250. When You Should Worry About LDL Cholesterol with Mike Fave

There's no money for pharmaceutical companies in telling people to stop eating processed junk food. On this week's podcast, I had an amazing discussion with my buddy, Mike Fave, who's been on the podcast before. This is his second appearance. We talked about lipids, cholesterol.

cardiovascular disease risk in the setting of insulin sensitivity, context for all of this, and whether you should be taking a drug to lower your cholesterol. Fempedoic acid, statins, ezetimibe, PCSK9 inhibitors, we break it all down in this. technical podcast. In some ways, this podcast is a follow-up to something I recently did with Derek from More Plates, More Dates. He had me on his podcast after I reached out to him, after seeing a clip of him and Peter Atiyah talking about

cardiovascular disease risk and the setting of different levels of LDL. So I went on Derek's podcast to help him understand context regarding... familial hypercholesterolemia and why Mendelian randomizations may not be the end all and be all when it comes to lipid levels and cardiovascular disease risk. So I'm going to send this podcast to Derek and show him some of these things which add context to everything we're talking about in that. And we go into much more detail in this podcast.

about all the drugs, risk benefit, all-cause mortality, et cetera. So if you have questions about your cholesterol, maybe it's gone up when you decrease seed oils and increase saturated fats, which automatically come with...

an animal-based diet, butter, ghee, tallow, steaks, then this podcast is for you. It's technical, but bear with us. You'll learn a lot. And I'm going to do my best to put in all the references in the video and in the show notes. So hopefully this video is very valuable for you. And if you have more questions about...

lipids, cardiovascular disease risk, or anything you'd like to see me discuss in future podcasts, please put it in the comments. On to the podcast with Mike Fave. All right, Mike Fave, thanks for coming back on the podcast, man. It's good to have you again. It's great. It's a pleasure to be here, Paul. Thanks for the invite.

I'll put a link in the description to our first podcast, which was in response to Robert Lustig on Andrew Huberman's podcast, kind of talking about fructose and, quote, sugar. And trying to respectfully, as possible, clarify some of the statements he made in there, which didn't sit well with you or I. So people can link to that in the show notes if they want.

If they're curious about fruit, there's been a lot made of fruit recently with Glucose Goddess kind of fanning the flames of fruit-fearing and honey-fearing, but that's for a different day. Today, I wanted to do a podcast about lipids.

I've done a lot of podcasts about lipids on my channel. Anyone that's watched any of my podcasts or listening to my podcast knows that this is probably number 17 in the lipids series. But the way we think about it, the way we talk about it always evolves. New data is happening. We can talk about Dave Feldman's recent study.

And this is partially in response to a podcast I recently did with Derek, the guy from More Plates, More Dates. And the whole story is just that I heard Derek talking to Peter Atiyah. I think it was on probably Derek's podcast. And he's asking...

Peter Attia, what do you think of these carnivore types who say that an elevated, quote, LDL is not a problem if you are insulin sensitive? And Peter replied, and they were talking about these high-end values that look like familial hypercholesterolemia. And I reached out to Derek and said, hey, you and I need to talk because there's some things you need to know about what happens in familial hypercholesterolemia. Though this came up in the podcast with Derek, which is strange, though it's...

thought of as a phenotype, it's really a genetic basis. Generally, this whole idea of familial hypercholesterolemia being a phenotype, it's never really sat right with me. And we can talk about that in the podcast here as well. But I think... We can dig into all this stuff, Mike, today. And I want to talk about LDL and risk and ApoB. We'll try to keep it as accessible as possible, but this is going to be a complex podcast. And in this podcast, I want to make sure we get to risk.

cardiovascular disease with different levels of ApoB slash LDL. When you've had a heart attack, when you haven't had a heart attack, so secondary or primary prevention.

We'll talk in the beginning about some other laboratory risk markers that might help stratify cardiovascular risk beyond LDL because most people go to their doctor and they just get an LDL. They don't get any of these other risk markers. And then definitely in this conversation, I want to get into some details around drugs and lipid therapy.

Because one of the questions that came up in my podcast with Derek was, are there lipid lowering therapies that have a risk reward ratio that is beneficial in humans? And again, we have to talk about primary prevention versus secondary prevention. We'll get into all of that today, and I think it helps clarify a lot of this. But let's just start out with this question. I think, as I said, I get this in my DMs all the time, Mike. People say...

I'm doing an animal-based diet or I'm eating carnivore. I'm eating more meat is essentially what happens. They're eating red meat. They're probably eating butter. They're eating rendered beef fat, which is called tallow. They're eating more saturated fat and they're eating less polyunsaturated fats because I'm...

recommending to people that they avoid seed oils. And inevitably their LDL goes up somewhat. If they're eating carbohydrates, their LDL doesn't usually go up that much, but their LDL goes up. They go to their doctor and the doctor says, you need to be on a statin.

And that's all they do. And it always frustrates me because I say, did your doctor do any other blood work to look at your cardiovascular risk? And they say, no, they just basically do a lipid panel and a basic metabolic panel. That's what happens. You get a, you know. a CBC, a complete blood count. You get a basic metabolic panel and you get a lipid panel and that's it. And they want to make a decision about statins or drugs, drugs, maybe not a statin for this person based on that.

what do you see as other blood work that people could ask their doctors for that might add to this cardiovascular risk profile? Okay, so... There's a lot to unpack here, but I'm going to answer a specific question and we'll talk about some of the details here, especially with like LDL and total cholesterol and HDL. But there's a variety of markers that people are going to want to look at to really get a sense of.

number one, where's metabolic function? Because that's intimately tied with cardiovascular disease. And then number two, what is actually going on in the vasculature? So we will stick with blood markers and we can talk about some of the other imaging techniques after because the imaging techniques will be really important when we talk about some of the risk factors and risk profile with LDL in just a couple of minutes here.

But there's the major ones looking directly at vasculature is high sensitivity CRP, homocysteine, oxidized LDL, myeloperoxidase, lipoprotein phospholipase A2. parathyroid hormone, D3, insulin, glucose, hemoglobin A1C, and possibly C-peptide if you're diabetic, a full lipid panel, which can also include looking at an ApoB level and then apolipoprotein A1.

a full thyroid panel, cortisol, the DHEAS and sex steroids. And the reason we're looking at all of this stuff together is because we're trying to gauge number one, the first series of values that I mentioned. are what is actually going on directly in the vasculature. That's going to be your CRP, your homocysteine, your oxidized LDL, myeloperoxidase, the LPPLA2.

And then the PTHD3 and the full lipid panel with the different components that I mentioned, ApoB and ApoA1. So when you're looking at all this type of stuff, it's going to give you a full idea of what is going on at the vasculature. and what are different problems you could be experiencing. If homocysteine is high, methylation imbalance, homocysteine creates oxidative stress. CRP is indicative of inflammation with different tiers, indicating vascular inflammation versus having infection.

oxidized LDLs, giving you an idea of some of the, the, the cardiovascular stress on the vasculature and the oxidative balance. You can all, the myeloperoxidase is immune marker.

The LPPLA2 is an idea of damage inside the vasculature. And then PTH is talking about vascular calcification in relationship to D3 with the lipid values telling you what's going on metabolically, right? And so... that's that the lipid values which is what the doctors are mainly looking at are really just indirect risk factors at best and they have correlations with different disease processes but you really need to understand them in context like why is hdl low

Why is LDL high? Why is total cholesterol high? What's going on with triglycerides and what's shifting all these things? But they don't, those need to be taken into consideration with these other factors that are extremely important to parse together. So that, you know, like if my LDL is high, am I just on a low carb diet with high saturated fat intake? Or is my LDL high because I have atherogenic dyslipidemia, which is very different lipid profile.

which we see with the lean mass hyper responders versus somebody who actually has this metabolic dysfunction, or do they have an active infection, which can also shift the lipid profile as well. So you need to understand what's going on amongst all of the values, which is total cholesterol.

ldl hdl and triglycerides and also vldl is another one that maybe a lot of people don't really look at or know about but that's also a really important one and that by itself is telling you what's going on metabolically but it's not telling you if there's vascular information or problems. It's just like giving you an associated value. The other things are telling you about vascular information, calcification.

and problems and when you start to look at hormonal profiles you have things like the the thyroid panel cortisol dheas and sex steroids which is telling you what's going on with your stress systems and with your thyroid systems which are intimately intertwined

with what's going on with the vasculature and then blood glucose regulation insulin glucose hemoglobin a1c and there's also home ir which is calculated off some of those values and then c peptides when you're looking at that it's telling you how well are you using substrate

How well are you using glucose? Are you having metabolic dysfunction? And so these values will give you a much more complete picture over cardiovascular risk profile and what's going on. And if you understand why they move and what they do.

It'll start to tell you what's going on with the vasculature and your risk with cardiovascular disease and what's going on. Because the studies are not so clear that LDL just like your LDL is high than cardiovascular disease. And when they look at things like coronary arity calcium scores.

and carotid intimal medial thickness test, which is an ultrasound of the carotid arteries, you start to see the LDL values are not correlated if some of those things are completely fine, like if CAC is zero. And so those are other metrics you can check is CAC and CIMT.

CAC is probably the gold standard for understanding what's going on with cardiovascular risk. But the problem is it induces quite a bit of radiation, whereas CIMT doesn't. It's just an ultrasound. So it's like probably one tier below CAC. without the radiation risk. So these are all the markers when I'm working with a client that I'm looking at if we are concerned about cardiovascular disease and getting a full profile, not just a lipid panel.

Flip it panel gives you like marginal amount of information overall, and you have to interpret it in terms of all of the values in relationship to each other instead of just, oh, LDL is high. And we could talk about this with like, how does it change in different contexts? We could talk about lean mass hypersponders, all of this type of stuff. Yeah, amazing. Thank you. And I think that if people are confused about the blood work, I'll make a comment below or I'll put in the description.

all of the things that Mike just enumerated in terms of. the things that you want to make sure your doctor is getting. I've done multiple podcasts showing my blood work as recently as a few months ago from even 2024. Most of the things on there are on my blood work because I'm always wanting to know what's my fasting insulin.

But inevitably, when I ask people in the DMs or when I meet them in the real world, did your doctor get a fasting insulin 99.9% of the time or perhaps even 100% of the time, the answer is no. And I think, okay, so this is really what I would say. an antiquated medical paradigm. And believe me, I was trained as a medical doctor, so I get it. In medical school, we are still not being trained to think about vascular health or to think about lipids in context.

And there is this prevailing notion, which is promoted by people like Peter Attia, who I respectfully disagree with, and many others, and Derek has bought into that because he's friends with Peter, that LDL or ApoB... quote, causes atherosclerosis. And this is where things get a little sticky, Mike, because as you mentioned, there are a lot of instances where...

ApoB slash LDL will basically use those terms interchangeably in this podcast. They're not exactly the same thing, but they're looking at the same metric. They're looking at the same sort of particles in the human body.

they don't always correlate with atherosclerosis, especially in people who have other indicators that their vasculature is healthy or that they are metabolically healthy. In humans that are metabolically healthy by a fasting insulin or by... HDL to triglyceride ratio, or by CAC scores, which is a coronary artery calcium score of zero, we don't see any real consistent sort of relationship between LDL levels and incident cardiovascular disease.

So if ApoB slash LDL are causing atherosclerosis, why does this correlation, why does this association break down? in people that are metabolically healthy. And this has been my concern. This has been my problem, my sort of pushback to the mainstream ApoB lipid thinking for many years now that it must be taken in context. I mean...

Years ago, when I was on Joe Rogan's podcast, I showed him a graph of the Framingham study and I said, look, look at what happens to the relationship between LDL cholesterol and cardiovascular disease if you stratify people in Framingham. by HDL, which is just a proxy marker for some degree of metabolic health. It's not perfect. The relationship completely changes in people that have high HDL, and that's a single marker. You enumerated probably 12 markers.

So if you look at any marker that indicates metabolic health, you will see the relationship between LDL and cardiovascular disease either massively attenuated or completely fall away. So what is going on here? How can LDL be causing atherosclerosis? And I think it's just, we get into this idea of semantics and I don't think we need to go too far down this rabbit hole, but that's the question that we're really asking overall. That's the question I was trying to ask Derek on his podcast.

And that's the question that I think has been glossed over repeatedly by mainstream medicine. And I think this is because of these Mendelian randomization relationships between LDL. and cardiovascular disease. And this is why I really wanted to go on Derek's podcast. Now he brought up a bunch of stuff that he didn't tell me we were going to discuss. And this is why we're having this podcast with you and I to kind of fill in the gaps there.

If you look at the high end of a Mendelian randomization, which is a type of study that looks at genetic polymorphisms that lead to, in this case, higher levels of LDL and the genetic polymorphisms that lead to lower levels of LDL, is there a relationship between LDL level?

and cardiovascular disease. And indeed there is, if you look at some of these studies. Now, the problem that I had with this, and this is what I told Derek on the high end, was that, hey, the people at the high end of the Mendelian randomization, those are people with something called familial hypercholesterolemia.

which is technically a, quote, phenotype, but it's really a genetic thing. This has always been distasteful to me. And as I mentioned on the podcast with Derek, to Derek, this is what I wanted to go on and educate him about, people with especially monogenic... familial hypercholesterolemia, which means familial hypercholesterolemia caused by one single gene mutation have very clear changes in the way that their immune cells function.

the propensity of the macrophages to take up LDL in the vessel wall is much higher. So people with familial hypercholesterolemia don't just have high LDL. They have an immune system that wants to gobble it up and form plaques more avidly than someone that doesn't have it. So it's an inaccurate representation, I think, of what's going on there. And as you mentioned, we can talk about this later in the podcast. We've really seen this play out to some extent recently with...

Dave Feldman's study. I had Dave on the podcast. We talked about the beginning of his recent study with lean mass hyper-responders, which are people who eat low carb, something that I'm not a huge fan of, something that Mike is not a huge fan of. But we know that when you eat low carb in some...

some subset of people, your LDL will go high. And when I was strict carnivore, my LDL was much higher than it is now. And so Dave took people who were lean mass hyper responders. That's his name for people who have high LDL in the setting of a low carb diet. And he did CCTA, which is basically coronary angiography, like CT coronary angiography. It's even more specific than a CAC, which is a coronary artery calcium score. And what he found with those people was that they did not have...

really any correlation between their level of LDL and the incidence of cardiovascular disease that they saw on a CCTA. And then he did this really genius thing. He compared them to a group at Miami Heart. which is a group of people that had a bunch of CT coronary angiograms that didn't have elevated LDL quote. And there was the exact same incidence of cardiovascular disease in people with...

quote, average LDL levels and people with significantly elevated LDL levels who are lean mass hyper responders. So again, we're starting to see this play out that this doesn't always work, especially on the high end.

You know, in these Mendelian randomizations, people on the high end are, excuse me, familial hypercholesterolemia. But here's Dave's cohort, which I think, do you remember how many people were in the study? It's probably like, I don't have the exact numbers. I think they had 70 or 80 people.

And they didn't, there's no correlation between- It was 80. It was 80, yeah. 80 people. There's no correlation between cardiovascular disease. So this is where we are and this is where Mike and I start asking these questions. Why don't you, I'm curious, Mike, like what have you seen with regard to this? Because there are, why don't we just dig into a few of the studies that have been done looking at...

relationships between LDL cholesterol and cardiovascular disease in people who have an absence of some of these risk markers, right? So either people with zero CAC scores. So zero calcified plaque on a coronary artery calcium score or other metrics that might suggest this, because this is actually pretty interesting data that I think people need to know about. So there's quite a few interesting studies here that actually look at this.

And so we have one that was done by Dave Feldman and Matthew Buttoff together. And then we also have one looking at familial hypercholesterolemia as well. And basically what we see with specifically the Dave Feldman study. They had people with a mean LDL-C. So the average LDL-C was 272 milligrams per deciliter and a max of 591. So something to put into perspective here is this is not total cholesterol.

This is just LDL cholesterol. And in these studies, HDL also tends to be high. So total was significantly higher. And what they see is that there's no relationship in this study between LDL-C elevations and...

plaque formation. They're not actually seeing any relationship. And there's an interesting graph where they show, like, you can see the LDL values, you can see the plaque scores, and they're not correlated by any capacity. Some of the highest scores have zero plaque burden. So that's the first thing.

and with with these people very high ldlc levels and we're not seeing this the the positive or the cac scores greater than zero or we're not seeing elevations and plaque burden overall as the ccta or the cac scores Which is, that's a huge, that's a huge thing to see because ideally if you have this, if LDL is directly causative.

in cardiovascular disease you would see you would assume a linear relationship or some type of relationship not necessarily always linear where the higher levels that you get the higher the higher the plaque burden and you're not actually seeing that another study that we have here It's titled Absence of Coronary Artery Calcification in Middle-Age Familial Hypercholesterolemia Patients Without Atherosclerotic Cardiovascular Disease. What they basically show...

is that about 45% of these people don't actually show cardiovascular, a CAC score greater than zero. So they say you're in five of nine included studies. So this N equals 970. So a thousand people almost were looked at. providing on-treatment lipids. The pooled on-treatment low-density lipoprotein cholesterol level was 158 milligrams per deciliter. So the people's average LDL-C while they were on treatment for the high lipids was...

158 milligrams per deciliter. They said among these nine studies representing these 1,176 asymptomatic heterozygous familial hyperclesterolemia patients, the mean pool prevalence of CAC. equal to zero was 45 percent so basically you have about 1176 people that have familial hypercholesterolemia so they have this genetic condition that leads to high cholesterol and basically

They had the average LDL-C of 158, which would be considered quite high by modern standards. And their CAC scores, 45% of them was zero. So 45% of these people with FH, with familial hypercholesterolemia. and elevated LDL-C levels are not seeing CAC scores greater than zero, and they're middle-aged people. This is not in young familial hypercholesterolemic people. So you have incidents, you have studies like this. Then there's a variety of other studies.

where basically there's some really interesting ones where they're stratifying people's, their LDL values into different categories. And then they're basically seeing that in each category, whether LDL C. was 77 milligrams per deciliter or whether it was 190 milligrams per deciliter. Again, LDL, not total cholesterol. If their CAC scores were zero, they basically had a minimal risk of cardiovascular events.

and and uh they weren't really like they weren't really showing increased heart attacks and all this type of stuff with with even with these high ldlc levels so basically what we're seeing here is that the number one most important thing is do you have black burden And maybe LDL is associated with black burden. Well, we know it is to some extent, but the association doesn't necessarily mean direct causation. And what happens is when we start to get into the weeds with these studies.

and you really can get into the weeds with these studies, what you see is because LDL is involved in plaque formation, there's going to be associations, but it doesn't necessarily mean that LDL by itself is just the driving factor. for plaque formation and cardiovascular disease. There's a variety of other factors that are occurring that are leading to changes and modifications in the LDL, which we can talk about. And that's usually driven by metabolic dysfunction.

and by inflammatory signaling and oxidative stress that modify LDL particles, trigger immune response, and then you start to get plaque formation. And so if we just hyper-focus on these LDL values, And I mean, like, oh, we need to just smash LDL all the way down less than 30 milligrams per deciliter with drugs so we can lower our risk. It's like, I guess that's one way that you could go about it. But it's kind of a crude fashion to go about treating heart disease.

When we need to, like the LDL itself needs to be modified and have this inflammatory signaling process and all this type of stuff go on to actually have this effect. And if anything, in different animal studies, when you knock out the inflammatory signaling through genetic deletion pathways. or you adjust some of the different receptors with antibodies or things like this, you actually completely eliminate or vastly eliminate atherosclerosis in these animals, even when they have really high...

LDL values because again, it's the atherosclerosis and cardiovascular disease is kind of like a cake. There's a lot of ingredients that have to go into this to have the effect. Instead of just you wouldn't just say, oh, it's just the frosting on the cake that's causing the problem because that's what we see. It's like, no, there's multiple pieces going into making this problem. And we need to understand those pieces altogether instead of just really hone in on one.

throw all of our eggs in one basket, and then try to smash it down with drugs when there's problems with doing that that are not being discussed openly by these other parties, including Derek on the podcast. So there's those are we need to understand risk versus reward and we need to understand the actual mechanisms before we make extreme treatment decisions. And I think that's one of the major problems.

that we're seeing with this this other model that's being that's being pushed it's like it's just ldl we just need to smash and it's like but there's all these paradoxes so like why don't we try to understand what's going on instead of really just honing in on this one thing. For me, it doesn't make any sense to just go really hard on this, especially because we're seeing people where LDL is super high and they're not having high plaque burdens.

They're not seeing increased risk of cardiovascular disease. And if anything, there's a lot of anecdotal evidence from keto people saying, hey, I went keto and I actually improved my CAC scores and things like this. Now, this isn't me saying that people need to go on keto to do that.

It's just me saying like, look, these are states where people get really high LDL values and they're eating a bunch of saturated fat and they're saying, oh, things are actually improving for me overall. And that's quite an interesting, that's quite an interesting profile because it's completely counter.

to the current narrative so there's a big paradox there and it needs to be rectified and that's basically what we're trying to do here is figure out like what is this what it where is the paradox and like why are we seeing this and because the general model I don't think is correct. The single best-selling supplement that we have at Heart & Soil is Whole Package.

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And I am excited to see what you think of whole package. Let me know. Find us at heartandsoil.co. I think the general model is incomplete. And I think it makes a lot of sense to me why the focus is mostly on LDL because that's where the money is, man. That's statins. That's PCSK9 inhibitors. I mean, who knows how much PCSK9 monoclonal antibodies cost a month, but I think there's thousands of dollars a month for Evolocumab.

now. So the money is in the statins and there's no money for pharmaceuticals. And this sounds conspiratorial, but I'll go out on a limb here. There's no money for pharmaceutical companies in telling people to stop eating processed junk food. They're not going to make any money. There's no...

There's no drug to treat metabolic syndrome, and there probably never will be. And if the drug is ever developed, it'll probably have major side effects, but you can treat the cause of it, which is your diet, very clearly. you know, it, it rubs me a little bit the wrong way. And I said this to Derek on the podcast that, look, I respect Peter Atiyah and maybe I'll have a debate with him at some point. I think he's going to host a debate between me and Leighton Norton later this year on seed oils.

I'm not speaking badly about him. I'm just disagreeing with his ideas, but it rubs me the wrong way when he's not willing to talk about nutrition or make any real statements about what he believes in nutrition. in light of all of this, right? Because I think nutrition and the quality of the foods that we put in our bodies is the key determinant of all of this other stuff that goes in the cake. You said something that I just want to clarify. You said there's...

I'll just say that there isn't always a clear relationship between LDL levels and plaque burden. I think that we both agree that LDL slash APOB containing particles, which are a few more particles than LDL, though LDL represents the majority of it. are involved in an atherosclerotic plaque. This is pretty clear. There are also animal studies in which ApoB is knocked out and they don't get atherosclerotic plaque. Like ApoB containing lipoproteins are involved in...

atherosclerotic plaque. And so Western medicine in all of its wisdom, that's obviously tongue in cheek, says, well, let's just put ApoB as low as possible. And I want to get into this with you in a moment because... You know, Mike, ApoB is vestigial. We have antibiotics. There really are no downsides to lowering ApoB. Neonata levels of ApoB are like 30. So we'll get to that.

What are the potential downsides to lowering ApoB? Is it really just vestigial? We don't need it. That doesn't make a whole lot of sense to me. But I'll just offer an analogy that I've thought of in the past that I think is instructive, which is the idea that just because something...

Participate in a process doesn't mean it causes it. This is like wood in a house. There's a house down the road from me. That's a wood. It's a wood cabin. And a lot of us haven't seen wood cabins, but you know that the house you live in or the apartment complex where you live is made from wood.

So work with me here. But you can imagine that if you have a pile of wood that you're using to build a house, you need wood to build the house. ApoB is needed to have an atherosclerotic plaque. ApoB is essentially the wood that goes into building a house. But...

If the house burns down or there's a fire, does wood cause the fire? No, wood is involved, but it doesn't cause the fire. You can have a huge stack of wood in your woodshed. And unless... a strike of lightning comes or you smoke a cigarette, which none of you guys are doing, or you have another fire, unless you have a spark, unless your gas tank explodes in your car or a meteor comes out of the planet.

comes out of the atmosphere into this wood pile, the wood pile is not just going to spontaneously combust. So just because something is involved in a fire, more wood can lead to fires, but it doesn't cause it, right? And so I think that what Mike and I are trying so hard to... enumerate here to explain is that in the context of a human being that has an inflammatory milieu, an inflammatory quote, soup.

with a high HSCRP, with a high fasting insulin, with metabolic dysfunction. They're going to have all the markers that Mike mentioned in the beginning that are going to be off. In that type of person, more LDL.

is going to equal more atherosclerotic plaque. And that's not necessarily confusing. That makes sense. If I have a wood pile next to a stove that's putting off sparks all the time, I'm going to have more fires. And the bigger that pile of wood is, the more fires I'm going to have and the bigger those fires are going to be.

But what about where there's no sparks? And this is why I mentioned wood being used for a house, because wood is valuable. ApoB and LDL are valuable. And I think that people like Peter, Atiyah, and Derek are missing this idea or don't understand the gravity of this.

that wood is used to make a house. Wood can build you a shelter. Wood can build you a playground for your kids. Well, you can do all sorts of things with ApoB and it has all sorts of valuable roles in the human body. You don't necessarily want to...

lower it unless you understand the consequences of that. Because you could chop down all the trees in North America and guess what? There would be zero forest fires. But do we want to chop down all the trees in North America? First of all, it would really ruin all of our wilderness areas.

And second of all, like if this, I'm not a huge fan of clear cutting and logging and all these things, but like some of that wood is used for valuable things for humans. It's used to make tables. It's used to make paper, whatever. So this is the idea that just because.

Wood participates in a fire doesn't mean that wood causes the fire. And I'll let you add anything to this and maybe you can jump off onto the roles of LDL and ApoB in the human body that are valuable, Mike, and whether we want to lower it.

Just because LDL is involved in an atherosclerotic plaque doesn't mean that it causes it. And this is where I think Peter is missing. I think he's missing the forest for the trees. What he's looking at and what most doctors are looking at is a very sick human population.

in whom 86 to 93% of people have some degree of insulin resistance. And this is where the argument comes for using drugs. And we'll get to that at the end of this podcast. Well, if the majority of the population is metabolically unhealthy, we need to treat them, Paul. And I agree with that.

And I also think it's really important to note that the most important thing is to figure out how they got there rather than just giving them a drug that doesn't really correct the root cause. So why is 86% of the population... metabolically unwell. That's the main focus of both of our work is trying to understand why we're getting to this place in the first place. But the context is everything. And that if you are the equivalent of a...

of a forge where somebody is making swords and knives and you have a very hot oven and it's shooting off sparks, if you are metabolically unwell, there is an argument to lowering your LDL. There's also an argument to shutting off the oven and stopping having a bunch of sparks. But if you're someone that's just a room or a woodshed, and you're using that wood to build houses, like your immune system with ApoB, you're using ApoB for valuable things.

the risk-benefit calculation for lowering LDL becomes a lot more complicated. And that's what I appreciate you speaking to, Mike, that in people who don't appear to have a lot of sparks, who don't appear to have a lot of inflammation slash metabolic dysfunction, there's not always a relationship.

These are people who have zero CAC scores, et cetera, like we just talked about. There's not always a relationship between LDL and atherosclerosis. So I'll just say this and then I'll kick it over to you. And we'll put a clip in the podcast of a recent... interview that I saw Rhonda Patrick do with Peter Atiyah. So, like, if you were to then estimate or speculate a level of ApoB that you could say safely...

Well, I guess there's two things. One, you're not going to die of atherosclerosis if you maintain a level. Yeah. So Peter Libby from the Brigham, who's one of the authorities on this topic, has argued, and I reference him in my book. that if you had an ApoB level below about 30 milligrams per deciliter, 20 to 30 milligrams per deciliter, it wouldn't be possible to develop atherosclerosis.

What about not dying from Athos? If it's the major cause of death globally, and let's say what it takes to get down to 30 probably is pretty... aggressive. Yeah. Most people cannot get down to 30 without a pharmacologic intervention. Yeah. He was saying, well, from an evolutionary perspective, you're making this VLDL because...

As you mentioned, you know, it's transporting things throughout the body to other organs, right? Cholesterol, triglycerides, fatty acids. It's also transporting, and this is where I was so intrigued, inflammatory. So cytokines. C-reactive protein also are being transported through VLDL. Now, that was important pre-antibiotics, pre-everything that we do now to combat infectious disease and viruses and bacteria, parasites, whatever.

Before that time, that VLDL did serve that purpose too. And that's why he thinks, you know, it's kind of a relic left over where the reason why we're constantly making is because it's a very large protein in size. It's like... tens of millions of the unit versus like 50,000 or something. It's very big. And so it takes time to make it. Peter is essentially saying that he's come to believe that LDL...

and ApoB containing the proteins might be vestigial. They might just be holdovers in our evolution. Maybe they were used historically to combat infection because this is something that gets talked about very rarely, but these particles do affect that. But now we have antibiotics, Rhonda says. And so maybe we don't need as much LDL. And now maybe this vestigial component is killing you because we live in a different world.

And this to me is just, I respectfully disagree with him. I think it's an interesting idea. It's a hypothesis and I think it's really wrong. So why don't you take it from there, Mike, and let's talk a little bit about why. What are the potential downsides of lowering LDL? We'll get to the medications and the potential side effects of those. But what do ApoB containing lipoproteins, what is cholesterol contained in LDL? What does LDL do in the human body?

Do we really believe that there's no problem with lowering this? What's going on here? So before I jump into that, I do want to speak to something because we have pretty much direct evidence here in the studies for what you're talking about.

with your wood pile analogy. And the idea here is that if you don't have the sparks, then you don't have the fire, even if you have wood present. And so what they talk about in the study is say, When stratified by the presence or absence of baseline coronary artery calcium, LDLC was only associated with cardiovascular disease in 47% of patients with a CAC greater than zero.

Well, no association was observed among the 53% of patients with a CAC of zero. So basically what they're saying here is that if you don't have a positive CAC score, then the LDLC is not associated.

with cardiovascular disease. But if you do have a positive CAC score greater than zero, there are associations between LDL-C and cardiovascular disease. And this makes sense because you basically, when you understand the process of the formation of plaque involves the movement of LDL particles, generally modified LDL particles across the vascular wall that basically triggers an inflammatory response in the vascular wall.

And then you have the immune system come in and the macrophages start to interact with the LDL, gobble it up and create these lipid loaded foam cells. And now you start to get plaque formation. And so if that process is already going on. and you have more cholesterol floating around, and in this state, the cholesterol that's floating around has many factors going towards it that are likely to modify it. There's oxidative modification.

There's deceleration modification. There's a negative charge modification and there's size and density modification. And these all happen in metabolic dysfunction. So metabolic dysfunction is leading to these modifications, inflammatory response.

impaired glucose tolerance, mitochondrial dysfunction. And then what happens is the LDL starts to become inflammatory when it interacts with the vascular wall and then you have the immune response. So with all of this going on, if LDL is higher, then yeah, it would make sense.

that you're going to have this problem because you have all these fires going on. And so the LDL has a lot of opportunity to interact with those fires and create the problem. But if you don't have the fires, then you're not going to have the oxidation of the LDL. And you're not going to have the plaque formation. And that's why you see people who clearly don't have the fires with a CAC source of zero. It's telling us there's no fire present.

The LDL is not associated with the cardiovascular disease. But when you have people where their CAC score is greater than zero, what is that telling us? They have a bunch of fires going on. And so all the wood they have floating around, that LDL is much more likely. to create plaque formation and drive cardiovascular disease. Now, is LDL the problem? No, it's not the direct problem. The fires are the problem, but the LDL gets involved in this process.

And so the primary focus here is putting out that should be, in my opinion, putting out the fires. We can look at LDL. And if you have somebody who has all the fires going on, you want to talk about lowering their cholesterol values to help. delay the progression of the disease process while you manage the fires, there could be rational arguments put in place for that. But if you don't have the fires present.

Just stratifying people by an LDL value or an A will be value and saying we need to smash everyone's values down low, even though there's no fires present is a relatively tenuous argument to make. It doesn't really make much sense because it's not contextually based.

And the context is the absolute key. The devil is in the details here. So we need to know what the person's context is. So that's really important. And this is why, sure, in the general population tying into the metabolically impaired population in the U.S. It's like, do we want to try to get their cholesterol values under control if they have atherogenic dyslipidemia? Yeah, we do. But do we want to just do it through a drug regimen that only marginally lowers the percent risk?

Or do we want to fix the fires? And it's like, we want to really fix the fires. And maybe you have some options that help to lower risk in the meantime. Fine. Make an argument for that if you want to. There are a lot of people are. But I think the primary focus is... Let's fix the metabolically unhealthy population. And we know at this point, at least in my experience, working with hundreds of people, it's diet and lifestyle and then supplementation, medication, hormonal assistance.

Those things have to come first. The diet and the lifestyle are absolutely key. The reason people are having these problems is because of their diet and their lifestyle. If you're loading up on processed, heated, polyunsaturated fats.

You don't have nutrient density present to protect you and have mitochondrial function work appropriately. You're creating dysbiosis in your gut from eating processed food, which is driving endotoxin leak into the bloodstream. And you have all this stuff going on. Plus you have chronic stress.

from whatever your specific lifestyle choices are with work, with family, with kids, whatever the thing is, you basically are creating the perfect recipe for metabolic dysfunction. You are creating the metabolic dysfunction cake. You have all the ingredients. And so those are the things that need to be targeted. And then the LDL, like, sure, you can use, you can manage multiple problems in that process of correcting this dysfunction, but you still need to correct this dysfunction.

But in modern medicine, that's not what happens. You get lip service from your doctor about, oh, go eat healthy, like do that Mediterranean diet thing. I heard that's good. Or maybe, maybe like eat less, exercise more. Or maybe eat food, mostly plants, not too much. Like these generic paradigms that are ambiguous, not specific, don't tell you what you need to do. And then, oh, but take all these drugs at this specific dose at this specific time.

And then we're going to stack them perpetually, right? First, you get a statin. Then maybe it's a zetimibe. then maybe they're going to start doing the PCSK9 inhibitors in different groups. Then you have Losartan. Then Losartan's not cutting it, so maybe you have to add on them Lodipine. And then maybe a diuretic, right? So it's like you start stacking on these drugs.

to manage the problem as it progressively gets worse while you never fix the other problems. And then you get down, you're like 60 years old and your cholesterol smashed and you're still pre-diabetic or diabetic. And then you get a heart attack and you're like, but I took all the drugs. It's like because you never solve the underlying problem. Are some of the drugs helpful to manage what's going on, the dysfunction? Sure, they are. There's no doubt about some of the drugs being helpful.

But you have to know what the risk reward is on each drug. And it's very specific to that drug. So just because a drug lowers cholesterol doesn't mean that it's a good drug to use. And we see this with statins. And I bet you money we're going to see this with these other drugs. And we'll talk about them.

But we don't really have all the information on some of these drugs because another thing to point out, and we'll talk about this, Paul, is that they are relatively new. And so while we have clinical trials, we don't have decades of research letting us know what the long-term implications of some of these things are either.

And you're not going to, this is why pharmaceutical companies have things like post-marketing surveillance where after they release a drug, they're like, oh, is there other stuff that we didn't know about from our, for our shorter term trials that will play out in decades timeframe? yeah let's just like survey and see what's going on and then all of a sudden down the line it's like oh wow we have to put black box warnings on some of these drugs

Because they, oh, maybe they cause increased risk of heart attacks or maybe they cause increased risk of diabetes like statins do or cancer with something considered with statins as well. So those are really important pieces to understand. And the other thing.

getting to your very specific question now about cholesterol. And then I'll pass you for one sec. Yeah, go ahead. Can I just add, I'm sorry to interrupt. We'll get there in one minute. I just want to add to this that of all the markers that you listed in the beginning, we know specifically. that seed oils raise oxidized LDL and they raise LPPLA too. So there are clear randomized controlled studies in humans.

showing that seed oils do both of those things. High omega-6 seed oils raise LPPLA2, which is lipoprotein phospholipase A2, and they raise oxidized LDL. And that to me is pretty interesting because those are more of the smoking guns with seed oil. So I just want to put that in there that if we're...

Because I know people are probably thinking in their mind, okay, what is causing the metabolic dysfunction? And you enumerated it. It's garbage food, full of seed oils, full of carrageenan or certain types of carrageenan. If you guys want to fix the problem at its root... just eat unprocessed animal and plant foods and you'll be fine. And that means meat, whatever type of meat you want, high level, there's all sorts of granularity there. And whatever type of plants you want, high level, fine.

Some people have more sensitivities to certain plants, and we've talked about that on previous podcasts. But if you just eat unprocessed animal and plant foods, you will basically fix your insulin resistance. And that is something I believe both of us agree with.

I just want to put that out there for people. So that's the answer. That's the huge takeaway of the whole podcast that Western Medicine is missing because they just give, like you said, Mike, these pithy sayings like, eat less, move more, blah, blah, blah. I'll just say this and then we'll get into the LDL stuff and the benefits or the potential downsides of lowering it before we get into the drugs. The United States Dietary Guidelines Committee recently came out.

And these are the people who are going to make the guidelines from 2025 to 2030 for the US Dietary Guidelines. Your United States government committee recently came out and said, we don't know if there's enough evidence yet.

to say that processed foods contribute to obesity. And they think they said, we need more studies, but like, when are those studies coming out? Not anytime soon. And this is crazy to me. So your dietary guidelines committee in the United States government is- feels like there's inadequate evidence to say that processed foods contribute to obesity, but they're more than happy, you know, similar committees with the IARC are more than happy to call red meat a carcinogen.

blah, blah, blah. But when in fact, the evidence for red meat being harmful for humans is incredibly weak and poor quality, and the evidence for processed foods, ultra-processed foods contributing to obesity is very strong, they're just not sure.

So the door is open, you know, it's just calories in, calories out, Mike. And I think that that is why I rebel against that so much because, and we keep going off on these tangents, we're going to get to the LDL in a minute because this is why I think this notion is so insidious.

Because if humans are confused, and I think this is a FUD, which is a Bitcoin term for a fear, uncertainty, disbelief. This is just something that's meant to be confusing for humans. And I think that those in the health community who are saying to people, you can eat whatever you want.

just eat less of it are missing the point because there's no equation for food quality. And when there's no equation for food quality, we end up with all of these ultra-processed food ingredients, like you said, that are potentially damaging the gut, increasing... lipopolysaccharide, which is endotoxin, contributing to evolutionarily inconsistent levels of omega-6 in the membranes leading to oxidation or mitochondrial dysfunction. All of that happens in a...

you know, hypocaloric state or an equal caloric state if your food is low quality. So this to me is a huge disservice to humans to not talk about food quality. And this is why glucose goddess drives me crazy because... All she seems to be saying is just keep your glucose low. You can eat whatever you want. And I just think that's completely wrong. I mean, she has on her website, you know, the advertisement for her supplement. And admittedly, I...

you know, I built supplement companies that sell organs. So I'm also, you know, a business owner, but on the supplement website, she has this rolling banner of just saying like, you can eat whatever you want. And there's cake. brownies, cookies, bagels, pizza, pasta, as long as you take my supplement, which will keep your glucose low. And I think, okay, this is...

I think she's well-intentioned. I think she's completely off base. So sorry, I'm rambling on that. I'll let you add anything you want and then we can go into LDL and why lowering it might not be a good idea. So I have three points that I want to touch on here. All right. I love it. Specifically to the glucose goddess one, I made a video on her on my channel, Mike Dave YouTube. And I basically pointed out that she doesn't even read the studies that she cites.

So she's like citing a bunch of studies for different things. And then she's not reading what the outcomes are and what's going on. And she's making like clear errors. And even when she's comparing things, like she compares orange juice to pure glucose or to Coke.

It's non-comparable in many different ways besides the fact that the sugar content is the same. So it's basically a fallacious straw man argument to say, oh, they're exactly the same. She's doing things like this. But I think it's a marketing ploy largely.

Because it speaks to people that are like, well, I don't really have to change the foods that I really like these processed foods. I just need to have less sugar. So people want this really simplified basic answer. And she's trying to speak to that. But that's if you want outcomes.

If you really want to improve your health, you want to put out the fires. That is not like managing blood glucose is but one strategy in an entire toolkit of strategies. And if you want to throw all your eggs and just a one strategy like basis.

it's a pretty like your outcomes are really i don't think are going to be that great overall not that blood glucose management isn't important it is but it's just like to just throw it on this idea that yeah i just eat less sugar and i manage my blood glucose and like i can still

eat all these foods that i don't want to as long as i manage or that are not good for me that as long as i manage this and that is like that's not going to get people long-term outcomes and i i know this because i work with people regularly so i think there's like

I think it's important. Like the value she brings is talking about blood sugar, but then everything, a lot of the other things after that are really questionable from a health basis. Especially if you like, I read the studies, like looked at some of her videos and I'm reading the studies that she's citing.

And I'm going through that. I'm like, I don't know what this lady's talking about in some of these places. So that's a big one. The next one I want to talk about is that I do have a guide on my website. It's called Nutrition Blueprint, where it runs down how to set up your diet. It's free.

video course in PDF that tells you how to structure out your diet. And so something to keep in mind with dietary structure is you want to know your needs, your caloric needs, that you're not massively overeating, you're not massively under eating. But again, that is one strategy.

So you know what your caloric requirements are, but then you need to know what protein you need, how much carbs you need, how much fat you need, what sources of foods work for your body that you want to use to hit those targets. And then are you hitting your micronutrients? And then maybe you take a liver capsule to cover some of those micronutrients. Maybe you take vitamin D to cover some micronutrients or go out in the sun and things like this. So there's a multi-tiered approach.

to managing the diet that's not just calories and it's not just blood glucose regulation. It's multiple steps to get things right. And there are specific targets to do this so that it is not ambiguous. And that's extremely important to get those right. This is what I'm doing with people. That's why I made that guide is to help people organize these things in a step-by-step fashion to get these things right because they make a massive difference. I mean, I have clients I'm working with.

I have one guy, we started out about 300 pounds on hundreds of units of insulin a day. And he's done all the doctors. He's done all the alternative practices. And we change his diet around. And now we're 100 pounds down. We're on one quarter of the amount of insulin he's using. His lipid profile moves into range that's not atherogenic anymore. Testosterone increases. And so you see these changes from diet alone.

We have supplements on board, but most of that was from diet because he was already supplementing out the wazoo. We're listening to all the podcasts and listening to all these influencers, but his diet wasn't right. And so once you get those things right, and the spoiler alert.

It was this diet is like steak, potatoes, fruit. And then I think he has some type of cooked vegetables in there or some type of vegetable and then some type of soup with some types of legumes because he liked it. That's fine. All of those things were fine. Whole foods diet, plant foods, animal foods. And again, like massive change in his outcomes. And he was on all the medications. He's on multiple medications. So I think it's really, I can't hammer home enough.

how important that dietary stuff is paul i want to reiterate that because i think you're 100 correct about that and i want to let people know that there are those multiple tiers to correct the last piece that i want to bring in here is i want to bring back to the poop that you were talking about And there's a great article. It's called Omega-6 vegetable oils as a driver of coronary heart disease. It's by James D. Nicolantonio and James O'Keefe.

And basically they have a rundown in this article talking about how linoleic acid is directly implicated in cardiovascular disease. And they have basically 21 points that obliterate. linoleic acid as as like one of the primary promoters and what they say here i'm going to read a couple of them they say greater amounts of linoleic acid oxidation products are found in ldl and plasma of patients with atherosclerosis

So they have oxidized LDL in higher amounts in people who have atherosclerosis. There's greater amounts of linoleic oxidation products are found within atherosclerotic plaques, and the degree of oxidation determines the severity of atherosclerosis. So the more oxidized linoleic acid you have in the plaque, the worse the plaque. A diet higher in oleic acid or lower in linoleic acid decreases LDL's ability to oxidize, susceptibility to oxidation.

So less linoleic acid in the LDL, less oxidation. Endothelial cells oxidized LDL forming linoleic acid hydroperoxides. So when you're getting these oxidized LDL... It's usually from linoleic acid hydroperoxides or oxidized linoleic acid. Linoleic acid is the most abundant fatty acid in LDL, is an extremely vulnerable to oxidation, being one of the very first fatty acids to oxidize.

So we know LDL is a polyunsaturated fat and can readily peroxidize under being exposed to fires, which we're seeing in the metabolic dysfunction. They say a meta-analysis of randomized controlled trials in humans found that when saturated fats plus trans fat is replaced with omega-6 fat, high in linoleic acid. There is an increase in all-cause mortality, ischemic heart disease, mortality, and cardiovascular mortality.

And then the last one I'll read here is that the oxidation of linoleic acid and LDL leads to conjugated dienes, which can conveniently bind to ApoB, altering its structure, creating oxidized LDL. Oxidized LDL is no longer recognized by the LDL receptor on the liver, but scavenger receptors on macrophages causing monocyte infiltration into the subendothelium bone cell formation and eventually atherosclerosis. So the...

When you get linoleic acid in the LDL particle and it oxidizes, it damaged the ApoB, which is the protein in the LDL particle. And that is one of the key initiating steps driving the activation of... the endothelial cells, and also the immune activation. So there's multiple pieces of evidence there implicating seed oils in cardiovascular disease. And just to tag onto this, if you look at the trends in cardiovascular disease.

Cardiovascular disease started ramping up until about the 1950s and 60s because people were smoking a ridiculous amount. And then... when the smoking calmed down with all the ads and litigation, all the stuff that went on during the 50s and 60s, somewhere around that timeframe, cardiovascular disease starts to taper off. But what happens is then we start to implement seed oils around this time.

And what do you know? The trend of cardiovascular disease worsens with diabetes and obesity. And now research is like, hmm, we don't really know why we're getting all of this cardiovascular disease. And then it's like, well, if you start to look at the trends, not with carbohydrate consumption, not with sugar consumption, but with seed oil consumption, omega-6, polyunsaturated fatty acids, soybean oil, canola oil, margarine.

these types of things, what you start to see is, oh, wow, there seems to be some type of relationship with these disease processes and metabolic dysfunction and these seed oils. And so you're seeing some of these trends play out and we have these relationships. And so the seed oil piece is a huge thing. And it's in every single food, almost every single food. You go to restaurants, they're cooking in seed oils. You eat packaged food, it's cooked in seed oils. And the worst thing is.

The seed oils in these foods are high temperature processed, which they're already damaged versus like people, oh, well, nuts and seeds have omega six. It's like, OK, I don't think that's ideal long term. But most people are really just sucking up heated. polyunsaturated fats from processed foods or even if you go out to a restaurant, they're rubbing your steak down in grapeseed oil or canola oil before they fry it. So these are things to keep in mind.

in terms of your exposure, because these are some of the major, at least in my perspective, from what I've read in the research, and I think we would agree here that this is one of the major components driving some of these problems. I completely agree. And yeah, thank you for hammering that home and pointing that out. I think that it's massive. And I'm just reminded that one of my vegan friends posted something yesterday on Instagram that my team sent me. And he said,

The overwhelming majority of evidence shows that omega-6 linoleic acid is cardioprotective. And I thought, oh, we still have work to do. I'm going to try and get him on the podcast for a debate. And like I said, I'm going to try and debate Lane Norton. on Peter Attia's podcast on seed oils. It's kind of like the cholesterol literature. It's confusing. And unless you read it carefully, you could be misled. So we'll see.

But let's get into, I mean, I think that that lays it out very clearly for people and hopefully they understand that seed oils and a lot of these things are causing LDL to become modified and oxidized. And oxidized LDL is very atherogenic and native LDL probably isn't. But it's the milieu. It's the sort of background. It's the stew of your body, the context of your body that determines how much that LDL is getting.

to that inflammatory state. It's getting to that problematic state. And that's what it's all about. You have to change. You have to change what's in your stew, guys. You have to change the total context of your body. So, Mike. LDL is vestigial. Let's just lower it. If we get rid of all the LDL, none of us will ever die of cardiovascular disease, which may be true. Are there any problems with this perspective? I think there's pretty significant problems with this perspective.

especially because we see that LDL isn't the direct causative agent in cardiovascular disease. It's part of that recipe, but it's not the main factor that's driving it. It's the fires, I would argue. And so then it means like from the... basic perspective is like, well, we don't, the question is not like, do we just smash this all the way down? It's like, well, let's put out the fires. And so this is like, this whole argument becomes tangential or becomes kind of irrelevant.

around like let's just lower everyone's ldl with all these drugs right once once you see it's the fires like why are we even thinking about that it's like let's focus on the fires so i think that's the first piece but in terms of ldls function in the body It's involved in a variety of different areas, right? So it's involved in cell membranes. So cells, all cells have a membrane around them and cholesterol constitutes about 25 to 30% of the cell membrane.

Now, the membrane can, the cells can produce their cholesterol, but they also take up cholesterol from LDL. And so something to consider with LDL is LDL is basically just a protein or a series of proteins. that is carrying fats in the blood because fat lipids and water don't mix. Fats and water don't mix, right? You don't mix oil and water. It separates. So you need to have a protein.

that binds all the lipids together and allows them to transport. So we're literally just looking at transports of different lipids through the blood with this thing, with this protein. The major one is ApoB100 is secreted by the liver onto VLDL. And then it eventually becomes LDL as the fats are kind of taken off over time and transported around to the tissue. So it's literally, it's just basically your Amazon guy. It's your Amazon truck or your UPS truck.

with a bunch of packages in the back of the truck, delivering those packages to all the neighborhoods and people. And those are your cells and your tissues. And so it's an important carrier molecule. This is what it's necessary for. And then the next thing is the L. With that said, while carrying lipids, it's also very important in immune function and binding up different toxins like lipopolysaccharide, endotoxin, and also binding up viral particles and modulating immune response.

The LDL also drops off the cholesterol and lipids to your testicles, your ovaries, and your adrenal glands so that you can produce cortisol. testosterone, dehydrotestosterone, estrogen and progesterone, all these very important steroid hormones. So it's necessary to actually have some of this. And interestingly, in some of the statin studies, if you do lower the cholesterol, you do also lower.

Not massively. It depends on how much you lower the cholesterol, but you do also lower pretty significantly or you significantly lower things like testosterone. So testosterone levels go lower when you use statins. It's about, I think, 70 point drop from total, which is not massive, but you do see this happen. So the question is if you even lower it further is a problem. And I think that it would be. The next thing.

is cholesterol is involved in bile acid production. So your liver produces bile acids, and these are essential to digestive function. So if you don't have the bile acids, and I know this personally because I have my gallbladder taken out when I was in high school, unfortunately.

It can really mess up your ability to digest fat-soluble nutrients, to clear out the small intestine of bacteria, to trigger small intestinal defense, to detoxify endotoxin, and to also emulsify the fats that you're going to eat on a regular basis. And so you really want to actually have adequate amounts of bile acids. So cholesterol is key. These are just some of the processes. There's more processes that cholesterol is directly involved with, but it's absolutely key.

in the body overall and it has a variety of necessary functions and ldl is important in transporting the cholesterol to all these tissues because the liver is a major production site of cholesterol so the idea that it's vestigial i think is like you would have a really hard time making argument for that so you can say whatever you want you can say it's vestigial but i would really like to see all the lines of reasoning basically discounting all these different components

showing that it's actually vestigial because there's so many functions of LDL and cholesterol in general that to just say like, oh, yeah, it's vestigials. You know, that's a that's a you need to have a big burden of proof for that. So that's the first piece I would say is the cholesterol and LDL have a, the cholesterol is a variety of functions. LDL is transporting that cholesterol and there's a variety of benefits to it. And I also, as we talked about already, the LDL, I don't think is.

causing the cardiovascular disease, it's the fires because as we talked about, the LDL actually needs to be modified. So there needs to be some problematic effect on the LDL structure. And the question is, what is more causing that? which I think invalidates this vestigial idea unless there's a bigger burden of proof on the person making the claim. It's actually like they provide that burden of proof. Yeah, so this is, I think...

one of the more important points for people to understand is that this is wood. And you use wood to build a house. ApoB, LDL has valuable roles in the human body. The immune response. There's really... interesting studies in animal models where they can induce infections and they can either lower or raise the amount of LDL or ApoB. And the animal's survival depends on how much ApoB they have. So the more ApoB, the better they survive, probably because...

These ApoB containing lipoproteins, including LDL, and also lipoproteins like HDL that don't contain ApoB, interrupt quorum sensing. They interrupt communication between bacteria and potentially even viruses. And they do, like you said, they can affect endotoxin. They can bind endotoxin. And that's a subject for a different podcast. And I talked to Jay about that.

You guys have a podcast together. Guys, Jay Feldman's been on the podcast in the past. And I mean, endotoxin in the human body is one of the major drivers of human disease at a lot of levels. It creates a lot of stress. And so lowering LDL means you have...

less of the catcher's mitts for a endotoxin at a very, you know, broad levels. There's less things there and it's participating in the immune response in many ways. It's a precursor for steroid hormones, testosterone, things that make our lives worth living and vital.

All of these things are critical. It's crazy to me that we're saying, oh, it's okay to have neonatal levels of LDL. There's no downside here. I think this is actually a great quick segue into some of these drugs because there are... as we said, some studies on genetic mutants of people who have very low LDL, specifically people with PCSK9 or other polymorphisms or mutations, I think in this case.

But we talked a little bit earlier about people with high LDL. These are people with familial hypercholesterolemia. And again, I think that is really a genetic disease, though mainstream medicine says it's a phenotype, which again, I disagree with. But let's just talk about these PCSK9 because this comes up a lot. These are evalocumab. These are monoclonal antibodies to the PCSK9 protein, which is involved in LDL receptor.

The only thing most listeners need to know here is that if you have a PCSK9 inhibitor, you're going to have much, much lower levels of LDL. So Mike, what do we see in people with genetically low PCSK9? people that then have higher LDL receptors and lower LDL. What do we see in these genetic mutants, PCSK9? So this was something that...

got propositions inside your podcast with Derek, where he's like, well, we don't really see any problems with people who have these genetic variants on PCSK9. And so actually that's not true. there actually are problems with the people who have the PCSK9 genetic variants. And I think this actually plays out in some of the Mendelian randomization analysis of these people.

which is some of the research that some of the lipid people really like to rely on. And so what they say here, the study is titled, for anybody who's interested, Safety and Tolerability of PCSK9 Inhibitors Current Insights. And they say in meta-analysis of genetic association studies for certain PCSK9 genetic variants, there was a 19% increase in the incidence of type 2 diabetes per one millimole per liter genetically predicted reduction.

and ldlc so for every 38.67 milligrams per deciliter of ldlc that was reduced for people who had these genetic variants with for pcs k9 there was a subsequent 19 increase in incidence of diabetes So the lower their LDL levels were with these genetic variants, the higher the risk of diabetes, which is not like, I don't know about you, Paul, but I don't really look forward to having a higher risk of diabetes by 20% almost for one, for the one.

millimole per liter drop in LDL. They say, furthermore, in a Mendelian randomization analysis, after adjustment for a standard decrement of 10 milligrams per deciliter in LDL-C levels, PCSK9 genetic variants were associated with 11.2% increased risk of diabetes mellitus. So this is a Mendelian randomization showing us this now. And they say, in addition, a large-scale Mendelian randomization study demonstrated...

that certain genetic PCSK9 variants scaled to one millimole per liter lower LDL-C were associated with a 29% increase in the risk of type 2 diabetes. Moreover, These specific PCSK9 variants were associated with adverse metabolic consequences, including increased fasting glucose, increased body weight, and an increased waist-to-hip ratio.

So basically what you're seeing is like those are the features of metabolic dysfunction. So messing around with PCSK9 and people who they have this genetically, like they're born like this actually leads to increased risk. of diabetes and metabolic dysfunction, which is highly problematic because it's saying you have an increased risk of developing the fires, even though your cholesterol is lower. And so that's a huge problem.

Now, I want to leave the floor here, Paul, but I do want to say there's also studies looking at people who have HMG-CoA reductase genetic variants, which are the same. uh, the same enzyme that stands target. And the same, we basically also have non-favorable effects, but we'll leave this. I want to leave this here for you. Cause I know this is something that, that, that, uh, Derek was quizzing you on the, on the podcast. And it's like, well, here's proof.

with mendelian randomization studies that there is actually problems with pcs k9 people who have genetic knockout or genetic alterations or variants of pcs k9 and he's saying well i don't really see any problems it's like I guess if you consider that having diabetes isn't a problem, then sure, there aren't any problems. But we see that there is an increased risk in that. So that puts caution to the effects of drugs. And we'll talk about it.

And we'll talk about it just a bit, the effects of these drugs and like their risk versus reward profile. But I want to leave it here. And then we can talk about the HMG-CoA reductase ones as well. Yeah, yeah. We can talk about HMG-CoA reductase. And there's a study we can talk about.

showing the same thing with HMGQA reductase polymorphisms, that there's an increased incidence of diabetes. And we know, as we'll talk about foreshadowing, we'll get to it in a moment, that statins appear to have a signal for increased diabetes. And so it's like, okay, let's just... be honest, like we said at the beginning of the podcast, let's be honest about the risk reward ratio here. I did a talk recently here at a conference and somebody came up to me at the end of the talk and said, well,

Why wouldn't I want to lower my LDL as low as possible? Because, I mean, the argument that Peter has made is that cardiovascular disease is the number one killer. Therefore... your main focus for living a long amount of time should be lowering your LDL as low as possible because we know that if you lower your LDL, you're less likely to die of cardiovascular disease. And that may be true. I think that's probably true.

The lower your LDL, the lower your risk of dying from cardiovascular disease. But what about your risk of dying from other things? Complications of diabetes, dementia, cancers. There are all sorts of other risks. And this is something that Dave Feldman has raised. Dave Feldman being one of the authors of the study that we mentioned earlier with Matt Budoff, cardiac radiologist. You know, Dave Feldman has raised this question like,

What is the effect on all-cause mortality of many of these lipid-lowering interventions? This is a really important question, and just so people understand. What we're talking about here is all-cause mortality versus cardiovascular mortality. Statins in people who have had heart attacks, they do lower cardiovascular mortality marginally. Yes, true, marginally, but not in people who have not had heart attacks, right? And we'll get to all this in a moment. We'll flesh it all out.

But then what about all-cause mortality, right? And then what about all these other drugs? What about bempadoic acid, which is what Derek asked about? What about PCSK9 inhibitors? Do any of these drugs really lower... all cause mortality versus cardiovascular disease mortality. So this is the question, like ultimately at the end of the day as humans, it's not important.

what we die of, it's just important that we don't die. And again, I'm sort of pulling, I mean, this is funny that I'm pulling Brian Johnson's thing, a guy that I disagree with on so many ways, but it's not like-

If you die all the same, if you lower your LDL and you don't die of cardiovascular disease, but you die all the same, what was the point? You just missed the point. Like if you didn't live any longer or your quality of life didn't get any better, and presumably your quality of life may have gotten worse.

then we have a problem here because we know that these medications cause a decline in quality of life. I can tell you, Mike, when I was a physician assistant before I went back to medical school, I was working in cardiology and I saw people all the time taking statins. I prescribed these drugs to people. I was a speaker for Pfizer. They paid me money to give talks about Lipitor. This is my previous life where I didn't know any better. So I gave talks for Pfizer about Lipitor because...

I'm a PA. I don't make that much money. And it's good money to talk about Lipitor. And I'm a good soldier in medicine. Lipitor being a tortoise statin. And I saw people all the time that I had prescribed statins to, that I continued statin prescriptions from the cardiologists to.

who had memory loss, who had decline in libido, sexual function, erectile dysfunction, muscle aches. And I've talked about this on previous podcasts, but the side effect risk profiles that are documented for statins are massively deflated. There are all sorts of ways that manufacturers, pharmaceutical manufacturers, can do washout periods and remove people who have side effects of the statins before they even go into trials.

To suggest that Lipitor has a side effect profile of two, one to 3% is just hogwash. Any clinician that tells you that what Pfizer, who's the maker of Lipitor, tells you about the incidence of side effects from Lipitor.

That's never going to be what they see in clinical practice. What I saw was more like 30%. So I'm just saying that in my clinical experience, Pfizer is completely misleading us, right? And I think we're being misled on a lot of the side effect profiles of many of these drugs. So I'll just put that in there. Yeah, I think let's talk about HMG-CoA reductase, polymorphisms, and we can get into statins, and then let's talk about the rest of the drugs, benfenoic acid.

PTSD-K9, ezetimibe, some of these others. And let's just flesh out these risk-reward profiles for people because it's just important to consider what is the effect on all-cause mortality and what's being... I think ignored by Peter Atiyah and many others in the space, is you lower your cardiovascular risk, but what's going on on the other side? And lowering your cardiovascular risk isn't without a cost. Like, how do you lower your LDL? Most people are going to have to take a drug.

Like you don't just lower your LDL unless you're, I mean, the way to do it with diet is to eat less animal fats, which have other nutrients. So anyway, none of this is without a cost. Yeah. Yeah. And also we'll talk about what the, what the actual risk is, like what the side of the profile and.

consider long-term risk for each drug. So I do want to touch on this HMGA-CoA genetic variant. Because this is something that Derek specifically had brought up as well. We have these people, have these genetic variants, and we don't see any problems.

and that is actually i mean or at least he was kind of asking or making mention of that but we do see problems so there's like and i'm gonna cite we'll cite the studies we have all the quotes pulled out and everything ready for everybody here but basically they they say here This is statin-induced diabetes incidence mechanisms and implications of the study. It's from Ganda in 2016. They say an exciting new observation, exciting, polymorphism leading to a reduced activity of HMG-CoA reductase.

This is the enzyme that statins block, is associated with lower LDL-C, a significant increase in body weight and features of insulin resistance. This observation was validated in the randomized statin trials. One particular allel was associated with significant increase in risk of new diabetes. Since the statins inhibit HMG-CoA reductase as their mode of action, this may at least partly explain their diabetogenic effect. And so we'll talk about statins' diabetogenic effect.

But basically, some of these drugs that are lowering cholesterol through interacting with some of these enzymes or proteins, PCSK9 and HMG-CoA reductase, when they have genetic knockouts or genetic variants. basically what you find is these people have increased risk of diabetes, which is the side effect profile that you see with cardiovascular disease, with the stat or with the statins. And so this is really important to point out because it's like.

Derek's point was like, oh, there's no problems. There is problems. And so this will lead us into the drug talk about some of the risk factors. So one of the things that I want to touch on that we didn't get to directly touch on, we kind of just mentioned. But basically, with LDL-C, there is a variety of research in different countries showing a U-shaped curve with LDL-C values and mortality, in general, all-cause mortality.

and basically what they find is that the ldlc that actually had this is just ldl not total cholesterol but the ldlc value that was associated with the lowest all-cause mortality is from like all things was about 140 milligrams per deciliter

and that's in people who aren't on statins and statins is about 89 milligrams per deciliter and they are able to replicate this across multiple studies and in multiple multiple different areas and there's tons of graphs here basically showing these relationships And then even for some of the cardiovascular disease risk factors, the LDLC values were really not as low as you would think they'd be in normal people. For overall, CVD is about 120.

for hypertensive disease is about 120. Ischemic heart disease is between about 100, it looks at here, it's about 90 to 100. Acute myocardial infarction. The values here go into nanomoles. So it looks about, I don't know the conversion off the top of my head in milligrams per deciliter, but it looks about almost two. And so we're looking at these and it's like, they're not really that low.

for some of the values for cardiovascular risk. And then for all-cause mortality, it's actually really not that low at 140, which is way above these specific targets. So there's a ton of papers from different countries showing this, even in cancer. There's also a U-shaped curve where basically about 142 milligrams per deciliter of LDL cholesterol was associated with the lowest mortality curve. And then the other thing is in sepsis and infections.

Basically, if you have lower LDL and HDL, it's associated with higher mortality levels. And also, that's in sepsis, and that's also in COVID infections, where basically they say low LDL serum levels. are independently associated with higher 30-day mortality in COVID-19 patients. And there's a ton of research here looking at this for infection. So this goes to your point, and the reason I wanted to bring this up is because you're talking about how...

You know, the drugs change cardiovascular mortality. And maybe some of them don't even change cardiovascular mortality. They just change cardiovascular risk for non-fatal events. but they but they're not changing all cause mortality there's a bunch of ways that you can die where and then those other ways the ldlc values are not as low as what the drugs are producing and the lower values are actually associated with more mortality so if we wanted to get a true risk factor picture

we would have to take in consideration things of intracranial hemorrhage, so like hemorrhagic strokes, which basically lower, higher cholesterol levels are protective of. Infection, that's respiratory, that's sepsis.

That's pneumonia. That's all of these types of things. That's COVID viral infections. And then we want to take a look at things like cancer and general all-cause mortality. And then we can look at cardiovascular mortality and cardiovascular risk profiles. And you want to put them all together.

and then say, oh, how low does the cholesterol have to be? Not just do we change these cardiovascular events as endpoints. So that's another really important piece that I think is... that I think would be necessary to consider to get a really comprehensive understanding of what's going on with lowering cholesterol because we are getting these U-shaped curves where really basically what happens is at the bottom, you have the lowest risk of all cause mortality.

And as you go higher, you get a higher risk. But as you go lower, you also get a higher risk. And so that also would be like, OK, let's pause for a second and let's try to understand. why that's the case. And like, is there a reason that we shouldn't push the cholesterol values that low? And these are signals saying that maybe we shouldn't. And then when we start to get into the drugs here.

And like some of the, what they're showing that I think that's also a really important piece to dive into is like the drugs are lowering it, but are, what are they really changing? What's getting worse? What's the possible side effect profile? and then take that in consideration with the all-cause mortality factors. And it actually makes it so that it's not really clear that just lowering cardiovascular disease with these drugs is necessarily a good idea.

And that is especially the case, which was your point, Paul, on Derek's podcast, in someone who is healthy, who is healthy by all means, but just has a higher than ideal cholesterol value. It's like, oh, well, maybe maybe we should actually really consider this and lay out all the factors for this risk risk reward profile. Like, let's do our Benjamin Franklin list, our pros versus cons and weigh this. And I think in these arguments from some of these other individuals.

They are not really doing their full pro versus cons list. And they're just looking at these like hyper reductionistic stratified groups with risk factors for different to think. different components related to cholesterol and trying to make determinations based off of that instead of taking the full context into consideration and then and then trying to trying to make decisions from there and trying to figure out the best strategy.

possible from like the reasons that these things are from the root reasons that these things are developing and so that's why we're that's why we're diving into this to see like well what's really going on now before we dive into the drugs something i want to mention is And I talked about this just a little bit before is that you won't know the full effect of a drug in a population until it's been in the population for decades. So if you have a drug.

For example, benbedoic acid FDA approval in 2020, like we don't know what its long-term effects are after people take this drug for decades. And so that's a huge problem. So like you can have all these fancy ideas because Derek really likes to promote on his podcast a lot of different fancy and complex drug regimens for a variety of problems. Or maybe he talks about them. Maybe he's not promoting them. I know he has a disclaimer, so I don't want to.

create that issue. But he's talking, oh, well, this drug, it only does this and it lowers cholesterol. But it's like, we don't actually know the long-term effects. And we'll talk about the mechanism. So that was in 2020. Then we have the PCSK9 inhibitors. They came out in 2015.

So we don't even have a decade under our belt of them and not many people are put on them because you have to be in a very specific subgroup to get them because they're extremely expensive insurance. I don't think wants to cover the prices on some of those. So PCSK9 2015, benbedoic acid 2020, ezetimibe was actually in 2002. So we have, what, 23 years of information on it.

So that's pretty good. But azetimibe is like the least beneficial of all of them. And it usually has to be combined with other drugs because its mechanism is it just blocks absorption. So like, sure, like maybe it's less risk, but the reward profile on it, at least even in their context, is really small. So whatever about ezetimibe. It's kind of a whatever drug. Maybe you add it on. But that's it's not the it's not the prime mover here.

And then statins, they were approved in 1987. So we have the longest profile on them. But something interesting to note about statins is in 2004, the basically... The guidelines on running trials or the guidelines to set up trials had to be changed because they were there was an unfair kind of an unfair.

influence of pharmaceutical companies on the researchers and people doing the trials and so we didn't we couldn't get a fair profile on statins until the guidelines changed in 2004 because the other styles The other trials that had been done before that timeframe had been possibly influenced by the pharmaceutical companies, marketing and the researchers, all this type of stuff.

So we really don't have a full profile on statins until 2004. And then even worse than that is we have a really negative effect of statins over time. that a lot of people are not using, whether that's myopathy, whether that's diabetes, whether that's cancer, whether that's infection. We'll talk about all those. But I want to read a quote here really quick just to hammer this point home.

So the paper, it's called Statins Stimulate Atherosclerosis and Heart Failure, Pharmacologic Mechanisms. And we're going to talk about this more when we get into the drug specifically. But they say since the introduction of statins to clinical medicine in 1987.

Several kinds of statins were reported to be effective in lowering LDLC and also preventing cardiovascular heart disease events. However, unfair and unethical problems were associated with clinical trials reported by industry-supported scientists. and new penal regulations on clinical trials came into effect in 2004. After 2004 to 2005, all clinical trials performed by scientists relatively free of conflict of interest with pharmaceutical

Industries reported that statins were effective in lowering LDL-C, but no significant beneficial effects were observed for the prevention of cardiovascular or coronary heart disease. Currently, the majority of scientists continue to claim that statins are effective in preventing coronary heart disease.

But these claims are based on meta-analysis of reports, including those published before the EU regulations of 2004. So basically, even if you look at meta-analysis now, if they're incorporating studies on statins before 2004, then you can assume that there is a risk of influence on those studies altering the actual values. And so then you can't take the meta-analysis into consideration then.

because you have papers that are possibly adulterated. And so then you have to take everything after 2004 and the paper, the researchers did this in a study and they're like, yeah, there's not really any associations. And this is the same thing with seed oils, right? A meta-analysis, which is a collection of studies being considered, has become a vehicle for hiding bad studies. And when people are trying to make arguments that seed oils are benign...

or even cardioprotective, they're looking at a meta-analysis. And in the meta-analysis, invariably with regard to seed oils, and here there's an example with statins, there are studies that are done very poorly that should be excluded. And nobody's saying that. They're just saying... look at the weight of the evidence, the sum of the evidence, the majority of the evidence, which is, in my opinion, it's just a shelter for badly done science and it's a lazy way to make a decision in medicine.

And it leads to bad decisions. So there's a real parallel there. And we see this happening all the time. What's your LDL, by the way, Mike? So my LDL actually tends to run low. My total cholesterol... I don't remember my LDL off the top of my head. My last total cholesterol was about a hundred and I think 35 or 43, something like that. You're total. Wow. I total now. And there are people who have these genetic.

I don't think that mine is 100% genetic. So I do think I genetically do tend to run low because my dad also tends to run low and his health is not necessarily the same as mine. I had my gallbladder taken out. And what I have issues with digestively from that surgery is I dump bile acids a lot. Like I don't absorb all my bile acids very well.

basically a lot of the drugs that they used initially to lower cholesterol were things that bind bile acids like cholesterol cholesterol mean or cholesterol and they pull out the bile acids which causes you to to have reverse cholesterol transport from the liver. And so I think my levels get pretty low when, um, when I have a lot of bile dumping. And so there was one point in time actually, and this, I know maybe tangential, but interesting.

My total cholesterol at one point in time was 88. And that's because I was eating persimmon, which the tannins bind the bile acids. And then I also, a lot of the fat in my diet. was coming from macadamia nuts and beef fat, which skewed me towards mostly monounsaturated fats, which do tend to lower cholesterol values. And then at the same time, like I was playing around with some thyroid hormone.

uh to like see if i get what happens if i bring my levels up into the upper quartile of the range and the thyroid the cholesterol binding the bile acid binding effect and monounsaturated fatty acids made it so that my total cholesterol levels were ridiculously low so i wasn't taking any drugs it's just a function of i genetically run low and i also have these other these other factors affecting it and something to be clear about paul is that you mentioned this before

People can get their cholesterol levels into like some of the standard ranges with dietary adjustments along the lines of the adjustments that we're making. You could still incorporate beef fat into your diet because when you look at the individual fatty acids.

beef fat is almost like 50 percent mono and then it has a large proportion of stearic acid and so that won't necessarily doesn't always bump people's cholesterol up and if they're having like a meal that's like some beef and an avocado or some macadamia nuts

where they put a little olive oil in their vegetables or something like that, you can skew the lipid profile towards monos and it will lower cholesterol values. And on top of that, if your thyroid function is working well or like you're metabolically healthy, you can also...

lower the cholesterol values. It doesn't mean that if you're higher, that it's necessarily a problem as we talked about, but you don't have to necessarily use drugs to get it to some of these levels. Now, I'm not saying people should be at 88. And I felt absolutely terrible at 88. I was like really having a bad time until I figured out what the deal was. And so that wouldn't say to necessarily go to 88 or anything like that, but just showing like there's a variation because I do eat.

beef i do eat and i'm eating but my my all my polyunsaturated fat intake is less than two percent of calories every day and my cholesterol levels genetically run low but are still low even with all this other stuff

with all the sugar and I do have saturated fat from the beef fat in my diet and things like this. I don't tolerate butter well personally because the bile dumping effect, but that these are things that to consider for people like, and even when I eat eggs, like I was eating eggs at that time. My cholesterol, when I took it, was still 123.

And I was still, I was still having four eggs a day. It wasn't affecting my cholesterol values. So these are things to, or as 143, excuse me. So these are things that, you know, it's possible to lower the values. And there's a lot of things that affect it besides just taking a drug regimen.

And I think that's important to know because people who are wanting to lower cholesterol, if they have the fires present and they have these high risk factors, you can do it with diet. And I regularly, even people who aren't lean mass hyper responders, I regularly will drop people's cholesterol.

I've had people drop cholesterol up like 100 points, 200 points, things like this. Once they lose weight, get in better metabolic health and all this type of stuff as well. So it's possible to do it without these drugs. It's interesting. The reason I thought about that, I didn't know that about you. So that's an interesting sort of aside. I see these all-cause mortality graphs and it's like 145. And it's interesting to me that...

You know, usually when I check my LDL, that's about where it is, 145 to 155. And that's not where it's always been. Like I said, when I was strict carnivore, it was 300 to 400. I think I had 360 was my highest LDL. No, that's not true. I had an LDL of 500 once, but it was just a one-time LDL. And the last CAC that I've done was when, I think it was probably five years ago, it was a zero. So even with an LDL of 500, it was zero. And again, these things take time to accumulate, but...

Going back to Dave's study, most cardiac radiologists would agree that even within a year, if your LDL is 300, you should see some plaque formation. It doesn't take that long. And with an LDL of 500 and having had an LDL... from 300 to 500 for years before that doing a carnivore diet, I probably should have had some clear plaque. Whether it was calcified or non-calcified is questionable. It's interesting that my LDL ends up in that range of like all-cause mortality, 145, 150-ish.

And, you know, when I was in medical school, I was eating more olive oil and more avocado. Those are not really a part of my diet now, even though an avocado is a fruit. I think it's fine for people. I favor tallow and butter personally over olive oil.

for a number of reasons. A lot of olive oil is cut with vegetable oils. I don't cook with olive oil. I don't think it's good to cook with olive oil. There's no real role for olive oil in my diet. And the other thing I want to point out is just that-

There are multiple studies, Leiden 85 is one that I can think of off the top of my head and another one that I'll think of, but I don't remember the name of the study right now, that show that in people who are older, higher levels of LDL are protective.

Just this idea that in Leiden 85 and multiple studies that are similar, in the cohort of people with the highest levels of LDL, they had the lowest rate of cancer, obviously the lowest all-cause mortality, lowest rate of dementia, and other things.

There's plenty of studies that never get talked about within the lipid space showing that higher levels of LDL are protective as we age. I think it probably has to do with genetics, these other factors you're mentioning. Without bile, your LDL is going to run lower.

It's just an interesting counterpoint for people to understand that it's not as cut and dry as many of the mainstream folks would make it seem. Before we go on too long, let's just hammer out these meds and wrap it up for people so they understand. But I do want to talk about the medications and then we'll... We'll wrap up the podcast. Okay. So I want to get into each drug specifically. So on the podcast with Derek, there is four major drugs discussed.

There's benbedoic acid, zetamide, PCSK9 inhibitors, and statins. These are the major drugs that are being used now. They're not really using the fibrates or niacin.

or the the cholesterol binders now so we're not going to go into those but so we want to talk about each of these these different drugs and the way i've broken this down is what we have the mechanisms of the drugs the effects of the drugs in terms of their effects on all-cause mortality and cardiovascular mortality their side effect profile their benefits compared to statins and then long-term concerns of these drugs

And so I think this will be important to understand because statins, I think, at this point are kind of like the standard. And so we need to see, are these drugs better than statins, which are the standard in risk and in reward? So the first drug that we have here is benpidoic acid. And benbedoic acid blocks an enzyme called ATP citrate lyase inside the cell. And ATP citrate lyase is basically a couple steps before you get to the move on.

meval milavanate pathway which is the pathway where cholesterol is created that statins block the hmg coa reductase enzyme so you're basically blocking things one step before, right? So, or a couple steps before you get to the mevalonate pathway or mevalonate pathway. And so there's something we have to look at with benbedoic acid. If we look at its beneficial effects.

it doesn't seem to specifically lower all-cause mortality. And so what they say here, there's a study. The study is called Benpatoic Acid in Cardiovascular Outcomes in Statin Intolerant Patients. This is from the New England Journal of Medicine, which is a very prestigious.

journal and they say the primary endpoint which was a composite of death from cardiovascular disease non-fatal myocardial infarction non-fatal stroke or coronary revascularization occurred in 819 patients in the bembedoic acid group and in 927 patients in the placebo group. Now, something to consider, first things first, in the benbedoic acid group, there is 11.7% of this primary endpoint.

And in the placebo group, there was 13.3%. So you're not seeing, you're seeing a one point something percent change between the two groups. So the effect is very small. The next thing to keep in mind is that this was a composite of these factors. So even though we're seeing a change in depth from cardiovascular causes, but it's composited with non-fatal myocardial infarction. So combined.

and non-fatal stroke and coronary vascularization into one metric, which may hide if the death metric wasn't that great because you're combining it with these three other metrics. And so they say the result for the other key secondary endpoints, fatal or non-fatal stroke.

Death from cardiovascular causes, though that's by itself, and death from any cause did not differ significantly between the benbedoic acid group and the placebo group. So basically what we're seeing is an extremely small percent. change, mostly from non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization in the bambidoic acid group. And the percent difference is it's like a one point something percent difference.

And so the other thing is something to keep in mind is what type of statistic are they using? And they're using a hazard ratio and hazard ratios or odd ratios can really inflate some of the percent changes. difference between the different groups as well, depending on how the statistic is done. So basically you're not really seeing a major change here overall in the, in the outcomes. Then when you start to look at.

Like when you, there's a table here that you can look at and you actually break down the table. Um, there's, uh, some really interesting like things that they don't really talk about. Um, what you have non-specific. a non-significant increase in deaths from any cause in the benbedoic acid group versus placebo. And you have a non-significant death from cardiovascular causes in the benbedoic acid group versus placebo.

The percent change is only small, but that's not reported. It's also non-significant. So the only thing that was really significant was the change in the non-fatal, some of these non-fatal cardiovascular events. And again, the change was very small. So we're not seeing a huge reward profile on the drug. Now, the next thing we want to consider, okay, so we have this minor reward in terms of people who have cardio, like.

with cardiovascular events, but not really changing all-cause mortality, which was the major thing we talked about. Side effects of the benbedoic acid that we know so far is that it increases uric acid, which is, if you're in the low-carb space, a big problem. especially if you're listening to people like Richard Johnson and whatnot talking about the problems of uric acid, it increases creatinine and increases BUN and increases the risk of tendon ruptures. So there's some problems with it.

The benefits of this drug over statins is that the effects are limited to the liver in blocking this pathway. So it's not across the whole body. So you don't, at least so far, we don't seem the same. mitochondrial problems and muscle tissue, heart tissue, all this type of stuff that statins may cause. But the thing is to keep in mind is that the long-term concern with this is that it's still blocking that same pathway in the liver.

And something that's important to know about this pathway, and we'll talk about it with statins, the mevalinate pathway is important for producing things like heme A, coenzyme Q, selenoproteins, and vitamin K. Heme A is important for hemoglobin, for a variety of mitochondrial proteins. Coenzyme Q is important for the mitochondria. And then the selenoproteins are important for antioxidant defense, like glutathione peroxidase.

or thyroid function like the diiodinase enzymes. So if you start nuking out this whole pathway in the liver where you're having some of these things produced, is there going to be a long-term side effect profile? in the liver because you're not able to produce these necessary and important proteins because you're missing a key component. It's like if you have to make a semiconductor chip.

and you don't have the specific metals to make it anymore you just don't get chips you don't get the semiconductor chips which means no ai which means no internet which means no uh you know whatever whatever the different areas piloting systems

any type of military equipment, like it goes out the window. And it's the same thing going on in the body. Statins do it across the body. Benfidoic acid does it just in the liver. And so I think that's a huge risk profile with this drug to stop those pathways in the liver.

and then also not really have a huge change in all cause mortality and a marginal change in cardiovascular benefits like what's what's i don't i'm not seeing the huge value here i i think it's especially in a healthy person maybe in somebody who's not healthy, you can try to make arguments for lowering the cholesterol because their CAC score is 400 and you want to figure that out. But it's like, okay, but we have this marginal change in risk from the drug. How much is it going to lower it?

And then can we do it with diet and lifestyle stuff? And I think we can. So then the risk profile for the risk reward profile on this drug starts to become not so favorable, at least in my personal opinion. Yeah. I mean, there's a lot of bad side effects there. Like, I mean.

This mirrors statins because it's in kind of the same pathway, but only in the liver. But there's a lot of nutrient deficiencies that can occur. There's a lot of biochemical. None of these drugs are perfect. And we have all these risk-reward profiles. So again, I think these drugs are... something to be considered in the case of an individual who cannot or will not change their diet. And it's all risk reward.

The podcast with Derek, he is someone that doesn't have documented coronary disease. He's a young man. I think he's in his early 30s. And he basically was asking, he said, my LDL runs, quote, a little high. He sometimes stays up late. He sometimes doesn't sleep well. He sometimes does things in his life that maybe could create some degree of inflammation at the level of the endothelium. And so he's saying, what is my risk reward for these drugs?

I felt like it still wasn't a benefit to him, net benefit, but I think he takes a small dose of a statin and I think he takes pempidoic acid. My admonition to him was, we don't know what that's going to do long-term. And it's impossible to know what it's doing long-term. And there's a lot of concerns about this. Like you brought up earlier, we don't have good long-term data on all these drugs. And this is...

for me, reminiscent of what happens in the longevity space these days, where good old Brian Johnson again is posting videos like, here's how I eat to live to 200. And I think... Dude, don't say that unless you're 200 years old right now, because it's just, I think it's disingenuous for people in longevity space to claim.

these are things that will help you live to 150 or 120 or 180. And we don't even know, you know? And it's a really good marketing space because in 50 years, nobody's going to care. Maybe we'll care about Brian Johnson if he's still alive. But I think a lot of people are not going to care about it and nobody's going to hold him accountable if the things he's saying don't work or if he has to walk it all back.

I think it's more efficacious to focus on things we can do right now to improve our quality of life, our hormonal status, our libido, our weight maintenance, and just basically, like I said, our freaking quality of life. How enjoyable is it to live our life? How strong am I?

How much can I serve? How much can I dance? How much can I spend time with my kids or my grandkids? How's my mental clarity? All this kind of stuff. It's interesting. So we just don't know. And that was my concern with Derek. To say that these things have no side effects is false. And I think...

I think you're barking up the wrong tree by doing this. I would just correct the lifestyle things primarily and see where that goes. But who knows? That was his choice. I think there's a lot of fear in these things.

For whatever reason, I think he may have had somebody in his family who had cardiovascular disease. We all fear heart attacks. And I don't think those in the lipid space have done a great job of helping people put this all on a level playing field. But for whatever reason, heart attacks are more scary than other things. But listen.

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Back to the podcast. I worked in a cardiac ICU. So I know like people weren't really like you come in, they had heart attacks and like it wasn't a big deal. It's not as much of a big deal anymore. As soon as they have it, we bring them in.

We get them under control. We get them on, depending on, we put them on aspirin, we get them on oxygen, we got the morphine going. They get scheduled to do a heart cath. Like people aren't really dying so much from heart attacks. Those numbers have actually improved.

But people are dying from being in the hospital, from being really frail and falling and breaking bones and getting pneumonia and getting infections and getting sepsis. Like I saw many, many, many people die from because I worked in ICU during COVID. from COVID, from sepsis, from all these different types of things, which some of these drugs may arguably worsen or make you more susceptible to.

And so I would be, that's where it's really important to actually hedge those risks. Because with a cardiovascular care now, if people have strokes, if people have heart attacks, the system is really good for these traumatic events and getting people under control.

The problems that we have in the system is stopping people from getting to those events and then stopping them from having them again after. And it's because it's mostly relying on this drug therapy. People really need to change some of these other mechanisms. But jumping into PCSK9 inhibitors.

So PCSK9 inhibitors, basically they are monoclonal antibodies. So they're antibodies that block this protein called PCSK9. And what PCSK9 does is it binds the LDL receptor and causes the degradation of the LDL receptor. So on your cells, you have this, this LDL receptor that basically accepts LDL cholesterol and it starts to pull it and internalize it, pull it in. And then the cell starts to use the different cholesterol components. And so.

What basically happens is when you block the receptor from being exposed or from being degraded by the PCSK9, then the cells take up more and more cholesterol out of circulation. And so what basically happens is this ultimately leads to more LDL receptors being expressed at the liver, and the liver takes up much more cholesterol overall. So this is how the PCSK9 inhibitors are basically lowering serum cholesterol values.

by letting the liver and cells take up a bunch more cholesterol. Now, in terms of the studies, this one's actually interesting. There's a couple of pieces to talk about here, but the major one that we see, the... I think it's evolucumab, doesn't actually seem to lower all-cause mortality, whereas alirocumab seems to decrease the risk. So we'll talk about this. And then there's some other interesting things that we can talk about as well.

So this study is titled Serious Adverse Events and Deaths in PCSK9 Trials Reported on ClinicalTrials.gov, a systematic review. So this is a systematic review. They say in clinical outcome studies, PCSK9 inhibitors in general... did not affect the risk of all cause serious adverse events compared to placebo, but alirocumab decreased the risk. The risk of death was not significantly different between the PCSK9 inhibitor versus placebo groups in the lipid lowering studies.

and clinical outcome studies however for evalucumab the risk of mortality was 1.18 times in lipid lowering trials and 1.12 times in clinical outcome trial for a year so it had a between an 18%, 12% increased risk of all-cause mortality for the evolucomat, which is, you know, great for everything else. Increased risk. Yeah, increased, increased.

They say the percentage of participants that died in the placebo group of four-year was 4.3%, and in the evolucomat group was 4.8%, so it was higher in the treatment group. This amounts to a number needed to harm of 213 for median follow-up of two-point years. 2.2 years. The risk for diabetes mellitus was non-statistically significantly increased in the PCSK9 inhibitor versus placebo groups in the lipid lowering studies and clinical outcome studies.

Similarly, the risk for neurocognitive events was non-statistically significantly increased in the lipid-lowering and clinical outcome studies. There's a nice chart here where we can see evolucumab versus alirocumab. And they looked at things like myocardial infarction, stroke, heart failure, diabetes, mellitus, neurocognitive events, all serious adverse events and all cause mortality. And if you look at some of those, some of these studies.

For evolucumab, all-cause mortality was higher in clinical and lipid-lowering studies. And then the risk for neurocognitive events, diabetes, mellitus, heart failure, stroke. was higher in the alirucumab studies and the 13 lipid lowering studies. So there's 2.04 on the odds ratio for stroke and TIA for the alirucumab, 1.23 for heart failure. 1.24 for diabetes, 1.55 for neurocognitive events. It's not giving me the p-value here, so the statistical significance for each of those.

But basically, you may be seeing a non-significant or significant increased risk of all of those things in the alirocumab, even though all-cause mortality was just a bit lower with that drug. Where the evolucumab, you're not seeing the increased risk of those things. You're just seeing increased risk of all-cause mortality. So not really a great profile overall here for these drugs. The only one that seemed to have some benefit was the alirocumab.

Yeah, again, we talked about the genetic polymorphisms in PCSK9 earlier. Knocking this out and or having lower cholesterol levels, it doesn't look to be benign. And we're back to the same place. which is risk reward, why not just start with what's actually causing the problem? But these are powerful drugs for cardiovascular risk.

because they lower LDL a lot. But when you look at these studies, it's questionable where you would employ them. You have to really take this into account. There's also other meta-analysis of randomized controlled trials that I'm not going to read here. But basically, they're not showing a significant cardiovascular mortality benefit. So they're not changing cardiovascular mortality in this meta-analysis of randomized controlled trials. I have two here.

basically showing that they're not showing any all cause mortality or cardiovascular or significant all cause mortality or cardiovascular mortality benefit. So we're not for, you're not really seeing this like change in cardiovascular mortality.

or all-cause mortality. Maybe you have a case for alirocumab, but there's an increased risk profile, at least in the study, that's showing some of the benefit. So it's kind of like you're not really... we're not really seeing this really high reward for the risk here for the PCSK9 is they're not as high as statins as far as we can see because they basically...

They don't block cholesterol production in any way like the statins do. They just increase the uptake of cholesterol. So I'd say the mechanism is a little bit more benign, but then they do lower cholesterol a bit more strongly, I think, than the statins do.

So then it's like, is there like with the really strong cholesterol lowering risk, are you increasing some of these other risks? And we don't have enough information on that yet with these drugs. Because again, 2015, not a lot of people taking them because they're really expensive.

So we can't we can't really know for sure. And that's part of the problem with this is like it's a little bit like we don't we don't have all the information to make a really good risk risk reward profile. But at least so far, we're not really seeing this massive benefit for all cause mortality.

or cardiovascular mortality overall. Uh, so that's, yeah, it's another, like there's a lot of fanfare around them, but I don't think that they're like, you know, all, all that they're cracked up to be based on the research here. And again, We're looking at randomized control meta-analyses of randomized control trials, which from these groups of people who are making these arguments, these should be like the top tier of evidence. I agree. I think it's a...

It's a weird class of drugs that I don't think we have data on yet. And again, I think there's better ways to do this. Yeah. And it's super expensive anyway. Yeah. Right. It's super expensive. I think they're in thousands of dollars a month.

So, and they're only approved for a very specific group of people, if I remember correctly. So, you know, Derek brought them up. That's why he mentioned them. But I don't think you're, you know, your average guy, your average Joe or Jane who's walking around. with the high risk profiles, like, yeah, let me hop on this multi-thousand dollar a month drug to bring my LDL from like 110 to 70 or something like this. Yeah. I think the main drugs are statins.

and probably increasingly bempidoic acid. So let's talk about statins. I think this is what people usually say in the DMs. My doctor once put me on a statin. We mentioned it earlier about the risk profiles and how they're probably deflated inaccurately.

Let's talk about statins for a minute. So statins mechanism here, they block the enzyme HNG-CoA reductase. We talked about this, which inhibits that whole nivolinate pathway. So you don't get like, and that this is important to know because it creates a whole bunch of problems.

Now, when we look at the statin studies, they basically, again, like we're not really seeing a change in all colors mortality. And some of the ones that we do were the earlier studies before the 2004 cutoff. And then even then the benefit was marginal. so we have uh they say stands for acute coronary syndrome here this is from the cochrane database of systematic reviews so this is like literally one of the gold standard top journals to get a systematic review from

And they say, based on moderate quality evidence, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction, and stroke at one month or at four months. And this is after people had had. acute coronary syndrome. There were no statistically significant risk reductions from statins for total death, total myocardial infarction, total stroke, cardiovascular death, revascularization procedures.

and acute failure at one month or four months, although there were favorable trends related to statin use for each of those endpoints. So the trends were semi-favorable, but they didn't reach statistical significance. So we're not seeing that benefit there. Then the other one here we have... I'm not going to read this full one. We could put it up in the quotes here for people, but there's a really interesting quote here where they talk about the Jupiter trial.

which was for rezuvastatin which is known as crestor and basically they talk about the reporting of the trial and they're showing like this huge percent benefit in the trial where they say more than the quote was more than 50 avoided a fatal heart attack But the reason that they're saying this is based on really weak statistical evidence that's not looking at a relative risk instead of absolute risk.

And so you can do some statistical chicanery with this type of stuff and show like these benefits. But basically the change was, I think. Let's see here. The difference in percentage was 2.8% versus 1.6% risk of heart disease. And that's where they're getting some of these 50% numbers.

like the differences between these risks. And so we'll leave it there because it's just a really long quote, but I think a lot of people would appreciate this to understand like how they're inflating the statistics. So basically with statins, we're not really seeing. the a significant benefit for all-cause mortality overall um and even the cardiovascular mortality endpoints are kind of questionable now the side effects of statins are really a big one and basically we see

myopathy, cognitive dysfunction, hepatotoxicity, and diabetes. And then possibly with the myopathy, if it gets to a certain point, it can cause issues with the kidney. Long-term concern for statins, diabetes, cancer. cognitive dysfunction, myopathy, inhibition of heme A synthesis, which is needed for cytochrome C. So basically disruption of mitochondrial function, inhibition of coenzyme Q synthesis, disruption of mitochondrial function.

Impaired production of selenoproteins, disruption of antioxidant defenses, and thyroid function, inhibitive vitamin K2 synthesis, worsening of vascular calcification. And so this... Worsening, yes, because if you can't have activated vitamin K to interact with some of the different proteins, you increase your risk of vascular calcification.

So you're disrupting energy production long-term, you're disrupting possibly thyroid function antioxidant status, and then you're inhibiting vitamin K synthesis. So these are the negatives of statins. The other thing to keep in mind with statins is that statins do have some pleiotropic effects.

In the sense that they have antioxidant effects, they have some anti-inflammatory effects. And it's somewhat arguable that the benefits of them are through those pathways and not through LDL lowering. And if that is the case. then why don't there's other things that have anti-inflammatory and antioxidant benefits that show like that show benefits in cardiovascular disease that we can use without having these, these toxic effects.

And so these are really important to keep in mind. And if you look in some of the studies, the risk for diabetes and cancer and some of the studies that we talk about here that we cite is pretty is like relatively decent risk. um inside some of the trials researchers try to play it off based on like the population selection or things like this but the there's a good paper and paul you actually were sending me this paper i think it's from

I think the author's last name is Diamond. I think it's David Diamond, something like this. And the paper that he discusses with the stand effects, it's really interesting when he goes through it. I'll tell you the name. right now yeah it's david i think it's david david and then also in pub med oof rask uh rav and scoff i can't pronounce it but those two authors have really interesting papers talking about some of this

the statins and cardiovascular disease and LDL. And remember that, like we mentioned, I just keep coming back to this. The side effects for statins are downplayed for sure. There's washout periods.

I had a gentleman on my podcast whose name is escaping me right now, but we talked about pharmaceutical corruption and how this type of thing happens and all of the data for statins. Just remember that if you're thinking about statins, and this is very granular, but I know the audience is pretty sharp.

Like Mike points out, data pre-2004 versus after 2004 tells a different story. So again, Derek, my friend, who I respect greatly, is on a low dose of Crestor. Is he doing the right thing? I don't know. It's his decision. but these are the risk reward benefits that you have to discuss here. And Mike brings up a great point that if the benefits of statin are the pleiotropic effect, which is just a fancy word that means probably basically not related to LDL lowering.

Well, we can improve endothelial health by drinking orange juice, actually, as a matter of fact. All the fruit juices that I've seen tend to improve endothelial function. A lot of the fruit juices actually decrease the propensity for LDL to become oxidized. glucose goddess, take note of this. But we can also decrease omega-6 seed oil consumption, which will decrease the propensity of LDL to become oxidized. You can eat more nutrient-rich food. There's lots of ways to achieve these effects.

that don't include inhibiting one of the central biochemical pathways in your human body that makes a lot of things for you. Heme, cytochrome, some of the cytochromes in the mitochondrial membrane, these are critical things that we're impairing. None of these things is without side effects. And I think these get downplayed. So, all right, man, let's wrap this up for people. I'm going to talk about azetamide. Yeah, let's get azetamide done. And then, yeah, so let's jump in.

So for azetamide, azetamide blocks cholesterol absorption at the intestine. And so like it's less.

less harmful than all the other drug options here because it's just blocking cholesterol absorption. The thing is, it has the weakest profile of all these drugs. So basically, they say here, Moderate to high quality evidence suggests that ezetimibe has modest beneficial effects on the risk of cardiovascular endpoints, primarily driven by a reduction in nonfatal myocardial infarction, which is heart attacks and nonfatal stroke.

but it has little or no effect on clinical fatal endpoints. So it doesn't do anything for mortality. The cardiovascular benefit of zetimibe might involve, so might involve the reduction LDL-C, total cholesterol and triglycerides. There is insufficient evidence to determine whether azetimibe increases the risk of adverse events due to low and very low quality of evidence. The evidence for beneficial effects was mainly obtained from individuals.

with established atherosclerotic cardiovascular disease, predominantly with acute coronary syndrome, has administered azetamide plus statins. However, there's limited evidence regarding the role of ezetimibe in primary prevention and effects of ezetimibe monotherapy and prevention of cardiovascular disease. So one, the effects don't do anything for fatal endpoints. The studies were combining ezetimibe and statins together.

And it was in people who already had cardiovascular disease. The paper here was ezetimibe for the prevention of cardiovascular disease in all-cause mortality events. Again, this is from Cochrane, Cochrane Databases and Systematic Reviews. So very...

highly prestigious journal. And so essentially we're not, you know, we're not seeing a huge benefit. If anything, it was the cardiovascular outcomes were with statins and it was only in people who actually had acute court predominantly out acute coronary syndrome. So. If you're a healthy person and your LDL is super high or maybe not even super high, just higher than their thresholds and all the other endpoints look good, I think it's arguable that a Zettabyte may not do anything for you.

especially like again if your CAC score is zero or your CIMT and the other values look good then it's like it's going to be a really hard there's not really too much risk we'll talk about it right now but there's also really not that much reward and so the because because azetimi blocks cholesterol uptake it also may affect other fat soluble things and so there's a paper here where they basically discuss azetimi affecting i think it was

people using warfarin's values because it blocked the uptake of vitamin K. And so you, vitamin K is really, well, this is really important for cardiovascular disease. Yeah. Because vitamin K prevents vascular calcification. So if you don't, if you're using a drug that may block that and lower your vitamin K status, then like long-term, you may increase your risk for vascular calcification overall, which is one of the primary endpoints for cardiovascular disease.

which is why you're looking at coronary artery calcification scores with CT scans, because you're trying to see where, because the plaques eventually become calcified. Besides that, the only, that's the major risk I see with the azetamide. then maybe lowering cholesterol too much, but it doesn't lower it that massively because it just blocks absorption. So I say its overall risk is much lower than the other drugs, but its reward profile is pretty pitiful.

compared to the other drugs in terms of like, if you, if you were to be in this idea that lowering cholesterol is like the cure for heart disease, it's like azetamide is at best an add-on to other drugs and not really a primary drug to use in of itself overall. And so that would be my take on, on azetimibe. And I would say in a healthy person and the risk reward ratio is not so much in favor of reward, even though risk is low. Yeah, I agree. I agree.

So let's frame this for people and help everybody think about this more broadly now. I think there are two groups of people that we're dealing with here, primary prevention and secondary prevention. Primary prevention means you haven't had a heart attack. And I think we could also, that's technically what it means. We could also say if your CAC score is zero, then you're in one group, right? Coronary artery calcium score is zero. You're in one group.

And the other group is secondary prevention, which is people who have already had a heart attack. Or maybe your CAC score is 100 or 200 or 300. You know you have calcified plaque. And if you're in the first group... I think that there's not a lot of arguments for any of the things that we've talked about today. Again, everybody has to talk about this with your doctor. I think it's clear if you're in the first group, if your CAC is zero, if you have no plaque burden.

It almost doesn't matter what your LDL is based on the studies we've looked at. Be insulin sensitive. But this is the genesis of this entire podcast and the podcast with Derek. He's sitting there with Peter Atiyah saying, How can these carnivores say that a high LDL in an insulin-sensitive individual is not a problem? And this is exactly why you can say that. Context is everything.

If your CAC is zero, it doesn't mean your CAC will be zero for the rest of your life, but I think that the chances that your CAC, coronary artery calcium score, is going to remain zero for the majority of your life are pretty good if you're metabolically healthy. All of those metrics we talked about at the beginning of the podcast, HSCRP, fasting insulin, myeloperoxidase, LPPLA2, sex steroids, cortisol to DHEAS ratio, et cetera, et cetera. These are how you know where you're doing.

Honestly, the quality of the food on your plate, what's in your refrigerator and what you put in your mouth today will probably tell you what you're doing. If you are... insulin resistant, say you have diabetes or you have a positive CAC or you have had a heart attack. It doesn't mean that you have to take drugs for the rest of your life. It just means the cat's out of the bag and you have these processes going on in your body.

probably because of the way you're living your life, whether that's an extremely stressful life, whether that's poor sleep, whether that's night shift, whether that's eating a poor diet or some combination of all of these, alcohol abuse, drug abuse, who knows.

There's no judgment here, but if you're doing those things, then that's what's causing your problem. And in those people, there is a different argument for lipid lowering, considering the fact that, you know, then the question is, are you going to change your lifestyle or not? And that's really how I see it. And so in someone healthy like Derek, who I don't know if he's had a CAC score, but he is primary prevention.

I think that it's hard to make an argument that he's not going to be at an increased risk of side effects from the benpedoic acid and the Crestor that he's taking relative to his risk of cardiovascular disease. That's his choice to make. And that was kind of what we were talking about on the podcast for, I think that podcast was pretty long as well, over two hours. And take home for me is kind of what we talked about in the beginning. Context is everything.

even though it gets left out of the majority of the conversations. I've never heard Peter Atiyah talk about this. In fact, he's poo-pooed it and said, it doesn't matter if you're insulin sensitive, if your APOB is high, quote unquote, you're still at an increased risk of cardiovascular disease, which I disagree with respectfully.

Context is everything. If you're eating an animal-based diet of steak and hamburger, tallow, butter, eggs, maybe some fruit, plus or minus, maybe sweet potatoes, whatever you're doing for carbohydrates. and you go to your doctor and your LDL is 140 or 150, ask him for a fasting insulin. Ask him for all of the labs we got that we talked about at the beginning of this podcast. And if the doctor won't do it, find a new doctor.

because that's how you can really get a full picture of your cardiovascular risk. And I think that it's much more complex than APOB causes atherosclerosis. I hope we've presented. plenty of evidence to get you questioning the fact that that is a direct causal effect. There's a lot of semantics that get thrown around here, and Peter likes to talk semantically about what cause means, and we won't go into that now, but I think that ultimately it's context.

you have to understand, are there sparks in your house that are going to light the wood on fire or are there no sparks in your house? And if there aren't any sparks... gosh, it sure looks to me like more wood is better to have. More LDL has all those protective things. So that's my take on it. What do you think, Mike? I'll give you the last words you can add to that and we'll wrap it up. Yeah, I appreciate that. I think...

I think if somebody is healthy and they have a high LDL and they're worried about a risk, then I 100% agree with you. Go look. Go see what the deal is. Go check the values. We've listed values here, a variety of different values and tests that you can use to see where you're at. Go and get.

Get the testing done and see where you're at and see where your actual, get a true risk profile, right? If you want to know the risk, then test the right values. So go take a look. And then I think if those come back and it's fine and your LDL is just high. then I would say based on the research that we discussed here today, that the risk is probably not really that high if everything looks okay in those different areas. I think that's fine. If you are somebody who is at a high level of risk,

And those values aren't looking too good. And there's, you have a clear atherogenic dyslipidemia profile. You're not a lean mass hyper responder. Your profile is not looking like that. And you check some of these other values and things are not looking okay. Then start to be like, okay, what do I have to do?

to put out the fires and start to put out the fires. Is it diet? Is it micronutrient deficiencies? Do you have chronic infections? Are you dealing with chronic stress? Do you have some things going on with toxic exposures? Are you, and then address those specific underlying pieces. Are you not moving enough? Are you heavily sedentary? Are you smoking? Are you drinking? Are you using drugs? Fix those problems. And then the next piece after that is.

There are other things you can do that directly target some of these problems. So I would start to look to target inflammatory signaling. I would start to look to target things like LDL oxidation, oxidative stress. look to target stress hormones. And then I would start to start to look to target like, again, like micronutrient deficiencies are going to be a huge thing in this process.

Because many of the micronutrients are cofactors for enzymes that are functioning to lower oxidative stress, to improve immune status, and to also get inflammation under control. And so there's a lot of very individual, very specific steps you can take. That's not just that or nothing or benbedoic acid or nothing to get these things under control. And I would focus on those areas. And then if you're doing all of the right things, you still have these risk profiles, which.

To be fair, I've never seen that happen personally where somebody really dials all their stuff in and they're still having all this stuff going on. If anything, you're trending your labs and you're seeing, well, maybe my CRP was three. I have a client. CRP is three.

We change his diet. He loses the weight. Now it's less than 0.3 on the CRP value. It's like, did he need to go on all these drugs to lower his CRP? He's like, no, he needed to lose weight and put out all the fires, which is what we did. So do that first. And then at that next point is like, okay, now I may have to consider using drugs or maybe in this regimen, if that's something that you want to do.

then consider those types of things and get a full risk risk reward profile, which is why we're making this podcast so that you can get a sense of what your risk risk reward profile is in your different context and then make a decision from there.

and talk with your doctor about it and present the information, go through a logical analysis of, is this going to make a difference for me? And for me, again, this is what I'm doing with clients. We're fixing the fires. We're seeing, are any of these things necessary?

And if they're not necessary, then we don't use them. If everything gets under control, these values are all changing and shifting in the right direction, then we don't really need to, like they get to a point where they're not even in the territory of needing to use these types of things because things are looking good overall.

And so that's what I would try to do. Work in a systematic fashion, get foundation right, and then use the strategies that make the best risk-risk-reward ratio profile for you to get the outcomes that you want. I think that's the ultimate. the ultimate takeaway for me and for me if i was dealing with cardiovascular disease that's what i want to know what do i have to do to put out all the fires and bring my risk down so that i can without really ruining the quality of my life

going forward and not worsening maybe other mortality risk factors and things like this. Yeah, man. Thanks for having the conversation. I really appreciate this one. I know it's technical for people, but I think those who were interested, there's a lot of value here.

are you accepting new clients? Yeah. So people can find me on my website, mikefave.com. And I also have a YouTube channel. It's Mike Fave on YouTube. I do have a wait list for clients currently, but in this next... month or so i'm going to be launching a course that's going or it's really a program because it's going to be like working with coaches to actually get these foundational components right get these ducks in a row

so that people can improve their health. And it's how to, you know, with the animal-based foods we talked about, the carbohydrate sources, how much do you want to use? How do you figure out which foods work for you? How do you structure out your diet? How do you make it easy to implement in your lifestyle, right? Because a lot of people say, oh, this person, they have all this time. I have kids. I have a family. I'm working. It's like you can still do it. I know I've done it working in the ICU.

60 hours a week and i was still eating in this type of fashion there's some modifications i had to make for certain things but i was still able to do it so it's like how do you implement it's very focused on how do you implement this stuff in your life to get the outcomes unless i'm like well there's this

this theory it's like no like this is what we need to do so that's that's what i'm currently working on that'll be out within the next month or so and yeah that's that you can find information about that and work me one-to-one on my website mike dave.com and i appreciate you having me on paul this is a really interesting conversation for me

I was excited to go through the research and talk about this. Yeah, man, I think it's super valuable. And I think I know a lot of people found value in it. So thanks, brother. I'll talk to you soon. Yeah, thanks, Paul.