The Cholesterol Debate: What the Keto Influencers Get Right (and Wrong)

Episode Summary

Dr. Greg Katz, preventive cardiologist at NYU Langone and co-host of Beyond Journal Club, joins Anish to dissect the online cholesterol debate — specifically the claims made by science communicator Nick Norwitz, who has maintained an LDL over 500 mg/dL on a low-carb diet for seven years with no coronary plaque on CTA. Katz takes the data point seriously, walks through the limitations of coronary CTA and the flawed Keto CTA study, and explains why he still believes the burden of proof lies with those arguing diet-induced hypercholesterolemia is safe — while acknowledging where the cardiology establishment, including the new lipid guidelines, overcorrects. The conversation covers the accountability gap between clinicians and content creators, the failure of risk calculators in young patients, and what a well-designed trial to actually answer this question would look like.

Chapter Markers

00:00 Introduction — Dr. Greg Katz, NYU Langone cardiologist and Beyond Journal Club co-host

01:40 What prompted the Substack: patients bringing in Nick Norwitz's content

02:51 Who is Nick Norwitz — LDL of 500, low-carb diet, and the clean CTA

05:38 Why Katz takes the question seriously but disagrees with the framing

08:01 Familial hypercholesterolemia outliers: why some FH patients never have events

10:05 The 50/50 problem — half of high-cholesterol patients have heart disease, half don't

12:27 The Jody Plute story: homozygous FH, Thomas Starzl, and the portacaval shunt experiments

17:37 Seven years of LDL 500 — is that long enough to know anything?

18:21 Limitations of coronary CTA: what it can and can't see

21:00 Why LDL gets put on a pedestal — and the cognitive dissonance of a diet that works

22:05 The conflict of interest argument — and why it cuts both ways

25:43 Burden of proof: mechanisms vs. outcomes data

27:16 Statins and GLP-1 levels — why a mechanistic claim isn't the same as a clinical outcome

31:38 Physician accountability vs. content creator accountability

35:24 The Keto CTA study: what it found, what it didn't, and why the blinding controversy matters

44:40 The new lipid guidelines: where they overcomplicate, where they overprescribe

49:38 GLP-1 deficiency framing and the over-medicalization of well people

55:54 Longevity medicine as "over-medicalization of well people"

57:35 What a well-designed trial would actually look like

1:00:01 Why the debate needs real research, not conjecture

1:02:37 How Katz talks to statin-hesitant patients in clinic

1:07:06 Wrap

Co-Host Handles

@anish_koka and @drdigiorgio

Show Handle

@drsloungepod

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Transcript

SPEAKER_00 0:00

You like your healthcare plan? You keep your healthcare plan. Nobody knew that healthcare could be so complicated. It finally beat Medicare. This is the Doctor's Lounge.

SPEAKER_01 0:16

Welcome to the Doctor's Lounge. This is a special bonus edition on a Sunday evening. And I'm extremely excited to have Dr. Gregory Katz on. Dr. Katz wrote is a very prolific high-quality writer, and we were just talking prior to getting on about how difficult it is to write a lot and write high quality. And he clearly is one of the few people that can do that. And he writes about writes and thinks about cardiology topics a lot. And it's obvious that he does. And so I'm super excited to have him on. A little bit of an introduction as to who he is and why I'm talking to him. He's a cardiologist at NYU Langone. He's an assistant professor of medicine at NYU Grossman School of Medicine. He's also associate program director. Again, I don't know how he has the time to do everything he does. He's his clinical practice centers on cardiovascular disease prevention, management of complex cardiometriolic conditions. He serves as counselor for New York Chapter of the American College of Cardiology, sits on the ACC's National Council on Diabetes and Cardiometabolic Disease. He also co-hosts uh Beyond Journal Club, a podcast. Um, that's in collaboration with Core IM and the New England Journal of Medicine. And he is a basically a New York lifer. He completed his MD, his residency, his cardiology fellowship at NYU. And he was also chief resident there as well as chief fellow. So so he's really he's a true product of New York.

SPEAKER_00 1:32

So they call it the purple cult, is how they refer that, yeah.

SPEAKER_01 1:35

Excellent. Dr. Katz, Greg, thank you so much for uh coming on. Uh welcome to the Doctor's Lounge. I'm thrilled to be here. Thanks for having me. Absolutely. So I wanted to talk to you because of the I've been wanting to talk to you for a while, actually, but uh the recent uh Substack that you wrote, I thought was really good. And it specifically kind of looked at one angle of what's talked about a lot, this the whole LDL and what do we do about LDL, whether we should reduce it, the cholesterol hypothesis. And but your angle focused on some of the media, uh sorry, media, not media, some of the online influencers and what they're saying specifically uh about the cholesterol hypothesis and LDL. You you focused on Nick Norwitz, and Nick Norwitz is an extremely popular influencer in the community, and he talks a lot about cholesterol and LDL, and he had a recent, very interesting post and video on something, and you kind of were responding to that. So can you can you just go through what prompted your recent Substack as it relates to Nick?

SPEAKER_00 2:38

The thing that prompted my recent Substack is the thing that prompts most of my writing, which is patients talk to me about it. And like when you see people all day, every day, you learn a lot about what ecosystem informationally people are experiencing. And so Nick Norwitz is a uh he's a really smart guy. He writes on Substack, he posts videos on YouTube, and he has this really interesting story. If you read anything about him, so he's an MD PhD, he went to Harvard Medical School, and he struggled with ulcerative colitis. And the only thing that seemed like it got his symptoms in remission was a super low carb diet. And then after he went on that diet and he felt really a lot better physically, he noticed that his LDL was insanely high, like in the 500 milligram per deciliter range, which is a level of LDL that you pretty rarely see in clinical practice. And the usual teaching is that you see that in somebody who has homozygous familial hypercholesterolemia, like a real genetic disorder related to cholesterol metabolism. But he experienced this with a low-carb diet. And the question that he raises, and a lot of his content is sort of centered around this concept of is that diet-induced elevation and LD dangerous from a cardiovascular perspective? And he posted this recent thing on um a bunch of his different channels where he talked about how he'd been on this diet for seven years and then he had a coronary CTA done, and the CTA did not have any plaque, no calcium, no soft plaque. We could talk about the limitations of that test, but it's a pretty fascinating result when he'd had seven years of an LDL in the three, four, five hundred milligram per deciliter range, which as he he remarks pretty uh pretty provocatively, like a lot of cardiologists told him that he was gambling with his life and that this was a catastrophic error. And then he shows them this CT scan as like, look at my arteries, proof is in the pudding. This is not a dangerous diet. And my patients who talk to me about this, they see this content and they wonder, like, does this apply to them? And I think that it's a really, really fascinating question. And so I came to his content basically through patience. And then I read about it, I learned about sort of what he was experiencing. And he's he's a really smart guy. If you read you, you you've read any of his stuff. He's he's he's really, really smart. He like he spends a lot of time going into going into research, going into mechanisms. He's thinking about this from a pretty sophisticated perspective. But the problem I have with this content is that he's so everything that's provocative is provocative against the hypothesis that LDL is damaging and LD like high LDL increases cardiovascular risk. And in medicine, there's a lot of things that there's uncertainty about. And we don't have complete hundred percent confidence in anything, but the LDL hypothesis is sort of one of the things that has the strongest body of evidence with it. And the reason that I care about this is because I don't want my patients to have heart attacks and strokes. It's as simple as that. And when people are exposed to different content, they're gonna draw conclusions and they're gonna think like, does this apply to me? And his content often will talk about statin's lower GLP1 levels, like this mechanism, oh my God, this is huge news. Like you you've seen some of this stuff, I'm sure. Absolutely.

SPEAKER_01 6:03

But Greg, before we get before we uh you had a very nice kind of structured critique. But but one of the things that was really interesting, which I don't see a lot coming from the establishment, is the interesting data point that he represents, right? So and and you and you and you brought that up front and center, which which to me, when I when I when I first saw his little uh his report on having an LDL of 500 for X number of years and having no plaque, I was, I was, I was like, look, I would not want to run that experiment, right? I mean, you and I would not want to run that experiment because of exactly what you're saying. And so you it represents an interesting data point, and you make the point that a lot of a lot of progress in medicine comes from uh understanding uh outliers, right? Before we get into your very nice structured critique of the different different issues, what what do you make of the of this LDL of 500 that he's had for a significant period? Do you do you think do you think that this idea that a lot of folks in the keto community especially have, which which is that that high LDL is not necessarily linked to progression of corner disease, are these a specific subgroup of folks? Like what what like how do you how do you how do you kind of square that uh level?

SPEAKER_00 7:13

I think it's I think it's a legitimately hard question to answer because and when you see patients all day, it gives you a different level of confidence about the level of certainty you have with any type of knowledge. And yeah, you just see a lot of stuff and it makes you humble about the limits of what we understand about any condition. That's just the nature of taking care of patients because patients will humble you. But so maybe there is something to the idea of if you are not insulin resistant and you are not hypertensive and you are less chronically inflamed than most people who are walking around on planet Earth in 2026, like maybe you're protected, but like maybe there is some other factor that is protecting people. And so if you look at the FH literature, like the familial hypercholesterolemia literature, some of those patients never have heart attacks and strokes. And it's probably not because they're eating a low-carb diet, it's probably because they have some other factor that is protecting them. But do I know that a low-carb diet-related rise in LDL is not the same or is the same as a genetic disorder of cholesterol metabolism? The answer is I don't know for sure. But when you have all of these lines of genetics and observational data and randomized control trials with multiple different medications that work on that idea, lowering LDL, increasing the like length of time that the LDL receptors on the surface of the patocytes and taking those particles in from circulation, when you have this body of evidence across all of these lines of study that says that LDL is causative or APOB is causative or non-HDL is causative, the burden of proof is to show that it's not. The burden of proof is not to say this N of one or N of 100 over a year with the keto CTA study, which we'll talk about in a little bit. I don't think that the burden of proof is to say that this outlier that we've seen is a definitive new biological entity. I think the burden of proof is to show that it's different in any sort of way than all of the other research that's that's out there.

SPEAKER_01 9:12

Yeah, I I I think that's such a great point, because I think it both gets to the idea that we may be simplifying things a little too much when you're talking about what most cardiologists are kind of trained to talk about in terms of LDL. And you you brought that up. 50% of folks who have familiar hypoglycerin out have heart, which is insane, right? I mean, that's an insane number. But on the other hand, 50% do not, right? Uh at that given time point, who knows, as you follow those out. And so I think we probably on our side are being um uh um making it to like a one this one-hit wonder when it comes to LDL. It's probably a lot more complex than than than just LDL. But but for every N of one story, um well, and by the way, we're we're gonna get to this uh in a minute. I just but the this is the FH uh patients, right? This is a like a extremely morbid group of patients. So you want to talk about like N of one disaster stories, right? So I mean I mean, I I remember the first story, and this is again, luckily homozygous FH is a relatively rare thing. So a lot of cardiologists will, especially community cardiologists, private cardiologists, will go through their years and years and years without ever seeing an FH patient because they're caught when they're young and they're then they're sucked up into these kind of academic centers, right? But to remind everyone, the first FH patient I read about was was a girl named Joy Jody, Jody Plut, you know, who who Thomas Starzel, the great liver transplant surgeon, uh wrote about. And Jody Plut, uh, you know, was this beautiful uh, you know, 13, 14-year-old girl who had suffered multiple cardiovascular events. And she was looking at looking at uh and and they'd already organized this whole thing where she was not gonna be able to graduate because things looked so incredibly bad. And they, you know, she had created a plan with her senior class. She was athlete, honors kid, I mean, much loved by her by her by her classmates, and there was gonna be an empty seat for her at graduation. Can you imagine this as a teenager planning this, right? Just incredible. And and they were in their infancy in the 1970s and early 1980s in terms of understanding why it is somebody like Jody was having these heart attacks. And so Tom Starzel felt extremely strong strongly, because he was a surgeon, um, and of course he was specialized in doing liver transplants. He felt extremely strongly that there was something about blood going to the liver, uh specifically to the portal system, that was was the problem. And if you could somehow divert this blood that was going through the liver, that you would you would delay or avert these uh these problems in in these kids, right? So he actually started doing porto-cable shunts. I don't I'm not sure if you're aware of this history. No, I haven't heard of this history at all.

SPEAKER_00 11:56

This is fascinating.

SPEAKER_01 11:56

Yeah, so he started doing porta cable shunts in kit in these in these young young people because again, they were desperate. They had nothing else to do. And and again, she has like her casket kind of picked out, right? And so he does this, he does these porta cable uh uh shunts. Um, this is before the LDL receptor was identified. This is before they quite understood what was happening. Actually, at the time, there were folks that thought the LDL receptor was uh was not just in the liver, but it was all across. And so they were like, oh no, the LDL receptor is everywhere, so just fixing liver won't cause causes problems. But Tom Starles was like, all right, I'm just gonna, I'm just gonna do this because I believe this because based on whatever basic signs I'm seeing. He did these, he did this, he did Porto Cavalchon on Jody on uh um Jody Plut, and uh and she uh uh cholesterol numbers dropped by like 50%, right? They were still very high, but they dropped by 50%. And he describes in his book about her the uh uh how the bags of cholesterol that were in her skin, right? These these xanthlesmas that it kind of uh that have created, he describes how they kind of were melting away over time because that cholesterol number was low, right? And then he describes how she would you would have angina, and that angina seemed to be getting better. And again, this is subjective, you know, plus who knows, placebo, but I'm not entirely sure why that would happen. But but when they studied her coronaries, she had pretty significant plaque at the time, like severe disease. And she was, again, teenager, right? So again, yeah, I'm I'm I'm very glad Nick has no coronary plaque after after seven years of LDL. But this is a 16-year-old with homozygous FH who has very high cholesterols, who has severe disease, and they have such a limited understanding at the time in the 70s and 80s that they're just running an experiment. They're saying, okay, we're hoping that this porta cable shunt, which dropped the LDL, is gonna now melt away the plaque in in the coronaries. You and I, of course, now would say, uh, that's probably not gonna happen if it's socked in and calcified and all that stuff. And you probably, depending on what you have there, and depending on what level of angine and level of ischemia you have, you know, that's another discussion about revascularization. Yes. You know, that anyway, that but he follows this girl, and again, she's she's doing her thing, and he describes again, he describes how mother, he describes how she ultimately was skipping down the road as a teenager and suddenly died, sudden cardiac, right? I mean, just brutal. And and he says at the time, he was like, you know, the mistake we made was thinking that that just fixing this liver and reducing the cholesterol to where it did, that that was going to be enough for her. We should have also done a double done a bypass for her, and maybe then she would have lived, right? And he so for from that, his conclusion becomes that we we need to not just do the porticavel shunt, we need to do liver transplants. And that's where the case of Stormy Jones comes in. Stormy Jones is this young girl who was, I think, nine or ten and had multiple heart attacks by then. And so he takes this girl and does a heart. And so his her heart is terrible. Her liver is also bad, and he takes her and does a double, you know, heart, heart uh liver transplant. And I think that's where that's kind of it's an important story to tell people. And one of these days, I'm not as prolific and as good as you are. One of these days I'm gonna write that story about like where does it come from? Because so many people believe that our prior comes from not, you know, not these stories, but the you know, this all comes from this idea of these homozygous FH patients who had these insanely high cholesterol numbers who were having all these events. But but the point is, just like his, just like uh Starzell's story, right, shows you, it is probably more complicated than that, right? It's probably something to do with hepatotropism, blood flow to the liver. There's something else going on that is probably also kind of taking and we and we need to study it. And probably zooming in and focusing on just LDL lowering constantly is probably not exactly what not the smartest thing, not the smartest thing to do. But sorry for the long story there, but um I I kind of wanted to set that. But anyway, so what do you you'd outline some things about specifically things that patients should know about in terms of yes, this is a very interesting data point, needs to be studied further. Is there something else going on which would allow very high LDLs in certain people? Maybe and be safe. But there are some important caveats, right? So for instance, is seven years of seven years of high LDL, is that sufficient, right? Is one anyway, you had you had maybe but like probably not for a lot of for a lot of patients. Right. And the question is it with seven years of an LDL of 500, right? What what is that? What what happens? You know, what could happen? And do we have the resolution to necessarily pick up for that?

SPEAKER_00 16:24

You've written in detail about the limitations of coronary CT. And, you know, like do we see fatty streaks? No, we don't. Do we see a 0.25 centimeter plaque? We probably don't see that. And so the limit and don't get me started on like the heart flow clearly AI enhanced interpretation because I can't believe Medicare is paying for that. It's that that's really fascinating, sort of hypothesis generating stuff with the AI enhanced um addition of the um of the like layer on top of the coronary CTA, but the coronary CTA is a limited tool. And also, it's only looking at the arteries around the heart. Like we didn't get a comment on is there any plaque in the aorta? We didn't look at the carotids, the vertebrae, like the cerebral vasculature, we didn't look at the renal arteries, like the atherosclerosis is a systemic disease of arteries, is what I tell my patients all the time. Like part of the reason medicines are good for that is because medicines work everywhere. And so the point is not, I think, that there's plaque in his carotids. The point is that it's limited data. And we should be humble about the limitations of what that data tells us. And we don't know. We don't know what his blood pressure is, we don't know what his family history is. All of these data points that my patients are like that's part of how we have a conversation about that. It's you can't just look at the LDL. And I don't think I think that one of the critiques that a lot of doctors get and a lot of cardiologists get, and it's probably fairly well deserved, is as you said, like we're hyper-fixated on LDL. And, you know, we can talk, we'll talk about the cholesterol guidelines and um the level of confidence in some of that data. Are doc do doctors do too much to lower LDL? Sometimes we probably do, but also like we we do it because LDL is a risk factor. And nobody with nobody's going around saying hypertension is not a risk factor for cardiovascular disease, diabetes is not a risk factor for cardiovascular disease. There's something like totally absurd to me. And it's it's almost like so mundane. Hypertension, hyperlipidemia, insulin resistance, metabolic syndrome, diabetes, like those are blood pressure, blood sugar, cholesterol. That's most cardiovascular disease prevention. And so I think that like LDL is a risk factor, just like hypertension is a risk factor. And I think that we almost it's almost put on a pedestal as this thing that is of such a higher level of importance than and it necessarily needs to be, because it's part of the story, but it's not the entire story.

SPEAKER_01 18:47

So and you and you bring up why do you think that is?

SPEAKER_00 18:49

So you know I think I think if you get into like what what was what is Nick Norwitz's story? It's the same as the story that a lot of my patients who do well on a low-carb diet have, which is they haven't felt good, their joints hurt, they have inflammatory bowel disease, they have some other condition, they had trouble losing weight, their blood sugar's never been able to get under control. And then they finally find this thing that makes them feel better, and then they get a scary result and their doctor wants to put them on medications and or change their diet, God forbid. And and so that cognitive dissonance of this thing is doing well for me. It works for my habits, it works for my preferences, it works for my blood pressure numbers, my waist size, the way my clothes, like it works for all of these different things. So the cognitive dissonance of, oh, but that could also be concerning to me over the long term. I think that's a real problem. And I've certainly seen patients who really struggle with the fact that something that's helping them could also potentially be hurting them down the road.

SPEAKER_01 19:48

Do you you you brought up this idea of um uh conflict of interest, right? Conflict of interest is of course thrown in the face of folks who prescribe uh the the classic LDL lowering, which is statins, which I never quite understand like why statins are four dollar generic meds. Like, I mean there I don't think there's any cardiologists that are in our practice.

SPEAKER_00 20:06

And also, isn't it more lucrative for the cardiologist not to prescribe a statin and skip the conversation and just bill a level three or level four visit and move on to the next bill? Like the the that concept of I'm doing this because I see royalty money, it's just like like the reason that I do anything with my patients is because I believe that it's going to be useful to them. And it's never lucrative to have a conversation with any like medicine does not pay for conversations and conflict of interests, like those exist. And medicine is not free of them. And you can look at any guideline that you want from any professional society, you can look at any bill that has ever been passed by any state legislature or Congress or whatever, like there, there are conflicts of interest exist. But isn't there also a conflict of interest of I think that your doctor is keeping from something from you, and I have this protocol, I'm never gonna get Alzheimer's, and so you'll never get it too. But you just need to subscribe to my newsletter and get behind the paywall, and then I'll finally give it to you. And the point is not, I don't mean to cast doubt on anybody's motives. The idea that I understand what's going on in somebody's head and what the the what their sort of reasons for doing something are. That's that the the point is not that I think that there's a true conflict there. The point is that you can like look at a lot of different things and find the appearance of conflict. But ultimately, this should be a conversation about what does the data tell us and where does the burden of proof lie? And how confident are we in the certainty of our of our answers and which risk do we feel more comfortable taking? Which risk do we feel more comfortable having our family take or recommending to our patients? And so to me, that's the interesting part of the conversation. It's not the conflict of interest question, but conflict of interests exists. And how naive would you have to be to not think that they're there?

SPEAKER_01 21:49

No, and and I and I think that I I've said all the time that I think just the existence of a financial conflict is not is by no means a reason to dismiss something out of hand. It's something to Note, though. And the the reason I find conflicts of interest interesting is because I find that it's not so much that I think most people are malevolent. I think there are some people clearly that are paid to say something. All right, that is that's on another level. But I think the vast majority of people are not. I think what conflicts of interest do, whether it comes from industry, whether it comes from the fact, whatever, whether you're a private practice cardiologist or whether you're an LDL skeptic who has a newsletter, et cetera, I think what it does is it actually creates this, it motivates how you critically think through things, right? And and I'm always trying to check myself. I'm sure it's it's not possible to step outside of yourself to look and see what's happening. But but yeah, it's easier to see it in others, of course. I think I I believe I believe Nick and the community 100% believe that, believe what they say. I I mean I would I would I would charitably say that. But but it does it does for all of us included, it does really motivate how you I think approach things. So like you ought to almost automatically are like cherry picking when you when you when you have a conclusion that you you want to be true.

SPEAKER_00 23:03

Yeah, you decide what what do you find interesting enough to read about? What do you find interesting enough to dive in and actually scrutinize the methods versus just accept what they write in the conclusion in the abstract? And you know, it's it's the sort of thing when you want something to be true, you're gonna look for evidence to support that thing. And I don't think that I don't think that I'm different than that. Like the fundamental attribution error is that everything that happens to you is based on circumstance, but everything that happens to other people do is based on a character flaw. Like I very much believe we are all, we all have cognitive biases, we are all imperfect arbiters of what the what the data actually tells us. But there's a difference between selectively quoting mechanisms that are scary to people about LDL lowering or about statins all the time versus talking about the bulk of the data and the sort of the weight of the entirety of the evidence. And one of the, I think the area that I find most interesting is where is the burden of proof in a lot of these questions? And is the burden of proof on me to show that satins are safe and first the correctly selected patient lowers cardiovascular risk and probably improves mortality? Or is the burden of proof on the person who thinks that statins lower GLP levels and so are raise GLP levels and so are going to kill you?

SPEAKER_01 24:17

Right. No, absolutely. And and you you know you brought that up because there's this mechanistic argument that's made about statin and GLP1s, for instance, right? That statins reduce GLP1 levels. And uh this is again some it's should have been breaking news.

SPEAKER_00 24:29

Why isn't everyone talking about this?

SPEAKER_01 24:30

Right, right. So why why isn't anyone talking about this this?

SPEAKER_00 24:33

Because it was a study and a handful of people and it looked at a mechanism and the level of a protein in the blood, and like this history of medicine is littered with all of these things that quote unquote should have worked. And then when they were actually tested in a high quality trial, they didn't work because biology is complicated and it's not like every uh, you know, all models are wrong, but some models are useful. And our understanding of the entirety of the physiology is just often incomplete. And the there's a real problem with saying that you believe something because of X, Y, or Z mechanism, especially if there's outcomes data that contradicts that thing, because ultimately nobody cares what their LDL is. People care, am I gonna have a heart attack or am I gonna have a stroke? And I like that's what patients care about. Patients don't want to read papers, at least most of most of my patients are not interested in reading a paper. They're interested in knowing what's gonna happen to me and what are the risks of doing this and what are the risks of not doing this.

SPEAKER_01 25:27

Yeah. There's mechanisms, there's mechanisms and they're mechanisms, right? And so I think you have to be really careful when it comes to uh complex biology. When you have a fra when you when you have a fractured fibula and you fail and you fix the fibula, okay, we probably we can lean on the mechanism of saying, all right, if we don't fix your fibula, then what happens to you know horses when they break their bones is probably gonna be what is gonna happen to us. We're gonna have to be put out to pasture. But the mechanism when it comes to like immunology, I mean it's extremely, extremely complicated. And I think it really begs uh the need for something more than I have a mechanism and therefore it works. And and again, this is not just from this this is as you said, from like his historically, it's just completely littered, and cardiology, especially completely littered. Yeah. I mean, HDL is good. Okay, let's let's artificially raise HDL that we create. So I mean, Pfizer spent billions of dollars and you know got to, I think, phase three, right? Um uh yeah, I think they got the.

SPEAKER_00 26:27

They were just looking at the CETP story from the wrong angle. It was the LDL APOB angle, which was probably right. And like this stuff is comp like all of this is complicated, and we just that that there's like a saying that the further out you go, the deeper the water gets. Yeah. Which it's that's my experience with clinical medicine, is when you keep doing this year after year, day after day, and you just see patients, you realize like the things that you thought firmly were absolutely true, just sometimes are not true or they're conditionally true. And this stuff is hard. I it's I I think that when you are coming at it with the idea of I need to draw eyeballs and I wanna be provocative, that sets you up to kind of overpromise in a way that, you know, you may sort of hedge in the fine print or in the text of the article, but I don't uh the patients who I see who consume this content really c come in from a perspective it's almost sometimes antagonistic about like what they think my motives are about how I want to try to help them get the outcome that they want.

SPEAKER_01 27:30

You brought up the um accountability uh aspect of this too, which is also interesting, which I hadn't thought about. Um the asymmetry the asymmetry of you know, a physician who tells their patient their LDL is two ninety nine. If you're the treating phys if you're the treating physician, you know, I mean, and you, you know, in this climate, keep someone's LDL at 290 for X number of years, and then that person has a heart attack, you have to answer to them if they survive. You have to answer to the family members, right? There's a level of accountability that makes it makes you be very that uh that creates you know climate where you want to be very, very clear about what you're doing because you have that hard accountability. Not even if you didn't have someone, the the billboard lawyers everywhere to think about, just just ethically, right? You got you want to be really certain that because no no one, none of us want want something bad to happen to a patient that we're treating.

SPEAKER_00 28:23

You've gotten you've gotten that call up from a patient of yours. I'm in the hospital, I just got a stent put in, or I just had a stroke. And the first thing that you do as a doctor is you think, what did I do wrong? What did I miss? What did I not treat? What did I not see? And you castigate yourself. I can't tell you how many nights I have not slept, or just been days where I have been just like tearing, just so stressed out about what did I do wrong? Why did this bad thing happen to this person who put their trust in me as a as a doctor? And um, I think that that's the natural human response when that like the relationship that you have with a patient. I always close the door and everything that happens in that room, like that's a really special relationship. And I owe it to that person to make sure that I'm giving them the advice that I would want my family to have and to take the data seriously and to talk to them about the limits of knowledge. And when you just post something on YouTube, you don't have that accountability in the same way. You get to say whatever you want, and you may believe it so firmly in your heart that it is the truth. But you're going when you talk to a person one-on-one and you hear what their questions are, it makes you hedge the certainty of your language in in a different way. And I just think it's really important to have the sense of like, who are the people that are consuming this content and who are the people that are talking to me in my office? Like, these are regular people who have lives and have families, and they don't want to spend time in the hospital and they don't want to have side effects from medications and they don't want something bad to happen to them. And they're trusting that the people who read the research, the people who are posting videos, the people who are they're seeing in an office, like they trust all of us, and that includes the the content creators to be giving them information that's helpful to them. I I don't think that anybody who is posting this stuff t doesn't take it seriously, but I think it gives it a different level of gravity when you have to answer to a human across the room from you.

SPEAKER_01 30:24

Absolutely, no question. It brings up a it's interesting how you frame that because you know it's not that having being a busy clinician and seeing patients all the time necessarily lends towards perfectly calibrating your treatment decisions because because you know, these calls, my goodness, like I it's just the worst thing about being a doctor by far is like waiting for some call on a patient that like you, you, you, you, you know, you're attempting to do whatever on, and then something something bad happens, it they're horrendous. But it does that by itself leads to an over-treatment bias, right? But it's like fine, I just want to, I just let let's just treat everything so that nobody can say if something were to happen that uh that that um that you didn't you didn't do enough, right? Um and it doesn't matter that there's you know if you try to treated a hundred patients like that, one of them ended up in a bad way, the 99 other patients are fine, right? It's that one patient that uh had something bad happen. So the ecosystem, interestingly enough, actually I think leads you over time, right, to uh to to to un to overtreat, if you will. So it doesn't necessarily we we don't necessarily calibrate ourselves or well, but but yes, there's no question though, of course, that the influencer who doesn't see patients, I mean, there's there's it's just it's just not the same in terms of that level of accountability. It's not even in the same universe, right? The other thing, of course, talk to me about the keto CTA uh study. So the give us a little background on the keto CTA study.

SPEAKER_00 31:47

This is this is again, this is this is part of what this content is really interesting. And these topics that all of these people who are posting about LDL and cholesterol how about there, there's really a lot of interesting things that we need to learn and that medicine does not understand. And so the keto CTA study is basically going back to that observation that Nick Norwitz made about himself, which is a low-carb diet really made his LDL levels go up crazy high. And the question of what does that mean for the progression of plaque is a question that is a little bit uncertain. So this group called, I think I believe the Citizen Science Foundation, if I'm uh saying that wrong, uh, it's not intentional, recruited a number of people, I think around 100 people who, on average, if you read the methods of their study, the the average person the study had been on this diet for about five years, and they had a mean LDL cholesterol level of around 250 milligrams per deciliter, which is really uh it's a heterozygous FH. It's like the 0.5th percentile of the populace to really, really high LDL. And they had them obtain coronary CTAs, so CAT scans with contrast of the arteries around their heart at time zero and then at time one year. And they looked to see what was the progression in atherosclerosis and also which were the individual mark, like biomarkers, that seemed like they predicted the progression of atherosclerosis. I think that this is confusing so when the paper was first published, there's a table in the supplement that basically looks at the amount of progression of their coronary plaque and finds that it was essentially as much plaque progression as you see in any other longitudinal study. Like it's uh it's plaque progression that suggests that this is a pretty high-risk group and this is a pretty atherogenic diet. When they dug into their numbers, what they found is that the absolute LDL was not the thing that predicted whose plaque was going to progress the most. It was who had plaque in their arteries to begin with. Some of this data is a little bit confusing because the initial person, the initial group that was evaluating uh the data was a company called Clearly. And then it sounds like there was a challenge with their blinding. And so they ended up, there's like this whole hullabaloo about retracting the study, but not getting into all of those data collection things because the the people who did that study stand by the sort of baseline findings, which is that the absolute LDL level in a group of people who had crazy high LD did not predict who was going to progress. What predicted who was gonna have the most progression of their plaque was who had the most plaque in their arteries to begin with. And so I kind of I look at that and it's like, duh, sicker patients are sicker. People who have more plaque in their arteries to begin with have something about their physiology that's gonna make them progress. But I I'm not sure that one, it's a hundred person study. Two, it's a year-long, it's a year-long observation period when atherosclerosis is a disease that for most people occurs over decades. And there's no control group, there's no intervention, there's we don't know, there's just so many things that we don't know. And it's a hundred people. And so it's a single data point in a sea of a lot of other data points, but it's really, really interesting. And it raises all of these questions. Like when I read that paper, I was thinking, this is really fascinating. And I wish that I had some better way of figuring out who was going to have progression, other than people who had plaque were gonna have progression. And you need a lot more people for a lot more time to really be able to draw any conclusions at all. But there's a lot of fascinating data that exists from a from a study like that. What we what did you think when you looked at it?

SPEAKER_01 35:34

Yeah, well, I for me, the whole thing fell apart as soon as I well, that fell apart. I mean, again, I I support I I want these studies to be done. I I really do think there's something else beyond LDL that explains why plaque progresses so quickly. I think LDL is an important risk factor, but I don't think don't think it's all LDL. So but so I'm not I'm not at all one of those folks that that that says, oh, we shouldn't even study we shouldn't even study this and stuff. There are folks, there's equipoys, and there are folks that are willing to have LDLs that are super high that would like to be studied. Hey, absolutely. That should be a uh fertile ground for for doing doing research. But the moment like I, you know, for me, I come from it from a background of like watching like coronary CTAs kind of develop over the last 10, 15 years. And I was really lucky to work with Ethan Halpern, who's a fantastic uh radiologist uh at Jefferson Hospital when I trained. He wrote he wrote a book on coronary CTA and one of the early, early guys who was in on it. And I spent a lot of time reading these coronary CTAs with him. And I mean it's it's incredible what what's what's happened, and it's incredible how coronary CTA has progressed over time. But it became it's pretty clear to me that with where technology is right now, coronary CTA is extremely good at ruling out disease, right? Corney CTA really, really struggles in terms of what to do when you have disease, in large part because of the technical limitations of coronary CTA, of corn CT, right? You have blooming, you have pla you have all this plaque that you see. And the question to cardiologists always is, okay, is it meaningful or not? And and so when I then saw these two companies come up clearly in Heartflow, that essentially are saying, okay, it's no big deal if you guys, you know, because essentially the the message to everyone, which is what it should have been, is that look, if you've got lots of calcium in your coronaries, like advanced cardiac imaging in the CT world is not for you. You're just gonna end up with meaningless noise, which you don't know what to do with, right? So and so, but then to see these two companies, Heartflow and Clearly, come out and say, no, no, can we we can we can take this stuff and we can put it into these this black box and it'll come out with these beautiful numbers and beautiful things that'll tell you what to do. I I already was like, come on, like it is not ready for that, right? And and so when I saw that initially, I was like, I don't know what to make about these AI clearly plaque volumes, like how are they validated? Go ahead and show me where what the validation is. I mean, you can talk about nuclear medicine and perfusion scans and um how how not well validated they are, but look, we've got really nice prognostic data in terms of what a normal scan looks like and what a scan where half the heart disappears looks like, right? So there's a level of data uh validity that that we have to other things which we don't, we're not even close to having for this, right? So before anyone runs around doing a clearly AI plaque volume thing, it's like, okay, well, how how do I know? Like that's based on what? What's the gold standard, right? And they don't have those answers. And then, of course, then so it's not surprising to me what happens as time goes on, which is the folks that were that in in a blinded fashion uploaded their their corner CTs. This is in the Kito CTA study, upload their CTs to um uh clearly, right? They got one answer when they uploaded in a blinded fashion. Then when they unblinded and then uploaded their studies, right, they got another answer, right? So again, when I initially read it, I was I was like, look, I think you know, it's garbage and garbage out in terms of like how we're measuring plaque volume. Like I would love to know what what's happening to plaque, but but one year is not probably nearly enough. And and we have a measuring tool that is like extremely poor. It's like it's like looking at the moon with with with with your old iPhone and trying to figure out like if there are new craters that are forming or not. It's like I don't care how much AI you do to that, you're not gonna go you're not gonna come up with a good answer. So that was you know that so yeah, so I think there's some significant issues there for anyone that's serious. But but I think it's a it's like you said it's a great valid valid question. Uh but you know, so this gets me this gets this is a nice segue into, you know, so we've been banging the uh uh the kind of the unconventional take on Clutch on LDL. You know, I saw you you also wrote an excellent piece after the recent lipid guidelines came out. Yes, there are major issues that we've kind of highlighted in terms of keto CTA and and and whatnot. So LDL certainly we've we've gone through why it makes sense to target. Um what are your thoughts on how we've kind of moved in terms of LDL lowering and the guidelines to to lower LDL? And this is you know, a few months ago was when the lipidemia guidelines came out.

SPEAKER_00 40:12

The the new guidelines, so all guideline documents are this they're a negotiated product with just like a ton of really smart people who are reviewing a lot of information, and most of them are subject matter experts. And um the guidelines, the guidelines often come out with sort of more opinions than maybe they should have. And the direction that the entire field of cardiology is going is as low as reasonably achievable for basically all of our risk factors, right? As low as you can get to with blood pressure without making somebody orthostatic, as low as you can get the LDL without causing somebody terrible medication side effects. I don't disagree with that in principle, but there's a couple of challenges. One is the question of diminishing returns. And so lowering an LDL of 72 to try to get it under 55 is very, very different than taking an LDL of 160 and trying to get it to 80. You know, it's I so I think that that's one issue. It runs into um patient, sort of like just patient-centered conversation. Um, the convoluted way that the guidelines recommend kind of assessing somebody's risk, it's this really complex algorithm that puts people in boxes and it relies on talking about talked about the imperfections of uh of CT for figuring out plaque. How about the imperfections of risk calculators for estimating risk? You know, risk calculators estimate risk across a population, but for an individual human, they're really not that great. And so I truly struggle very, very deeply with the idea of I'm going to put somebody's information into a risk calculator and then I'm gonna believe what the result says. And part of the reason that that is, is risk calculators systematically miss the group that's like the most important to treat, which are young people who are at elevated cardiovascular risk. And those are the people where you like there are people who come into my office who their family history is everybody dies or gets bypass surgery by the time they're 40 years old. And none of those people meet criteria for lipid lowering based on the guidelines because their LDL is 165 and it's not 192, and their 10-year estimated risk is 4.3% because age is the dominant variable in the risk calculator. And so you have this fundamental problem with risk calculators miss people on both sides. They overestimate risk in old people who are going to be fine no matter what. They underestimate risk in young people. They try to sort of adjust for risk-enhancing things like obstetric risk factors like pre-eclampsia or gestational diabetes, PCOS, or PMOS, I guess, is the new nomenclature. They try to adjust for things like LP little A, although nobody knows exactly how to use that. And the sort of overarching thing is I find the guy I find the guidelines to be strangely too convoluted, but also too prescriptive. And it's it's the sort of thing where maybe it's just I do this all day, every day, and I'm constantly thinking about patients, and I see people where the risk estimate that I think is right is different than what a risk calculator spits out. But I think that it's really, really challenging to think that we should be drawing all these conclusions based on data that we don't know. And one of the things that would be a really fascinating way of actually testing this stuff is test this, like randomize people to the strategy of following the guidelines to the letter versus following clinician expert opinion. And like randomize the strategy because it that's the way that you're gonna figure out are the guidelines better than what people are doing? And I'm not gonna pretend I make mistakes every day of my life in clinic. It's not because I'm trying to, it's Because our jobs are really hard and we're imperfect humans. But the I I think that the idea that these I hear my residents will quote guidelines. I'll hear other doctors quote guidelines. It's a class one recommendation in the guidelines, and it's like it's written on a stone tablet and not just the product of a negotiated conversation. And so the like the guy, the people who wrote the guidelines are smart. They spent a lot of time. They took it really seriously. They knew, they know a ton of a ton of data. I don't want to impugn how they came up with the those recommendations, but I truly I have like fundamental critiques and fundamental disagreements with what that guideline actually produced. And it's not it's not commenting on the motives of the people who did it. It's like reasonable people can look at the same information and can have a difference of opinion about how valid that information is. And that was my take on what the guidelines were.

SPEAKER_01 44:52

Yeah, and it it kind of lends credence to folks that say, look, you're doing too much, right? And so when because there's there's clearly a there's always going to be a large group of folks that are gonna be resistant to being like, what? So you're saying that I'm born with a statin deficiency and a GLP1 deficiency. I mean, you know that pharma basically, I mean pharma, the talking points given to given to reps, I you know, I I don't, I don't, I mean, they're just doing their job. I, you know, I I get it, I and I and I like reps. You know, I learn learn lots about what what you know what what the what the other side is thinking and stuff, right? But one of these really interesting things, which is why I like talking to reps, is like, you know, they essentially told these reps with the GLP1s, is like everyone has a GLP1 deficiency, most of the population has a GLP one deficiency. I was like, it's so weird that everyone in the United States has a GL1. It's like that's the highest prevalence of GLP1 deficiency. Some reason North Korea has no GLP1 deficiency. Like, why is that? I think I asked her that.

SPEAKER_00 45:45

But it's almost like an in obesity is an environmental condition and not a genetic condition.

SPEAKER_01 45:50

Almost. But but so but but the but that's the that's the problem, right? I mean, you have like you have this really strong, as you said earlier on, it's a relatively strong level of evidence. Not relatively, we have a strong level of evidence to suggest that LDL is a risk factor. And their evidence comes from a lot of different places, right? We have, we have, you know, and it and it's by the way, this predates the whole pharmaceutical conflict of interest, right? I mean, these Lebanese villages where people with familial hypercholesterolemia who had these bags of cholesterol on their skin, right? Uh underneath their eyes and on the on their on their Achilles and elbows. You know, you draw these family trees and they're all like dropping dead. This is before we even knew what cholesterol was. And they had these, you know, this is what some clinic clinician was seeing, and they're they're dropping dead in their 20s, right? So we have a really, really strong evidence that LDL is certainly a very, very important risk factor. We have Mendelian randomization, you know, we have these PCSK9 loss of function, you know, mutants that exist in the wild, right? There's this somewhere in North Africa or something, West Africa, sorry, you know, these folks have lifelong LDLs of 15 and their cardiovascular event rates are are near zero. And again, so we do have, you know, we have this. I told a story about that familiar hyperclitima in the natural history there. Then on top of that, right, on top of that, not in only, we have then the statin RCTs, right? We have all these randomized control trials starting from 4S now to 4 in Odyssey. That every single one of them seems to show that as your LDL goes down, your cardiovascular event rate goes down. But the problem is that the folks that are, that know all that and believe that have in some ways become, correct me, and you tell me if you think I'm getting this wrong, they've almost become LDL zealots, where, you know, they're your LDL, this idea that you talked about, and which I've mentioned all the time to patients, like the law of diminishing returns applies, unfortunately, to LDL. It's not, you know, as you as your baseline LDL gets lower and lower, the amount of risk reduction you get with further LDL lowering is is smaller, which is what we're seeing in the trials from the beginning of uh of of statin trials. But but there's seemingly a desire to not recognize that among certainly the folks writing the guidelines.

SPEAKER_00 48:00

Is that I I mean, I I don't know I'd go so far as to call them zealots, but I I think that when you live in that world and you treat high risk prevention, that's what you that's what you see. And um I I think that it's when you're asked to comment on what does the lipid lowering evidence say, the most direct, straightforward interpretation of that is that at lower numbers, cardiovascular risk is lower. I don't think it's a I I mean, I I'm not in any of their heads, and it's but and if you look at the blood pressure guidelines, aren't they kind of the same thing in a lot of ways, which is that when you look at the sum total of the evidence, lower blood pressure seems to protect against cardiovascular disease, heart failure, kidney failure, dementia. And it's really, really easy to see all of the benefits. And in the real world, in day-to-day clinical practice, you see a lot of people who don't tolerate medications, who have side effects, who don't like to be on medications. And so if you hold those guidelines up as the platonic ideal of how things would be practiced, you're going to not be able to achieve that in the real world, taking care of real people. And um I think about heart disease as you have a bunch of different pathophysiologic things that are going to increase what's going on. And L LDL is one of them. You know, I think that the guideline committees probably overcomment on too many things that maybe they don't need to necessarily comment on, but I do think it's coming from a good place, is my read of all of that. But, you know, I it's easy it's I it's real you anyone who puts things out in the world, you know that it's really, really hard to create something and put it out in the world. And it's really, really easy to talk shit about it and play Monday morning quarterback. So I I'm very hesitant. I I I disagree with plenty of things in those guidelines, but I'm I'm always hesitant about just impugning the character or motives or even just like making questioning the way that somebody is going about it. Fair point.

SPEAKER_01 50:08

Fair point.

SPEAKER_00 50:09

I know how hard it is to put something out in the world.

SPEAKER_01 50:11

No, that's a that's a very good point. The I guess how do we how do we combat? Maybe the better question I asked is do you do you see this as a path to over-medicalization or over over-prescribing or kind of yeah.

SPEAKER_00 50:23

So it's over-medicalization is really, really interesting because it's sort of a thing. But then what are all the rich people doing? And like what am I increasingly seeing in my in my practice is I'm seeing longevity. And longevity is just it's like the over-medicalization of well people. And the the question of is medicine doing this or do people want this? And like, what is the revealed preference of how everybody spends? I think that this stuff is psychologically complex, and I'm not sure I'm qualified to comment on it. But like, yes, don't do we have increasing diagnoses, like is pre-diabetes an ICD 10 code that you can put in is overweight with a BMI of 25.0 to 29.9. Like, are those ICD codes? Like we do over medicalize. We have pre-hypertension, we have all of these different um things. That's all there's also this element of people like having names for things. Um, you know, I I I think it's uh it's a hard, it's a really hard question. It's above my pay grade to really have a sense of that.

SPEAKER_01 51:28

I like it. I think all right, good. Tell me, uh moving on to something that is uh perhaps more uh more um productive in terms of how do we make something meaningful and useful. What was this what would be the study that you would do? Would you how how would you test the hypothesis that there are folks with high LDLs that don't have meaningful plaque progression, given all the things we've talked about in terms of how difficult it is to measure plaque? Like how would you study that?

SPEAKER_00 51:52

I think it's really hard to study, especially if you're if one of the arguments is that a diet-induced rise in LDL is different than a non-diet-induced one. Diet like nutrition research is impossible because you can't randomize, like you can't blind people, you can't randomize. If you change one thing, it means you're actually changing two things because you're either eating less of something else, if you eat more of one thing, you eat less of something, or you eat fewer calories overall. It just it's too complicated. And so the way I would actually approach it is I would, I think, and I think it would be really hard to have an IRB agree to not treat high LDL. But I think you would need to take a group of people who want to be on this diet and are accepting that this diet has some unknown cardiovascular risk. And they need to be people who are going into it like with appropriate informed consent about what the diet may do and what a lot of cardiologists are worried the diet will do. And then I think that you randomize half of them to LDL lowering and half of them to placebo. And that's I think the best way of evaluating is this actually a phenotype where people are at increased risk? But I think you can file like you could recruit. You could rec yeah, yeah. I think you need outcome. I think you need heart attacks and strokes. I don't think that plaque is the right surrogate right now. And I think that yeah. Well, what I what do you what do you think?

SPEAKER_01 53:11

Well, yeah, what the question is yeah, uh I would love that too. But that I mean that that's a large trial. Like, how do you well uh again, what what number, Greg, would you say if if they randomized well, I guess you have to come up with what the event rate is, right?

SPEAKER_00 53:22

Well, I'm not gonna go enough with stats to know that off the back uh in the back of the envelope math. But what what I will tell you is like the Well, Greg, here let me ask you a question.

SPEAKER_01 53:31

What do you think the expected event rate would be? And and this is very interesting if you say, I mean, you're not sure, but what should what is the expected event rate for somebody with an LDL of 500 over five years?

SPEAKER_00 53:41

That that depends what their baseline is. And so if the the baseline in that group is a 50-year-old with normal blood pressure who has an LDL of 500 and they've had it for five years before, the expected event rate over the course of a year, I don't know, 3%, 4%. Like I'm expecting a pretty low event rate because it's a pretty healthy cohort to start out. And so it's hard to power something like that. The idea that I think that when with a lot of these hard questions, it doesn't make sense to not study them because if you don't study them, you don't get answers. And we can have the same tired debates over and over again, just like filling everyone's mind with like mindless, like useless conjecture. But ultimately, I I really applaud people who are trying to figure out what's happening and trying to study difficult to study subgroups.

SPEAKER_01 54:36

Yeah, no, I I think yeah. I I it'd be it'd be lovely to figure out it uh to come up with some speaks to the need we have for some surrogate that's actually high quality, not what we have right now, which is basically uh you know a wallet biopsy uh at worst. Or I mean I mean the fact that Medicare pays for these things. I've written about both of those things, it's it's just just nuts. But uh but yeah, it would be interesting to think about like what number, but you probably you probably need yeah, and I think the only people can do it would be the NIH. Uh, you know, I mean P. Corey is what what exists to kind of do some of this stuff. So it'd be super interesting if if somebody who knows and designs trials could take two, three, four thousand people and and kind of you know randomize them so that they're you know and and see what happens to them over five, five is five years enough. But yeah.

SPEAKER_00 55:20

But hopefully by five years, do you have to s do you screen everybody and make sure they don't have a 90% LED before like the before you ran? I think that the question of who randomize, yeah. Who you randomize is and how you design a study, like the devil's in the details with anything like this. And I think that we're pretty unlikely over the next decade of our lives to have clear answers to this. And so, like ultimately, we need to make a decision today or tomorrow or Thursday in clinic about do we let the LDL just hang out? And the question of like which risk are you willing to take and what do you feel more comfortable, like which uncertainty do you feel more uncomfortable with it is a really hard question. It's gonna come, it's gonna be different for every person. I know that I personally don't have enough confidence that a diet-derived high LDL is safe to not recommend treatment for my patients who have very high LDLs, but your mileage might vary.

SPEAKER_01 56:18

How do you uh how do you approach patients, or what what do you tell patients that want to not be in a statin, have high LDLs? But of course, they're concerned, so they they're coming to you for assessments. How do you do how do you yeah?

SPEAKER_00 56:31

I tell them a few things. One is that you and I have the same goals, which are I don't want you to have a heart attack, I don't want you to have a stroke, I want you to be able to live your life and not be a permanent patient. And I also tell them, I've read a lot of papers and I have thought very deeply about what that research has shown. And I have seen a lot of patients who have side effects from medications. And one of the nice things about statin side effects, or really like side effects from almost all of the medications that cardiologists prescribe, is that if you go on a medication and you have side effects and we stop the medication, the side effects go away. And so, my goal in the in any conversation I'm having with the patient, especially somebody who's coming in having already digested a lot of this information, I'm not trying to persuade anybody that the information is incorrect. I'm trying to lower the temperature of how big a deal a lot of this stuff is, because I think that statins have occupied this place in the zeitgeist that they don't deserve to have because they're just like boring drugs that are like a lot of the other drugs that we use, which is 8% of people are gonna have muscle aches and your A1C will go up by 0.1 or 0.2. Those are the big risks from being on those medications. And if those things happen and you're not happy with it, we stop it and they go away. I really come at it from a place of like, I will work with you and I'm not gonna fire you as a patient if you don't think that my my recommendation is correct. My goal is to have alignment of interests and a shared value system come out of that and a lower stakes of what all those decisions are.

SPEAKER_01 58:03

No, yeah. I mean that that's right. That that that's fantastic. Yeah, I think you have to work with folks in terms of where they are, and it's it's a conversation to have over time in terms of what is the thing. But I I do think people do need to understand that we are running an experiment. If you're if you're doing this, okay, um, I understand this is the info that this is what I know for you to try to make you know a good decision or try um, but it's important that people understand that you know you you are one of these brave pioneers that's kind of running an experiment and maybe it goes well, but maybe it doesn't go well. Yeah. Yeah, absolutely. You know, the the the one interesting thing about the keto CTA trial, which which is which is a great takeaway. I don't know what to make about the plaque volume stuff at all, all right? You know, this whole like if you believe it, okay, you know, if you believe it, I think that's a that's a very reasonable interpretation. Okay, folks that that already have a lot of plaque, those are the ones that are gonna progress, you know, because we've talked about how you know there's something else that these folks may have in addition to having high LDLs that that causes that to happen. But one of the interesting things that it does kind of give you is a sense of, okay, 100 people with very high LDLs, what is that natural history in terms of what is the event rate, right? So in terms of ultimately designing a trial, which is a randomized control trial, which requires a knowledge of what an event rate is in a control population, right? Um, because otherwise, how do you power this without that? And I don't think we've got a good sense of that because clearly the FH patients, their risk is is much, much, much higher because there's something else going on. Folks that are from a dietary standpoint have these elevations in LDL, their risk is lower. We in cardiology don't have a great sense of what exactly that number, that that that event rate number is.

SPEAKER_00 59:38

So I mean, maybe you need a registry before you can actually run a trial.

SPEAKER_01 59:41

Yeah, and and maybe these folks and and and you know, Nick and and company are hopefully going to that's something that we will at least be able to arrive at in terms of what is the event. We already know the event rate. How many did any of them have a heart attack?

SPEAKER_00 59:54

I don't think so. It wasn't reported, at least. Yeah, it's not reported. I'm looking at that. These are these are smart people who ran that who ran that study. I would love to see them devote their efforts to trying to figure out the natural history of this group rather than just talk about a study of 25 patients and statins and GLP1 levels. I I think that the energy is really it's like misallocated to me. And I would love to see it allocated in a productive way to try to answer questions for people who are interested in them.

SPEAKER_01 1:00:23

And I think part of it is breaking the silo. So I'm hoping I'm hoping Nick and company will still talk to me after we've done this.

SPEAKER_00 1:00:28

I'm open to a conversation. Like I I I think that they're really I think that they're smart people who are curious and um want what you and I want, which is to have fewer people have heart attacks and strokes. Absolutely.

SPEAKER_01 1:00:39

Well, uh Greg, this has been a fantastic conversation. I know I uh thank you so much for for coming on. Uh we've run about 15 minutes over. And again, I'm mindful of of uh how important your time is. So thank you again for coming on. Thanks for having me. Yeah. All right, this uh hold on while I shut the c shut down and then.