Superagers, statins, the latest cholesterol pill and the truth about heart disease risk | Dr Terry Simpson

0:03Well Terry, it seems our first episode was a big hit. I had many people from the community requesting that you came back, including my family. So I listened. I was a good boy and here we are. It's always good to listen to family. And this episode, we're going to approach a little bit different to the first one. So the first episode, I would encourage people to go back if they haven't listened to it. We shared your story and we went into detail about your use of GLP-1s and your career working as a bariatric surgeon, etc., and covered a whole lot of other topics within that episode. Today, what I wanted to do with you, because you've become very well known on the internet for this, is to discuss some of the new exciting things that perhaps we're seeing to maybe get some things off our chest that we're seeing online that are perhaps irritating or are pieces of misinformation that we would like to address.

1:07And then we've also brought a few studies, new studies that we can go through. Why are they interesting, exciting? And what are the take-home messages for the listeners? So why don't we start with the good stuff? Is there anything new or exciting that you've come across recently? Well, there have been a few things. I think probably the most interesting thing came out this last week when it was talking about the super-agers. And these are people who are in their 80s who haven't undergone any cognitive decline, but their brains are equivalent to people who are 20 and 30 years old. So they said, well, let's look at these people and see what their genetics are.

1:49Let's look at APO. You know, the APOE allele is the one that we look at if you have an ApoE4 or a double ApoE4, you have an increased risk, not complete risk, but an increased risk of developing Alzheimer's disease. And if you have an ApoE2, you have a kind of a preventive. And we've done a lot of dietary studies, like the MIND diet, Mediterranean diet, showing that these people have decreased their incidence of cognitive decline. So this is an interesting group of people. They're in their 80s, and they looked at them and said, let's look and see if any of them have better genetics than others.

2:22Are these Americans? This wasn't done in Europe. So already they have better genetics. And the thing was, they found no relationship to genetics at all. So these people had sort of this equal distribution of the genes that we would think might confer an increased risk or a decreased risk. And we don't know why these people in their 80s are still cognitively functioning. Now, it didn't look at a lot of the lifestyle factors at all. It just looked at genetics. But I found that remarkable because you would think that we would be able to say and say, oh, I bet all these guys are ApoE2 and none of them are ApoE4.

3:01And it turns out that's not it. So we have these people, which gives people like me who are older than you, and you'll start thinking about this later, is you want to maintain your brain as long as you can and know that genetics is not your fate in terms of that is, I think, remarkable and great. So if you were to speculate, now zooming out based on the totality of evidence, what do you think explains their good brain health into their 80s? I think they're probably doing a few things right. Probably the basic boring stuff. They're probably keeping their blood pressure under control. They're probably taking medications to keep their lipids under control.

3:41They're probably eating a reasonable diet with more fruits and vegetables than the average person. And they're probably exercising and having a community. all those kind of boring things that are preventative in public health. I would say when we start looking at them, I would say that would probably be fairly high on the list. You mentioned the MIND diet. If you had a couple of minutes with someone and they said, just quickly give me the recipe for the MIND diet, how would you explain that? So the MIND diet is a combination of two other diets, which is Mediterranean and the DASH diet. And briefly, it's increasing fruits and vegetables.

4:17So a person should have about 250 grams of fruits, 250 grams of vegetables a day, increase of pulses or things that we would call lentils, beans, decreased red meat, more monounsaturated fats like olive oil, whole grains instead of refined grains. And the MIND diet has sorted that out into a 15-point scale. So if you're perfect, you get a 15. And there have been two different studies looking at this. And guess how many people got perfect 15? 5%. Zero. Wow. So that's great, though, because that tells us we don't have to be perfect. One of the things that always bothers me on the Internet is when people say you must eat perfectly.

4:55If you only ate perfectly, you wouldn't have all of these issues. So it was nice to see that the people who had the most effect were in the upper quartile, which is around 12.5 points out of 15, which is still pretty good. It means you're eating lots of fruits, lots of vegetables, legumes, etc., decreasing red meat. But you're not perfect. And I think that's probably good because perfection bores me. And what are the main ways in which that pattern is different to the Mediterranean diet? Well, it's kind of a combination because it incorporates the DASH diet. So it's still the same fruits and vegetables and stuff.

5:28But it's a little bit looser in terms of you have a little bit more meat, a little bit more dairy in it. So it's a little bit changed, a little less salt. And so they both basically came out of the same time frame. When you look at the Mediterranean and the DASH, Mediterranean was a European version saying we have all this information about these food groups, let's see which make a difference. The Americans did the same thing. And so on the American side, we were looking at those sort of things, but instead of calling it a Mediterranean diet, we were interested in approaching to hypertension. And we put out basic formulas of how you can do it.

6:07I remember reading a book by Martha Morris from Rush University. and she was the one that came up with the Mind Diet with her team there. Sadly, she's passed away. I did want to have her on the show. If you can get her on the show now, that would be interesting. Yeah, it would. But her books are still available for people to read if they want to kind of deep dive the origin of that research as well, which is interesting. It was nice because it was validated outside of her institution. I mean, she had a huge study, I think over 900 people at Rush, and that Columbia went back and validated that with their own study and found essentially the same thing, that people who followed this diet, who adhered to a diet of probably today we would say less hyper-palatable, less ultra-processed food, but lots of good whole foods, they put off developing dementia for years.

7:01And that's probably the best we can do. I saw you also did a post on the new oral PCSK9 inhibitor. Yes, Lipendra. So for those who don't know, we have a couple of ways that we can decrease atherosclerotic burden over the long term. The most common way is statins, which cost pennies. Like I take a statin, it costs me 75 cents a month to take it. Used to cost$180 a month. It's cheap now. And then it came along, the PCSK9 inhibitors, which prevent the LDL receptor from being destroyed or downregulated. So your body has lots of LDL receptors. So it sucks out all the LDL. So it keeps your ApoB proteins, your atherogenic forming problems, less.

7:49It showed a couple of interesting results. One interesting result was when it was combined with a statin, not only did they have much lower levels of LDL or ApoB, but they actually saw a reversal of plaque and in addition to stabilization of plaque. So I think it's fascinating how we look at heart disease now. And do you think that's just from driving APOB down further, or it's a different effect of the PCSK9? It's hard to say. Simplistically, yes. But as we learn in biology, most things aren't that simple. We certainly know that statins have a broad anti-inflammatory effect on vessels. And so there's certainly that effect.

8:34But there's probably more to it. You know, the ability to stabilize a plaque. So we used to think of plaques as like plumbing. But plaques aren't plumbing. And I know you're very into heart plaques these days. I think plaques are more geology. So I want you to think about a plaque like this. If you have a volcano over magma, that's like that erupting plaque. Lots of lipids in there, lots of stuff in the core, lots of inflammation going on. It erupts. The pyroclastic flow you might think of as a thrombosis afterwards. That's a volcano. What we want is we can't get rid of plaque. I mean, physically we can.

9:12I've gotten rid of plaque surgically. You can go in and take it out. But what we want to do, you can't do it in coronary arteries. But what we want to do is make that plaque from that erupting thing to like an extinct mountain, extinct volcano or a dormant volcano. And that appears to be what most of the medications are. So it used to be that once we discovered we had these lesions, the first stage is, all right, let's treat all the lesions. then you may remember that almost every cardiologist in every hospital was throwing stents. If you had a 30 % lesion, they were putting a stent in. And then the studies came out and said, it doesn't change the outcome.

9:46You're not getting better outcomes. Yeah. You're still getting the same number of myocardial infarctions. You're still getting the same heart disease. You're still getting the same deaths. Just as well as you do the other. And all of a sudden, invasive cardiologists, you know, had nothing to do. Could catch up finally on their medical records. So we learned that didn't work. But, and then we tried other things. We said, oh, look at the marine peoples of North America. They have less heart disease. They actually don't. But in the sample they looked at, they have less heart disease. It must be what they eat.

10:17It must be. And then we went through the whole thing of let's raise HDL. And so we had drugs that raised HDL. And guess what? Didn't do a thing for heart disease. Might have even made it a little bit worse. Then we started looking at, you know, all of the different fish oils we could do. Let's get fish oils. That'll help us. It kind of changes things a little bit. But in the long run, it doesn't change myocardial infarctions. So that's kind of where we have seen all of this go over time. You know, we went through the whole thing. Well, it's an ionized particle. We have to keep it anti-inflammatory.

10:49No, it's not an ionized particle. It's the size of the particle. Smaller ones are worse. They get in. And now we know it's actually just particle burden that's the problem. Which brings us to one of your favorite studies. Yeah. Let's double click a little bit more though on this. because I have a few things to say. And also my personal use of a PCSK9 inhibitor, I think, ties in nicely to this. So that point that you made about sort of getting that mountain or that volcano to become dormant, there is some evidence that you can, if you get your APOB down below a certain level, that you can also make that volcano a little bit smaller.

11:27You can potentially get some regression. And kind of seal it a little bit. Right, so you can shrink it, maybe, and then you can stabilize it, which makes it, as you say, dormant or less likely to rupture and cause a problem. If you've been listening to me or some of my guests talk about the gut microbiome, you'll know that it thrives on very specific types of fiber and polyphenols and resistant starch, many of which the average person falls short on, despite the very best of intentions. That's why Dr. Will Balsowitz and I founded 38Terra, a gut health company where science meets supplementation.

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12:47And this ties into the new oral PCSK9 inlicatide, decanoate or something like that. Yeah. They're always a mouthful, these drugs. And they're always an ide or an adol or something. Yeah. Anyway, so that's an oral PCSK9. And to give people an inhibitor, and to give people the background here, the drugs, the PCSK9 inhibitors that have been approved prior to this are injections. Right. And there's different types. There's the monoclonal antibodies like Repatha that people may have heard of. And then there's all the way through to inclicerine. which is a different mechanism. SiRNA gets into the cell and basically changes gene expression and says don't make this protein that is going to break down the LDL receptors.

13:35And as a net result, you get more LDL receptors, clearing more cholesterol. ApoB comes down. And it's also, you know, once a month to, you know, starting out once every two weeks and then just a once a month injection. Totally. So whether you go with the monoclonal antibodies like Repatha or there's another one, Preluin. Yeah. Or you go with Inclisirin. It's injections repeated. Some of them you can do at home. Some, like Inclisirin, you need to go in and see a doctor. Some people just don't like injections at all anyway. I don't like injections even though I do every week. Right. So perhaps there's better adherence with the oral version.

14:13Well, certainly drive down price, right? And pricing could be a big thing. So from an economic point of view, It could be prescribed to more people. It's easier to manufacture them. You can get it up to scale much more quickly. And when you can do that, you're going to drive the price down. Because when you have injectables, especially when you have injectables that are biologics, it costs a lot of money to go through the purification thing, to develop, to go through those standards. When you get, you know, that's just a lot. And so this should help. And there's another one, LaRochol. I don't know if you've seen that.

14:46but that's not a monoclonal antibody, but it's similar in that it binds to PCSK9 in circulation, so essentially does the same thing. And that one's a little bit different to Repatherin, that it doesn't have to be refrigerated. I'll come back to that because that's what I ended up starting with. The question I have for you here is, you've got inclycerin, you've got the new oral PCSK9, and then even Lorochol, which is the one I've started. We know from trials, like the trial that just came out that these lower LDL cholesterol or ApoB by about 50%, maybe even more, 60%, right? It's a big effect. And a lot of people are undertreated.

15:28So, there are a lot of people who are on a statin but haven't yet got to the goal, right? And so, this is an important class of drugs. But when making a choice, so I know you're not a cardiologist, but I'm sure you think about this. Repatha has outcomes, data, showing that it lowers events. All these other ones just show that it lowers ApoB and LDL cholesterol. Right. We have mechanism. We don't have data. And that's always the Achilles heel of medicine. So what do you do right now? Right now I do Repatha. That would be the gold standard. Because you know what it does. And actually, if it was me personally, I would probably just pick one of them.

16:09I mean, I think that any of them are going to be good, and I have, but that is that Achilles heel. If you're going to go just on clinical results, you do repathopralin. If you are going on convenience, great technology, do you like to be injected or not? And I think ultimately when we see the data, I believe it will be the same. However, there are way too many instances where we find that it isn't always. It's just something for people to be aware of. Those clinical trials are coming down the pipeline. They'll probably be out in a year. I mean, the thing is, it's so prevalent. The disease is so prevalent that getting the data just isn't that hard.

16:50So we'll see it. Probably by the time this comes out, we'll see. Yeah. I started with LaRochol and my decision for that was it's ambient. So the way that the molecule is produced, it's actually stable. Unlike the monoclonal antibodies, they need to be refrigerated. and I travel a lot between here and Australia. So for me, I know that you can take a little thing on the plane and stuff that keeps things cool, but it just seemed like a kind of more bulletproof way to travel. Now, did you get that prescribed or are you paying out of pocket for it? So I had that prescribed, yeah. And I think that's important to say.

17:27These are not as cheap as statins. So out of pocket for Repatha, I think in the U.S., is a couple hundred dollars a month. Yeah,$200 to$300. And then if you get like a copay, I think it gets it down to about$25 a month. But that's still a lot more expensive. It's a Netflix subscription. Then what did you say? Mine's about$0.75 a month. $0.75 a month. So technically speaking, the guidelines say PCSK9 inhibitors, especially monotherapy, are for people that have tried statins and were intolerant to those. And I really tried to get my cardiologist to say that I was intolerant of statins, but I'm not.

18:05You know, I'm just not. And my LDL is down in the 40s. So it's really, but now we have better ways of looking at plaques than we used to. So when I was a young vascular surgeon, we had to use intravascular ultrasound, which is really pretty cool. It's still around. And now we can not only, we have mechanisms now where we can look at plaques. So here's the question. If you have plaque, do you want to then go on and invest and let me get a CT angiogram to see what does my plaque look like? Where is my plaque? And how aggressively do I want to treat it? Is that going to be the gateway to are we going to add another drug?

18:46Or are you just going to say, well, I've got a positive calcium score. Where are we going to start drawing the line? I have a lot to say about that. I know. And I think, again, importantly, this is something you would speak with your cardiologist who knows your history and your overall risk profile. It's going to vary. But I've published that I went and did a CT angiogram. And I'm someone that is considered low risk on paper with a very small amount of plaque. That's important context to understand here. And then I went and did it again 16 months later. and I had multiple tools that analyze the plaque, analyze it, and I got a lot of different results.

19:33Generally speaking, they all agreed that it's low plaque and there's not like significant progression or anything to be really scared about, but the actual absolute amounts and the direction of change between baseline and follow-up, it varied between these. And when you get in and look at validation of these tools. This is the take-home point for people to understand. You mentioned IVUS, right? So, IVUS is gold standard, but it's invasive. So, if you're thinking primary prevention, you don't have serious heart disease, you're not going to go and get IVUS done. No. By the way, that's intravascular ultrasound.

20:10So, you're not going to subject yourself to that because the risk outweighs the benefit. it yeah and so you can do a ct angiogram but the these tools like clearly and heart flow that are ai analysis analyses that look at plaque morphology and tell you how much plaque you have and how much of that is non-calcified and low attenuation plaque and calcified plaque they are validated in people who have a lot of plaque against divas because they can't run a validation study right but that's the problem that's always the problem totally so it's it's unethical for them to run the study in people like me who have very small amounts of plaque because we're not going to subject ourselves to ivus the the issue we run into here is that these tools are not we don't know that they're firstly that accurate at measuring very small amounts of plaque where there's a lot of measurement noise okay it's like if you step on an old scale and that thing is wobbling around and then you pick up the cup, their weight on there might not shift at all because it's not sensitive enough to that change.

21:16Does that make sense? That's been the problem with angiograms for years. Yeah. I mean, in angiograms, we're looking at really big things. We're better at them now. But the early angiograms had that same problem, meaning that when you got, is that a 70 % lesion or is it a 50 % lesion? And you could give this to 20 different cardiologists and have 20 different results. Now with AI, at least, it's counting pixels better. But the problem is, is that when you're talking about minor amounts of plaque, you're talking about plaque that you have to, if we were to take out your artery and look at it under a microscope, which would be bad for you if we did that, but if we were to do that, we're looking at microscopic plaque.

21:54It's essentially what we're doing. And we are depending upon the electrons that are excited that can be read in a CT scan in 2026 to be able to make that differential. That's just hard to do. And there are guidelines on this, and they say, look, if you are going to go into a CT angiogram and you're someone who has a very small amount of plaque, you definitely need to wait at least five to seven years between scans to have really any idea of what's going on. So my scans being 16 months apart, but it's not even long enough to really detect change. Well, I think they're not waiting because it's long enough.

22:35I think they're waiting to see as you build more plaque, and you don't want to do that. I'm guessing your mindset. Your mindset is, A, in one, curiosity, and two, I don't want to wait until I have bigger plaque so that they can see it. I want to see what I can do now to minimize my plaque burden or reverse it if I can. Totally. So that's my personal. But the guidelines, I think, are saying wait five to seven because there's so much measurement noise. And we're going to get better at the results. Right. And so you're right. Like for me, my decision making was this. I did that testing from an academic curiosity point of view.

23:08Really, it didn't change my decision at the end of the day. Right. I looked at everything and said, strong family history of heart disease. I would bet you a dollar that if you would have said, I'm going to go through all these studies to see if I'm going to get on this PCSK9 inhibitor, I would have said, you're going to get on it regardless of what it says. So it gave me different information from different tests. But I'll give you an example that's just almost the opposite of you. My mother-in-law is 80-some years old. She has familial hypercholesterolemia. Her father died of a heart attack at 55 on a squash court in great shape.

23:46She had a CT angiogram. She has a lot of plaque lesions. I mean a lot. Now, in the old days, someone would have said, let's just do an angiogram on her. Well, they don't want to. So now they're going to do on her side, because she has so much plaque, they're going to do a PET scan. Now, the PET scan will be able to see if the flow through those arteries is significant enough that they need to do an angiogram, or if at her level of activity, and she's pretty active for an 80-some-year-old person, if it's not. So that's on the opposite scale of you. Now, she didn't have the benefit of for years being able to have statin, statin therapy, but she's got some significant, I mean, she's got at least on the CT angiogram, some 50 % plaque.

24:35So there's somebody who I think should be on one of the PCSK9 inhibitors in addition to whatever medication she's on. But that's the opposite. And what you want to do, if I'm interpreting your motives correctly, is you don't want to get where she is when you're 80 you want to have the arteries you have now yeah i think with this disease we know that the earlier in life you get your apob down the better because it's a cumulative burden and it's that area under the curve and so because i have even if it's just a small amount i don't want to i want to make choices now that can help prevent having a heart attack or stroke when I'm in my 60s or 70s.

25:18And with lifestyle alone, I could get my APOB down so much. But back to what we were saying earlier about how do you get that plaque to go dormant? The research is pretty clear. Below 50 milligrams, some cardiologists might say 40 milligrams per deciliter. And I'm fortunate with the lifestyle changes and then taking the PCSK9 inhibitor, I can get to that level. and I chose back to La Rochelle. I chose that just because it felt right in terms of the travel. But now, having looked a little deeper at the research, I'm actually thinking about shifting to Repatha just for the time being given the outcome data.

25:56No, it's not a bad choice. I mean, I don't think any of those are bad choices. With Crestor and Zidia, my LDL got down from the 190s and I had a pretty intense lifestyle with the Mediterranean diet. I got mine down to 180 with Mediterranean diet and lots and lots of fiber. But I got down to the 60s and when I started with the GLP-1, it got down to the 40s. So I think I'm at a good spot. The GLP-1 lowered your LDL cholesterol by about 20 milligrams per deciliter? Wow. Now that may be in this range. Who knows how accurate that is? I'm going to have the labs repeated in the next couple of weeks. But, you know, it brought it down even further.

26:42But I sort of look at myself and say, you know, I have a positive coronary artery calcium score, family history. I think I'll probably want to get a CT angiogram. Why not? Why not get a CT angiogram, see what's there, and see if I shouldn't add something to protect it? Have you ever had an ultrasound of your carotid done? Yes. Yeah. What do you think about that? Well, the nice thing about the ultrasound of the carotid is, you know, I mean, I have really minimal atherosclerotic disease in the carotid. It's an easy way of checking things, but it doesn't always relate to the heart, you know. And again, on the one side, when you start looking at plaque burden side, more plaque burden, it relates great to the heart.

27:21When you get to people like me who, fortunately, I don't, I was expecting to have a lot of atherosclerotic disease. I don't. But it's like, you know, they said, well, you have really clean arteries, which is really a nice thing to say. If you ever want to compliment, you know, somebody say you have nice arteries. But it doesn't really, it's still a good test to have and it's easy to do. Why were you expected to have significant atherosclerosis? Well, because my guess is, is that because of my familiar hypercholesterolemia, I had, And, you know, I mean, my LDL in medical school was probably around 200.

27:55So for how many years did I have that before I started aggressively treating it? So I expected it to be higher. Why do you think it is that some people can have a higher LDL cholesterol or ApoB seemingly for the same time as someone who has a lower level but have less plaque? Again, it's sort of like we have all this land mass in the Middle West and no volcanoes. and we have this tiny landmass in Hawaii and we have volcanoes. It really is a matter of the plaque morphology and where it is because you can have that single individual who is metabolically healthy, a runner like Jim Fix, etc., etc., and have the plaque in the exact wrong place and be gone.

28:38So it really is that matter of luck. And plaque burden, as you know, plaque doesn't come across universally. Now, Paul Saladino, one of our good friends here, always says, well, if this is true, why don't you have plaques and veins? And it's sort of like, well, Paul didn't come to that lecture at medical school. It seems like a very silly argument. It lacks a lot of logic. Right. It is. But I think he's not appealing to – he doesn't want an answer. There are some people when they give you these questions on social media and you give them an answer, they ignore it. and I've come to discover that you have two types of smart people on social media.

29:20You have the smart people on social media who, like Paul, who's smart, but he's a marketer. So he is going to stop at a study that tells what he wants it to tell and not go any further than that or deny it. And then you have people who will say, you know what, I'm going to change my mind. You know, something happens, I've got to change my mind. And on this side, which I hope I'm on this side, we have to be careful because sometimes we get too caught up in things, right? It's just like when you said, Repatha has all the data, these others don't. And I'm saying, you know, I'm kind of going with that, oh my gosh, what would I probably do?

29:56And it's like, you know, probably do Repatha because it has the studies. And maybe that's the wrong approach. But certainly this is not the right approach. And, you know, we can go on for all these people on social media, and I know we have one coming up, but back to plaques. So I think that it's where you have the plaque burden, where you have the alternate flow, how the vessel's anatomy is. So if you, for example, have the LAD coming off at an acute angle, you have more laminar flow and hoop stresses on the endothelial cell, which causes more disruption, which then causes more plaque burden than if you have less of a shepherd's hook and more of a gentle curve.

30:36That's part of it. So there are these other factors there. Also, obviously, if you smoke, if you live in an area where there are a lot of wildfires. Right. We have a lot of... So just like there's a difference in the local environment between a vein and an artery. Yes. Which makes APOB containing lipoproteins more likely to infiltrate and go into that sub... And endothelial cells of veins have minimal LDL receptors. Right. So whereas an endothelial cell in an artery has hundreds of LDL receptors, let's just give it a number. An endothelial cell in an artery will have 100 LDL receptors. an endothelial cell in the vein will have 0 to 1 LDL receptors.

31:15The membrane between the muscle in the vein and the endothelial cell is not something where plaque can form because the macrophage can go in there, grab the LDL, recirculate it, and put it back into circulation. Whereas in an artery, you have that huge glycocalyx membrane where the macrophage goes in to try and recycle. cycle, it can't. It gets trapped and you develop the foam cell. So there's also that morphologic difference. Again, Paul doesn't want to hear that. Right. So in lay terms, what you're explaining there, and so Paul's point is, hey, if you have these APOB-containing lipoproteins that are, you guys are saying are atherosclerotic, that they cause plaque, their concentration is the same in veins and arteries.

32:04Why aren't they going into that space and getting stuck? You're saying that the physiology, the anatomy of the artery is different to the vein. Absolutely. And it means that more of those particles are fluxing, going into that space, and then there's differences inside that space which make them more susceptible to getting trapped and kick-starting inflammation. And then your other point was that there might even be some differences between individuals, which makes even at the same APOB level, those particles more likely to go into that space and get trapped and kick start inflammation. And you can increase ApoB particles transiently, right?

32:42I mean, if you were to smoke a cigarette now, your ApoB particles would go up. If you were to develop diabetes, your ApoB would start going up. So there are different things physiologically that happen that will increase and drive the ApoB particles. And, you know, and I sort of look at my, you know, when you look at the volcano of a plaque, Maybe sometimes the analogy is better as you have a ton of TNT there, and that's the, you know, the TNT is the atheroma, and the fuse is inflammation. And when you have people who have, for example, high levels of inflammation, they have more heart attacks.

33:19People who have autoimmune diseases have more heart disease, right? People who have, and on the other hand, you can also do the opposite. This is what is crazy about this. you can take someone and put them on immunosuppressives and you will have a greater risk of heart disease. I always find that fascinating. It's like if inflammation is all this, and I know this sounds like a Paul Saldino question, then why is it that we have people who have transplants and they have the highest level of heart disease around because we put them on the most powerful anti-inflammatories to prevent rejection? Again, that answer is we don't know and we're going to figure that out.

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36:57And to bring this back to the overall conversation around lowering ApoB, I mean, where we're getting at here is that there's still things to learn and understand. Yeah, but we do know. But the strategy of lowering ApoB is saying let's get less TNT here. Right, right. Let's move the geologic plate so we're not sitting over magma and having inflammatory, big lipophilic atheromas sitting there that can cause a problem. And the more you can lower it with statins, with azetamide, with PCSK9 inhibitors, the data is pretty clear the fewer cardiac events you have. And it looks like it's getting stable.

37:37More data to come. I think it's pretty interesting just to kind of close the loop on PCSK9 inhibitors that there's Eli Lilly, and this is not a promotion for Big Pharma, I just find this stuff fascinating, are working on Verve. So this infusion that essentially goes in into the cell, edits the gene permanently, that expresses PCSK9. And I think they've done it now in humans and have like 14-month data to show that it lasts at least 14 months. but it might be possible and it seems like it's going to be in the near future, maybe five, 10 years where that type of CRISPR technology will be available to permanently lower someone's apathy.

38:27We use it now for a lot of other therapies, right? I mean, so it's really, it's the gene editing that we've been waiting for, for, you know, years. I mean, I think of my son who's 16. It's like, boy, I wish he could get that, right? He's got my genes. He needs that. speaking of immunosuppression so i've got my good news of the week okay i was reading a study and an editorial really on developments looking at functional cures for type 1 diabetes i'm not sure is this something that you've read anything on so for the for the listeners we spent a lot of time talking about type 2 diabetes it's more prevalent a metabolic disease which largely driven by having excess fat, particularly in organs like the liver and pancreas.

39:20But type 1 diabetes is different. It's an autoimmune condition. Yeah. And the body is attacking the beta cells, the cells that produce insulin. And it gets to the point where this person no longer produces insulin on their own or not enough and requires exogenous insulin. and there are companies that are currently looking at creating or synthesizing stem cell derived islet cells and you know this stuff i'm saying this more for the listeners but islet cells are essentially a kind of matrix of the beta cells that produce insulin the alpha cells that produce glucagon and other things and they they can synthesize these now and inject them into the liver through the portal vein and it was fascinating to me is that those cells don't even the islet cells don't have to get to the pancreas right they just take up residence in the in the liver and they start solving glucose homeostasis because most glucose homeostasis occurs in the liver right Right.

40:28So all of a sudden you have, and this company Vertex has now shown this, you have these stem cell-derived islet cells, you inject them into the person who has severe type 1 diabetes, and all of a sudden they're producing enough of their own insulin, maintaining blood glucose levels such that they don't need exogenous insulin. And you mentioned immunosuppression. So the thing with this therapy right now, while it's very exciting is that those islet cells are still foreign they're seen as foreign right so these people have to go on pretty intense immunosuppression that can come with all sorts of complications increased risk of cancer infections tuberculosis and and for this reason this this particular therapy is going to be fda approved it looks like but it's only going to be made available to people who have very kind of poor awareness of hypoglycemia.

41:28Yeah, brittle diabetics. So if someone just is unaware that they're getting to like a fatal blood glucose level, it's going that low, then this could be a therapy that could be life-saving for that person. And then the trade-off is that they're going to be on immunosuppression for life. where where i think this gets fascinating is it's like a watch this space there's a different company that i was reading about that was using donor islet cells so not these weren't ones that they were produced in in the in the lab they were from deceased individuals the problem with donor islet cells is that it's not really scalable but they're just using this as a model for now and they used gene editing to get in there and reduce expression and increase expression of certain genes that make those cells undetectable to the immune system to stop the attack to stop the body seeing them as as foreign and they've shown now in human where they've been able to give um inject these islet cells into the human and i think it was a 12 months 14 months later the cells are still there producing insulin and are not...

42:44Without immunosuppression. With no immunosuppression and not being attacked by the immune system at all. There's no immune response. Now, it's important to know they're wanting to prove safety on that technology. So they did a very small amount of islet cells to begin with. Not enough such that this person could fully come off insulin. But enough to show that those cells were producing insulin. they could lower their exogenous insulin requirements. And now that company is saying, how about we combine these two worlds? Instead of islet cells that are from a donor, let's do stem cell ones, and then let's edit them genetically.

43:24Why couldn't you take the person's own stem cells? I think you could do that, but I think the issue is scalability and cost. So if you could solve this... Because you'd have to pull them out, you'd have to culture them, you'd have to grow them, you would have to do all of that. Yeah, and so there are a lot more steps there. And that's a very personalized approach to solving this. And I bet there are companies looking at this. And people can look this up. Vertex was the first company that I mentioned. But SANA Biotech, they're the ones doing the CRISPR editing. And now they're going to look at doing that to these kind of lab-grown stem cells.

43:59Well, and you don't necessarily have to use islet cells to do that, right? because the genome is available on any cell. So you can take any cell and, you know, with enough, you know, putting the right promoter on, develop that. Yeah, I think I did read about some other companies that are taking a skin cell or a fat cell and turning it into a cell that can produce insulin. One of the things that I find fascinating about type 2 diabetes is that when we diagnose type 2 diabetes in somebody, they've already lost 50 % of their pancreatic islet cells. And so when I hear people out there saying, I've reversed my diabetes and, you know, I get picky.

44:44You've seen me get picky on this. It's like you haven't reversed it. You put it into remission because you've lost 50 % of your cells. You've lost them. And that whole mechanism of as the islet cell is producing more and more insulin, the insulin isn't always misfolded. So I like thinking about like a cardboard box factory. If you're making tons of cardboard boxes, you all of a sudden start misforming some, and you put them in the factory and put them aside. And eventually your factory is so filled with these misformed cardboard boxes, you have to shut down the factory and clean them out. And sometimes it gets so bad that the factory just can't ever go get started again.

45:21Same thing happens with insulin. You start making more and more insulin. Ultimately, you make a lot of misfolded proteins. They stay in the cell. They don't go out. and eventually the cell gets kind of so clogged up that the cell can't produce anymore and it stops. And eventually the body will come and say, you're not producing anything and so it will, by the process of apoptosis, get rid of it. And that's where diabetics are. So when you see people saying, well, I've cured my diabetes, it's like you haven't cured your diabetes. You actually still have functionally half of your cells are gone.

45:55They're not coming back. where this will have an impact not only in type 1 diabetes, it'll have an impact in type 2 diabetes. Because as people go on in type 2 diabetes, we eventually get to where they are also insulin dependent and become brittle just like we can. That's a great point. So what you're saying, and this is not a finance show, is going by shares in Sarno Biotech. One of them. One of them is going to win. Yeah, it's an arms race. It is to be an arms race. It's kind of like, you know, but beta was better than VHS, but VHS won. So you never know who's going to win. But it stands to have an enormous impact on healthcare and quality of life.

46:33Like essentially for someone with type 1 diabetes, this is as close as at least in the near term future, we will get to a complete cure. You know, I remember the first pancreatic transplants we did. And people have done so remarkably well when they had their pancreas transplants. Whether they were type 2 or type 1s. their whole lives changed and for the better. They, you know, were starting to develop neuropathy. Their neuropathy reversed. They didn't have to inject themselves with insulin. They just did better. And then we started getting to islet cell transplants. And so it's really an exciting time, you know.

47:14Better if you don't get diabetes, but not everybody has a choice. Get it off your chest? Sure. Did you bring anything today? Well, tell me about Rhonda Patrick. What do you know about Rhonda Patrick? Because here's what I know. So I really don't, I mean, no influencer wants to be told by another influencer, I don't know who the hell you are, but you're wrong. So that's what I did with her this last week. She came out, she was on the Mel Robbins podcast, which, you know, another podcast. And she was making smoothies and said, this is what I put in my smoothie. And it was all fine. She says, but I don't put a banana in my smoothie.

47:47And Mel Robbins says, uh-oh, why don't you put a banana in your smoothie? She says, well, there have been multiple studies. There's been one study. By the way, that all seemed very staged and it was very theatrical. It was, yeah. This is why I need you here, Rhonda, to tell me what to put in my smoothies. Like, oh my God, Mel. Most of Mel's podcasts are like that anyway. So a bunch of us called her out on it and said, you are looking at a study of eight individuals of which six completed the study and it was not the major polyphenol. It was a minor polyphenol. And the minor polyphenol as it broke down has no clinical consequence whatsoever.

48:19So why are you telling people to put a$3 avocado in there versus a 50 cent banana? And then she came out and doubled down and said, well, I'm trying to maximize my polyphenols. And it's like, all of us who have large egos have been in the position where we have been wrong and doubled down. And my advice to Rhonda Patrick is, it's time to stop doubling down. Just say, you know what? You're right. It was wrong. Because the public would much rather hear you saying, I was wrong. You're correct. I overcalled it. than to double down and say, I'm trying to get more polyphenols because you have no data for that.

48:55It was an over-interpretation of a study. And it wasn't even blueberries. I spoke about this two years ago on the show. Did you? But, I mean, it seems like it's majoring in the minors in the first place when you look at the average person's diet and what we need to be encouraging people to do. As you say, it wasn't even – Well, they didn't actually mix the blueberries with the banana in the study. They mixed it with cacao. Cacao flavonoids. Yeah. Right. And by the way, most of us, I make a smoothie most mornings, and I make a banana berry smoothie. And it's like the berries are frozen. The polyphenol oxidase is probably not even going to work with frozen berries because it has to work at a temperature that's closer to about 20 degrees centigrade.

49:44I think the root cause of this problem is… Mel Robbins? Is that podcasts in general are competing with one another and they're looking for something new and exciting. And clutching at something that maybe someone hasn't heard before and will create a good 15-second clip. And because of that, you run the risk of finding a study and over-interpreting it. Yeah, I mean, I think we're all guilty of that to some extent. And I've been thankful for people who've corrected me on things because it's like, oh, for example, I made a mistake in one of my recent subsects where I said one in six people are hospitalized for food poisoning.

50:29It's actually one in six people get sick and a percentage of those are hospitalized. So someone corrected me on that. It's great. I'm glad you corrected me. I fixed it in the thing. Thank you. Because we're all going to make mistakes sometimes. We're not going to, you know, but yes, I do think that there is the clickbait aspect of it. Like, let's make a headline. And there's plenty of headlines to be made just with medicine itself. It's fascinating stuff. A little esoteric for a lot of people, but it's fascinating stuff. The interesting thing is really being called out and then having the humility to say, you know what?

51:05I got that wrong. earns you more respect in the long run. Yeah. Than pretending that, you know, doubling down or just pretending that you get everything right the first time. Well, as you know, the algorithm is once you see one of her things, you see another. So I saw another little thing of hers came in saying, if we would only double the amount of RDA and protein, then we will prevent sarcopenia in women in an old age. And it's like, no, Rhonda, that's not what it works. That's not how it works at all. And it's like, I'm not going to call her out. I guess I'm calling her out. It's like, no, sarcopenia has to do with more increasing resistance exercises, not increasing protein.

51:47You can increase all the protein you want. I mean, best example, I have a 16-and-a-half-year-old golden doodle. He has sarcopenia. He's losing weight in his back legs and muscle mass and stuff. He gets a ton of protein. I mean, this guy gets a lot. It's not going to help. I mean, you know, it's just some part of it is inevitability of aging. Some part is not. Some part is being able to do resistant exercises. I just can't get him to lift in the gym. The average American gets about 1.2 grams of protein per kilogram, which you can build a lot of muscle on. But like 90 % of Americans are not meeting their resistance training guidelines.

52:24Yeah. Yeah. That's something that's come up on this show multiple times is this protein session. Well, if exercise were a pill, it would be the most successful pharmaceutical ever. Ever. And when people say, what's the one thing that I can do besides diet? It's like take a walk. I mean, it's a little bit of resistance, but it's more than most people will do. Do some planks. Do something. Whatever you can do, do it. And I think I mentioned this last time I was on. It's like in my many years of practice in surgery where I have rearranged guts, do you know how many people that I've seen with protein deficiency in my career?

52:58A half dozen. So these are people who I take out parts of their stomach, rearrange their guts, And protein deficiency is so uncommon because of our diet that that's really not our problem. Our problem is we don't lift heavy things. So why do you think someone, and I'm asking you to speculate here, Rhonda's a smart individual. I know her content. She's educated. Why do you think someone like her can't look at the data like we have and understand that sarcopenia, this isn't a protein problem? Not for most people. and that the main driver of this is living a sedentary lifestyle? I don't know. And I also don't know if, you know, I saw 20 seconds of a clip on TikTok with her saying this.

53:43But I would think in those 20 seconds, you would want to get the message across that, yes, sarcopenia is a bad problem. Frailty is a bad problem among aging people. They are not absorbing as much protein, but they're also not getting exercise. and exercise is the primary driver to A, absorb more protein and B, maintain independence as long as you can. That's a good point. I mean, in fairness, I have heard her talk about exercise. So it might have been that that clip is taking it out of context a little bit. But you would, yeah. And again, it's like, so that is the hard thing because it may have been that clip.

54:19But when you see one clip like this and another clip, it seemed a little click-baity again. Like this is the answer to all the problems. And when did anybody listen to what the government says about our diet anyway? I mean, they just don't. Nobody listens to what the government says. How do you feel? Did you get that off your chest? Probably. Yeah. Do you have anything else you want to get off your chest? Or do you want me to? Oh, let's go. So mine, I mean, the theme today with everything that I'm bringing is related to cardiovascular disease. Oh, good. Now, we're not movie review people. But I know you watched a movie that I did.

54:53So I would love to hear your take on the latest movie of the X space. What did you think about The Cholesterol Code? So let me start with the good because I think there was some good in there. I think that Dave and the team produced a high-quality documentary. It was creative. It was engaging. I watched the whole thing. It tested my patients at times because there were things that the general sentiment I didn't necessarily agree with. But there were stories of individuals in there who have adopted a ketogenic diet and I'd like to believe what they're saying is true in their experience and have really turned their health around.

55:36And I think I have empathy for those individuals, anyone who has had an experience where their health has declined. and then I really respect the ability to to be strong and to make changes to their lifestyle and just to try and course correct things to be motivated so that I think I think that was inspiring hearing those individuals but I think overall the the documentary is very premature because the general sentiment is that was questioning the diet-heart hypothesis and questioning this idea that cholesterol contributes, causes heart disease. And there are some quotes that I've written down here.

56:28Here's one. We only care about LDL because of drugs, for example, is a quote that comes up in this documentary. And I would say, no, we don't only care about LDL because of drugs. We care about drugs because of biology. And we care about drugs because of observational studies, Mendelian randomization genetic studies, randomized controlled studies, all pointing in the same direction and showing us less heart attacks and less stroke consistently across different populations. But we also will say when we're wrong, we used to care a lot about HDL. And we have a number of drugs that are HDL which are now off the market because they didn't work and they caused problems.

57:15So we can raise HDL with drugs. We have drugs that will raise HDL, but they do not impact cardiovascular disease or strokes. So we can do a lot of, you know, to say we're going to do it to one and not do it to another means that they don't understand in that world. We want clinical outcomes. And even though we have great mechanisms, Mother Nature has shown us time and time again about if you don't have the clinical studies for it, you can have all the mechanisms in the world. It's just, you know. So I thought quotes like that were kind of setting this whole thing up as it's a big conspiracy, like the entire diet-heart hypothesis.

57:59All doctors lied to us. Is about some sort of agenda to line the pockets of pharmaceutical companies. And I'm not saying pharmaceutical companies are perfect, but there is very strong evidence that exists for statins and PCSK9 inhibitors and ezetimibe and benpedoic acid. The list goes on. And I think if I just zoom back out, so I said that there were these personal stories in there that I empathize with. this this whole idea of lean mass hyper responders which is what the documentary is on and maybe we should i should explain what that is essentially it's someone who has good metabolic health they are relatively lean although that's not objectively quantified and they adopt a very low-carb ketogenic diet and despite having good metabolic markers like blood glucose control and triglycerides, their APOB goes through the roof, very high.

58:57And that's called a phenotype. So I do think that's another interesting thing this documentary puts forward. It says, hey, there's this population of people who respond to a ketogenic diet like this. But when I zoom out, what I think is happening here is these people often with certain symptoms, whether it was mental health or they had an autoimmune condition, they adopted this low-carb diet, had some improvement, in their experience of their symptoms, but then had a blood test. And their LDL cholesterol and ApoB is through the roof. And there's a whole community of people out there that just want to believe that's not a problem.

59:35And this documentary and Dave's work really caters to engaging that community and, in my view, giving them false hope. And I say that because Dave himself comes out and says he's cautiously optimistic that high APOB in this population is not a problem. And I don't know how you can be cautiously optimistic given all of the evidence that points to the contrary. And this group, you know this, they published a study that I thought at face value had some interesting elements to it. It's not a randomized controlled trial, but they took 100 people, similar to what I did, 100 people, baseline scan, and then a follow-up scan a year later.

1:00:19here in LA with Matt Budoff. And they were wanting to look at progression of plaque in that time. Now, this is not a randomized controlled trial. And it's not looking at events or outcomes. Okay. So it's not the strongest study, but it's interesting nonetheless, and maybe a stepping stone to other studies in the future. But there are many problems with the design that affect your ability to kind of interpret the data. And what I'm seeing from this group is over-interpretation, similar to what we were just talking about with that banana study from Rhonda Patrick. The first study came out and was retracted.

1:01:00It had a whole host of problems, and I can link to some videos that explain that. It ended up being retracted by the authors themselves. After they had a lot of feedback. After they had feedback, and I think this is important because if they were here to kind of quote unquote defend themselves what they would say is that the the analysis done on the plaque was not blinded and they thought it was going to be blinded so they took issue with that and they haven't really fully released enough data to explain that decision in my view they put some graphs up on social media but i don't think that cuts it for me.

1:01:41And so that study was retracted. And then they published a new study that looks again at the exact same data. It's not a new study in terms of new scans or anything, same data. But this time, looking at the analysis through using two different tools, Q-Angio and HeartFlow, instead of Clearly, which was used in the former retracted paper. A lot of people online are getting confused and people are citing the retracted paper or some people are citing the new paper. The new paper is a preprint. It hasn't passed peer review. So, just to kind of underscore this, the documentary's out. Right. First paper, retracted.

1:02:21Second paper, not a randomized controlled trial, not looking at events. It's in data. It's a preprint. New analysis. New analysis, preprint. Now, this study, it measures, I think I need to dedicate a full episode. It would take a couple of hours to go through the entire study, the methodology, the results. They report a lot of different outcomes and ways of kind of measuring plaque, like non-calcified plaque, total plaque volume, percent atheroma volume, these different ways of measuring plaque and comparing between people. What's really interesting to me is just when you read the abstract, the bias from this research group just shines through.

1:03:08they for example in the abstract in the results they emphasize that 15 percent of participants exhibit exhibited plaque regression despite sustaining elevated ldl cholesterol and yet in the original paper it was the opposite and even if we just discard the original the original paper what i want to show you is just some of the graphs looking at at change in in plaque and you can look at this for yourself and tell me what you see. It's not just the things that we can see, taste, smell or feel that shape our health. Some things slip by completely undetected. BPA from plastics and receipts. PFAS from clothing.

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1:06:24what we're seeing here i'll put up on screen for those watching on youtube is the annual change in total plaque volume okay if you're measuring if you're talking about regression or progression you want to be looking at total plaque volume right you're not going to look at non-calcified because non-calcified could go down or up but calcified could go up or down you want to look at total plaque volume it's a scattergram so i will dedicate a complete episode to going through this but what i want to show you now is the graph from from this study in preprint looking at total plaque volume so if we were going to talk about regression or progression where we're going to look at total plaque volume not non-calcified or calcified right because you could have a decrease in non-calcified and an increase in calcified that nets out or is a total increase and the only way to know if someone has had true regression or progression is to look at total plaque volume okay i'm showing this kind of scatter plot here for you and the the y-axis is looking at the total change in total plaque volume in millimeters cubed okay okay anything below this dotted line means there was a reduction in total plaque volume.

1:07:40Anything above it is an increase. Okay. What's the first most obvious thing that you see there? It's all increasing. So besides one, two, three, four, five outliers that had some regression, and you'll see regression in a lot of studies, particularly when you measure over 12 months with instruments that are not that sensitive in people with low plaque so you have five people with with regression but the bulk of people either sit kind of around where they were a little bit of progression or where they were but then there's you know 30 percent or 20 it's it's 21 to 29 percent of people had significant plaque progression.

1:08:23Yeah. Yet the abstract doesn't talk about that at all. The abstract only talks about that notably 15 % of participants exhibited plaque regression despite sustaining elevated LDL cholesterol and APOB. How can they make that conclusion? So what they've done, what I can say they've done is, because that's not even 15%, these five. what they have done is they have looked at the annual change in non-calcified plaque volume here you see a few more people that had regression a few more data points but still the bulk number of subjects have an increase in non-calcified plaque correct the same yeah so that to me seems like they wanted to to kind of emphasize what fit their narrative in the abstract which a lot of people read that's just not how science works and then hide the the finding about progression more in the discussion and and what's one last point i want to make here is that when you're comparing progression between individuals actually looking at absolute amounts so millimeters cubed isn't the best way of doing it because we all have different size arteries right so percentage atheroma volume which is the percent of the total volume of the artery that's occupied by plaque is a great way to compare between people okay because if you have say 100 millimeters cubed of plaque in person a and the same 100 in person b but person a has larger arteries.

1:10:07Well, if one's in the aorta and one is in the coronary artery, it's too big. It has a different effect on blood flow, right? So, in the research to be able to kind of normalize it and create better comparisons, PAV or percentage atheroma volume is used. And generally speaking, anything over and a 1 % increase in PAV per year is considered rapid plaque progression. yeah it is okay what percentage of subjects in this keto cta trial do you think had rapid plaque progression oh i would say about 85 percent less than that less yeah so i mean as you can see the majority of people had plaque progression right and the the the the average change increase in in plaque in absolute amounts was 18 millimeters cubed in in a year a median of 6.6 which tells you actually if the average is 18 but the median is 6.6 that's that's not an even distribution there's a lot more people that had progression but the number of people who had a rapid progression based on that one percent increase of pav over a year was 21 to 29 percent depending on which analysis you looked at.

1:11:27Now, just to give that some kind of perspective for people, very interestingly, Ron Blankenstein published a paper just in the last few months called Nature CT. And this is fascinating because they essentially went out and got a group of people average age 55, same as keto CTA. These were people who were not at high risk of cardiovascular disease. They had good metabolic health. They actually had a higher BMI than the keto subjects, if anything. But the main difference between the groups was they had an LDL around 110, 112, whereas the LDL in the keto CTA study was near 200, I think. and they looked at the percentage of rapid progresses and it was just three percent so in a metabolically healthy cohort that has lower ldl cholesterol not even at that crushingly low these were not people on medications only three percent of subjects had rapid progression over a year, but in the Cato CTA, it's between 21 and 29 percent.

1:12:50There is that cognitive dissonance that we all have to worry about in science when we publish a paper, which is saying, I know the result I want, but I really have to be disciplined enough to get the result I don't want, and then try and figure out if I have to change my thinking. That didn't occur here. It didn't occur. And then they do mention that more than one in five people had rapid progression. It is mentioned in the discussion. But what they do is they kind of downplay it and say this was subjects who started off having more plaque. Oh, that's their plaque begets plaque theory. It's the plaque begets plaque theory.

1:13:29Yeah. Yeah. As opposed to you have more ApoB, you're going to have more plaque. I mean no one's talking about the fact that there's a handful of individuals who had a huge increase in total platform the question is is there any relationship between those people and what were their LDL levels well I don't think they didn't provide the analysis and that's a great point because that's what I wanted to know when you look at rapid progressives was that relationship there LDL or ApoB because that would be a fascinating thing to say is like because if that were truly different if plaque begets plaque and not related to apob or ldl then they should be able to show that on that data then that would be fascinating the rapid plaque producers had ldl that was 100 that would be fascinating it wouldn't happen but that would be fascinating so i think that a more objective way of kind of communicating the results from this study would be that there are more rapid progressives than a similar cohort of people cohort of people who are older well they're similar they they were average age 55 in the nature ct which was the same as the keto cta oh was it yeah i thought they were younger in the keto ct average age is about 55 okay yeah So similar age, the main difference was LDL cholesterol levels.

1:15:02So LDL does have something to do with cholesterol and plaque burden. Well, when you compare and contrast those two studies, certainly there's a difference that I think needs to be acknowledged. Now, at the same time, I think people on the other side of the fence will say, but why did some people not have rapid progression? and and why are some people getting regression and i would say to that it's an interesting question but if if you're a person that's out there on the internet and you adopt a ketogenic diet and your apob goes sky high do you want to take the gamble that you're an outlier and we don't know what their pcs pcs canine status is right they could have one of the genetic variants One of the great things about PCSK9 patients is, those who have the genetic variant, is they die of other things.

1:15:59They don't die of heart disease, obviously. Those are the people who are smokers that don't die of heart disease. So there are other factors that we don't know that would be interesting to study. You're saying we're not sure if these people with high ApoB, that they don't have a gene mutation? A gene mutation. Well, it's similar to PCSK9, but not that mutation. That they don't have a gene mutation. Like an unidentified gene mutation. And that would be fascinating to find. Those are the people, the outliers are always the fascinating people to study because that's when you find how your model can be.

1:16:37I see what you're saying. In this case, it would be some type of gene variant that is protecting them from cardiovascular disease despite the high APOB. So, for example, maybe their glycomatrix is thinner so that the macrophage can go up and recirculate the plaque. Maybe, so we don't know. Those are the fascinating questions. I think that's interesting. And so I do think some interesting things, like I said, this could be a stepping stone. Some interesting things could come out of this. What I wish was we didn't rush to over-interpreting it. And I think some people will say, hey, but in the documentary they did speak about drugs, this and that.

1:17:18listen the overall sentiment and you all you have to do is go and look at the comment section of the cholesterol code documentary on youtube is hundreds and hundreds of people saying you know dave you should win a nobel prize congratulating the team talking about the fact that they're rejecting medications that they with their doctor these are people that believe that this science is settled that you not only settled that you've overturned decades of science showing lda is causal in the role of atherosclerosis. And that is a communication problem that, as a physician, you have to be careful of.

1:17:56So if there's any MDs on their team, they are the ones who should be saying, we cannot over-interpret this. We cannot tell people not to take this. We need to be very clear with this. Because that's our ethic as a physician. Because we know the overwhelming data is atherosclerosis causes heart disease. Atherosclerosis comes from ApoB. You should take your medicines. And I've heard Nick say you should take your medicines if your doctor prescribes it. But clearly it's not coming out that much today. There's more clickbait when you say this is the lie the medical school told me. Well, the cynical side of me, and I could be wrong, thinks that Dave and Nick have realized there's a community of people out there that want nothing to do with Big Pharma.

1:18:39And these guys have been put on a pedestal by that community. and by generating content and questioning that consensus consistently, they get deep engagement. Yeah. And then you can build a business around that. And that's their model. That's their business model, right? My business model is telling people about medical science. Their business model is saying, let's appeal to the people who want to say, I want to eat what I want, I want to eat steaks, whatever, and not have to worry about my cardiologist always telling me that I have my LDL is 300 and I shouldn't worry about it. Because you won't see the results of that for years.

1:19:18If I was betting my life on it, if I was a subject in this study, and in fact, I've done this, I've made this decision in my own life. I know. I would just look at it and say, look, it could be interesting. It's very premature. I'm gonna start some type of lipid lowering therapy and get my APRB to a level where it's clear people quite often see regression. Because you don't see regression in there. Or when you do see regression, I would submit, and I haven't looked at that in depth, that I would submit that we're probably looking at more noise than anything else. When I look at that, what I see is a lot of noise because we're dealing, yeah, that whole area around that, that's noise.

1:19:56Well, can I tell you what's interesting is when they say 15 % of people had plaque regression, they're including someone in there because the confidence intervals are there. they included someone who had minus 0.02 millimeters cube regression yeah you can't be serious the instrument cannot measure that they lumped all those people into that group of regression whereas that 21 having rapid progression that that was actually significant progression as per that increase of one percent in pav or more right not just everyone who progressed. If you just said anyone who progresses above zero millimeters cubed, it would have been like 70 % of people.

1:20:40And just to make it clear, when we look at rapid progression of atherosclerosis, you think 1%, that's not much. But this is a cumulative problem over time, right? So it's like getting the one penny, and then the next day you double it, and the next day you double it, and the next day you double it. This 1 % a year is, over the course of 10 years, it's not just you're going to get 10%. It is cumulative. You are getting a significant plaque burden with that. It's exponential. Yeah. And people just think, oh, it'll be 10 % in a year. And 10 % of small numbers is small numbers, so it's not that big a deal.

1:21:13It's like, no, this is a very, very big deal with plaque. Even if it wasn't exponential, 10 % per decade, if you're only 20, that matters. That's bad. And we see this in arterialized. So there's a procedure we do with people who have kidney failure where we will take a vein and hook it up to an artery so that they can use that to get on a dialysis machine. Okay? And so these are where the veins become arterialized and where we see rapid increase in two things. Number one, a rapid increase. We will actually see atherosclerosis then in those veins because the vein morphology changes, the glycocaelex matrix changes, all those factors change.

1:22:00And we can see very, very rapid progression. Some of that has to do with the scar tissue at the arterial vein anastomosis, hypercellular scar changes. Not those, but there's actually atherosclerotic changes that occur. and they can occur very rapidly and cause those arterial venous fistulas to shut down. Last thing I want to say on this study before I hand it over to you. If someone wants to see a deep dive from a data scientist who's looked at the actual statistical analyses in this preprint, I'm going to link to a video done by John Slow and his partner. And he kind of walks you through the various problems with this paper, which may even just make interpreting any of this data that we're talking about near impossible.

1:22:58And have seemingly significantly increased the likelihood of finding a null kind of result, which is what they found between the relationship of ApoB and plaque progression. and so he is questioning a number of things and kind of waiting for a response from the the the team on that and i am also hoping to get matt budoff who is one of the the researchers on this study in here because he has done a lot of of great work and i don't necessarily think it's it's all of the authors that are contributing to the the kind of confusion online equally anyway Well, when you make a movie about a study that hasn't been published yet, but it's been retracted once.

1:23:41I mean, that kind of speaks volumes, right? Yeah. Anyway, that's enough from me on that. You're very invested in that. I think the other one that's on my chest is this. Hang on, hang on. Before you get... Okay. Am I too invested? No, I don't think you are. I think you need to be as invested as you are because, A, we have one shot at this life as far as I know. And to be able to say, I can make these changes to decrease plaque burden, you have to. The last thing you want to find out about your plaque burden is when you're dialing 911 and going to a cardiac lab. And I mean, I've seen that firsthand with my dad.

1:24:24Yeah. When he was taken to hospital in a helicopter after having a heart attack. And so I don't think I take it lightly when I read those YouTube comments and see people turning down medical care and also doubting their physician based on a documentary. And I haven't seen those YouTube comments, but the YouTube comments I've seen are on some of the other keto people where they come in and they say, I had a stroke going on this carnivore diet and I think it must be because I was running too much. Or I've developed all of these funny lesions on my face and you see all of these xanthalazomas and high cholesterols.

1:25:02Or I had a heart attack. And then, you know, I really like the carnivore diet because I was eating better, but I had a heart attack. Now what do I do? And I, you know, you see these, like Sean Baker has a bunch of them on his comments. And it's like, none of them are answered. And they're all ignored, but they'll always focus on, I had psoriasis and I went on the carnivore diet, my psoriasis is gone. It's like ignoring that psoriasis is episodic and will change and come and go and ignoring whatever you may have stopped eating that caused it. It wasn't vegetables. Well, if you amplify the success stories and you ignore or downplay and say, well, they didn't do the diet right or whatever it is, the stories where people had problems or adverse effects, then you can continue to sign people up to whatever program you're selling.

1:25:49It makes Rhonda Patrick's problem look very small, doesn't it? Totally. Let's put things in perspective. You don't want a banana in your smoothie, that's fine. I want better polyphenols. Okay. Put a little cacao in there, you'll be better off. Yeah. Okay. Hit me with your first study. So we've talked about this, and we've talked about some things that are truly miraculous in terms of CRISPR, and we've talked about monoclonal antibodies. We've talked about some of the most amazing parts that science has to offer. You have to have the Faustian bargain now. Which do you want for public health more?

1:26:25If you had a limited budget, you have two choices. You have that versus the field I'm going to talk about. Today, we now have more measles outbreak than we've had for 25 years. We have cyclospora outbreak in our lettuce. We have more E. coli, Shigella. All from things that are very inexpensive that we've done for years. Isn't it amazing the simple stuff, vaccinations, clean water, sanitation, following up studies, are still causing a huge burden. So if you had an amount of money, where would you spend the money? Where would you stop? Well, fortunately, we don't have that problem. We have made that a problem, though, because we've stopped spending money for public health.

1:27:10and we've defunded studies for mRNA vaccines, for example, and other things. So we have done a total decrease in that when we went through the Dodge program. And I just brought it up as a point of concern that sometimes we get caught up in these very, very interesting things, and yet we've had 155 people, most of them kids, that were hospitalized for measles in the last year. we've had bad lettuce has cost us so far this year $5 billion in healthcare costs. That's billion with a B. That's just lettuce. And to consider that all of these things happen because we're defunding some of the parts of public health that we've known for years, it's kind of sad because on one side we have all this brilliant stuff we're doing and I never want us to forget the simple stuff like MMR vaccine, simple and it's cheap.

1:28:03Clean water is simple and it's cheap. Sanitation is simple and it's cheap. And they make a huge difference, not only in acute illnesses, but in chronic illnesses. Because the major chronic illnesses of the turn of the century, the last turn of the century, the 1900s, came from infectious diseases, right? The main cause of heart disease prior to 1955 was rheumatic heart disease caused from streptococcus. The major cause of death among infants was because they didn't have pasteurization of milk-and-milt products. The major cause of morbidity and mortality came not from measles itself so much, but two years after because of the amnesia from it that caused chronic problems with tuberculosis.

1:28:45So sometimes I think it's fun to go down into these molecular pathways. I just want to bring us back to public health too. What's responsible for the illness coming from lettuce? Well, winter lettuce is good, summer lettuce is bad. The reason is that we grow lettuce all year round. When you grow lettuce in the summer, you have to irrigate the lot. When you grow lettuce in the winter, it comes from rainfall. When you irrigate the lot and you have ground contamination, leafy green vegetables, of all the vegetables and all the contamination, leafy greens are the ones that are responsible for the vast majority of foodborne illness.

1:29:24and that's why. That's why, you know, I'm not a big lettuce person, but it's like, this is the time of year when I never bought, this is summertime now, this is the time of year when I never get a, I don't get my Caesar salad this time of year unless my neighbor has grown the romaine lettuce and brings it to me, which she does, she said. What's the risk? It's very small, but think about this. One in six people get a foodborne illness every summer, one in six. and the hospitalization, we hospitalize somewhere between 110 ,000 to 160 ,000 people a year from foodborne illness and some of those will die.

1:29:57Some of those will go on to get chronic diseases. If you get Shigella, you probably can go on to get arthritis. So it's a fairly significant burden. Have you been keeping an eye on the reports around an increase in colorectal cancer in young people? Yes. Do you have any views on, I know a lot of people are interested in that, perhaps a little scared by that, hearing stories of people in their 30s and 40s that are early 40s now that are diagnosed with colorectal cancer. Do you have any views on what might be driving that? Well, so let's be clear. That's always been there, but it's increased by about 2 % a year since the 1960s.

1:30:37So even when I was a surgical resident in the 80s and the 90s, We had young people that would come in every year with colorectal cancer. And usually by the time we found it, we found it when it was metastatic and it was a tragedy. So we've always had that population. That population seems to be growing. It's been growing, like I said, since the 50s and 60s. When we look at what has changed, you know, the environmental factors, clearly ultra-processed food is one of the things that have changed. And the lack of fiber in the diet is that part that's changed. So that's a factor. We know when you increase fiber in the diet, you decrease your risk of colorectal cancer.

1:31:14We know people who eat a lot of meat and increase their fruits and vegetables decrease their risk of colorectal cancer. And we know looking at the diets that that has changed. So that's one thing. People who eat a lot of meat? People who eat a lot of meat have an increased risk of colon and rectal cancer. If they increase their fruits and vegetables, that risk of colon and rectal cancer goes down to population baseline. so i mean i think that's one of those things that we look at and say and what is it when we look at fiber in the united states 92 percent of people don't get adequate amounts of fiber so if you just let me double click on that if you eat a lot of meat but then you eat fruit and veg that will normalize your risk of all cancers colorectal a colorectal specifically yeah so So if you look at the risk of increase of cancers over time from people who eat a lot of meat, you have an increased risk of colorectal cancer.

1:32:10The variance is like 1.3. If you increase fruits and vegetables or look at that population of an increased risk of fruits and vegetables, their rate is the same as people who don't eat. I didn't know that. Yeah. So I think that's one of the great things showing that, you know, we're not getting our fruits and vegetables bananas in. Thanks, Rhonda. And we need to do that approach. The other thing is we need to lower our age of screening. To 40? Yeah, absolutely. And maybe even earlier, maybe doing some of the fit tests even earlier. What does screening involve? So there's two types of screening.

1:32:49One type of screening is Cologuard and fit tests, which they're looking for blood in the stool or signs in the stool that you have cancer. The other type of screening is a colonoscopy. Colonoscopy means we put a little device up there and we look out your whole colon. If we find something, we can treat it. The advantage of colonoscopy is we can find precancerous lesions like a polyp and remove them and you are cured. A polyp will advance to cancer in 7 to 10 years. It's inevitable? Yeah. Not all polyps. Okay. There are certain polyps that will advance to cancer in 7 to 10 years. And when they take them out, they know if that's going to be one that advances or they just take all polyps out?

1:33:29They take all polyps out because you don't know and you look at them. And generally, if you have polyps, all polyps, and it doesn't matter what kind, even the non-cancers, even what we call inflammatory polyps, the risk of colon and rectal cancer increase for that group also. So there are a group of cancers that arrive from polyps. So all colon cancers are derived from polyps. They all start out as a polyp. What is a polyp? So a polyp is, it looks like a mushroom, right? And it's an abnormal collection of cells that have formed this, like a wart inside the colon. And so when you look at it, it looks like kind of a little mushroom in there, and you can take the person who's doing the colonoscopy can put a little sling around it, lasso, take it off.

1:34:14But they're pain-free. Like you wouldn't know if it was there. You wouldn't. Not one bit. And when you cut it out, is there any pain associated with that? No, typically not. Typically not. Now, my producer, whom you met, had a colonoscopy after listening to this, and they found on her, I can't say her age because that's publicly, you know, they found on her a polyp, which was one of the bad polyps that leads to cancer. And it was fairly large. It was 1.4 centimeters. And she ended up with a bleed after her colonoscopy a couple weeks later, which can happen to some people. But they saved her life.

1:34:49Had she waited for the FIT test, which she had taken before, which was negative, had she waited for that to change to cancer, then we would have caught cancer early. But because we did the colonoscopy, now she'll have another colonoscopy in three years, we prevented a tumor from forming. I've been using WHOOP for over six years, and I can confidently say it keeps me on track when it comes to my sleep and exercise routines. The next generation of WHOOP isn't just tracking your workouts. It's monitoring your sleep quality, your recovery state, and even giving you insights into your biological age.

1:35:30No screen, no distractions, just continuous data on what your body actually needs. And here's what matters. Daily WHOOP wear is linked to increased physical activity, to better sleep, and improved heart rate variability. I have no doubt that my Whoop is helping me train smarter, recover faster, and make decisions that support my long-term health. Head to join.whoop.com forward slash Simon. That's join.whoop.com forward slash Simon to get one month off your first subscription. So screening early. right now it's 45 and that would be covered by most insurances insurance but if you're a 40 it's elective I guess you're going to go out of pocket and out of pocket can be expensive but if you're 40 and you couldn't afford that you could start with a stool test you can get at home tests that are pretty affordable they're about 50 bucks, stool test is about 50 bucks, so colonoscopy depending upon how greedy a gastroenterologist is the GI doctor gets about$300 to$400 for a colonoscopy.

1:36:41They will charge you thousands of dollars for a colonoscopy because— You must be in and out pretty quick then. Yeah. Interesting. And that bleed, is that bleed from the removal of the polyp or is it from damage done during the colonoscopy? No. When she had the polyp removed, they had to clip it because it was bleeding. The clips fall off after a couple of weeks, and she woke up and had blood in her stool and, you know, and fortunately she didn't need—you know, it stopped. nor most of them do. But it's pretty traumatic when you have blood in the toilet. Totally. Yeah, I remember I ate a lot of beetroot once and I thought I had blood in the stool.

1:37:16That's always bad. Cold mom. So yeah, so the one thing we think can change is dietary intervention, which of course we preach about all the time for colon and rectal cancer. But the thing that really is going to help you, screening. Okay, so all I want to put on people's radar and then I can explain kind of how to use this information and feel free to jump in as well. The new 2026 guidelines for managing dyslipidemia came out. Oh, yes. This is a very big document. I do suggest downloading it out of the show notes. You can put it into AI as well along with – I find it's helpful to put the actual PDF in there and then you can put your history and everything in there.

1:38:02it's not a substitute for medical advice, but it might point you in the right direction with regards to questions or things you want to talk to your physician about. See what your cardiovascular risk is. See if you follow the category. See if you follow the category. Yeah. Yeah. So much information. And if you put in the right information, it will be able to identify kind of at least where the guidelines are suggesting would be appropriate for you in terms of things that you want to test or when medications would be recommended, et cetera. Yeah. Now, it's 200 pages, so clearly we can't highlight all of the new things, but I wanted to highlight a few things that they've added.

1:38:41The first is that they recommend, as an adult, doing your lipid panel at age 19. Agree. And then they say, which I think maybe we could debate a little bit, they say to, providing it's fine and you don't have to go on medication, you don't have FH or anything, to then do another lipid test every five years. And I believe that that's an economic argument more than anything and like a public health kind of load burden of doing yearly testing. I wonder what you think about that in terms of if someone's 19 and they have the means, the resources, would you be opposed to a yearly lipid panel? Well, it's not going to change that much in a year.

1:39:26It is going to change more over five or ten years depending on the person's change. But, for example, I take statins. My son's mother takes statins. So my son, who's 16 when he's 19, he's going to absolutely get a lipid panel. And then so we would look at him as being high risk over time. And we would want him to, you know, put off this disease. So your family history is going to matter a lot too. But even if it wasn't, I would say, because, you know, you'd never know who the mother of the child is. But always the question is that from a public health standpoint, will this help? The answer is overwhelmingly yes.

1:40:03So first lipid panel as an adult at age 19, but here's an interesting one. All kids should be screened around age 10, and that is to detect FH early. Now, it's screening even earlier, even at the age of about 2 in the guidelines, if a child has a parent that has FH. And the idea is to detect if someone has genetically very high LDL cholesterol so that they don't go 20 years untreated. Well, it's like the 35-year-old that drops dead of a heart attack but is perfectly healthy on the tennis court and turns out they have familial hypertension. Cholesterolemia. Hyperlipidemia. we could have prevented that there's an entire lipid group that takes care of kids they do nothing but deal with kids you know what's one of the fascinating things about kids and statins none of the kids have adverse reactions to statins and so I asked one of the lipidologists I said why in your group of all these kids and they have kids that are 7 years old that are on statins because of familiar hypercholesterolemia why don't they have it?

1:41:17you know what he said? nocebo effect yeah they don't read they don't read the package inserts i mean that's a known effect yeah but it's still a real effect yeah you know because people hear about all the the terrible things about statins and then they start them and they experience the side effect to them the side effect is still real right yeah it's unfortunate because there's so much negative talk about all the adverse effects when in fact the the true adverse effects associated with stat news while they are there, they're very small and very unlikely. So I would say in my career of medicine, I've seen one patient have a severe adverse effect that landed them in the hospital.

1:41:59But I've seen certainly a lot of patients who've died of heart disease. So that was the guideline for children. And then they added in for the first time, testing LP little a at least once per lifetime. How's your LP little a? It's low, thankfully. Mine's high. Yeah. And yet you have less plaque than you thought. Yeah. But I don't know where the plaque is in my heart. I have a positive, it's like 96 on a calcium score. A couple of interesting things on LP little a, there was a recent study that came out that was looking at plaque morphology and associations with LP little a levels. They're also looking at LDL cholesterol and ApoB.

1:42:46And that study seemed to suggest that LP little a disproportionately affects plaque vulnerability than plaque volume. So while it still does affect plaque volume, like LDL, low-density lipoproteins do, it's to a lesser extent. And it seems to be particularly problematic because it increases the vulnerability of that plaque, which I thought was fascinating. I hadn't really seen that result. Well, that would make sense, right? Because when you see the LP little a is considered the genetic factor for heart disease, it makes sense that the plaque vulnerability would be worse with a higher LP little a.

1:43:27And since with statins, we decrease plaque vulnerability by stabilizing the plaque, increasing the capsize, even though your LP little a will go up, we have that discordance in what that means. We don't know what that means yet. I think probably the best analogy I've heard for those who aren't LP little a and LP ApoB is every LDL has an ApoB. It's a protein molecule. So if you think of your LDL as a truck carrying cholesterol, think of the little a as it has the hitch that can carry more cholesterol or it can back up things and cause more of a problem. and about 20 to 25 percent of people have elevated lp little a yeah so it's it's a it's not a small number of people and it it increases not only atherosclerosis and vulnerability of plaque but also calcific calcification of the aorta as well thrombosis and inflammation so it kind of seems to contribute to heart disease in a variety of ways.

1:44:37And a lot of people ask me, they say, well, I measured my LP little a and it's high. What do I do? And at least my answer for now, and you can tell me if you would add anything to this, is the drug trials are ongoing. This year, we should get the first drug trial, Horizon, which is looking at, if you give someone with high LP little a over about 125 nanomoles per liter a drug that specifically lowers it do they have less events right and that's a big thing it's huge right so that's gonna probably change the way that these patients are managed you know depending on that result particularly if it comes out as positive but for now and the guidelines kind of emphasize this if you have high LP little a because we don't have the outcome data and drugs that lower it to support that, it's really just saying, hey, you have a genetic trait that is increasing your overall risk of heart disease.

1:45:36So now we've identified that. Let's make sure we fine-tune all of these other risk factors that we do have treatments for, right? So that we get your overall risk down as low as possible despite that genetic predisposition. Agreed, because that's all we have. Now, what we should have good trials on is what happens if we take people with a high LP little a who are on maximal drug therapy with low LDL. We don't have that data yet, but I think that's the fascinating data because that's kind of where we are in real life today. Yeah. And then if you add on top of that, so that's what this trial horizon must be looking at people that are already treated with statins.

1:46:16And then if you add on top, do you get any extra benefit? Similar to the PCSK9 trials. So that's kind of a, I guess, a bit of a watch. It just gives more anxiety to people like me who have high LP little As. Well, and the other thing to note, and I know a lot of people are doing this when considering the choices of lipid-lowering therapy, is that there is one lipid-lowering therapy drug class that does lower LP little A by about 25 to 30%. That's the PCSK9 inhibitors. Now, that might not be clinically meaningful, but it could be. Yeah, and for someone like me, I mean, I think my last LP little A, I've had it checked several times.

1:46:55And my last one was like 225. So lowering it down, will that matter at all? Now, we also could be looking at another HDL story. The HDL story was we chased HDL for years. And we found that when we brought HDL up and got it up and made the so-called good cholesterol, it didn't matter. So it could be that we can, it may be an interesting marker that says something like frank sign as opposed to something that if we lower it it will benefit us or not that's why we have to wait for it's not just the one study there's a handful of these studies yeah and they're all using different drugs that lower lp little a through different kind of mechanisms yeah so will i be on another therapy this time next year maybe the last thing that the guidelines recommend for lp little a which i kind of remember hearing from tom day spring in a conversation was when you measure LP little a, it can come back as two different units of measurement, concentration or mass.

1:48:01So there's what you and I are talking about. I believe the 200 you're talking about would be nanomoles per liter. Right. That's a concentration. And milligrams per deciliter is mass, right? The reason that with ApoB, mass is fine. You measure ApoB, it comes back as milligrams per deciliter. is because that apolipoprotein B universally between people, between lipoproteins, is the same mass. Right. And from there you can calculate, because there's only one per particle, you can get an idea of the number of particles. Whereas with LP little a, and I hadn't really stopped to think about this since first hearing it, that apolipoprotein little a is very variable in mass.

1:48:53Correct. So mass isn't really going to give you a kind of, isn't going to associate necessarily with concentration. So another way of thinking of it is you can have a train with three cars or you can have a train with 100 cars, but they're still measured as a number of trains. And the same with the LP little A. If we're measuring mass, it's going to be different than if we measure particle number. So the recommendation is to measure in nanomoles per liter is going to give you a better information in terms of determining what level of risk you are, low risk, intermediate, or high risk. And I'll put into the show notes within the guidelines, they walk through what those thresholds are.

1:49:38Yeah. I think we did it. We did. So the question is, who should get a CT angiogram? The person who speaks to their cardiologist firstly, that refers for it. But that's a good question. I think understanding if someone is secondary prevention, let me go there first, and you're treating them. I'll throw this out as a hypothetical question to you. Hypothetical case study. Secondary prevention. They go on lipid-lowering therapy. and you get them down to 40 milligrams per deciliter, and before the treatment you had a scan, is there any point in re-scanning them at five years or so to see how their plaque is changing and the morphology of the plaque?

1:50:31Would it change treatment? Might it change the drugs that they're taking or the intensity of those drugs? Yeah, because first of all, the drugs have changed, right? We're now in fourth generation statins where we have PCSK9 inhibitors. so changing it every five years would be beneficial because you would see and change the plaque volume. Once you start getting the plaque being built, it's going to keep being built. You know, you have the genesis of the plaque there. I'm not saying plaque begets plaque, but you have the genesis of the plaque there. And even though you drive your LDL down, you still have a focus of plaque and you want to see it.

1:51:10So yes, I would say it's secondary prevention. And I'd say even for primary prevention, I would say that if you have a positive calcium score, you have heart disease. And if you have heart disease, you might want to know, do you have just sort of a general calcified plaque that is like a dormant volcano? Or are you sitting over magma and you have a big problem with an atheroma that you need to be more intensive and get more intensive therapy with? And do you think that that interval should be around five years between scans? I think that's reasonable. I think at that time you'll start seeing change.

1:51:44I think many of us would probably be crazy and do it every year, but I think every five years is pretty reasonable. I don't think that's a huge burden. It's getting less expensive. I'm pretty sure the guidelines actually don't even really talk about CT angiogram. They talk about coronary artery calcium score, but not the CT angiogram. One of the things that always bothers, speaking of something to get off my chest, one of the things that always bothers me is it is true that once you have a positive coronary calcium score, putting you on statins decreases your risk of heart disease by a tremendous amount.

1:52:17And if you think about it, it makes sense. What bothers me is those people who say, don't even start a statin until your calcium score is positive. It's like saying, why would you do that? Why would you wait until you have the disease to start a statin? Why wouldn't you want to prevent that? So let me throw another hypothetical at you. Let's say you were in the keto CTA study. feels fitting to finish on this study it does and i couldn't eat that much meat let's say your apob was in the 200s or low 300s okay but you did a ct angiogram and you didn't have plaque or very little plaque and you didn't have calcium would you take lipid lowering therapy yes would you just rescan in five years?

1:53:03No, I take lipid lower therapy. And what would your kind of personal clinical rationale for that be? Because I don't want to get to the point where you have plaque, because plaque, once you have it, you have it. Once you have plaque, it's there, and it can result into a catastrophic problem very quickly. Which kind of is the author's, that's their central argument, plaque begets plaque. Well, plaque doesn't beget plaque. Plaque shows that you have said something that's developed plaque, and the mechanism we have, which is very worked out is a transcyclosis of the ApoB molecule into the endothelial cell of the back of the glycogen matrix.

1:53:35We have the mechanism very well studied. And it does beget plaque because once you have that area there, that's where the problem is going to be. So yeah, I would definitely, if I were in that study, and even though I was a hyper-responder, whatever it is, yeah, I'd definitely get on lipid. I would be like Nick. I would get on lipid-lowering therapy. Well, he's done that for brain health. I don't understand the brain health thing. I mean, it's confusing to me. There's far more evidence to support azedemide for heart disease. Didn't he go on a statin but couldn't tolerate it or something? I don't know about that, but I know he's run some experiments throughout the years with statins.

1:54:24Or maybe he's increasing his Oreo cookies. Yeah. You know. But you're right. he and others within that community have commenced or, you know, have been on lipid-lowering therapy for a while. Yeah, and that's wise of them to do it, you know, because not all, I mean, we've known for years from the Keyes equation about LDL and saturated fat and the raising, but still, the vast majority of your LDL is probably genetic. and why would you tempt fate when we can have a way to prevent things? I thought I had one more question for you, but... I mean, 75 cents a month is not that much. I don't have one, but I'll leave you with something else.

1:55:12What happens when a frog's car breaks down? What? It gets towed. Oh.

1:55:22All right, I've got to let you get out of here. Thanks for coming back. happy to let's do it again there you have it friends i hope you enjoyed this episode if you did and want to stay up to date with future episodes be sure to hit that subscribe button on youtube and follow on apple or spotify finally thank you for showing up and the effort that you're making to take control of your health i look forward to hanging out with you again in the next episode