Hey everyone, welcome to the Drive

Podcast. I'm your host, Peter Aia.

[music]

Lane, thank you for making another trip

out to Austin.

>> Always pleasure to be here.

>> Okay, this is going to be a kind of a

different episode, so I'm going to set

this up um and we're going to give it a

shot. So, originally, we were planning

to do this as our inaugural uh debate

series. People have heard me talk a

little bit about how I desired to do a

debate series, which was uh to have two

people on who had um opposing views on a

topic. Um but I've been very vocal of my

criticism of debates on podcasts in that

I think that they are um

I think I could charitably call them

useless. um which is to say that anybody

can sort of say anything and um in real

time it's almost impossible to verify

what people are saying. Um and it's not

to say that people are necessarily

lying. I think it's that people are

maybe taking liberal interpretations or

not interpreting things the same way.

And you know it would be much more

valuable if uh everybody could be

looking at the same thing. So anyway, we

had this whole idea where we were going

to have two people that were going to

presubmit all of their evidence to me

and my analysts. So 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, uh people could only

reference things that were presubmitted.

In other words, we're going to make it

feel a lot like a courtroom. And I say

that in the through the lens of we have

a process in court where you have

discovery and the opposing lawyers have

to submit everything. So, this idea made

a ton of sense. Um,

my 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, which is seed

oils.

How long did we spend on this? about

nine months, a year maybe.

>> Oh, I think it was over a year we

started talking.

>> So, so we identified you 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 uh

nutritional risk. Um, and for reasons I

honestly don't even remember, that

individual at some point just decided

they didn't want to do it. Um, I think

there was some concern that my personal

view leaned more towards the side that

seed oils are probably not that harmful.

I always am pretty vocal about my biases

and I was very vocal about stating I I

don't really see something here, guys.

Um, but I was also clear to point out

that I'm simply the judge and not the

jury and ultimately the jury decides and

they're going to also decide if I can be

a fair judge. Nevertheless, the person

decided not to do this. And that left us

sort of asking the question, well, it is

still a topic that people care about and

therefore we view ourselves on this

podcast as kind of the authority about

going really deep on topics that matter.

So, we thought we would do it anyway.

However, we are going to do this a

little different than a normal podcast.

Instead of just a regular interview, I

am actually going to make my best

attempt to steelman the case for the

other guest who is not here. Because

again, in the process of whatever we

spent a year together, I did come to

better understand the arguments for why

a person would think uh seed oils are

uniquely harmful as a class of of fatty

acids. So, with all of that said, would

you like to add anything before we jump

into this?

>> No, I I think that

when speaking to bias, I think it's

important to point out that everyone has

bias. Everyone has personal beliefs they

developed and um that is just a human

characteristic. There's no way to get

rid of that. I have my own personal

beliefs, but I what I will say is I'm

very upfront about my biases. Uh if

we're on a topic where I have a

different opinion than perhaps the

consensus of the literature or some

other experts who I do consider to be

good evidence-based experts and I have a

different opinion, I 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. Um, and I

think that that's about as best as you

can do. And and one of the things I

told a friend the other day was, you

know, people think that like funding or

money is by far the biggest driver of uh

people essentially like not sticking

with the evidence. And I would say that

in some cases that's true. But I think

that personal beliefs are actually just

as powerful, if not more powerful. I

mean, look at how many people spend

hours online arguing over politics that

get zero money from arguing about

politics. And I just think that the

current day and age with social media,

with clickbait, that

things are very information siloed and

there can be a lot of talking past each

other. And 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. And just

to be clear upfront, um, if anybody has

a bias against, uh, seed oils, it

probably should be me. I came from a lab

that was very much in line with the

lower carb way of thinking of that maybe

saturated fat isn't as bad as we

thought, maybe LDL doesn't matter. And I

got into graduate school in 2004 when

that was a pretty popular idea that

okay, well maybe it's not just saturated

fat, LDL, maybe it's the particle size,

the oxidation status, LDL to HDL ratio.

And what I'll tell you is I said those

things for a long time and eventually

changed my mind with the evidence. And

just to point out one more thing, my

research was funded. I got money from

the National Dairy Council, the National

Cattleman's Beef Association, and the

Egg Board. So, and I'm not I'm painting

with a broad brush, but I would say most

of the anti- the very very rigorous

anti-seed oil people tend to air on the

side of either low carb, animal-based,

or carnivore.

And if anybody has a bias towards high

high quality animal protein, it's me.

So, I just want to start there. um and

say that

I think 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 and what I

will say is the scientific method

is perfect it is a perfect method but it

is done by people who are not and 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

you'll probably hear me talk about a lot

today because I do think there's 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.

And so I just want to put all that out

there because

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. And so

that is why it's important I think

people like what you and I do which is

trying to kind of cut through that noise

that other people who have aren't

equipped to read research simply can't

do.

>> I'm going to tell you what I've heard as

the four main arguments for why

seed oils should be viewed as

potentially harmful. And we're going to

kind of talk through these um in in not

necessarily in this order, but I'm gonna

I'm gonna kind of go through these. So,

one comes down to um the mortality

literature on some of the large RCTs.

We're going to talk about two 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, 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 ASCBD. The question became, hey, can

we substitute something else for

saturated fat? This is kind of think

margarine versus butter. Um to lower

cholesterol. So these a couple of these

studies were done and these studies

while lowering cholesterol did not lower

mortality. So we're going to we're going

to talk about that. We're then going to

get into some really mechanistic stuff

and talk about LDL through the lens of

oxidation. And you you you alluded to

this a little bit with your uh your your

your change in thinking around LDL

particle size, but this goes kind of a

step further than just particle size.

and we get into the the really granular

biochemistry of what is happening to to

an LDL particle that renders it

pathologic versus maybe not so much.

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. And in other words, is there

something about the process of making a

seed oil commercially that introduces

something that's harmful as a byproduct?

And then finally, we're going to talk

about this from maybe an evolutionary or

first principles perspective, which is

look, you know, if we were having this

discussion 100 years ago, there were no

seed oils and people were a lot

healthier. So maybe, you know, the

introduction of seed oils should be

viewed as potentially problematic.

[snorts] Um, so let's let's let's kind

of start with the Minnesota Heart Study.

Okay, so I've talked about the Minnesota

Heart Study before. Um, this is a study

that took place in the 1960s.

I believe it ran 7 yearsish.

Um, 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. So these

were mentally institutionalized

patients. They were inatients in a

hospital and the experimental design was

quite elegant which is the subjects were

divided into two groups. One group was

uh 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. Now I believe it

was mostly linoleic acid that made the

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 of

course then be the canas, the

safflowers, sunflowers, things like

that.

>> Yeah, I think in MCE it was um mostly

corn oil and then margarine.

>> Now, here's what was really interesting,

Lane. This study completed in I believe

1973. So, I think it ran from 66 to 73.

I think that was the seven years of the

study.

And

the study found that indeed uh the total

cholesterol of the patients on the

higher polyunsaturated fat diet again

this was isocaloric. So these patient it

wasn't like we were playing tricks with

calories and no no this was they were

getting the same amounts of calories

from the macros even it was just we were

substituting saturated fat for

plunsaturated fat. The patients on the

lowsaturated fat diet had a significant

reduction in total cholesterol at the

time. That was the only tool you had at

your disposal. You didn't have you

didn't even have LDL cholesterol, let

alone Apo B 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,

I believe, 13 years. Um, so the

Minnesota Heart Experiment or the

coronary Minnesota, I forget, there were

several different names for it, but this

this study was not published until the

80s. Um, but

as as someone trying to make the case

that there's got to be something wrong

with polyunsaturated fats, how could we

otherwise explain that that there was no

improvement in mortality despite the

fact that total cholesterol went down?

And and total cholesterol went down

quite a bit. Again, I don't we don't

have the data to say if it was

astrogenic 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. So, so let's maybe

start with that study and and and say,

doesn't that at least suggest that there

could be something nefarious about um

the substitution of lard to uh to those

polyunsaturated fats?

>> Yeah. Yeah. And 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.

And I want to be really clear 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. And so it's

always easy to Monday Monday morning

quarterback these things. Uh but I think

it was a very well-designed study.

The kind of big takeaway was for every I

can't remember exactly the number. I

think it was a 30 milligram per

deciliter decrease in cholesterol total

cholesterol that there was like around a

20% increase in mortality.

>> 22%.

>> Yeah.

So the biggest thing that I'm going to

say right off the bat that really

confounds all these outcomes is the

inclusion of trans fats. So the

polyunsaturated fat group, they were

getting quite a bit of their

polyunsaturated fats from margarine.

Margarine at the time was around like 25

to 40% trans fats. And we know that

trans fats are absolutely aogenic. Can

we pause for a minute? Um I maybe should

have done this earlier.

Um, 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. Um,

let's go one and one just to speed this

up. A saturated fat is a hydrocarbon

where every bond is saturated. That

means there are no double bonds. Um so

every carbon is attached to another

carbon but it has two hydrogens on it.

They can swiggle around and that gives

it unique properties. So one of the

properties of a saturated fat is it is

more likely to be solid at room

temperature.

Um, 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. Um, but that's

what a saturated fat is. So then tell us

what a monounsaturated fat is.

>> Uh, so a monounsaturated fat means there

is one double bond in the fatty acid

chain. And 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 don't they're not just

like individual fats. They're arranged

into kind of what are called myels 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, of course, is that

if it wasn't that way, they could never

travel around our body because to travel

through the the uh 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.

>> Correct? And then so you have all these

tails kind of pointing towards the

center. And then if you think about even

on cells, the the phosphoipid billayer,

the tails are pointing towards each

other.

And when you for natural unsaturated

fats like monounsaturated fats or

polyunsaturated fats,

most of those double bonds are what are

called cy double bonds. And I don't want

to get too far into the biochemistry of

it, but essentially if you have a cy

double bond, it puts a kink in the fatty

acid tail. If you have a trans double

bond, it doesn't change it. It still

essentially looks like a fat or

saturated fat in terms of structure

besides the double bond.

>> And it's actually easy to picture that,

right? So, um,

>> I almost wish I brought a a chalkboard

to draw on, but anybody who's taken a

biochemistry class will remember this,

but a cis double bond forces the two

carbons up or down, but they are on the

same side of the double bond. So, that's

the real kink.

>> Whereas a trans double bond, you have a

carbon here, a double bond, and then the

other carbon is here. That stays much

straighter than if you force the kink up

or down. And as we're going to talk

about later when it comes to like LDL

aggregation and whatnot, the actual

membrane fluidity is actually very

important when it comes to the

progression of cardiovascular disease.

So the the membranes and the fatty acid

composition of these lipoproteins

actually becomes very important and it's

very important to keep that in mind. 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 aogenic effect.

>> Yeah. And the aogenic effect of trans

fats was so significant that they have

effectively been banned by the FDA.

>> Right.

It's also important to understand how

they came about

when the

uh when the belief and realization

around saturated fats which have been

you know I think probably overdemonized

historically you know uh

when that took place food makers looked

for a substitute right and you brought

up an interesting point a moment ago

which is if 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. So it's not like

butter is just saturated fat. Um, in

fact, it's probably made up of mono and

polyunsaturated fats if my memory serves

correctly, as is even the fattiest

ribeye.

>> And actually has some natural trans fats

in it as well.

>> Low low amounts. So, but if you're

trying to, you know, 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, you and you and and

we were going to deprive you of

saturated fat. We had to put in

something that at least behaved like

saturated fat. So, when that margarine

that was made up of high amounts, 25% is

really high. 25% of that is trans fats.

Hey, you you initially 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.

>> Yep. And and part of that is likely

because and again as we'll talk about in

a little bit um 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. And that

is actually very critical in terms of

particle recognition by the LDL receptor

and also aggregation, but we'll get into

that a little bit later. 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.

>> So do we know how much trans fats was

consumed by the low saturated fat group

in the Minnesota coronary experiment?

>> So as far as I understand, we don't have

the specific numbers. We just know that

it was likely a significant portion of

the polyunsaturated fat they ate based

on they essentially got a lot of their

polyunsaturated fats from either corn

oil or margarine. Now,

we don't, as far as I know, we don't

know the exact composition of each. I

wasn't able to find

>> Chris Ramston at the NIH, who I believe

did a re-evaluation of this, was he able

ever to identify the raw data on that?

>> I'm not sure to be quite honest with

you, I didn't see it anywhere. And so

maybe if uh people smarter than me are

are watching or familiar with it, I

would love to know if they did. I I do

know like there's some other studies

where um they kind of looked at dietary

adherence by looking at LDL in the blood

or looking at like linoleic acid

incorporation into lipoproteins. But as

far as this specific study, I I don't

think they did. And again, like this, we

have to remember as you said, this study

started in 1966. So, this was 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, um, they had no reason to suspect

that these trans fats were going to be

uniquely delarious.

And the other thing that's I think

important to point out, two things are

important to point out with the MCE.

The second is that during the time that

this study was going on, I think uh laws

changed to essentially where people who

were in psychiatric wards could just

check themselves out. And so many of the

people in this study were not

continuous. In fact, I it kind of threw

a wrench in the researchers protocol

because I think they had originally

planned that these people were going to

be continuously housed in these uh

psychiatric wards for the duration of

the study. So now you've got another

confounder where okay, they're 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.

Now what I would say if I was going to

make a counter-argument to that is well

this is why randomization is important

because the likelihood is okay if

they're changing what they're eating

while they're out

>> it should affect both groups equally.

>> Yeah. It's probably equally distributed.

Yeah. So I think that's a a far less

significant criticism compared to the

inclusion of trans fats. And then I

think the other thing that's important

to point out is

it's really hard to do very long RCTs in

humans. And 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. And so, Peter,

for example, what I like to compare it

to is investing. If you and I um start

investing 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. I mean statistically in

terms of significance probably won't be

a significant difference but if we look

40 years out there's going to be a major

difference and it's important to

understand and when I we get into the

mechanisms of LDL cholesterol this is a

total lifetime exposure risk and so 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 they didn't know any of this

stuff back then they didn't have those

tools available to them and so I think

it's also important to point out when

you're looking at these studies where I

think the average follow-up time in this

study was about 1 to two 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 end

points. 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 the corn oil trial.

>> Yeah, let's let's talk about that trial

because I was going to say the to get

around your point about duration, the

Sydney heart study, which is the one

you're referring to,

>> attempts to solve this. So, it was a

much smaller study than the Minnesota

coronary experiment, which had nearly

9,000 subjects. This one had um a little

under 500 subjects, but they were

selected to be very high risk. So, 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. Right.

>> Right. And remember, back at the time of

the Sydney Heart Study, you were most

likely to die from a heart attack. So,

you're you're already pre-selected to be

pretty lucky. You 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 PUFFA intake, that's

polyunsaturated fatty intake, 6%.

So the instruction set for the

intervention group, they were

randomized. The the the low saturated

fat group was instructed to increase

PUFA to 15% and reduce saturated fat to

10%. Now that's not draconian. Um but of

course these people were not in you know

they were not housed right. Um the

manner in which they were doing this was

basically through safflower oil and

safflower margarine.

Um, and let's talk about what happened.

So,

in this study, there was no difference.

I'm pardon pardon me. There was a higher

mortality in the control group. Uh,

meaning the group that was that stayed

on the saturated fat. Uh, and it was 32%

versus 20% at 3 years, which again, it's

good to I mean, good in a bad way. It's

good that you can see a high mortality

in three years because you've started

with such a sick group.

Um so again this would at least suggest

that that group that lowered saturated

fat raised polyunsaturated fat they had

a higher mortality risk um in a short

period of time. Again it's could it

could suggest that there's something

wrong with the safflower oil.

>> Yeah and important to point out a lot of

anti-seed oil people will specifically

talk about linoleic acid and safflower

oil is very high in linoleic acid. So

the strengths of this study were it was

longer like you talked about and these

were people who already had

cardiovascular disease. So the

likelihood that you could see more hard

end points 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. They've already had a

lifetime of accumulation of plaque. And

so how much difference can you really

make on this truck that's already

rolling down the hill? Right?

Again, the main criticism of the study,

which I I think is quite frankly the

biggest confounder with these trials, is

the inclusion of trans fats. So they

again there was a most I don't want to

say most a large portion of what they

consumed was safflower based margarine

which at the time again was 25 to 40%

trans fats.

So again, it's really difficult to pick

out is this a polyunsaturated

fat problem or is this specifically a

trans fat problem?

And I would say and I will argue that

the human randomized control trials that

were not confounded by trans fats were

actually probably better designed

studies and better powered.

But I acknowledge that, okay, we're

seeing some of these trials where higher

cholesterol in the blood is actually

associated with lower mortality.

One other thing it's important to point

out is really sick people

sometimes you can have what's called

reverse causality with especially with

cholesterol. And let me explain. 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 kind of just

overall poor health. That 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. And so 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. But

even though the Sydney heart health

study was, as you said, a

longer study, it was lower number of

people and even though they'd had a

cardiovascular event, the overall number

of deaths was still pretty low. I

believe I think it was somewhere around

I think it was under 100.

>> Yeah. Total deaths were pretty low. 37

>> Oh yeah.

>> in the treatment group, 28 in the

control.

>> Right. So again, and that's a situation

where 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 have swung the significance. And

if you look at the confidence interval,

[sighs]

the confidence interval nearly crossed

the one. And when a confidence interval

crosses the one,

>> now was that in the original analysis? I

know in the Ramsden reanalysis,

it was 1.03 to 2.8. Was that what was

originally published?

>> I actually don't recall if that was what

was

>> or maybe that was the original one.

>> Um actually, no, I'm sorry. That that

was the original published, I believe.

>> Yeah. And so like you know that

confidence interval is relatively wide

um considering

what the the risk it's showing.

And so

again I I don't want to because of

course the studies that support my

contention there's limitations on those

as well. But I think that again the most

powerful thing if I was going to pick it

out it's really the inclusion of the

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.

>> Okay. So

again I'm playing the role of I believe

seed oils are bad. So the biggest

contention we would have if we go

through the RCTs

is because these RCTs were done at a

time when trans fats were the

substitution fat dour. Um

I don'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 you wouldn't have an

argument. Correct. Is there any other

argument you've got besides trans fats

on this?

>> Uh I think the relatively short duration

is is another thing because if we talk

about some of the other studies where it

wasn't confounded by trans fats, some of

those were longer. Um, and the overall

actually I wouldn't say the overall low

number of deaths. Let let me put it a

different way. Let's let's say that

let's just say that we take the trans

fats out of it. Let's do that. And this

was in the Rams and 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?

>> Yep. Yep. So if we include so there's

Ramsden also did an analysis I believe

where some of the trials that showed a

benefit to PUFA were confounded by the

fact that there was omega-3s included in

them. Now I 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.

So he took those out and then showed,

okay, when we take out omega-3s, we see

an increased risk. But of course, that

still includes the trans fats

confounders.

So 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. And so what I would

say if the the statement is seed oils

are uniquely delletterious 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 I call it 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. Right? Otherwise, we just got to

find the ones that take both of them

out.

And so, in that case, the net effect is

still no harm.

And so, that would be

>> what's the other confounding variable?

The EPA and DHA.

>> Correct. So, we can if you want to start

talking about some of these other

studies, I will touch on the the one

other study they cite is the Rose corn

oil trial, which I quite frankly I don't

know what to make of it because it was

only like I think like 70 people in the

entire thing. Yeah, it was um 26 people

in a control group, 26 people on an

olive oil uh group, and 28 people in a

corn oil group. So again, this is a

2-year study. This was in people with

significant uh cardiovascular disease.

So the people in the control group,

business as usual, um three of those

people died.

Five people died in the olive oil group,

but eight people died in the corn oil

group.

>> Um

now that sorry, that was total deaths

for what it's worth. Cardiac deaths, one

in the control group, three in the olive

oil group, six in the corn oil uh group.

Now again the confidence intervals on

this were very large because the sample

size was very small.

>> Um

this one is a bit challenging because

the participants were given their oils.

This is a lot like um you could think of

this as kind of a an early version of

the predimed study where it was a freel

study but the participants were given

olive oil when they were in the olive

oil group. There were three groups

right? There was a low fat and then

there was high MUFA high monounsaturated

fat through olive oil and you were given

a bottle of olive oil every week or

through nuts and you were given the nuts

every week. So here it was a free living

study but you were given your corn oil

or you were given your olive oil but

other than that we don't have dietary

recall.

>> Now the the benefit not confounded by

trans fats. There was no confounding

with trans fats here. So that would be

you know a positive but I think you know

the first thing I would say is when it

and you I think you said this the

cardiovascular disease deaths were 1

three and six.

>> Yes.

>> I

I don't know what to make of that. But

those are such small numbers 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. And let's just take the olive

oil group. Even people who are anti-seed

oil typically acknowledge that olive oil

is heart healthy. Well, you had three

times the deaths from cardiovascular

disease in the olive oil group compared

to the control group. And so again, it

just it doesn't fit with the evidence we

have and it's so small and like you said

the confidence intervals I mean if we

want to talk about the confidence

interval being wide of 1.03

to like yeah to 2.8 as being wide the

confidence interval in this I believe

was like6

to uh 37.

>> I mean

>> so not statistically significant either.

No, no, it it was absolutely massive.

But and here's where um you know my PhD

adviser used to say if you torture the

data enough it will confess what you

wanted to show. And so if you just say

well there was six times the number of

deaths in the polyunsaturated group.

You're technically correct but you're

leaving out a really big portion of the

data. And again when we plop when we

plop all these studies into the

metaanalysis

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 I think in 2017 where they put

together all the trials that looked at

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. I

think it was around 20% reduced

mortality risk. I

no it was even more. I mean I have the

luxury of cheating because I'm looking

at the actual figure. So the rose corn

oil trial has the largest hazard ratio

of any trial ever done. [laughter]

>> It is sorry of this trial of of this of

these trials it was 4.64

>> right? 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 your point

because the hazard ratio confidence

interval, the 95% confidence interval

was 0.58 to 37.15.

So

um if we limit ourselves to this body of

literature and the 1 2 3 4 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

>> if we include the trans the

>> Yes. So, this is a bit of a messy

analysis to your point because we're

including the MCE, we're including

Sydney, but we're also including Rose

Corn Oil. So, we're we're we're we're

just trying to get as many bodies as

possible through the through the engine

of the meta analysis. Um, and we don't

reach significance. In fact, the only

study that reaches statistical

significance is the Sydney heart study

and that had a 74% increase with a

confidence interval of 1.04 to 2.91. So

it it got there but you know and I guess

your argument is going to be yes but

that they were at 25 to 50% trans fats,

>> right?

>> Yeah. So,

this is a tough one to score, Lane,

because on the one hand,

you know,

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 uh VA

study.

>> Well, there's a few different uh human

randomized control trials. So, the the

VA study was So, there's several

strengths to this study.

>> First off, it was

>> Tell us what the study was about. Yeah.

So it was in uh so it was in veterans

homes. Um the food intake was

controlled. They provided it to the

participants and it was I think around

850 participants and the average

follow-up I believe was just under nine

years. So that's actually a pretty long

study for this

>> not confounded by trans fats.

>> And they did show I I again I don't have

the raw numbers in front of me. I think

it was around a 20 or 30% reduction in

risk. It was though it did not reach

statistical significance as well. So it

had a it it didn't have a wide

confidence interval. It was actually

quite narrow but it crossed unity.

>> So it had a 18% reduction in overall

risk. Uh but it was.56 to 1.21 was your

confidence intervals. Um but this is one

that's on the other side of what you

said a moment ago. 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 or does it just not matter?

>> I mean this is why we do meta analyses

right because when it comes to single

studies sometimes especially when things

are messy like this with hard endpoints

um even if 800 people sounds like a lot

but when you're trying to get hard

endpoints like mortality and

cardiovascular disease events

>> it's pretty small. It's pretty small.

And so

that's why there are some other trials

out there. So like there's the um the

Oslo heart health study that was only

400 people, but that showed I think like

a 47% risk reduction again confounded by

omega-3s.

Then there was um

probably one of the strongest studies I

think is the Finnish hospital study and

the reason is not confounded by trans

fats, not confounded by omega-3s.

People did each diet for six years. So

it was a crossover design. So it's I

guess it's important for me to cover

what a crossover design is briefly. So a

crossover design is when you take people

and you have them do both treatments.

Now there are downsides. The downside is

okay what about a crossover effect where

okay maybe you have let's say 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 on the pre from the previous diet?

The way researchers attempt to get

around that is by

essentially making the um 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. Now

here's the weakness of the study. They

didn't random randomize individually.

They had two hospitals. One hospital

started with one diet, one hospital did

the other diet and then they switched

them after six years,

>> which completely makes sense.

Understandable logistically. Yeah. Yeah.

Otherwise, you're trying to like

>> figure out if Bob in bed A is on this

diet versus Sally in bed B.

>> Exactly. So, I I understand why they did

it for sure. Um, I guess the 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

that were more prone to people getting

cardiovascular disease. I would say that

risk is probably pretty low, but it's an

argument that can be made. But the

benefits of this is it was 1,200 people,

but since they crossed them over

effectively, it was like 2400 people.

So, one of the benefits to a crossover

experiment is you can up your power.

Yeah. I I hope somebody listening is

sharper than I am in my statistics

because it's been so long and I used to

know the answer to this. I think it's

actually even more impressive than 1,200

to 2400. I I think it's even more uh not

to overuse the word power, but it's even

more powerful statistically when you do

a crossover because every person gets to

be their own control.

>> Exactly. So that and that is probably

the largest benefit which is as you said

it's the way you do the t test and the

statistical comparisons. Each person is

their own control. Because when you're

doing a parallel group design, which is

where um 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 guaranteed,

I don't want to say guaranteed, but you

are 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.

And so you can take out some of those

lifestyle or you can not take them out,

but there's less risk of bias from

inherent lifestyle differences as well.

Somebody having more stress versus less

stress. you know, those sorts of things.

And in this study, again, not confounded

by trans fats, not confounded by

omega-3s,

and um pretty well powered for a long

duration, six years on each diet, 12

years overall. And they saw a pretty

significant reduction in the risk of

cardiovascular disease events and

mortality.

>> Yeah. 41%

reduction in the treatment group. That

was and just to give folks what the

actual intervention was.

So the highsaturated fat or control arm

was 18% saturated fat, 4%

polyunsaturated fat, 3 to four. They

gave some wiggle room. The treatment

group was 14%. So they increased to 14%

polyunsaturated and cut saturated fat in

half to 9%. These were kind of similar

targets to the MCE study. I want to say

they measured linoleic acid uh in tissue

too. I believe they did that.

>> I don't know.

>> Yeah, I if I'm if I'm wrong, I'll eat

crow, but I think that they actually

looked at like tissue and blood

biomarkers of linoleic acid and showed

an increase in linoleic acid content to

verify the the the dietary treatment

worked.

>> What would be your best explanation for

this? Because again the finished study

um I mean 41%

relative risk reduction in

cardiovascular disease with that low

saturated fat, high polyunsaturated fat.

Um

and the confidence intervals are really

tight.

>> Yeah. And I think again this is why

this is a situation where okay I'm

acknowledging

what seems to be a negative effect of

polyunsaturated fats in some of these

studies but I'm explaining why I think

that the studies that show reduction in

risk are on balance better and not again

not making a criticism of the

researchers because as we talked about I

think they did the best they good at the

time with the information they had. So,

this isn't an indictment on the

researchers whatsoever.

But 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. And that seems

to be I think 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. And again, there was a metaanalysis

in 2017, and I can't remember the name

of the the lead author, um, but they

basically did a meta analysis of the

studies not confounded by trans fats.

Now, they included some of the ones that

had fish oil in them, um, or omega-3s,

rather.

>> Y,

>> but they showed overall I I I again, I

want to say it was around a 21 it was

29% reduction in risk.

So again, that's if you look at the

Ramston analysis

when they

in their best case for polyunsaturated

fats being bad,

it's

a small it's a smaller increase in risk

and the confident confidence intervals

are very wide. So let me play devil's

advocate for a moment.

>> Yeah, do it.

What if,

and again this is sort of a maybe a

silly argument,

but what if this says more about

saturated fats harm than polyunsaturated

fats benefit?

>> Well, and this is a situation where you

know when you're doing nutritional

studies,

>> you have to substitute something,

>> right? Right. Because

>> if it's going to say isocaloric,

>> one of the things when we were talking

about doing this debate with the other

individual, I was very clear in saying

I'm not saying that there's no

delotterious effect to seed oils

whatsoever because added oils in the

diet are a major source of calories and

excess calories are not innocuous. And

so we have to compare apples to apples,

which is when you are substituting in a

1:1 ratio,

what is more what is more beneficial?

The reality is I think 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

molecule or a a nutrient or a particular

food activates positive or negative

pathways. And I I say that very broadly

because as you and I both know 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. And I explain

this I'll use another financial example.

So when we're talking about these

pathways we're talking about mechanisms

which are important. It's a if 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 so

what I mean by that is I could take a

mutual fund that's doing really well,

say up 20% year-over-year, but I could

find a few stocks in it. I'm like, "Oh,

you don't want to invest in this. Look

at these stock. They're down like 50%."

But what matters more, those individual

stocks that are down or the overall

mutual fund is killing it? then you care

about what the overall mutual fund is

doing. And just an example of this, um,

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.

>> We should just point out to listeners,

it appears to be the nicotine that is

causing that benefit. I don't want

anybody with Parkinson's disease or at

risk for Parkinson's picking up

cigarettes. If you're going to do

anything, just choose some nicotine.

Choose non-tobacco nicotine, please.

>> But perhaps a better comparison would be

um we know I believe it's I believe

aspirin is anti-coagulant overall, but

it also activates some pro-coagulant

pathways, but the overall effect is

anti-coagulation. So do we if I just

wanted to pick out and say well look it

activates these pathways

that not that it doesn't matter but on

balance on balance it is a net positive

for anti-coagulation and so when it

comes to looking at polyunsaturated fats

versus saturated fats and we will get

into the mechanisms of these 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 your original question,

is this a effect of polyunsaturated fats

being beneficial or saturated fats being

a negative? I think 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, right?

So if you're going to take saturated fat

out, you got to put something in. And so

if we look at, you know, studies where

you substitute carbohydrate for

saturated fat, not really much change. I

would say that probably depends on the

type of carbohydrate very much. If you

were doing like fiber in sources of

carbohydrate, I'm pretty sure you'd see

a reduction in risk. 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

even if

let's make it very basic even if there

was no net

if polyunsaturated fats didn't do

anything cardiorive

it's still cardiorotective in that when

you put them in in place of saturated

fat you have improvements in outcomes

and so I I would argue that there are

mechanisms in place that explain why

polyunsaturated fats are cardio

protective.

But I my point I'm making is I think

it's difficult to disconnect those two

questions.

>> Do we know if the Cochran analyses on

this question have blended and included

the studies across those that contain

trans fats and those that don't?

>> The one from 2017.

>> Yeah. When they look at all the PUFA

versus SFA studies.

>> No. So they specifically excluded ones

that were confounded by trans fats.

Ramsden had one where, you know, it

included basically all of them, right?

Net effect being null, nothing. And when

he picked out the when they pulled out

the ones that were confounded by

omega-3s, they showed a negative effect

of polyunsaturated fats. So,

>> but with trans fats still in,

>> but with trans fats still in.

>> Okay. Right.

>> And Cochran had no trans fats.

>> No trans fats,

>> but did have omega-3s.

>> But did have omega-3s

>> and had a slight benefit to PUFFA.

>> Yeah. Well, pretty decent. I think what

what did you say it was? It was uh 20 I

want to say it was like 23%. Oh, no.

31%.

>> Yeah, 29 or 31%. Okay. Yeah.

>> Yeah. Somewhere around there. I I

apologize for not remembering the raw

numbers. Um I there's a lot floating

around in there.

>> So, has anybody done the analysis of

excluding omega-3, excluding trans fats?

>> Well, I mean, you're basically

>> I know you're you're down to very few

studies.

>> I think you're down to like two studies

now. I want to say I know the finished

study.

>> Sorry. I just want to point out another

or ask a question. I apologize to

interrupt.

>> That's good.

>> When you say omega-3s,

are you talking linoleic acid or are you

talking EPA DHA?

>> I believe they're specifically talking

about the the EPA DHA, but I know like

alpha

>> alpha linoleic acid.

>> Yeah, alpha linoleic acid omega3 as

well.

>> Alpha linoleic acid.

>> Although no, that that was that was part

of it. That was part of it as well

>> because it 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?

>> Right. Uh it wasn't clear in the

research literature I read. It was just

basically like, yeah, there was some

omega-3s in the diet. Um, there's

basically, I think, two studies that

were not confounded by trans fats, not

confounded by omega-3s, and that was the

finished study that we talked about, and

then STARS, which STARS was not looking

at hard cardiovascular disease

endpoints. This was looking at plaque

progression. So, I believe this was a

one-year study and they looked at either

people doing saturated fat vers or or

doing low saturated fat, higher

polyunsaturated fat versus higher

saturated fat, lower polyunsaturated fat

and they looked at the progression of

plaque. So not hard outcome but I would

say that the strength of this is since

you are looking at the progression of

what we know causes these myioardial

events even if you don't have a

mocardial event you can get a really

good idea of what's going on and so for

example and I'm just going to make a

hypothetical here 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 age,

right? But no mioardial event in the

time where they were measuring it and

they just came up as that's you know a

risk reduction, right? But in reality,

>> right, the disease progression,

>> right? So the benefit of this is you

kind of get to you still get a a harder

endpoint than just biomarkers,

but you can you can get a little bit

more granular than just looking at some

of like kind of a I guess the way to

describe mortality and cardiovascular

disease events is big blunt instruments.

So

>> So let's talk a little bit more about

these mechanistic things now. Um because

again most of these trials were done

with a brute force tool of like you know

the hardest outcome is all cause

mortality but again that's a high bar.

So you're tra when you when you do

clinical trials you trade off between

outcome and barrier to outcome for lack

of a better term right so if you want to

use all cause mortality that is the that

is the ultimate measuring stick but it's

a high bar to clear. So then you can go

disease specific mortality. Okay, we're

now going to look at major adverse card

or sorry coronary death. Great. Then you

can go one step lower and an example

would be mace major adverse cardiac

event where we're going to use heart

attack and stroke and cardiac death. Um

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. Um

and you get more and more insight into

disease process or you know I guess

below mace you would go disease

progression would actually be your next

thing. Yeah. Yeah. Okay. So, now let's

let's let's go from the macro to the

micro. Right.

>> Before we do that, I think now is you

may disagree, but I think now would be a

good time to talk about the mandelian

randomization studies.

Unless you want to do progression first

or unless you want to do the mechanism

first.

>> Okay. Do you want to talk about

mandelian randomization through the lens

of LDL?

>> Yes. Um, okay. So,

first off, I think it's important to

point out why I'm bringing this up now

because when it comes to

these studies, I think that these are

the most powerful because as you

mentioned, mortality is a difficult

outcome to get. It's a high bar to

clear. The benefit to Mandelian

randomization is that essentially you

have a lifelong randomized control

trial. Now, mandelian randomization

takes advantage of the fact that at

birth, genetic variants are randomly

assigned. So, in a research study, if

you and I are in a research study,

Peter, the research is just going to

through whatever randomization process

they have. Okay, Peter, you're doing

this, Lane, you're doing this completely

random.

Mother nature actually does that by

design which we can we now know

identified I think around a dozen

variants that will essentially change

your LDL cholesterol levels right and

they're variants that deal with uh LDL

clearance LDL production uh how much

cholesterol you absorb there's all

different kinds of variants

now this does so the benefit to this is

you have you can look at someone's

lifelong LDL cholesterol exposure and

attempt to see what is the risk of

mortality and cardiovascular disease.

That is very powerful. And these are

studies where I mean some of these have

hundreds of thousands of people in them.

And again the randomization of this

process by nature is so important

because now we can 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.

>> Now there's a caveat here which is

to for a mandelian randomization to be

useful

a couple things have to be true. what

you said has to be true. There has to be

genetic assignment to the variable of

interest. So that's true for many

things. It's true for height. It's true

for body composition. Uh it's true for

uh many psychiatric disorders. I mean

there's lots of things for which

genetics play a significant role.

>> Uh and LDL cholesterol turns out to be

one of them. 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

for sure. And and that's why they do

tests for pleotropy, which we talk

about. And when I talk about the

results, I'm going to explain why it's

very unlikely that these differences

were due to pleotropy. But it does

require us to make one assumption. Okay.

So, and and this may seem ticky tacky,

but I'm trying to be um I'm trying to be

logically consistent here, which is 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.

>> State another way, this is a test of LDL

causality.

>> Correct. not nutritional. It's it's a

leap to then make the statement about

what does nutrition do to this. I'm

going to give you another example of

this that is off the beaten path but

related to LDL but unrelated to our

topic and I believe I included this in

my book although it may have got left on

the editing floor. I know I wrote about

it. I can't remember if it made the

final cut and it came down to the

question of so this is me taking off my

debate hat and just doing an aside on MR

because it's interesting. Um

there were a handful of studies that

showed that people taking um or people

with lower cholesterol were more prone

to cancer. And so the 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. Um, and 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 know, you weren't

randomizing to to find that. So 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

Mandelian 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

ASBD. So, that's a great explanation.

And again, like I think it took me a

while to wrap my head around Mandelian

randomization when I first started

reading about it, but these really were

the studies that made me change my mind

on on LDL.

And again, I want to point out 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 um you can get a large number of

subjects for their lifetime. And it's

randomized. So it's not a cohort study.

Those are the benefits. The one downside

is again we're having to make a leap of

okay, we're not directly measuring

people eating saturated fat versus

polyunsaturated fat. But I 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 and

raising PUFAs and lowering saturated fat

significantly decrease LDL cholesterol.

I think in most studies you get like a

around a 15% change in LDL cholesterol

from substituting in polyunsaturated

fats for saturated fat.

Now I will tell you there's a paper from

I think it's for in 2012 was the first

big MR study with cholesterol and if you

look at the figure where they take all

the genetic variance and you look at how

the line goes almost straight through

it. I mean, we're talking about an R of

probably above 0.9, which in

free not free living studies, but

studies like this, that is an incredible

association

for every

1 mill mole reduction in LDL or

>> which is about 37 milligrams per

deciliter.

>> It's 39.4 milligrams per deciliter.

Yeah.

>> There was a 50 to 55% risk reduction in

cardiovascular disease.

And that so the again the pleotropy

argument is pretty much null and void

because it didn't matter what kind of

variant it was. If it increased um LDL

clearance, if it decreased production,

no matter how it affected the metabolism

of LDL cholesterol, it had the same dose

effect. The the only exception to that

was some of the CCTP variants, which

when it came to drug trials as well,

CCTP variants, basically I believe they

raise HDL and they lower LDL. But, and

here's the the big point, the lowering

of LDL with those variants in those

drugs, it lowers the cholesterol mass,

but there's a discordant lowering of

APOB or LDL particle number. So 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.

And so 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 varants there is a small risk

reduction but it's basically explained

by the small decrease in apo

and you don't get the predicted risk

reduction that you would get with

reducing LDL cholesterol but amongst the

amongst the variants that decrease LDL

and correspondingly decrease apo

it is a very very consistent effect and

again regardless of the genetic variant,

it has the same risk reduction. And then

we look at the statin trials,

regardless of the way that LDL

cholesterol gets lowered, and there's

different statins that work different

ways, um, it is the same dose response,

which is about 22%.

>> Yeah. So I was going to ask you why do

you think that when we look at the

totality of the Mandelian randomization

and Tom Desping has a figure that lays

every single MR study, every single

uh RCT study and every single

observational epidemiology study on the

same graph with three lines the the

>> basically the linear regression through

each.

And what do you think is the best

explanation for the following

observation which is when you do all of

the MR studies and just again so people

can especially because most people are

listening to us not watching us so I

don't want to use my hands too much but

on the x- axis you have LDL

concentration and on the y- axis you

have mortality or cardiovascular

mortality and as you pointed out these

lines are just going straight down

meaning as LDL cholesterol is going down

either genetically or through drugs

cardiovascular mortality is going down.

But why is it that in the MR study which

in theory would be the most pure study

every mill or every roughly 40

milligrams per deciliter reduction in

LDL cholesterol is giving you 50 to 55%

reduction but when you do the same thing

with a statin you 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?

>> Well, again, as you mentioned, there's

still a risk reduction. And the

difference

>> or Yeah, let me state it another way.

Does that suggest that while statins are

net positive, they're doing something

bad?

>> This is because think about when people

are getting on statins, right? Usually

it's and so I say this as somebody again

my bias should be that I hope that LDL

cholesterol is not bad because my whole

mother's side of the family runs high

LDL even with low saturated fat diet

even with high dietary fiber intake I

run about 150.

I started taking a statin when I was 40

years old.

But my endthelium,

my my blood vessels have already had 40

years of LDL exposure at that level. And

so even if I get on a statin at age 40,

every single day to the day I die,

there is still some LDL cholesterol that

has penetrated that endothelium and has

contributed to some degree of

uh atheroscerosis. And maybe it would be

I mean I had a coronary calcium score

done. It was pretty low. Um overall my

net risk was very low for my age because

I have good insulin sensitivity. All

those sorts of things. Important to

point out as well when we're talking

about LDL we're not saying everything

else doesn't matter. We are just saying

that this is an independent risk factors

is what I'm saying. Insulin sensitivity,

metabolic health, all those things still

matter. These are not mutually

exclusive.

But when you have a 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 and when

it comes to how much gets into the inima

it is concentration dependent and it's

basically dependent on the number of

particles in your bloodstream with apo B

that are under 70 nmters because any

lipoprotein under 70 nmters in diameter

with an apo can penetrate the

endothelium and get retained there. So

when it comes to these mandelian studies

the reason you see such a powerful

effect it's just a time effect because

most people when they get I don't know

what the average age somebody's

prescribed a statin but I'm imagining

it's probably around my age. Yeah. Yeah.

So you're really just looking at the

difference in like that investment

analogy we used earlier 40 years you'll

see a big difference but 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

and while it may be kind of a rud

rudimentary comparison

uh these problems compound over time and

so what you're doing with somebody who

has high LDL put them on a statin

you're obviously like 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.

>> Yeah.

>> Okay. So,

>> and sorry, I want to point out one more

thing. Important to point out that they

also there was a regression they looked

at where they looked at each, you know,

one one mill reduction.

>> So, regardless of the variant, same

reduction. And in the drug trials, the

statin trials, regardless of how the

statins worked also with like surgeries

like I think uh it was a little bypass

or things that reduce LDL through

absorption.

>> No, I think you um yeah, different drugs

that are depend independent of the

mechanism by which LDL is lowered.

>> Yeah.

>> Yeah. you'll see the same benefit

>> and then also with dietary reduction of

it in terms of the risk when they when

they look at some of these cohort

studies. And so if you want to argue

it's pleotropy or you want to argue it's

uh possibly something else, it's a

really hard argument to make when it is

a very consistent effect and the dose is

also very consistent. That is when we

talk about converging lines of evidence.

So your argument you so so because

there's an argument to be made which is

not necessarily the argument we're

having today but I I'll and I can't I

won't even attempt to steal man it but

but I'll just I'll just state it. The

argument is that

um

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. And you're arguing that

that's that's a tough argument to make

in light of the all of the MR coupled

with all the clinical trial data.

>> Yeah. I mean, you would just see if that

was the case, you would see a difference

in the dose response. You would see uh

inconsistencies in the trials with

similar designs. I mean, I'll give a a

comparison that's kind of out of left

field, but maybe it'll it'll make the

point. And that is for example

u I don't believe that

unprocessed red meat specifically is

inherently

carcinogenic

a 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 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