-linolenic acid doesn’t convert very efficiently to EPA and DHA

So does that mean that these studies that contain omega-3s are going out of their way to supplement with EPA and DHA, which of course you can really only get in high quantities from marine sources?

• It wasn’t clear in the research literature
• Layne recalls 2 studies that were not confounded by either trans fats or omega-3s The Finnish study discussed earlier STARS was not looking at hard cardiovascular disease endpoints but plaque progression

• Layne believes that STARS was a one-year study, and they looked at either people doing low saturated fat, higher polyunsaturated fat versus higher saturated fat, lower polyunsaturated fat, and they looked at the progression of plaque. He would say that the strength of this is since you are looking at the progression of what we know causes these myocardial events, even if you don’t have a myocardial event, you can get a really good idea of what’s going on He makes up a hypothetical case: you could have somebody in one of these other studies where they got right up to the point where they got like a 99% blockage, but no myocardial event in the time where they were measuring it and they just came up as that’s a risk reduction But in reality they had disease progression The benefit of this is you still get a harder endpoint than just biomarkers, but you can get a little bit more granular than just looking at mortality Layne describes mortality and cardiovascular disease events as big blunt instruments

• The Finnish study discussed earlier

• STARS was not looking at hard cardiovascular disease endpoints but plaque progression

• He would say that the strength of this is since you are looking at the progression of what we know causes these myocardial events, even if you don’t have a myocardial event, you can get a really good idea of what’s going on

• He makes up a hypothetical case: you could have somebody in one of these other studies where they got right up to the point where they got like a 99% blockage, but no myocardial event in the time where they were measuring it and they just came up as that’s a risk reduction
• But in reality they had disease progression
• The benefit of this is you still get a harder endpoint than just biomarkers, but you can get a little bit more granular than just looking at mortality
• Layne describes mortality and cardiovascular disease events as big blunt instruments

What Mendelian randomization says about the causal role of LDL cholesterol in ASCVD [A: 56:45, V: 1:00:34]

Let’s go from the macro to the micro

• Let’s talk a little bit more about these mechanistic things now
• Because most of these trials were done with a brute force tool of… the hardest outcome is all-cause mortality But again, that’s a high bar

• When you do clinical trials, you trade off between outcome and barrier to outcome (for lack of a better term)

• But again, that’s a high bar

So if you want to use all-cause mortality, that is the ultimate measuring stick, but it’s a high bar to clear

• And then you can go disease-specific mortality (coronary death), then you can go one step lower An example would be MACE (major adverse cardiac events), where we’re going to use heart attack and stroke and cardiac death

• And then you can go one step below that and say, “ Well, we’re just going to look at a change in cholesterol or we’re going to look at a change in LDL cholesterol. ”

• An example would be MACE (major adverse cardiac events), where we’re going to use heart attack and stroke and cardiac death

Below MACE, you would go to disease progression, and you get more and more insight into disease process

• This is what STARS did

Before we get into that, this would be a good time to talk about the Mendelian randomization (MR) studies through the lens of LDL

Layne points out, “ As you mentioned, mortality is a difficult outcome to get. It’s a high bar to clear. The benefit to Mendelian randomization (MR) is that essentially you have a lifelong randomized control trial. ”

• Mendelian randomization takes advantage of the fact that at birth, genetic variants are randomly assigned
• So in a research study, the research is just going to do whatever randomization process they have (completely random)
• Mother nature actually does that by design
• We have now identified around a dozen variants that will essentially change your LDL cholesterol levels There are variants that deal with LDL clearance, LDL production, how much cholesterol you absorb

• The benefit to this is you can look at someone’s lifelong LDL cholesterol exposure and attempt to see what is the risk of mortality in cardiovascular disease (that is very powerful) And these are studies where some of these have hundreds of thousands of people in them

• There are variants that deal with LDL clearance, LDL production, how much cholesterol you absorb

• And these are studies where some of these have hundreds of thousands of people in them

Layne explains the advantage of MR studies, “ Again, the randomization of this process by nature is so important because now if we see differences between groups, we can assume it’s due to that assignment of that genetic variant versus some kind of confounding variable .”

Peter points out a caveat, “ For a Mendelian randomization to be useful, a couple things have to be true .”

• 1 – There has to be genetic assignment to the variable of interest That’s true for many things: it’s true for height, it’s true for body composition, it’s true for many psychiatric disorders. There’s lots of things for which genetics play a significant role and LDL cholesterol turns out to be one of them
• 2 – But this is the other important thing that people often forget when talking about MR, which is that those same genes cannot have a direct impact on another variable that affects the outcome of interest because if they do, your randomization just got wonky
• And that’s why they do tests for pleiotropy When Layne talks about the results, he’s going to explain why it’s very unlikely t hat these differences were due to pleiotropy

• But it does require us to make one assumption : this is not a lifelong test of saturated fat versus polyunsaturated fat; this is a lifelong test of what we expect to happen to LDL cholesterol by substituting polyunsaturated fats for saturated fats This may seem ticky-tacky, but Layne is trying to be logically consistent Stated another way: this is a test of LDL causality

• That’s true for many things: it’s true for height, it’s true for body composition, it’s true for many psychiatric disorders.

• There’s lots of things for which genetics play a significant role and LDL cholesterol turns out to be one of them

• When Layne talks about the results, he’s going to explain why it’s very unlikely t hat these differences were due to pleiotropy

• This may seem ticky-tacky, but Layne is trying to be logically consistent

• Stated another way: this is a test of LDL causality

Peter adds, “ It’s a leap to then make the statement about: What does nutrition do to this? ”

An aside on MR: another example that Peter wrote about in his book (but can’t remember if it made the final cut)

• A handful of studies showed that people with lower cholesterol were more prone to cancer
• And so the concern became, “ Well, gosh, we shouldn’t be lowering people’s cholesterol in an effort to prevent heart disease if it increases the risk of cancer. ”
• Of course, on average, that didn’t seem to be the case, but there was always one study that might have suggested that, and you never knew if there was a confounder because cancer, you weren’t randomizing to find that

This is where MR became potentially valuable

• Provided you believe that the genes that regulate cholesterol synthesis, absorption, and LDL receptor expression don’t also regulate a cancer process

⇒ And if you believe that, then the Mendelian randomization was quite clear that there was no relationship (neither good nor bad) between LDL, cholesterol, and cancer

So that meant that LDL had no causal role (one way or the other) on cancer, whereas as you’ll probably talk about, it has a relationship towards ASCVD

Back to MR and the causal role of LDL cholesterol in ASCVD

• It took Layne a while to wrap his head around MR when he first started reading about it, but these were the studies that made him change his mind on LDL

Strengths of MR studies

• The strengths to this lifelong exposure, which based on the lipid hypothesis, we would expect to see a linear effect of lifelong exposure to LDL on the risk of cardiovascular disease and mortality
• And you can get a large number of subjects for their lifetime, and it’s randomized
• So it’s not a cohort study

The one downside

• We’re having to make a leap of, okay, we’re not directly measuring people eating saturated fat versus polyunsaturated fat

But Layne would say that this leap is pretty small because it is very well established that increasing saturated fat intake increases LDL cholesterol and increasing PUFAs decrease LDL cholesterol

• Raising PUFAs and lowering saturated fat significantly decreases LDL cholesterol

⇒ In most studies, you get around a 15% change [decrease] in LDL cholesterol from substituting in polyunsaturated fats for saturated fat

The first big MR study with cholesterol

• Layne thinks it’s Ference in 2012
• If you look at the figure [shown below] where they take all the genetic variants and you look at how the line goes almost straight through it ‒ we’re talking about an R of probably above 0.9, which in studies like this, that is an incredible association

For every 1 mmol reduction in LDL there was a 50-54% risk reduction in cardiovascular disease ( 1 mmol/L LDL-C is 38.67 mg/dL )

Figure 8. Log-linear effect of each unit long-term exposure to lower LDL-C on risk of CHD (vertical lines represent 1 SE above and below the point estimate of proportional risk reduction) . Image credit: Journal of the American College of Cardiology 2012

Figure 9. Comparative CHD risk reduction of earlier and later LDL-C lowering (genetic studies shown in blue compared to statin trials shown in red) . Image credit: Journal of the American College of Cardiology 2012

• Again, the pleiotropy argument is pretty much null and void because it didn’t matter what kind of variant it was If it increased LDL clearance If it decreased production No matter how it affected the metabolism of LDL cholesterol, it had the same dose effect
• The only exception to that was some of the CETP variants (some variants raise HDL and they lower LDL) But here’s the big point, the lowering of LDL with those variants and those drugs, it lowers the cholesterol mass, but there’s a discordant lowering of apoB or LDL particle number

• Remember every single LDL particle has an apoB protein on it (and when we get into the mechanisms, this is going to be very central to the lipid hypothesis)

• If it increased LDL clearance

• If it decreased production

• No matter how it affected the metabolism of LDL cholesterol, it had the same dose effect

• But here’s the big point, the lowering of LDL with those variants and those drugs, it lowers the cholesterol mass, but there’s a discordant lowering of apoB or LDL particle number

⇒ If you lower cholesterol mass, but your apoB doesn’t drop that much, you basically have just made each particle smaller

• And what we see is in that particular subset of variants, there is a small risk reduction, but it’s basically explained by the small decrease in apoB You don’t get the predicted risk reduction that you would get with reducing LDL cholesterol

• You don’t get the predicted risk reduction that you would get with reducing LDL cholesterol

But amongst the variants that decrease LDL-C and correspondingly decrease apoB, it is a very, very consistent effect [on reducing risk of ASCVD]

• Again, regardless of the genetic variant, it has the same risk reduction

⇒ And then when we look at the statin trials, regardless of the way that LDL cholesterol gets lowered (and there’s different statins that work different ways), it is the same dose response, which is about 22% [risk reduction for ASCVD]

Why do you think that when we look at the totality of the Mendelian randomization, that as LDL cholesterol is going down (whether genetically or through drugs), cardiovascular mortality is going down?

• Tom Dayspring has a figure [shown below] that lays every single MR study, every single RCT study, and every single observational epidemiology study on the same graph with three lines, basically the linear regression through each.

Figure 10. Log-linear association per unit change in LDL-C and the proportional reduction of risk of cardiovascular disease (CHD) . Image credit: European Heart Journal 2017

[How to read the graph above

• The blue line is from Mendelian randomization studies, the green line is from observational epidemiology studies, and the red line is from RCTs
• Compare the change in proportional risk (y-axis) by looking at two different LDL-C concentrations (x-axis) For example, follow the yellow lines on the graph

• Compare a change in LDL-C going from 39 mg/dL to 23 mg/dL (which most would say there is no need to treat) ‒ this is a 16 mg/dL drop The change in proportional risk is the difference in the percentage shown on the y-axis Mendelian randomization studies show the risk goes from 53 to 35%: an 8% drop Observational studies show the risk goes from 33 to 23% (10% drop; typically 4-6 years difference) RCTs show the risk goes from 22 to 12%: a 10% drop, typically 2.5-5 years difference]

• For example, follow the yellow lines on the graph

• The change in proportional risk is the difference in the percentage shown on the y-axis

• Mendelian randomization studies show the risk goes from 53 to 35%: an 8% drop
• Observational studies show the risk goes from 33 to 23% (10% drop; typically 4-6 years difference)
• RCTs show the risk goes from 22 to 12%: a 10% drop, typically 2.5-5 years difference]

The compounding effects of life-long exposure to high LDL cholesterol [A: 1:06:45, V: 1:12:09]

Why is it that in the MR study, which in theory would be the most pure study, every millimole (or every roughly 40 mg/dL) reduction in LDL cholesterol is giving you 50 to 55% reduction. But when you do the same thing with a statin, you still get a benefit and that benefit appears non-ending, but it’s only 22%.

Doesn’t that tell us that statins are bad?

• There is still a risk reduction

Peter states it another way, “ Does that suggest that while statins are net positive, they’re doing something bad? ”

• Think about when people are getting on statins

• Layne’s bias is he hopes that LDL cholesterol is not bad Because his whole mother’s side of the family runs high LDL

• Because his whole mother’s side of the family runs high LDL

Layne’s LDL cholesterol and statin use

• Even with a low saturated fat diet, even with high dietary fiber intake, he runs about 150 mg/dL
• He started taking a statin when he was 40 years old, but his endothelium, his blood vessels have already had 40 years of LDL exposure at that level

So even if he’s on a statin every single day till the day he dies, there is still some LDL cholesterol that has penetrated that endothelium and has contributed to some degree of atherosclerosis

• He had a coronary calcium score done and it was pretty low

• Overall his net risk was very low for his age because he has good insulin sensitivity It’s important to point out when we’re talking about LDL, we’re not saying everything else doesn’t matter LDL-C is an independent risk factor Insulin sensitivity, metabolic health, all those things are not mutually exclusive

• It’s important to point out when we’re talking about LDL, we’re not saying everything else doesn’t matter

• LDL-C is an independent risk factor
• Insulin sensitivity, metabolic health, all those things are not mutually exclusive

When you have a genetic variant that lowers LDL, from the day you are born

• Your entire circulatory system is exposed to less LDL cholesterol

⇒ When it comes to how much gets into the intima, it is concentration dependent, and it’s basically dependent on the number of particles in your bloodstream with apoB that are under 70 nanometers

• Because any lipoprotein under 70 nanometers in diameter with an apoB can penetrate the endothelium and get retained there

When it comes to these Mendelian studies, the reason you see such a powerful effect, it’s just a time effect

• Layne doesn’t know what the average age that somebody’s prescribed a statin, but it’s probably around midlife

Back to the investment analogy

• If you start investing from the day you were born, in 70 years, you’re going to see a massive difference due to compounding interest
• 40 years [of investing], you’ll see a big difference
• And while it may be a rudimentary comparison, these problems compound over time

Layne explains, “ What you’re doing with somebody who has high LDL, put them on a statin, you’re obviously pumping the brakes. But that truck still started rolling down the hill. Whereas with people who have lifelong low LDL, it never really got started. ”

Layne makes a point: plaque regression occurs when LDL-C is reduced

• There was a regression for every 1 mmol/L reduction in LDL-C Regardless of the variant, regardless of how the statins worked, independent of how LDL is lowered

• Regardless of the variant, regardless of how the statins worked, independent of how LDL is lowered

Converging lines of evidence

• It’s really hard to argue it’s pleiotropy or something else when it’s a very consistent effect and the dose is also very consistent

• There’s an argument to be made (not the argument they’re having today): if you look at all the literature of statins and you see reduction in mortality, that doesn’t mean that it’s because it’s lowering LDL It could be because it’s doing something else, it’s lowering inflammation, or it’s doing something else

• It could be because it’s doing something else, it’s lowering inflammation, or it’s doing something else

That’s a tough argument to make in light of all the MR, coupled with all the clinical trial data

• If that was the case, you would see a difference in the dose response You would see inconsistencies in the trials with similar designs

• You would see inconsistencies in the trials with similar designs

Layne uses a comparison to make his point

• He doesn’t believe that unprocessed red meat specifically is inherently carcinogenic And the reason is, even though you see it come up as carcinogenic in some of these cohort studies, the effect isn’t always consistent And when they control for overall diet quality, where people are eating enough fruits and vegetables, because again, if people eat more of one thing, they tend to eat less of another, when you control for some of the overall diet quality variables, you don’t really see a consistent association of red meat with cancer He could be wrong, but he’s not convinced

• But when it comes to dietary fiber’s effect on cardiovascular disease and cancer, there’s a dose response, and it is very consistent in the research literature In fact, he’s not really aware of hardly any study looking at dietary fiber and reducing the risk of cardiovascular disease, cancer, and mortality that doesn’t show a benefit If there’s a forest plot of all the studies out there, everything is going to be the protection side

• And the reason is, even though you see it come up as carcinogenic in some of these cohort studies, the effect isn’t always consistent

• And when they control for overall diet quality, where people are eating enough fruits and vegetables, because again, if people eat more of one thing, they tend to eat less of another, when you control for some of the overall diet quality variables, you don’t really see a consistent association of red meat with cancer

• He could be wrong, but he’s not convinced

• In fact, he’s not really aware of hardly any study looking at dietary fiber and reducing the risk of cardiovascular disease, cancer, and mortality that doesn’t show a benefit

• If there’s a forest plot of all the studies out there, everything is going to be the protection side

Layne feels very strongly because of the dose effect and because of the consistency of the results

The argument could be made, “ Well, it could be other things. ”

• Maybe it’s not the smoking that causes lung cancer, because we can’t really do randomized control trials on smoking, because it wouldn’t be ethical
• Layne’s response is, “ Well, then what do you think it’s doing? What would explain this very consistent effect? ”
• It typically ends up being an argument of, “ We don’t know for sure. ”

It reminds him of in graduate school

• He was giving a talk on leucine content of dietary protein sources
• And he did a dose response experiment with different dietary protein sources that varied in the leucine content
• It pretty much showed almost a perfect association between the amount of leucine in those protein sources, the ability of those protein sources to increase plasma leucine, and the effect on protein synthesis
• And there were other scientists in the audience who said, “ Well, but you can’t say that. These other protein sources, they have different other amino acids in them. It’s not just leucine. There’s other things that are changing. ”
• Layne replied, “ Okay, do you have anything else that would explain this? ”
• It was kind of like they didn’t really have much to say

Yes, Layne grants that it’s possible. It’s just highly improbable based on the data

Does the linoleic acid (omega-6) content of seed oils cause inflammation? [A: 1:13:45, V: 1:20:49]

What about the idea that if you’re eating a diet that’s high in polyunsaturated fats, (Seed oils to be specific), we acknowledge now you’re getting a lot of linoleic acid

• Well, you now have LDL particles ‒ maybe you have not only fewer of them, but they have more linoleic acid [18:2 (n-6)] in them, aka omega-6 fatty acids ]
• And linoleic acid can easily be converted to arachidonic acid [20:4(n−6)], which is inflammatory

Peter points out, “ We know that the single most important part of atherosclerosis is indeed the oxidative inflammatory process .”

• In fact, people don’t die because their coronary arteries just slowly get occluded
• They die because the body, in an effort to repair and respond to the oxidative damage in the artery walls, creates an immune response

So inflammation here is the game

Are you not concerned with the fact that a diet that is high in linoleic acid (which is the precursor to arachidonic acid) is going to lead to more inflammation, more oxidative LDL, and therefore ultimately more atherosclerosis, even if you see lower LDL cholesterol?

• This is going to be the fun part of this talk because Layne learned so much researching this stuff

• Let’s just take the broad 10,000-foot view first, and then we’ll zoom in on the mechanisms and talk about the lipid hypothesis Because it’s important to understand what it is and how this disease progresses so that then we can unpack all these side quests

• Because it’s important to understand what it is and how this disease progresses so that then we can unpack all these side quests

Layne takes what Peter said a step further

• Linoleic acid is a precursor to arachidonic acid, which is a precursor to prostaglandin production (which are inflammatory)

• Also, polyunsaturated fats are much more prone to oxidation than saturated fat We know oxidized LDL is more atherogenic on a per-particle basis And people who have MIs (people who have cardiovascular disease) have higher levels of oxidized LDL

• We know oxidized LDL is more atherogenic on a per-particle basis

• And people who have MIs (people who have cardiovascular disease) have higher levels of oxidized LDL

Layne addresses one of the core tenants of the argument that seed oils are harmful

When you substitute polyunsaturated fats for saturated fats, you are creating an unstable lipoprotein more prone to oxidation, and that is what is going to cause CVD to really progress

• From a 10,000-foot view, if that were true, what we would expect to see is people who eat more linoleic acid have higher rates of heart disease And what we see is the opposite

• There was a cohort study with around a million people from various different countries showing that people who had higher levels of linoleic acid intake had lower levels of cardiovascular disease [this is a meta-analysis of 18 studies that reported association between dietary linoleic acid intake (assessed by food-frequency questionnaires) and mortality outcomes]

• And what we see is the opposite

• [this is a meta-analysis of 18 studies that reported association between dietary linoleic acid intake (assessed by food-frequency questionnaires) and mortality outcomes]

Peter points out, “ These people are probably substituting linoleic acid because they’re healthier people to begin with. ”

• What Layne would say when it comes to healthy user bias is, “ What you typically see is no effect of something that should be bad, or it’ll be inconsistent in the research literature. ”

But it’s hard to argue converging lines of evidence

• If your position is that seed oils are uniquely deleterious, it’s hard to argue converging lines of evidence when one of the major things you really should see is: if people eat more linoleic acid, the effect should be so powerful
• If they’re the primary driver of cardiovascular disease (which is what some of these people claim), that effect should be powerful enough that even if they were doing other healthy behaviors, that you should still see something, and certainly not a protective effect

• To take it one step further, dietary recall studies are problematic Anybody who’s ever done some of these knows Layne doesn’t even remember what he ate yesterday

• Anybody who’s ever done some of these knows

• Layne doesn’t even remember what he ate yesterday

⇒ But one of the great things about the essential fatty acids you eat, is if you eat more of them, it shows in your tissues

• If you take an adipose tissue sample, if you take a blood sample, you’ll see more of that essential fatty acid incorporated into the phospholipid bilayer of your cells

And indeed, in studies where they look at tissue amounts of linoleic acid, they see the same thing: a reduction in risk of cardiovascular disease

• So this is from a 10,000-foot view
• To Layne, that’s a pretty damning thing right off the bat

Layne adds, “ If you’re going to argue that polyunsaturated fats are bad for you, we’ve got to argue that saturated fat is really bad for you. ”

• This where logical consistency is important
• If data existed showing people who ate more saturated fat had lower rates of cardiovascular disease, if you even thought about talking about saturated fat being bad, the people in the anti-seed oil camp or carnivore camp would lose their minds
• So it’s kind of like this picking and choosing of what data you want to talk about that fits
• We don’t see that

⇒ We also don’t see that when people eat more linoleic acid, they don’t produce more arachidonic acid

• That conversion apparently is already at saturation
• Just eating more linoleic acid doesn’t have a feed-forward effect ‒ you’re not actually getting more arachidonic acid production

Layne thinks the prostaglandin pathway is not something we really need to be too concerned with

• Because again, we’d expect to see increasing amounts of arachidonic acid

Does the linoleic acid (omega-6) content of seed oils increase oxidized LDL? [A: 1:19:30, V: 1:27:50]

The oxidized LDL argument is what Layne struggled with the most before he really dug into this

The lipid hypothesis and why it’s so important to understand where LDL gets oxidized

• The lipid hypothesis basically states that really any non-HDL cholesterol that is under 70 nanometers in diameter can penetrate the endothelium Which VLDLs can fall into that LDL obviously falls into that IDLs can fall into that depending on the IDL Basically, any lipoprotein that contains an apoB protein t Lipoprotein is under 70 nanometers in diameter can penetrating the endothelium and are getting into the intima, and this is concentration dependent This has been very well established in the mechanistic literature

• Which VLDLs can fall into that

• LDL obviously falls into that
• IDLs can fall into that depending on the IDL
• Basically, any lipoprotein that contains an apoB protein t
• Lipoprotein is under 70 nanometers in diameter can penetrating the endothelium and are getting into the intima, and this is concentration dependent
• This has been very well established in the mechanistic literature

Layne points out, “ Just penetrating the endothelium is not enough to cause progression of cardiovascular disease, because those molecules can come back out into the bloodstream. ”

• What can happen is that apoB protein can be enzymatically modified into a proteoglycan Basically, enzymes inside the intima can act on that apoB
• That enzymatic modification causes that LDL or VLDL or whatever particle it is to be retained inside the intima
• Once retained, that causes an oxidation
• Oxidation can increase on those lipoproteins
• That can attract macrophages (the immune response), and those macrophages begin to engulf some of these particles (LDL, VLDL, whatever)
• These particles start to clump together in a process called aggregation
• Macrophages infiltrate, inflammation trying to repair this
• But those macrophages engulf them, this produces foam cells

• And over time, the smooth muscle starts to thicken, and this is eventually what’s leading to this closing of the blood vessel

• Basically, enzymes inside the intima can act on that apoB

Oxidation is part of this process

One of the core components of this anti-seed oil hypothesis is that if you have lipoproteins that have more polyunsaturated fats, they’re more prone to oxidation

That is true, but we need to understand where oxidation is occurring

• The anti-seed oil people would have you believe that the oxidation occurs in the plasma, and that those oxidized LDLs (in the plasma) penetrate the endothelium and that causes the progression of cardiovascular disease

⇒ Less than 1% of LDL is oxidized in the plasma

• Because LDL is mostly cleared pretty quickly from the plasma It’s on the time course of hours (an hour or two)
• Once apoB is enzymatically modified [after penetrating the endothelium], that can be retained for weeks
• And in your plasma, you have antioxidants: vitamin E, vitamin C, beta-carotene Those stabilize polyunsaturated fats, and you don’t really have that much oxidation occurring in the plasma

• But in the microenvironment of once it penetrates the endothelium, gets inside the intima ‒ in that microenvironment, it’s thought that those antioxidants are not as available, and so the oxidation can begin to occur there

• It’s on the time course of hours (an hour or two)

• Those stabilize polyunsaturated fats, and you don’t really have that much oxidation occurring in the plasma

Oxidation of apoB particles occurs after they penetrate the endothelium

What’s the proof?

You’re saying that because plasma oxLDL is such a small fraction of total LDL concentration (say 1%), that means that we’re not getting a lot. But it could be a lot if that 1% disproportionately aggregates inside the sub-endothelial space.

You don’t need a lot of LDL particles to cross the endothelial barrier, right?

• Layne is glad Peter group up aggregation because that’s important here
• There can be positive and negative aspects that you activate for any nutrient you’re talking about
• So aggregation, once you have LDL inside the intima and you have this oxidation occurring, you have these things occurring Aggregation is how these cells clump together
• Lipoproteins that are enriched with polyunsaturated fats, per particle, they are more prone to oxidation, yes, inside the intima

• But keep in mind, what gets into the intima is concentration dependent

• Aggregation is how these cells clump together

Polyunsaturated fats overall lower the amount of LDL getting into the intima ‒ so you have less getting in, less being accessible for oxidation, since it occurs there mostly, not in the plasma

A bigger point is, there’s other aspects of these lipoproteins that make aggregation happen

• We talked about polyunsaturated fats increase membrane fluidity
• 1 – That actually helps with LDL receptor recognition ‒ it helps LDL get cleared, so you have less in the bloodstream
• 2 – The apoB molecule itself is less prone to enzymatic modification on LDLs that are enriched with polyunsaturated fats compared to saturated fat
• Further, LDL molecules [that] are enriched with saturated fat, their membranes are stiffer and more rigid because of the packing that we talked about Whereas those enriched with polyunsaturated fats are less rigid, they’re more fluid, and that has a big impact on aggregation
• There’s an enzyme called sphingomyelinase ‒ when it acts on a saturated fat-enriched LDL molecule inside the intima, it rapidly produces ceramides

• And those ceramides actually, for lack of a better term, can collapse these particles and cause them to clump together much more readily

• Whereas those enriched with polyunsaturated fats are less rigid, they’re more fluid, and that has a big impact on aggregation

All that to say, oxidation is part of the process of aggregation, but how much those aggregate is a more important factor than oxidation of PUFAs

• Because the oxidation is bad because it increases the aggregation of these molecules

Layne argues, “ The overall effect is, polyunsaturated fats decrease the number of particles that are getting into the intima. They also overall decrease them being retained there. The apoB is less prone to modification, and they are less prone to aggregation if they are retained there, compared to lipoproteins that are enriched with saturated fat. ”

Layne’s analogy to explain why lower LDL particle number outweighs higher per-particle oxidation risk when comparing polyunsaturated fats to saturated fats [A: 1:26:15, V: 1:36:05]

Layne’s analogy to understand this

• Think about apoB-containing particles in your bloodstream being a bonfire, and there’s a whole forest around it
• Now, the forest around it is your blood vessels
• And if you start a forest fire, that’s cardiovascular disease

Now, bonfires, they give off sparks

• Let’s say each spark is an LDL particle
• You don’t want the forest to catch on fire
• If you have polyunsaturated fat-enriched fatty acids, maybe each individual particle is a little bit more flammable or a little bit more prone to oxidation

But when you eat high polyunsaturated fats versus saturated fat, your bonfire shrinks quite a bit

• The amount of LDL in your bloodstream shrinks quite a bit
• You give off way less sparks, way less sparks hit the forest
• More accurately, some of those sparks are much more likely to bounce back into the fire compared to staying in the forest where they can start a fire
• Also, even if these particles get into the forest ‒ these sparks, they tend to not clump up and be prone to causing a forest fire They tend to scatter That’s polyunsaturated fat-enriched lipoproteins

• So even though on an individual level, the sparks may be a little bit more flammable, the bonfire for saturated fat is way bigger

• They tend to scatter

• That’s polyunsaturated fat-enriched lipoproteins

The bonfire for saturated fat casts off way more sparks, and those sparks are more likely to clump together and start a fire compared to the fire from polyunsaturated fats

The role of oxidized LDL in CVD: exploring differences in a diet high in polyunsaturated fat (seed oils) versus high in saturated fat [A: 1:28:00, V: 1:38:22]

And you’re rejecting my idea that, even though only a small fraction of LDLs are being oxidized in the periphery, that those ones don’t disproportionately concentrate in their ability to either make their way into the sub-endothelial space and get retained?

• Peter feels like we’re potentially overlooking that as a potential driver [of ASCVD]
• Because LDLs can traffic in and out of the sub-endothelial space

So the question then becomes, what are the factors that would increase retention, adhesion, oxidation, and then the cascading effects?

And do we not believe that an oxidized LDL versus a non-oxidized LDL would be more atherogenic?

⇒ On a per-particle basis, yes, an oxidized LDL is more atherogenic in the periphery/bloodstream

• Peter wants to make sure they would agree that potentially it would also be more atherogenic outside because it has a greater probability of becoming retained and remaining oxidized and inciting the inflammatory response
• Layne points out that it’s such a small amount that gets oxidized

Has anyone looked at a study or asked the question: If you are on a high polyunsaturated (or seed oil) diet versus a high saturated fat diet and you normalize for total LDL (which obviously will be quite different), do you have an equal percentage of oxidized LDL in the periphery?

• Let’s just assume you put somebody on a high saturated fat diet and someone else on a high seed oil diet (high PUFA)

• And let’s assume that the PUFA person (the seed oil person) has got an LDL cholesterol of 100 mg/dL, and the high saturated fat diet person is going to be at 200 mg/dL Let’s assume that’s concordant with apoB (2 times the particles, 2 times the concentration [in the person with the high saturated fat diet])

• Let’s assume that’s concordant with apoB (2 times the particles, 2 times the concentration [in the person with the high saturated fat diet])

Do we expect there to be the same ratio or delta or fraction that’s oxidized?

Or do we think that the person on the high seed oil is going to have disproportionately more oxLDL in the periphery (where you can measure it) and therefore is likely, even though their gradient is less favorable, they might get more particles in there?

• There was one randomized controlled trial with soybean oil that saw oxidized LDL in the periphery go up

• But it’s such a small number To make up numbers, normally maybe 0.5% is oxidized and now it’s 0.7, 0.8% [Oxidized LDL is reported in table 1 , comparing those on low linoleic acid (LA) diet to a high LA diet at follow-up: Low LA diet: LDL-C 129.1 mg/dL and oxidized LDL 69.1 U/L High LA diet: LDL-C 143.3 mg/dL and 67.9 U/L]

• To make up numbers, normally maybe 0.5% is oxidized and now it’s 0.7, 0.8%

• [Oxidized LDL is reported in table 1 , comparing those on low linoleic acid (LA) diet to a high LA diet at follow-up: Low LA diet: LDL-C 129.1 mg/dL and oxidized LDL 69.1 U/L High LA diet: LDL-C 143.3 mg/dL and 67.9 U/L]

• Low LA diet: LDL-C 129.1 mg/dL and oxidized LDL 69.1 U/L

• High LA diet: LDL-C 143.3 mg/dL and 67.9 U/L]

That’s such a small number compared to once a particle gets inside the intima

• Layne thinks he saw estimates about the rate of oxidation can be anywhere from 30-80% of those particles
• Layne had a long conversation with Tom Dayspring trying to understand this
• Because if oxidized LDL in the periphery was really driving cardiovascular disease, why have the studies where they give a bunch of antioxidants not decreased cardiovascular disease?
• Studies in rabbits, where they put oxidized LDL into their bloodstream and see atherogenesis progress, but when they do it with antioxidants, that doesn’t happen

That is because most oxidation is occurring inside the intima ‒ so your biggest lever to reduce your overall amount of oxidized LDL is to prevent as much from getting into the intima and retained as possible

• When we look at people who have higher levels of oxidized LDL, it’s typically a downstream effect of how much LDL got into their intima in the first place
• Because even after it gets into the intima, retained for a while, oxidized, some of those oxidized molecules can still come back out into the bloodstream

Do we know if the oxidized LDL that we measure in the periphery was oxidized in the periphery, or is escaped LDL that was oxidized in the endothelial space?

• Layne doesn’t know the exact answer to that question because that would be difficult [to study] You’d have to do some sort of metabolic tracer study You’d have to track it for a really long time, at least weeks to months, to see if that happens
• In people who undergo myocardial infarctions (where you have this kind of rupturing), they do see short-term oxidized LDL go way up Presumably, that’s because it’s coming out of the intima since there’s that rupture

• Layne is not sure if they have ever done a study to link it together with a stable isotope

• You’d have to do some sort of metabolic tracer study

• You’d have to track it for a really long time, at least weeks to months, to see if that happens

• Presumably, that’s because it’s coming out of the intima since there’s that rupture

The important point is: the less apoB that gets retained inside the intima, the less chance there is for overall oxidation to occur

• And aggregation is the endpoint that’s much more important

⇒ Oxidation is only “bad” because it’s more prone to aggregate

Layne explains, “ On balance, that saturated fat-enriched particles are more likely to aggregate than polyunsaturated-enriched particles due to the differences in membrane fluidity, as well as the ability for apoB to be modified, and because of the sphingomyelin content and ceramide content of the saturated fat-enriched molecules. ”

Let’s grant that those polyunsaturated fat, per particle, are more more prone to oxidation

• You still having to weigh it against the other things that progress cardiovascular disease
• And on balance, you’re still better off with the polyunsaturated fats because they do lower the amount that gets into the intima They lower the amount that gets retained, because it’s less likely that sapoB will get enzymatically modified

• And then those saturated-enriched particles, because they’re rigid, because they produce ceramides, they’re more likely to clump together and cause that fatty streak and that lesion

• They lower the amount that gets retained, because it’s less likely that sapoB will get enzymatically modified

Examining whether industrial processing and solvent extraction of seed oils—especially residual hexane—could plausibly cause long-term harm [A: 1:34:00, V: 1:45:37]

Industrial processing used to extract seed oils

• To get a bottle of corn oil or any of the other seed oils, you have to do a lot of industrial processing to refine these oils Heat these things up Use industrial-grade solvents to extract them
• It seems very likely that both of those processes can contribute to the negative impact of them, independent of what we might see if we were talking about something pure

• In other words, everything we’ve talked about so far is assuming a pure form of linoleic acid

• Heat these things up

• Use industrial-grade solvents to extract them

What if Peter is now saying, “ Yeah, but I’m going to heat, reheat, cool, bastardize this molecule, and oh, by the way, I’m not going to be able to get all the hexane off this molecule, and I needed to use hexane to extract it ”?

• We don’t like to talk about it, but food processing is big industrial chemistry

Layne responds, “ The actual processing of the seed oils removes oxidants and removes some impurities that are maybe negative. There are some things that do increase… we’ll talk about that. ”

The hexane itself

• To get the oils out of these seeds, you need to either do mechanical or chemical extraction

• Most people would say, “ Well, I’d rather have the mechanical extraction, ” because less chemicals But it is much more costly, the yield is lower, and economics is a thing

• But it is much more costly, the yield is lower, and economics is a thing

Peter asks, “ Is that an opportunity? Can you go into a grocery store and choose to have safflower oil that was mechanically extracted versus chemically extracted? ”

• Layne has no clue
• [cold-pressed safflower oil is available on Amazon ]

Let’s talk about why hexane is used

• They take these seeds, they wash them with hexane
• Why hexane? Hexane is a nonpolar solvent and you’re dealing with oil
• Polar solvents are much more popular because most things that we try to get are polar Most things like to interact with water ‒ it makes sense based on our biology and our biochemistry [ water is polar ]
• Oils are different ‒ oils you have to do very unique things to

• Hexane is a nonpolar solvent, so it will mix with these oils, and it has a relatively low boiling point, so you can evaporate it off

• Most things like to interact with water ‒ it makes sense based on our biology and our biochemistry

• [ water is polar ]

These seeds get washed with this hexane, it extracts the crude oil. So now you’ve got the oil mixed with hexane.

• Next they bubble steam vapor through the oil, and that evaporates off the hexane
• That the steam and the temperature is pretty low
• In order to really start getting oxidation of seed oils , it depends on the oil specifically, but most of them, you got to be well over 200 degrees Celsius, and you’ve got to do it for hours if we’re talking about in a large vat Layne read that soybean oil, if you heat it at 240 degrees Celsius for 3 hours, you will start to get 8% of the oil being oxidized But even after 5 hours, it’s still a pretty small percentage points of oxidation
• And this process of removing the hexane is on the order of 90 minutes (it’s a pretty short period of time)

• Layne believes hexane’s boiling point is 69 degrees Celsius ‒ you only got to heat it up to a point a little bit above that to start getting it off

• Layne read that soybean oil, if you heat it at 240 degrees Celsius for 3 hours, you will start to get 8% of the oil being oxidized

• But even after 5 hours, it’s still a pretty small percentage points of oxidation

Now, can you get all of it off?

• Well, as anybody who’s had basic chemistry, you know that no compound you synthesize is 100% pure You can get 99.999%, but you always have residual atoms in there You always have residual molecules in there

• You can get 99.999%, but you always have residual atoms in there

• You always have residual molecules in there

The question becomes, how much hexane is in the end product, and how much is required to cause harm?

• The amount of hexane in the end product, most seed oils are well under one part per 1,000,000
• In fact, a lot of them have non-detectable levels of hexane, which means there’s probably some in there, but the instruments we have to measure it simply aren’t sensitive enough to pick that out

Layne read that the amount of hexane in these oils is anywhere from 0.05-0.5 parts per million for most of these oils

⇒ The danger with hexane is not from ingestion. It’s actually from inhalation.

“ People who have had toxicity from hexane, it’s from inhaling it. ”‒ Layne Norton

• When you actually look at how much hexane you’d have to get Layne tried to look up hexane poisoning cases where somebody died: it doesn’t exist There’s a case where a guy literally drank straight hexane and basically got a tummy ache
• They’ve done rodent studies where they were able to get toxicity and death Basically just to get mild liver and neurotoxicity, it was 5,000 mg/kg of body weight

• Now, when we do human equivalent dosage, that dosage becomes smaller.

• Layne tried to look up hexane poisoning cases where somebody died: it doesn’t exist

• There’s a case where a guy literally drank straight hexane and basically got a tummy ache

• Basically just to get mild liver and neurotoxicity, it was 5,000 mg/kg of body weight

To put it in perspective as a bottom line, Layne did the calculation on this: what you would need to consume from hexane to even have mild side effects is 11,340 kg of oil at one time

• That was NOT to die but to have mild side effects

How do we know that accumulation of hexane or some other industrial solvent couldn’t be leading to a chronic process?

• We’ve just talked about how all the diseases we care about, whether it be neurodegenerative diseases or cancer or cardiovascular disease, these things don’t happen overnight
• They don’t happen in weeks, months, even years Many times, they happen in decades

• If we’re talking about a lifetime exposure to these things, how do we know that that’s not increasing our risk?

• Many times, they happen in decades

Layne points out, “ When we talk about lifetime exposure from something like LDL, that’s a relatively high concentration in our bloodstream, and it’s always present. You always have a baseline level of LDL. ”

• You don’t really have baseline levels of hexane in your bloodstream, at least not to any appreciable level
• And there is a process through your body where your body converts this to something innocuous and gets rid of it

Really, when it comes to things that don’t bioaccumulate, the question is: If we have some of this, is it in an amount that can be cleared quickly enough to where there’s not negative outcomes?

• This is the example Layne gave of the amount of oil you would need to consume to possibly get mild side effects [11,340 kg]

• Let’s just say your body couldn’t process this out: Who’s drinking 11,000 kg of oil in their lifetime? Probably almost no one

• Probably almost no one

Layne doesn’t see the possibility for hexane having a negative outcome for people

• Especially when you consider that it’s a very, very low concentration
• It doesn’t bioaccumulate, and your body has a way to process it out
• And the amounts that you get are incredibly small from these seed oils

The evolutionary and “ancestral diet” argument against seed oils [A: 1:40:45, V: 1:53:55]

• Let’s consider the fact that about 100 years ago, less than 3% of total food availability was made up of linoleic acid
• Today, that number is probably closer to 10%
• Layne read a book that was anti-seed oil because he was trying to understand the argument The figure they quoted was a 75x increase in linoleic acid over the last 150 years or so That’s more than what Peter got; that’s an enormous increase
• To make it even more stark, this means that we did not evolve in an environment where people were consuming seed oils in much quantity at all
• And yet today, some people are probably getting 10-15% of their total calories from seed oils

• Tissue levels of linoleic acid are up more than 100%

• The figure they quoted was a 75x increase in linoleic acid over the last 150 years or so

• That’s more than what Peter got; that’s an enormous increase

Isn’t there just sort of a first principles argument to be made here that says, how would that be a good thing? How would that be anything but negative?

• We’re starting to tie into the naturalistic argument

Layne makes the point again, “ You have to be logically symmetrical with how you approach these things. ”

• Even people who think they eat natural these days, the human diet now is not in any way, shape, or form what it used to be
• People will point out, “ Well, look at how these vegetables and fruits and plants have been modified. ”

• But we’ve done the exact same thing to our animals If you think having a fatty ribeye is an ancestral diet, it’s not Those cows are much different than they used to be; and it’s not wild game (these are very different things)

• If you think having a fatty ribeye is an ancestral diet, it’s not

• Those cows are much different than they used to be; and it’s not wild game (these are very different things)

Take that out of it for a moment and try to really zoom out and think about what is the purpose of biology

• The purpose of biology is to pass on your genetic material

• When it comes to survival and longevity, there’s a reason things start to kind of go downhill after age 40 or whatever: it’s because you’re past breeding age Evolution’s done with you You’ve done what you can do You’ve passed on your genetic material Hopefully you can stay around a little bit longer to raise the next generation, but you’ve done your job

• Evolution’s done with you

• You’ve done what you can do
• You’ve passed on your genetic material
• Hopefully you can stay around a little bit longer to raise the next generation, but you’ve done your job

The idea of longevity, living a very long life, that’s not really something that’s essential to a species surviving or even thriving

• Some of the most prevalent species on the planet don’t live very long

What matters is that they get to pass on their genetic material, that the favorable traits are passed on in the genetic material

• When it comes to cardiovascular disease, yes, rates of cardiovascular disease have gone up because you actually have the chance to get cardiovascular disease now because you’re not killed by a virus, or you’re not killed by a warring tribe, or you’re not killed by bacteria Even if we go back into the 1860s … a book Layne read, one of the things it said was: cardiovascular disease is a 20th century disease, it didn’t exist before that No, it existed: people just fell over dead, and nobody knew why And for the most part, people didn’t have much chance to get cardiovascular disease

• Even if we go back into the 1860s … a book Layne read, one of the things it said was: cardiovascular disease is a 20th century disease, it didn’t exist before that

• No, it existed: people just fell over dead, and nobody knew why
• And for the most part, people didn’t have much chance to get cardiovascular disease

Layne adds, “ Forgive me if I’m wrong, but you stated basically, if you live long enough, everyone at some point will get some form of cardiovascular disease. It’s just a time and exposure issue as we talked about. ”

• This massive increase in cardiovascular disease, Layne points out that everyone lives longer now He doesn’t know if it dipped recently, but he thinks we’re still right around the longest age lived on average
• The point being, even in the 1860s, if you live past age 10, I think your average life expectancy was still something like 55 to 60 years old; most people didn’t have the chance to get cardiovascular disease, or they died from something else
• [To put this in perspective,] this is back when we used to bleed people to try and treat them (get rid of the toxic blood)

• We didn’t have the tools to understand what we were looking at

• He doesn’t know if it dipped recently, but he thinks we’re still right around the longest age lived on average

This is one of those arguments that people, when they say, “ Well, everybody’s sicker now. We’re more unhealthy now .”

• That’s true
• But part of that is we just have had the chance to get unhealthy
• Evolutionarily, we’re taking one step out like we do with the MR studies

High LDL cholesterol is not ancestral

• If we look at the best estimate we have of what our ancestors did, which is the Hadza Which are basically a tribe that are essentially untouched by humanity We have studied them quite a bit because this is our best guess as to what ancestral was The foods they eat, it’s about as untouched as you can get

• Which are basically a tribe that are essentially untouched by humanity

• We have studied them quite a bit because this is our best guess as to what ancestral was
• The foods they eat, it’s about as untouched as you can get

⇒ If you look at the LDL of the Hadza who have almost non-existent rates of cardiovascular disease, they’re 50 to 70 mg/dL on average

• Layne thinks they only found one Hadza individual who was over 100 mg/dL LDL-C
• Again, we’re not talking about linoleic acid (obviously), but we do know that linoleic acid lowers LDL

Layne would argue that what the anti-seed oil people would suggest should be an ancestral diet is not supported by the evidence either

Regardless, there’s a reason naturalism has its own fallacy associated with it

• You can find a lot of things in nature that are horrific toxins
• You can find a lot of synthetic things that are quite good for you

• Layne thinks we tend to romanticize the past on every single level We romanticize past relationships We romanticize, “ 50 years ago, things were so much better. There was less crime. ” And then when you actually go pull up the FBI statistics, it’s not even close: crime is way lower now We romanticize the past and how things used to be

• We romanticize past relationships

• We romanticize, “ 50 years ago, things were so much better. There was less crime. ”
• And then when you actually go pull up the FBI statistics, it’s not even close: crime is way lower now
• We romanticize the past and how things used to be

Using what we think might be natural is NOT necessarily a good barometer for what is conducive to living the longest, healthiest life

• You’re getting the order reversed

• Mankind evolved in this environment where one of the reasons we were able to thrive is we were some of the most adaptable creatures out there Obviously smarter as well, but being so adaptable to our environment helped us greatly because we used to think, “ The strongest survive. ” And really, we know it’s actually the animals that are most adaptive survive

• Obviously smarter as well, but being so adaptable to our environment helped us greatly because we used to think, “ The strongest survive. ”

• And really, we know it’s actually the animals that are most adaptive survive

Layne puts it in perspective, “ When we look at all the data together, the question really shouldn’t be, did we evolve eating seed oils, or did we evolve eating this? The question should be, based on the best evidence we have, what is the overall net effect of these things? ”

Weighing concerns about industrial processing of seed oils against the totality of metabolic and cardiovascular evidence [A: 1:47:30, V: 2:02:15]

Back to how seed oils are processed

• Sodium hydroxide gets used, and there’s very little of that in the end product
• Activated clay gets used

• Basically, if we look at these things, the amounts that you would need to consume of this oil Assuming that pure sodium hydroxide stays in the end product And these are all theoretical negative effects Sodium hydroxide basically turns into soap and water when you have a chemical reaction

• Assuming that pure sodium hydroxide stays in the end product

• And these are all theoretical negative effects
• Sodium hydroxide basically turns into soap and water when you have a chemical reaction

But even if the amount you put in stayed in there until the end, you’d still need to eat 200-700 kg at one time of the oil

• When we look at the end product of the oil manufacturing process, there’s measure they can use (a peroxide status ) to look at how oxidized oil is in there

Oxidized oil goes down by a factor of about 5 to 10-fold [after processing]

• Another measurement of the aldehyde amount in the crude oil versus the actual refined oil is much lower
• Layne thinks that polymerized triglycerides do increase a little bit, and you have some formation of trans fats during this process (about 0.5% of the oil)

The amount of polymerized triglycerides and trans fats is very far below the threshold of what would cause negative effects

• Now, there’s no safe amounts of trans fats, but again, we’re taking this on balance

• If we have this refined oil with a very small amount of trans fat, but we know it lowers LDL so much, and then we have all the other mechanistic data (what we call the converging lines of evidence), the mechanism is clearly elucidated The cohort trials agree with it And then the studies that are not confounded by massive amounts of trans fats agree The Mendelian randomization trials agree

• The cohort trials agree with it

• And then the studies that are not confounded by massive amounts of trans fats agree
• The Mendelian randomization trials agree

“ One other point I would make is linoleic acid and polyunsaturated fats. When we trade them out in a one-to-one ratio for saturated fat, they either have neutral or positive effects on inflammation, liver fat, insulin sensitivity, and overall metabolic health. ”‒ Layne Norton

• That’s been very clearly shown in numerous studies
• Again, if we boil down to it, regardless of what we think was an ancestral diet (which we don’t even know if that’s necessarily the healthiest diet), on balance, if you’re going to make the argument that polyunsaturated fats are bad, you have to be okay with the argument that saturated fat is really, really bad

Practical considerations around dietary fats, cooking oils, and real-world food choices [A: 1:50:00, V: 2:05:17]

How do we land this plane for folks? If you’re out there, and you’re trying to make sense of social media

• Peter was out at a restaurant recently, and the menu made a point to say there were no seed oils used in the preparation of the food
• This is clearly a part of the popular zeitgeist
• Peter is pretty sure that the chef at that restaurant isn’t familiar with a single argument that has been made here today

“ We’re talking about an argument that has sort of transcended a scientific discussion. Seed oils are culturally persona non grata. The question is, is that warranted? ”‒ Peter Attia

For the individual listening to us, is there a precautionary principle?

• Layne would say, if you don’t want to consume seed oils, fine

But find something to displace the saturated fat in your diet with

• Leaner cuts of proteins of meats
• Lower saturated fat sources of protein

⇒ While monounsaturated fats don’t seem to have the same effect on LDL cholesterol as polyunsaturated fats, they do lower it when exchanged for saturated fats

• They do appear to be cardioprotective to a certain extent
• It doesn’t appear to be as cardioprotective as polyunsaturated fats

If you are concerned, and you’re not going to listen to logic that we’ve laid out here for 3 hours, then try and find some monounsaturated fats like olive oil, avocado oil

• There’s other sources of oils that you could use that are still relatively cardioprotective or beneficial
• [the table below compares the fatty acid content of many cooking oils]

Figure 11. Fatty acid composition of major fats and oils in the diet . Image from: Circulation 2017 [data on avocado oil added from Scientific Reports 2023 ]

Another point about oxidation of oils

• [When seed oils are processed,] it should be pointed out that this is unique in that when these oils are in a large volume: the rate of oxidation is low , even with heating All the heating and the processing of these oils is done under a vacuum, which means there’s no oxygen, which means virtually no chance for oxidation, even when heated

• In restaurants, however, when you are frying something , especially if you are frying in a thin layer of oil, the research shows going from around 1 cm to 5 cm oil: there’s a huge difference in how quickly oxidized and negative products will start to form If you are having oil that you are frying, refrying in over and over and over (certainly with a thin layer), within 20, 30 minutes, you can start to have significant amounts of these negative products accumulating And then if you have it in a vat that’s being heated all day, you’re probably going to have a significant amount of oxidized trans fats

• All the heating and the processing of these oils is done under a vacuum, which means there’s no oxygen, which means virtually no chance for oxidation, even when heated

• If you are having oil that you are frying, refrying in over and over and over (certainly with a thin layer), within 20, 30 minutes, you can start to have significant amounts of these negative products accumulating

• And then if you have it in a vat that’s being heated all day, you’re probably going to have a significant amount of oxidized trans fats

Would we be better off when it comes to heating oil using lard?

In other words, if I’m going to have french fries, should I at least have my french fries made in lard as opposed to polyunsaturated fat and seed oil?

Both are bad

• Let’s just say I understand that french fries are hypercaloric, and let’s just put that aside
• I’m going to have french fries sometimes
• When I do, do I want McDonald’s going back to lard, or do I want them sticking with whatever seed oil they’re using?

That’s a hard question to answer because you have competing mechanisms at play here

• And if we don’t have a human RCT looking at frying with one way versus frying with another way Looking at what happens with LDL and then the components of LDL Layne is not aware of any such study, but maybe there will be some in the future

• Looking at what happens with LDL and then the components of LDL

• Layne is not aware of any such study, but maybe there will be some in the future

But you’re answering this purely through an LDL lens. Is there any other reason to care?

• To Peter, it feels intuitively that when you heat up the saturated fat, you’re less likely to introduce more ROS and other things

And if I can control my LDL through other means pharmacologically, do I really care about my saturated fat consumption?

• The saturated fat is less prone to oxidation

• Again, when we’re looking at balance, what’s going to negatively affect cardiovascular disease the most? Layne doesn’t know What he would say is, if you’re going to have french fries, just have the french fries If you want to have it fried in lard, fine. Whatever. You can decide what you want to do.

• Layne doesn’t know

• What he would say is, if you’re going to have french fries, just have the french fries
• If you want to have it fried in lard, fine. Whatever. You can decide what you want to do.

“ You’re basically saying, ‘Don’t treat my fries in lard as health food. ’”‒ Peter Attia

• That’s a really important point to bring up

• People think food companies care about which foods you buy ‒ they just want you to buy The pivot to, “ We’re going to have tallow or lard (or whatever) ” Food companies don’t care; they’ll just make those then You don’t like red dye 40? We’ll take that out, and then we’ll market about how healthy our cereal is now

• The pivot to, “ We’re going to have tallow or lard (or whatever) ”

• Food companies don’t care; they’ll just make those then
• You don’t like red dye 40? We’ll take that out, and then we’ll market about how healthy our cereal is now

Food companies are marketing how healthy their french fries are

Layne puts this in perspective

• This really only becomes a problem if you’re consuming french fries pretty regularly
• Then we have to ask the question: Which is worse out of these two really bad options?
• But when you’re marketing as some kind of victory, that we’re using beef tallow or using lard or whatever it is as opposed to seed oils, if you’re not having this sort of communication, people, what they’re going to interpret that as is, “ These are actually healthier now. I can eat more of them. ”

When these topics are communicated in social media

• One thing Layne has realized (being so in-tune with the public and reading comments on social media over years and years and years) is, “I realize how, if I’m not extremely careful with how I word things, how misinterpreted it can get.”
• As communicators, a format like this podcast is great
• When you say, “ How do people navigate on social media? ” that’s where it’s really tough This is not social media It’s not 30 seconds of how do I hook somebody in? It’s not 5 reasons why seed oils are toxic That’s going to get a lot of attention And they’re going to list things that there is an element of truth to every single thing that they say, but they’re leaving out all of the context that we just put multiple hours into covering
• Layne hopes this podcast gets listened to by hundreds of millions of people, but the likelihood is pretty unlikely

• What’s more likely is somebody puts up a TikTok, and it goes viral, and 10 million people see it

• This is not social media

• It’s not 30 seconds of how do I hook somebody in?

• It’s not 5 reasons why seed oils are toxic That’s going to get a lot of attention And they’re going to list things that there is an element of truth to every single thing that they say, but they’re leaving out all of the context that we just put multiple hours into covering

• That’s going to get a lot of attention

• And they’re going to list things that there is an element of truth to every single thing that they say, but they’re leaving out all of the context that we just put multiple hours into covering

“ I think it’s very difficult to communicate this stuff with the public. To them, there are so many mixed messages. ”‒ Layne Norton

• Layne heard this all the time where people say, “ I don’t trust scientific research because one study says this, and one study says that, and they all contradict each other .”
• What he says to people is, “ Did you actually read the study, or are you just looking at the social media hot takes? ”
• Because his guess is you’re probably looking at the hot takes
• Going into those studies, when they seemingly have a weird outcome, almost any time he has seen a headline or a social media hot take on a study that doesn’t make sense When he reads the actual study, 99 times out of 100, he walks out going, “ I see why they found what they found. ” Either the way the control group was designed or the difference in levels between groups or whatever

• Layne’s Ph.D. advisor used to say, “ If I wanted to design a study to show no effect or the study to show an effect, easiest thing in the world ”

• When he reads the actual study, 99 times out of 100, he walks out going, “ I see why they found what they found. ”

• Either the way the control group was designed or the difference in levels between groups or whatever

This is why we look at converging lines of evidence. We look at: What does all the evidence state?

• What do the most high-quality, most rigorously controlled studies find?
• Yes, there are elements of truth to the criticisms of seed oils
• But on balance, when we look at these hard outcomes, when we look at what we are very sure we know to be true …

• One of the things to point out in science: you can never prove anything We can only disprove things But we can have relative degrees of confidence in various data

• We can only disprove things

• But we can have relative degrees of confidence in various data

Layne has a relatively high degree of confidence that apoB-containing lipoproteins are atherogenic based on everything he’s read (the converging lines of data, especially the Mendelian randomization studies, especially the statin trials)

• He feels relatively confident about it
• Could he change his mind? Sure, but it would take a lot of data over a long period of time

Back to Peter’s question: Why care about nutrition if you can just control this with statins?

• Peter clarifies, “ No, that was in the context of why care about the effect on LDL if you can pharmacologically regulate that anyway? And therefore, should we be focused on other negative health benefits in the case of the frying? That was really my question. ” He was asking specifically in the context of the frying oils
• Layne doesn’t have a great answer for that

• One of the other frustrations with the general public is when we point out limitations of studies, Layne and Peter know they’re not necessarily saying, “ Hey, these researchers are idiots. They did it wrong. They should have done it this way. ” Every study has limitations There is no unifying study that explains the entire universe

• He was asking specifically in the context of the frying oils

• Every study has limitations

• There is no unifying study that explains the entire universe

Pointing out limitations is not necessarily saying that a study is bad. It’s just pointing out: we’ve got to be careful how much interpretation we give to this, how broadly we interpret it.

• And yes, there are studies that are more well-designed, well-conducted, that have more statistical power, that have better measurements
• And scientists try to account for that when they look at: How much weight am I going to give to something?

At the end of the day, Layne’s recommendation when it comes to seed oils

• If you don’t want to consume them, okay

Try to limit your saturated fat, eat enough fiber, but outside of that, there’s so many bigger levers that you can pull for your health than just worrying about seed oils

• Layne put up a thing a while back He said the average calorie consumption in the United States is 3,500 calories per day, and the average physical activity is less than 20 minutes per day

• People are spending all this time worrying about what your fries get fried in

• He said the average calorie consumption in the United States is 3,500 calories per day, and the average physical activity is less than 20 minutes per day

We’re stepping over $100 bills picking up pennies

• Again, he’s not saying don’t worry about the little stuff, but you got to keep it in context of what really is driving so much disease in the developed countries A lot of it really is an energy toxicity issue

• A lot of it really is an energy toxicity issue

Comparing the health impact of seed oils with that of caloric intake and activity levels, and how to prioritize interventions [A: 2:00:15, V: 2:18:26]

If you’re looking at the macro trend of declining health in the last 50 years, you’re going to argue that caloric imbalance and activity levels are contributing how much more than increasing seed oils? A little bit more? A lot more? Medium more?

• Layne would say a lot more and here’s why
• There’s no direct comparisons
• Layne’s going out on a limb ‒ these are tenuous assertions by him, his opinion
• You look at the hazard ratios for mortality talking about obesity We’re talking about class 3 obesity Even with healthy blood markers, healthy obesity You’re not talking about 20%, 30% You’re talking about 80% to 200% You’re talking about massive increases in the risk of mortality [for those with class 3 obesity]
• When you’re talking about things like exercise: your strength, your lean mass, your activity levels Enormous predictors of how long you will live To the order of hundreds of percentage points of magnitude when it comes to VO 2 max, grip strength, overall strength
• Layne doesn’t think there’s anything unique about grip strength ‒ it’s just a proxy for overall strength

• That’s not to say, hey, if you can make adjustments that make a benefit overall … he doesn’t want to be a whataboutism person either, but just make sure that your time effort is being spent in your mind space (he likes what Peter has said about that) Your mind space is being spent on the things that will move the lever the biggest

• We’re talking about class 3 obesity

• Even with healthy blood markers, healthy obesity
• You’re not talking about 20%, 30%
• You’re talking about 80% to 200%

• You’re talking about massive increases in the risk of mortality [for those with class 3 obesity]

• Enormous predictors of how long you will live

• To the order of hundreds of percentage points of magnitude when it comes to VO 2 max, grip strength, overall strength

• Your mind space is being spent on the things that will move the lever the biggest

Layne thinks if you’re controlling your caloric intake and exercising regularly ‒ you don’t want to eat seed oils? Don’t eat them

He would also say, “ Try to limit your saturated fat as well, and try to make sure your LDL is under control. Get your apoB measured. These are things that are modifiable. If you can modify them, why not? ”

ApoB and LDL are NOT the only things that drive cardiovascular disease

• Blood pressure
• Cardiovascular fitness
• Insulin sensitivity
• Inflammation
• These things all matter
• For example, you could have high LDL, but every other factor is low, and your overall risk for cardiovascular disease might be low You could have high LDL, and you might live to 90, 100 years old (that can happen)

• But there’s also people who smoke for long periods of time and live to be old

• You could have high LDL, and you might live to 90, 100 years old (that can happen)

That doesn’t mean that you should smoke or that it’s not negative because statistics are just probabilities

• These are NOT hard, “ This is definitely going to happen. ”
• Of course, you can always find an individual to show a difference

All Layne is saying is that, everything else being equal, having your LDL lower is better

Peter’s final point

• Peter tends to agree with the point of view that Layne put forth
• He doesn’t think this was necessarily as interesting as it would’ve been in its original format where we could have done it as a genuine two-person point of view

Peter’s nomenclature on this is that we’re majoring in the minor and minoring in the major ‒ frankly, he doesn’t think it matters all that much

There’s another confounder with seed oils: they tend to show up in low-quality foods

• Therefore, if you make the decision to restrict your seed oils, you are probably doing a net benefit to yourself because you are simply going to eat less Oreos, less potato chips, less junky salad dressings and crappy sauces and things like that

The substitution effect will probably work in your favor, but you don’t have to be maniacal

• If, for example, when you’re making a salad, you prefer the taste of safflower oil or canola oil over olive oil, it doesn’t seem like you’re killing yourself by doing it based on the data
• And you probably don’t need to go to restaurants that are adamant that they exclude seed oils because if it’s a good restaurant, whether it uses seed oils or not, it’s probably using good ingredients otherwise, and you’re probably going to be just fine

Layne agrees, “ You make a great point about it’s probably more about what comes along for the ride ”

Layne adds another comparator: sugar intake

• People cut out sugar, and they say, “ Well, I felt better .”
• You cut out a bunch of junk food

• But then you have people who get maniacal with it and start cutting out fruit because fruit has sugar Biochemically, it’s basically the same thing once it gets in your body Now, that’s a bridge too far

• Biochemically, it’s basically the same thing once it gets in your body

• Now, that’s a bridge too far

Layne would argue the same thing, that most people who are experiencing negative effects from seed oils just have an overall probably low-quality diet

• This isn’t a problem for people who are going to cook with some canola oil today and maybe use a seed oil-based salad dressing here and there
• What is happening is people are eating a lot of potato chips, french fries, whatnot, and then the kind of anti-establishment people come out, and they say, “ Look at how much our seed oil intake has increased. And we did what the government told us to. ”

Peter’s only wish to come from this podcast (in addition to public education) is if you’re a restaurateur, and you’re listening to this, please take the “no seed oils used” off your menu

• It insults Peter and anybody who’s been patient enough to listen to this episode

Selected Links / Related Material

Episodes of The Drive with Layne Norton :

• #235 ‒ Training principles for mass and strength, changing views on nutrition, creatine supplementation, and more | Layne Norton, Ph.D. (December 19, 2022)
• #205 – Energy balance, nutrition, & building muscle | Layne Norton, Ph.D. (Pt.2) (May 2 2022)
• #163 – Layne Norton, Ph.D.: Building muscle, losing fat, and the importance of resistance training (May 24, 2021)

Minnesota Coronary Experiment (MCE) : [14:30]

• Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73) | BMJ (C Ramsden et al. 2016) | [14:340, 49:00]
• Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey | Arteriosclerosis (I Frantz et al. 1989) | [1:48:15, 2:09:30]

Sydney Diet Heart Study (SDHS) : [28:15, 41:00]

• Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis | BMJ (C Ramsden et al. 2013)
• Low fat, low cholesterol diet in secondary prevention of coronary heart disease | Advances in Experimental Medicine and Biology (J Woodhill et al. 1978)

Cochrane reviews on reducing intake of saturated fat and the impact on risk of cardiovascular disease : [35:00, 53:45]

• Reduction in saturated fat intake for cardiovascular disease | The Cochrane Database of Systematic Reviews (L Hooper et al. 2020)
• Reduced or modified dietary fat for preventing cardiovascular disease | The Cochrane Database of Systematic Reviews (L Hooper et al. 2011)

Ramsden’s review of trials replacing saturated fat with polyunsaturated fat and effect on cardiovascular disease : [34:15, 54:00]

• Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73) | BMJ (C Ramsden et al. 2016)
• n-6 fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials | British Journal of Nutrition (C Ramsden et al. 2010)

Ramsden meta-analysis of interventions replacing dietary saturated fat with polyunsaturated fat found little benefit (figure 7) : Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73) | BMJ (C Ramsden et al. 2016) | [34:15, 53:45]

Rose Corn Oil Trial : Corn Oil in Treatment of Ischaemic Heart Disease | BMJ (G Rose, W Thomson, R Williams 1965) | [36:30]

PREDIMED Study : [37:30]

• (reanalysis) Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts | (R. Estruch et al. 2018)
• The Mediterranean Diet, its Components, and Cardiovascular Disease | The American Journal of Medicine (R Widmer et al. 2014)

2017 Meta-analysis of 4 studies not confounded by trans fats where saturated fat was replaced with polyunsaturated fat (figure 2) : Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association | Circulation (F Sacks et al. 2017) | [39:30, 48:45, 53:30]

Los Angeles Veterans Administration trial of a lower cholesterol, higher linoleic acid diet : [41:45]

• A Controlled Clinical Trial of a Diet High in Unsaturated Fat in Preventing Complications of Atherosclerosis | Circulation (S Dayton et al. 1969) pdf
• Discussed extensively in: Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association | Circulation (F Sacks et al. 2017)

Oslo Diet-Heart Study : [43:15]

• The Oslo Diet-Heart Study : Eleven-Year Report | Circulation (P Leren 1970)
• Lifelong benefits on myocardial infarction mortality: 40-year follow-up of the randomized Oslo diet and antismoking study | Journal of Internal Medicine (I Holme, K Retterstol, K Norum, I Hjermann 2016)
• Discussed extensively in: Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association | Circulation (F Sacks et al. 2017)

Finnish Mental Hospital Study : [43:15]

• Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study | International Journal of Epidemiology (O Turpeinen et al. 1979)
• Discussed extensively in: Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association | Circulation (F Sacks et al. 2017)

STARS study : Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS) | The Lancet (G Watts et al. 1992) | [55:30]

First big Mendelian randomization study with cholesterol, Ference 2012 : Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis | Journal of the American College of Cardiology (B Ference et al. 2012) | [1:03:30]

People with higher linoleic acid intake have lower levels of CVD : Dietary intake and biomarkers of linoleic acid and mortality: systematic review and meta-analysis of prospective cohort studies | American Journal of Clinical Nutrition (J Li et al. 2020) | [1:16:30]

oxLDL increased in a low-fat diet : Impact of 8-week linoleic acid intake in soy oil on Lp-PLA 2 activity in healthy adults | Nutrition & Metabolism (M Kim et al. 2017) | [1:30:15]

People Mentioned

• Christopher Ramsden (Principle Investigator and Chief of the the Lipid Peroxidation Unit within the Laboratory of Clinical Investigation in the National Institute on Aging (NIA) and a CAPT in the Commissioned Corps of the U.S. Public Health Service) [24:30]
• Tom Dayspring (Fellow of both the American College of Physicians and the National Lipid Association, certified in internal medicine and clinical lipidology, cardiovascular/lipidology educator) [1:05:45, 1:30:45]

Layne Norton earned his B.S. in Biochemistry at Eckerd College and a Ph.D. in Nutritional Sciences at the University of Illinois working with Dr. Donald Layman. Layne founded BioLayne to provide science-based coaching. He is a natural pro bodybuilder, professional powerlifter, and a physique coach. He has won numerous bodybuilding and powerlifting competitions and currently holds the world record for the IPF 93 kg class squat (303 kg, 668 lbs). Layne finished 1st at the 2022 IPF World Masters Powerlifting Championships in a drug-free tested division. He is the co-author of several books, including Fat Loss Forever: How to Lose Fat and KEEP It Off , as well as several research publications. [ BioLayne.com ]

Website: Biolayne

Podcast: Physique Science Radio

X: @BioLayne

Facebook: Layne Norton

Instagram: @Biolayne