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And I kind of came in as like a loving step parent later on, but we're having a moment right now, where I'm like a watching eye partner, like speak pridefully about the baby he carried. You know, if we were to do have done this research 50 years ago, it will be in a silo being talked about in academia and there wouldn't be much charge around it because they would just be academic questions, which are totally fair questions. But now we're at a point in time when there's access to information. And so there's this tension. Pleasure once again to bring Dave Feldman and Nick Norwitz on the episode here to talk about probably cholesterol stuff, I'm guessing. So in low-carb stuff without further introduction, most of you guys know these guys. So let's get rolling. So I mean, I guess the big headline here is the lee mass hyper responder is now in final publication, formerly see initial data set collection, baseline data. With that, I'll let you just add to that, Dave. Yeah, basically, we've chat about this before and probably many people will follow the low-carb space already know that these data have been discussed both in presentations. And before now, we also had the methods paper just recently published and we had the abstract published, but the abstract was behind a paywall. It wasn't the complete manuscripts. So really, this has been the moment that I've been waiting for a long time. And if I can get a tiny bit nostalgic, Sean, of course, you and I met, gosh, I want to say six years ago, seven years ago, it predates even the founding of the Citizen Science Foundation and us playing together, the protocol and everything. So this has been well over half a decade in the making. And this is now officially our first full paper with findings from the study. And it's great because they'll now have not only its own DOI, it's literally something you could print out and look at directly, but on top of that, it's open access. So everybody will be able to see it pretty easily. I'm glad you did open access because it's always frustrating because I don't have a university affiliate. I don't want to pay $40 a day on paper. It's just frustrating. Maybe we should figure out a way to purchase one of those for a company. But in the persistence, you're absolutely right. I remember you guys talking about this year, this little idea. And it's obviously metamorphosized into something that you, I'm sure you did. I wonder if you anticipated it would take as long as it did. Was that your initial thought? Did you think it's going to take me frigging seven years to get a paper? Yeah, I remember very early on talking to a researcher who was like, Oh, you're really serious. You're going to try to do this from the outside because, of course, I'm not a formally trained researcher. And I was like, yeah, when I'm at a partner with pros, I'm hoping we can get this banged out like a couple of years. No problem. And no, I founded the Citizen Science Foundation in 2019. It, I don't know if you noticed, but something came up in 2020 for the whole world. So that also held up the process a bit more. And then yes, actually the IRB, I thought that we would get it within a few weeks because it was through a university. They were saying, no, give it more like a couple months. It took us nine months to get this initial study protocol approved by the IRB. And then eventually we announced recruitment in 2021. But even then recruitment, the recruitment cycle took a bit longer than six months and took closer to I want to say 15 months. So it took some time. It definitely took a lot of time to get to this end. But truly, this is the end of one chapter in the beginning of another, because until this moment in time, we did not have a fully published paper on any of our findings, that certainly one that's open access until this moment. So that's why it's cathartic for me, because now we're finally like yielding what actually we're getting. I need a finding to respect to risk profile specifically. Yes, for an effect. And I was speaking in the context of this, right, to definitely give a big nod to Nick. In the meantime, before this had happened, we've had, I want to say, nine papers that we published on the mechanistic side for which Nick and of course, Adrian Sotomayor have been especially instrumental in helping us get together. And that's been fantastic, because now we have the mechanism to match with this risk data that we're having coming out at the same time. Yeah, let me and obviously there's been no shortage of criticism about the whole process about the findings, the data, blah, blah, blah, which is fair. You want criticism of this scientific discourse. I guess one of the criticisms criticism was it was really hard to recruit patients because they don't exist. So I would find people to fit the criteria. Was that, is it just because it's so rare because we were you were trying to keep such a narrow definition? And this may be more, I don't know the speculative, but it may be more broadly applicable if you would loosen the criteria a little bit, you'd probably find similar findings. What do you thoughts around that? There seems to be some of those criticisms. There seems to be this common, I don't know, it's hard to keep up with a lot of the statements that are being made, because as I mentioned before, some are accurate, some are inaccurate, some are just demonstrably false. But a lot of what was a challenge was that we required evidence from our would be participants such as they needed to prove to us that they had prior labs that showed they had 160 milligrams per deciliter of LDL or lower before, and that there was an increase of at least 50% or more to 190 milligrams per deciliter higher. 50 milligrams per deciliter, not 50%. No, 50%, 50% increase in LDL, that there had to be a move from 160 milligrams per deciliter at least or lower by 50% or more to at least 190 milligrams per deciliter or higher. In essence, the value of doing that is that we're proving the hyper response. Now, while that may sound like a fairly easy thing to show, what we often found were people who were bona fide lean mass hyper-smonders and who absolutely met our eligibility criteria, they themselves would often not have their prior health data available. And it's not because they didn't know that they had gotten it. It's just that oftentimes difficult to get it from a former office, like sometimes that they've moved and so forth. And so we had a lot that had pre-screen failed because they could not show us all the documentation, even if they would have otherwise qualified for it. Yeah, you guys have repeatedly mentioned that lean mass hyper-responder does not necessarily correlate with the actual physical characteristics of being particularly lean. However, meta analysis paper on a low carb diet showing the rise in the LDL is associated with the BMI sub sub 25. Is that kind of what your cohort looked like? Anyway, were the people generally not obese and overweight? Or were they generally in the normal to low? Well, it does poorly. It's just not a definitional criteria. So the BMI was around 22. So are there any 400 pound lean mass final response walking around? Is that what if they were one 600 pounds and now they're 400 pounds with the directionality maybe have the same sort of thing? We sometimes see blips for people losing fat really quickly, or there's a blip in LDL. But I don't think it's enough, at least not in that extreme example, where you would see a full on lean mass hyper-responder penis. I'm not saying it's impossible because everybody has different, let's say fat cell dynamics in morphologies, call it a personal fat threshold if you want for maybe an LMHR emergence phenomenon. I don't think I've seen nobody with class two obesity in a full on LMHR phenotype. I don't know about you date. I have not to date. And to be sure, this isn't me saying it's impossible. It's just that clearly, at this point, even if we did, it would be an enormous outlier. Oh, I will need to, sorry, I will need to modify that. Shavon Huggins would jump in right now and point out that we do have some examples. I'm not sure if they reach class two obesity, but that could be considered obesity who have lipodema. But this actually plays into the lipid energy model itself. You're not familiar with lipodema. There's subcutaneous fat mass that has different phenotypic characteristics such that you could say it's less online, if you will. So it's more sequestered fat that doesn't participate in the energy flux. And so from a relevant perspective, per the lipid energy model that we propose, it's almost as though that's less bioavailable, relatively speaking. And that could make sense as to why it would associate with the greater lean mass-type responder phenotype. I guess it probably makes sense to take a minute or two just to discuss the mechanism, the lipid energy model for those who aren't familiar with it. I know I've talked about it quite a bit. I know you guys have, but it is a neat mechanism, I think. And it seems to make sense in a lot of ways about a lot of things. Maybe you could just briefly touch on that, but either you guys, if you want to do that. Sure. You want to do it? I'm happy to sit. If people know me, they know I love to talk. They're probably like, what's wrong with Nick? Is he sick? He's sick, right? His name talks. Let me just have a moment to speak and not even on this. I just want to reflect on this moment for me, because for those of you who don't know the story of this, Dave alluded to it. I feel like I'm Dave's co-parent, but he's been gestating something for almost a decade, and I came in as a loving step-parent later on. But we're having a moment right now, where I'm watching my partner speak pridefully about the baby he carried from the beginning. And so, honestly, I'm partly sleeping right, but I'm enjoying that moment as well. So, if you want to take away the lemon, Dave, and just chat around, I'll sit here quietly, until I can't help myself when I pop in. Yeah, it's end to pass some credit right back to Nick. Sean, it's because I'm not a formerly trained researcher. I've really appreciated how much Nick has been able to codify and put together all of this to get it into the literature and has expanded on it, along with further insights and some other things we're cooking up that may be coming soon. Okay, the lip and energy model. Here's the gist. The gist is, if you're going to be powered by fat, that's relevant because you're going to be consuming less carbs and therefore necessitate more movement of fat around in the body. And that's important because fat needs to be carried. It's unlike glucose, it's not soluble in your water-based blood, and therefore, there needs to be carrier proteins or as you might call them lip or proteins. So, as you go lower and lower in insulin levels, you're going to release more and more fat from your subcutaneous fat. And if you're metabolically healthy, more of that's getting picked up by the liver and is getting repackaged into triglycerides, which is the storage pharma fat, onto VLDL. And VLDL is the lip or protein we're the most interested in because as it leaves the liver, if it's coupled with a higher turnover, as in it's delivering more of those triglycerides back to your fat cells, like adipocytes and also to your oxidative tissues, like muscles, particularly your heart cells and your skeletal muscle and so forth, then with that turnover, you have more of the VLDL transforming to their lipid pore LDL. LDL is basically just VLDL, but its cargo has been delivered. Its triglyceride cargo has been delivered. And because there's more of that turnover along with more of the secretion of the triglyceride rich VLDL, that means there's more successive LDL particles. Now, when those VLDL shrink in delivering their cargo, they release more of their surface components, phospholipids and free cholesterol. And those surface components are picked up by HDL particles, nascent HDL particles, which are like starting out as small, will get large picking up these components. So, an easy way to think of it is VLDL is part of the APOB lineage of lipoproteins, and their job is to start big, load it up with cargo, and to get small. And conversely HDL, its job is to start small and get large. And that happens through this turnover, through this delivery process as it's delivering fat. And so you get somebody like, say, Nick Norowitz, who probably is very rapidly trafficking a lot of these APOB lipoproteins, well, then he's going to be turning over a lot of these VLDLs into LDLs. And that's why his LDL is higher. But on top of that, intrinsic to this turnover is HDL is going to be higher as well, because it's a tracer almost for how much of that activity is going on. And that's why we see this triad, this combination of high LDL cholesterol along with high HDL cholesterol and low triglycerides that puts together this phenotype of lean mass hypersmonders. Yeah, and so it's interesting because based on that, and I dumb it down for my thought is like, I've got hungry cells, there's not a lot of glucose available. So we've got to flux out more more fat in the system. And that's why we see that. But you can make predictions based on it. Let's just let me just give you a scenario and you can make a prediction based on a lipid energy mouth. If I were to exercise significant amount of exercise, what would you predict what happened in that situation? Depends what kind of exercise? Exactly. Okay, so let's do a prolonged steady state cardio for an hour or something like that. What do you think would happen lipid wise? All other things being equal. If you had lean mass hyper responder physiology or close to it, your LDL will go up. We've seen this. Yeah. What about if I fortified what if I fasted for several years? We already know and lean insulin sensitive people. LDL goes up. Yeah, what if I were to give me give myself a drug that would deplete me of glucose, i.e. SGLT to inhibitor. What do you think would happen? It depends what's happening to your you can think of it. I think it's the way we think of it is like there's a liver store. So are you taking enough SGLT to inhibitor to actually get sleep your liver store of glycogen? I think probably not. You're just going to be peeing out a little bit of glucose. Yeah, I'm just because I don't classically fit your lean mass hyper responder. My HGL has never been high enough to get there. I'm probably not BMI wise low enough in many ways. And I'm using that energy replete. I'm using pretty energy replete because I eat a hell of a lot. So I'm not after like in a fairly fasted state. But I did a little mini experiment where I checked my total cholesterol. It was 154 milligrams per deciliter. Told perfectly normal happy number. And I literally fasted another 18 hours and had a couple of decent pretty solid workout and went to 345 within 18 hours, which I thought was quite quite a big flux, which I think is conceivable. But yeah, it's the model makes a lot of sense when you look at other things. But I guess the paper, the big reveal of the paper is. Actually, because I think it's important. Sure. Good. Of course. We were talking about how lean mass hyper responder is rare on a population level, right? For somebody to meet all three of these cop points is rare. And that's intentional. Generally, if you want to really pick out a particular phenotype, you want to create criteria that maximizes specificity. So you're really isolating out that. Sure. But it doesn't mean the findings in this population aren't more broadly relevant because the lipid energy model speaks to physiology that should be common to all humans, whether or not it fully manifests in all people. So that example you just gave, you don't have a full lean, mess hyper responder if you don't have any yet. The principles, a lipid energy model, would predict the response you had and are consistent with other literature as I think important, especially in the context of people still thinking that cholesterol moves glacially. When all of us here on this call demonstrated that you can modify your lipid levels very rapidly with lifestyle change far more quickly than people think pharmacotherapy even can modify. Lipid levels. And that alone, while accepted in, let's say, expert circles is pretty revolutionary, even to your late clinician, that cholesterol dynamics are incredibly dynamic, not glacial. And that is a massive shift in thinking that I think needs to occur with respect to medicine, physiology, the pathology in general. Yeah. Correctly from that, we've talked about this before, but I think they've known about the dynamic nature of cholesterol for many decades. Now, this is a brand new science. This has been, this exists in a literature since the 1960s, I believe, if I'm not mistaken, it's just no one's ever really delved into it to the degree that I know you had initially when you were doing your lipid drop experiments as a back five, six years ago. And a lot, that's because they believed it that it all comes out in the wash. They believed any of the short term dynamic shifts were genuinely short term. And that's the concept of you would go on a particular diet, be powered by fat and because you're powered by fat, your cholesterol levels would change as part of that dynamic milieu. That's definitely new, but shouldn't have been because, to your point, a lot of those dots were there to connect, I think it just was a matter of doing something like those initial experiments I was doing. I also want to add a note to the last thing you said, and particularly the difference that you have. You may already be familiar with this, Sean, and granted, this isn't part of what we had published. In fact, it's something Nick and I still occasionally chat about a bit offline. But I think for folks who are especially managing a lot of muscle mass through anaerobic exercise, I believe that they literally are consuming more of those lipoproteins, quite literally muscle mass for both growth and repair. I believe there's more endocytosis, endo being internalizing and cytosis being a process of the cell, or endocytosing those lipoproteins because they're making use of those same phospholipids and precholesterol I was talking about before to incorporate into their cellular bilayer. And there happened to have been a natural end of one experiment after I'd been speculating on this for a long time with our good friend, Don D'Agostino, was maintaining a larger muscle mass for the longest time, and then chose to let it reduce a little bit by a certain amount. But to be sure, and everybody who knows Don D'Agostino, he's still quite muscular anyway. So you just have to see both the before and after. But sure enough, when I found this out, and I chatted with him, I think this was about a year and a half ago at low-carb San Diego, I immediately jumped in. I was like, "Oh my gosh, you may be the one person who ceased lifting but was in a ketogenic context, I predict that your LDL cholesterol will have gone up substantially." And he said, "That's exactly right." Your LDL, HDL, or LDL cholesterol, had gone up substantially. And that is the case. In the case with yourself, Sean, and others who might be on an otherwise very low-carb diet, if this hypothesis fares out, it could be the reason that there's not as much HDL is because there's less of the turnover that's delivering into the HDL fleet, because you're quite literally taking them out of circulation entirely, the A/B/B lipoproteins. Does that make sense? That's, and again, it's an hypothesis to be sure something that we need to test. But I did do an experiment of my own that was 20 days long, where I had two inducements of resistance training, and it's actually up at cholesterolcode.com. I think it was in 2018 or something on those lines. And I eaten exactly the same way, exercised the same way the entire time, saved these two interventions of anabolic exercise, insure enough, it did show a dip in both those cases. So it's still very experimental, but that's what I think may be the confounder in that case. Yeah, interesting stuff. Well, let's talk about the risk profile, because that's a real thing we've got here. Because Nick is saying we can potentially make more broad, maybe there's more broad relevance to this physiology than just the narrow criteria of the roline mass hyper response, which is obviously dangerous territory. And obviously it becomes dangerous when you try to broaden your predictions in there. But as far as, let me just make a statement and get you guys response, is it fair now to say with a reasonable level of confidence that LDL cholesterol, A/B, total cholesterol, whatever metric you want to use, is a dependent variable in the process of atherosclerotic cardiovascular disease. Could we say it's a dependent rather than a completely, I guess, necessary and sufficient as people will say it's both necessary and sufficient. Is it sufficient by itself at this point? Can we say that's not the case or what do you guys think? This is a funny one. First of all, I want to just go back a sec and say when I was talking about generalization, I was talking to the physiological principles, not necessarily the risk profile. No, I get it. I get it for sure. I'm trying not to. Oh, no, I'm too tired to even remember what your question was. Oh, so I think it's part of the causal pathway. I'd say it's an independent risk variable. The way I like to explain it, and I had that little like Godzilla versus like on deco analogy, but if you even if you assume play devil's advocate for a minute that like exposure to LDL app will be part of it. Let's say that's X axis exposure over time, and then the Y axis on a class you accumulate, even if we say for every single person in the world. Now, this is just making the devil's after I've made, but it's so optimal as in it, my LDL world lower, my risk would be lower. That's the assumption, right? It doesn't imply, you know, what the slope of the risk is the slope of that will be exposure versus population, which will differ person to person dependent on context. So even if you assume that it's an independent variable that is quote, at some level, sufficient, it doesn't give you a measure of the absolute threat. So I think we can agree it's necessary. Let's say it's part of the causal pathway. We don't know what the absolute risk is. The question, though, even is it sufficient? The funny thing is I feel like a lot of people who are so gung ho about lower is better. We'll use the statement it's not sufficient. So pure idea will say it's necessary with not sufficient. But I don't know, I wish I could ask him like what he exactly means by that, because I think, I mean, David speculated about what people, including a TI days bring with mean by these sorts of statements. Because if you pin them down and say, will somebody definitely develop ASCVD, if they have LDL at a certain level, irrespective of all of the factors, I think it'd probably say yes. So I'm not sure why they're claiming insufficiency, but talking about it, low light insufficient. That's always been an interesting point for me. Yeah, I guess over a long enough timeframe, if you lived to 300 years or whatever, we see this, obviously it's correlate higher with age for sure. I think there are some people out there that would say they know the Slope guy, Muhammad, Aloe, and some of these guys are pointing out posted, statins reduce mortality in every study. And he showed a graph, except for all the ones that did not show improvements of hospitality, but you just don't have any data. Yeah, Dave used to say, and I don't know if you still agree with the sentiment, it's like, why is a cholesterol elevated? It's not the fact that it is, but why? Why is it, why? Because I look at like, why might you have inflammation, exercise inflammation? Is that necessarily mean it's bad? Glucose may go up in response to intense exercise, that being glucose is bad. So we have these physiological things with nuance and reason behind that. And so are you still in the position that it's not the fact that the cholesterol is high, it's why is it high? And obviously we can speculate and say we may think it being high in a lean mass hyper responder situation is not as problematic as some would think. What do you think is going on with other people when they have high cholesterol, say that the standard American diet metabolically unhealthy, is it just the cells are too damn full and they can't take any more cargo? Or why is it high in those cases? Yes. So first, a big yes to, I believe it is relevant as to why it is high, which does get to the heart of making a claim of independent causality. Because if you say something is independently causal, what you are really saying is that it doesn't matter why it's high, it being higher will always be dangerous, right? So even to make a statement, oh, I think the reason for why it's higher could be relevant in its association. So getting to what you said before, and I use this term often, I like to point to the relevant distinction between functional versus dysfunctional lipid metabolism. Nick summarizes is broken versus not broken metabolism. And the problem is virtually all of our data, all of our data that associates the LDL cholesterol with corresponding atherosclerosis in individuals who have higher LDL cholesterol, typically involve or exclusively focus on populations that have some form of dysfunctional lipid metabolism. Either it's something that they're born with that's genetic, such as monogenetic FH, or exactly what you just described, if somebody has insulin resistance syndrome, they tend to have higher visceral fat, they tend to have hypertrophic fat cells, for example. And they, and yes, as you probably seen in some of my presentations, I believe the failure of delivering the fat to those cells, having a downstream result in higher apobiolipar proteins, particularly triglyceride rich liver proteins, showing that profile of atherogenic dyslipidemia. I believe that the lipid profile in these folks are more a consequence, they're more a result of, rather than potentially a cause of the atherosclerosis independently. Now, as always, I'll emphasize that this is just my hypothesis, and that's why I wanted to test it. And that's where lean mass hypersmometers give us this unique scientific opportunity, because if there is a relevant difference between dysfunctional versus functional lipid metabolism, why not go with these people who I would speculate, do have a functional lipid metabolism. And particularly, if they just happen to have the one marker of interest that we're interested in, the high LDL, the high abobi, in isolation with all of the other risk factors that tend to cluster with the higher LDL, higher abobi apart from it so that we can find out experimentally if it will associate with the higher formation of plaque. Given the very sort of dynamic nature of lipid serology or whatever it changes all the time, right, is there a, could you say after looking at this stuff for almost a decade now or do you guys Nick, is there a reasonable pattern to distinguish between dysfunctional lipid metabolism and normal lipid metabolism as is as maybe the lean mass hyper responder? Could you look, is there a set of blood test is any good or is it all some kind of imaging? That's interesting. I think we look for patterns. And that's where, broadly speaking, that's why I think it's important when we're talking about lean mass hyper responders. And as best we can talk about the triad. Because what it is a signature of what's going on physiologically. And so there are other signatures that suggests dysfunction, including a very high triglyceride to HDL ratio, which you can do it from that, something about the lipid broken profile, like more pattern B, more ponderances, small dense particles. And that's because of what's going on with respect to trafficking, which is longer resinsed, lesser uptake. And I will consider that dysfunctional, but it's not black and white, it's not super categorical. Even if you say we have say pattern A and pattern B, we create cut corns to help us organize our thought processes, but it's all very spectrumy. And in addition to that, like you said, can you only do it with imaging? I think that then speaks to what is the impact on, quote, functional or dysfunctional lipid metabolism, which does occur along a spectrum on outcomes, and different people are going to have different sensitivities based on broader metabolic contexts. And then how long need to wait for that to emerge? Because no problem, I would say it's now not just how I now we're just like putting high in a category of bad, but how long? So it's a matter of like, how high, how long, and what is the degree because it's a spectrum of the dysfunctional metabolism, and the potential independent role of just having a high APOB or LDL particle count. Because again, to be clear, we're not ruling that out. We're just saying based on the literature, it's very reasonable to ask the question, what is the risk profile in this group? Because we know, and we alluded to this earlier, where somebody did, when I have three hours of sleep, we're forgetting you said what, but that cause matters with respect to risk. And this is in the literature elsewhere, where you look at people that are matched for LDL, and it's either high LDL, because they have one gene dysfunction, a poly gene dysfunction, or no, no genetic cause. And they have different risk profiles. And then you have this new group, look, the lean mass hyper responder. Now you could say, oh, we must cross turns to no, no genetic cause. But that's, again, not fully fair, because that particular group in the studies that have been done are people on a mixed diet, generally with some degree of metabolic dysfunction marked by hypertroglyceridemia. So the study I'm thinking of in general cardiology, the average shrinks, for example, in the high LDL, no genetic risk group were something like 170. Lean mass hyper responders are completely new phenotypes. You get to ask the question, what is their absolute risk profile? And the frank answer is, we don't know. Now that doesn't mean they're a low risk profile. And it also doesn't mean it functional in the metabolism, quote unquote, includes lean mass hyper responder physiology, as explained by the Levenerge model. It could still be that's completely healthy, adaptive physiology for the moment, but with long term consequences. All of these are unknowns. And it's just a kind of funny time to be discussing this, because if we were to do have done this research 50 years ago, it will be in a silo, being talked about in academia. And there wouldn't be much charge around it because they would just be academic questions, which are totally fair questions. But now we're at a point in time when there's access to information. And so there's this tension between what is a very clinically sensitive topic, and what are very genuine, authentic, and legitimate scientific questions. And what we find is those are popping heads a lot. Here's an interesting observation. And maybe I'm just sensitive to this, but it seems you guys are bending over backwards not to be aggressive with their claims, saying this is very nuanced stuff. And yet there has been a slew of papers come out that are almost anti lean energy lean mass hyper responder studies that are coming out where the claims they are making are really not supported very well by the data they're using. They're really expanding upon what the data actually shows and making these statements and conclusions. Have you guys noticed that? And if so, do you want to share some of those? Apple, I'll let Nick take this one. Yeah, no, I have a good cop backup, a different bad cop, so I'm putting my bad cop hat on here, but my fair bad cop. The first example, which was really striking to me was that circulation abstract. I know we've talked about it before, but to reinforce and for those who don't remember or haven't heard us talk about it, there was an abstract out in the journal circulation that was presented at an American Heart Association Conference that named lean mass hyper responders. It was something to the effect of patient stops satin goes on ketogenic diet. It was rapid progression of coronary artery disease after stopping a statin and starting a ketogenic diet in a phenotypic lean mass hyper responder. I'm trying to remember, but I think word for word, that was the title. They're literally saying that there was rapid, the title speaks for itself. I hope the retro CAD after stopping a statin and starting a ketogenic diet in the field, the mass hyper responder. We read this and it's clearly targeting LMR. So the first thing you assume is, okay, they actually have an LMR example, where there was rapid, but Russian now that there are thousands of tens of thousands of lean mass hyper responders, both Dave and I, we saw this title and were like, okay, they found an example. Fair enough. The point of a case study, a retrospective case study, you can share a big example in the world you want, probabilistically they can find one. Okay, first thing I noticed is it wasn't a lean mass hyper responder, which was interesting. But then you saw the patient narrative because this is just a little, it was actually like a case study abstract. So it's four paragraphs. There's no hiding this. And this was what the patient story was. It was a gentleman who after having an LID left anterior descending artery obstruction for which there was a procedure, PCI, where they went into that artery, so it will be stunted and open, while they were in there, bear in mind, he had never tried a ketogenic diet at this point. While they were in there, fixing his stuffed up artery, his left artery is left anterior descending, they noticed, oh, the right artery has some moderate disease. They face a procedure and then they're like, all right, he's had an event. Now we're going to put him on a statin because it's a secondary prevention and all of that goes off for a couple of years. During this years, again, these next two years he's on statin, he's not on a ketogenic diet. He's presumably on whatever mixed diet he had. Again, he's had disease. He's on a mixed diet. He's on therapy. Then at some point, he stops the statin and tries a ketogenic diet. They never said what the ketogenic diet was. Never verify it was a ketogenic diet. It could have just been, he said he was eating a ketogenic diet when really he was just upping his bacon intake for one week. And then they found he had more severe RCA, right coronary artery obstruction. He had a right coronary artery stemming. And it was the most absurd narrative, because first of all, this is an elite mass hyper-responder. It's a guy with severe history, a prior event on a mixed diet, then multiple years over which his disease could have progressed from moderate disease that was already in his right artery, during which he was on pharmacotherapy and on a mixed diet. And then he tried a ketogenic diet, quote, because they never defined it for an unknown period of time. And all the blame gets placed on the ketogenic diet for his black progression, which was never demonstrated. Aside from the fact he's not even a lean mass hyper-responder, and this was published in one of the premier cardio journals, it was jaw dropping. And just as an aside, because I know how to doubt my eyes and cross my T's, I went to write a letter to the editor about this. I wrote it with cardiologists, because even people that are like pro, I will be long. This is junk. This is trash. What rubbish is this? They don't accept the letter to the editors or e-letters on abstracts. So they just wouldn't accept any recourse. And it wasn't technically peer reviewed. They looked at it, but it wasn't a full peer review because it was an abstract thing that presented a conference that was never converted into a full paper. So they were like these loopholes, they just let it stand. And that was example one, but it's become a pattern. There was another paper out in Jack and Vance's. This was a full paper where they reported that a low carb high-fat diet led to, or was associated with an over two-fold increased risk, 2.18, I think was the hazardous ratio of major adverse cardiovascular events, which is pretty shocking. Oh, you're eating a little carb in this double the risk of having a stroke or a heart attack. But the funny thing about how the abstract is written, this is a full paper, but they say there's this massive risk. And they also say, oh, low carb diets increase LDL. They don't say how much it was increased. Which is suspicious. You think they know they'd probably share that kind of credible piece of detail. And then you look in the paper, the increase was so tiny. It was 3.48 milligrams per deciliter. And on top of that, the differences were the low carb group also had more obesity, more diabetes, and more smoking. And in the population at large, they took that table and shoved it into the supplement. Not only is there clearly a screwed up narrative here, because I don't think anybody in the right mind will believe a three milligram per deciliter increase in LDL will convert to an over twofold increase risk, a major adverse cardiovascular events. But the paper is structured in such a way that if you're in academia, this is suspicious. You're taking what you you are proposing or implying is the main mediating variable, pulling that out of the information that you're highlighting in the abstract, and then taking the major confounders and while you made knowledge from the text, shoving them into a supplement. It does seem very... I have a hard time finding this on an actual... And this includes the LDL itself, right? Wasn't the LDL delta you just mentioned of the three? Wasn't that in the supplement and not in the major body of the paper? The main figures were actually for a subgroup, weirdly enough. I had to do with the food frequency questionnaire and the timing of it. Oh, that's another thing. The dietary intake was based on a single day food frequency questionnaire that if you delve into the reference, they don't show what the instructions were for the FFTC questionnaire or the food intake questionnaire. It was a 24-hour dietary survey. They're like, "Oh, it's one of these things where C prior reference 4." And then you have to go into that reference and then go to the references of that reference to see what the instructions were, but if you dig deep enough, there's a line that literally says when they administered the survey, it was a 24-hour dietary survey. And one of the instructions is, if what you did not eat yesterday, was not representative of your normal diet. We don't care. It doesn't matter. This is what we want you to report. And on top of that, when they did a subgroup analysis where they include people with just two, at least two food frequency questionnaires, significance disappears. So, like, there's so many layers of absurdity with how people are trying to do mental gymnastics to push forward a narrative. Now, I actually think that there is a large body of, let's say, stronger data supporting the typical liberal hard hypothesis, even if it has some holes. But I just see it as an incredibly weak show to try to... It seems it does seem intentional. Go after, in part, lean mass hyper-sponsored things like that abstract work, try to reinforce and push against the dangerous counterculture of a low carb by putting out publications like the one I just explained, with the three milligram per deciliter difference, the two-fold pose as with ratio. And then lipidologists, there was one lipidologist, some may not have one talking about, but this gets published. And he immediately reflexively says, "Finally, good science." And I'm like... And there wasn't any deeper dive until this is what they did, bubblebys. Oh, look, low carb bad, good science. Yay. And then you look at the paper, I'm like, this is the rubbish paper. I don't know how they got published. I'm literally looking at the visual abstract right here, and they've got the differences between LDL cholesterol. And they're literally almost identical. That's the one with the more extreme difference, because they took a subgroup, and then made that the main figure. If that's figure one, that is more extreme than the population of large, which I think has a 2000 number that I think that was the low carb group. But the actual large population was in the... That's them making it basically, that figure is them trying to make the difference of the large as they possibly could report. Can we? Yeah, let me just interject here, because I think it's almost to you guys that you have people defending this now. They're trying to get ahead of this by putting out this kind of, I don't want to call it disinformation, but weak studies to counter what I think is what you guys are being more rigorous about to get different data out there. And so we're seeing these sort of flailing attempts to try to shut it down. And the average person is not scientifically literate. They don't see this, they read the headlining. Many people won't get past the title. Some people get through the abstract. Can I, can I capitalize? Because I did find the specific case report, and it's worth literally reading it verbatim. It says rapid progression of CAD that's coronary artery disease, rapid progression of coronary artery disease, after stopping statin and starting a ketogenic diet in a phenotypic lean mass hyper responder. So that title, I can't help but feel often from the outside, as I said, I'm coming in from the outside, that often the methodology, the process in the same way that Nick was just describing, doesn't typically support the rather broad, loud headlines that often are the case for these studies. And nowhere did that become more obvious even before I was getting into research than how the term low carb, for example, or even keto has been getting redefined by research studies that don't provide positive reinforcement for the low carb community in that regard. It feels as though, for example, that the definition keeps getting stretched in order to accommodate worse data that's incoming. To which I would want to say, look, if you're, I think that there's plenty of places where you can be critical of low carb, but get good data for it, it doesn't, I think it makes your case worse. The more that you're taking pains to do things that are outside of what the low carb community themselves would consider to be valid low carb practice, in order to gather data to then try to make the case against it, then there's no way you can see it than anything other than either being deceptive or misguided. Yeah, fair enough. And back to this Jack study, you could say mace and you could say low carb causes diabetes, causes you to be obese, cause you to smoke more, maybe if you want to go there, because when you look at the difference, you've got a 50% increase in diabetes on an absolute on a relative frequency. That is so much more powerful than the miniscule elevations, just maybe they weren't, maybe that's what they weren't sent out to study, but you can't ignore that. Yeah, it's a one day survey. And I think you've probably reported about this was just not a good study. But the fact that it got out, because you didn't, the journals did not have to accept this study. And the fact that they let it have a particular spin was I thought problematic. And just to be clear, other people who are very much, even who have been critical of our work, but respectfully political with what I tweeted about this study really ripping into it, Michael Mindrum retweeted it and basically just agree that this is garbage study. And the problem here is, I would say it, it's not per se that it makes low carb look bad, because as you made the point, are alluded to somebody and that person in this case is me, is going to call BS on this. And it's going to make it very clear how much BS this is. And then it's just going to exacerbate polarization because people hate being lied to and they hate being patronized. And so if you're trying to spin a particular narrative and you're putting out dirt studies like this and dirt interpretations, it's going to get called out. And then what's going to happen is they're just going to be further erosion of trust in the conventional ideology. And so if you're trying to project a conservative and clinically cautious message, the last thing you want to do is put up weak sauce like this, because you're just undermining yourself and exacerbating polarization because I don't know what you're supposed to do. Yeah, I see the same thing with the criticism of this carnivore thing. It's like the criticisms are based on no data because there's really no data in either way. And put good or bad, there's just no data that we have these nicks, we're trying to get some stuff done. And it's we're fighting with different roadblocks. Let me switch gears a little bit. Because I a little bird me birdie told me this might be an interesting topic. So tidy per calorie has become the latest thing. And it's there's been a lot of dissension in the low carb community do this. And do you guys have any thoughts on that? Is it just as it just carries in carries out rebranded again? Or is there do you think it's got legs and it's going to go somewhere and I've interviewed Andreas and Ted and I think they're both good guys and well meaning guys. And I wish them all the luck and hopefully maybe they have discovered the magic formula. I don't know about thoughts on that guys. If you care to. When I first heard of the concept, I thought it was an interesting alternative tool that some people might be able to use. And I'm all for options. Let me be clear. Be that carnivore, be that hopeful plant based raw vegan, be that's a tidy per calorie. I don't care what helps you if it helps you. And if you get better and healthier and are feeling good, I will always celebrate that. That said, I'm also someone who I really have an hard time with intellectual dishonesty. And the way that's a tidy per calorie under Ted Naaman and Andreas and felt has developed has been, in my opinion, incredibly intellectually dishonest and honestly, a good case study in what happens when marketing and science butt head. And I won't delve too deeply into it because I've spoken about it a lot previously and I'm going to do a little more comprehensive video on the topic. But the thing is, it's not scientifically valid in any way, shape, or form. What they do is they take these arbitrary variables, which they fully had made or completely made up in arbitrary at some level. So the sonic factor made up the weighting of the variables made up. And you cluster them together and imagine that the composite is going to be better to the composite of, Oh, we find protein valuable. We find fiber valuable. We find low hedonic factor, whatever that means, valuable. So we're going to throw them together and the composite is going to be better than the some of its parts. And that sounds really good. But it's flawed in many respects and will always generate. I spurious and in combination with that, the claims they're making are just, I think, toxic. So Andreas will pander and put out a tweet saying, what is the healthiest ice cream for weight in metabolic health? And then quantify it. So it gives scores to these things showing that halo top ice cream or arctic chocolate peanut butter chip ice cream is healthier is better for metabolic health. This is their quantified claim that's an avocado or bacon or egg yolks. And then pretend that they have the holy grail of having solved obesity. And it's there are a lot of things they could do to improve their approach, I think. But the one simplest would be to market what they have is what it is. It's a toy that you can play with as a heuristic that maybe could be helpful for you. That's fine. But it's not science. And they have refused to either validate the tool, which I realized would cost some resources, but also just be transparent about their methodology. Why are you changing scores and when? Because they do it arbitrarily. If I say this is weird that apple juice and pepperoni of the same score, they'll be like, all right, I'm changing the algorithm. But it then just propagates other problems. And there's no transparency with respect to the data they're using to formulate their score or what their system is for pulling information from those data sets to generate the score. And I think without that, it just ends up being a project in marketing and selling a product rather than being intellectually honest about the science. And I think it's a very slippery slope to pretend you have science when you clearly don't and not engage in good faith efforts to discuss the science properly and make claims that are pseudoscientific, which they both have. I'm happy to debate them further on this topic that they wish to show up. I'm sure that I'm sure Andreas would be happy to talk to you about these pretty stand-up guys as is Ted. I think and like you, I think anybody that can get healthy in any particular route they want to fall, I'm happy for. I don't care if they're vegan, I don't care if they're Mediterranean diet or keto, low carb, carnivore. I'm always happy for that person. Likewise, I'm sure they would echo the same sentiment. And then I guess Ted will say there's plenty of data on protein. You could isolate these variables and say, we've got good data that shows a higher protein diet has beneficial cardiamental effects. And you would say fiber, too. And by combining them, it must be synergistic. Maybe it is, maybe it isn't. I guess that's the hard part that you'd have to contend with. And we'll see what we'll see over time. Maybe they'll publish results two years from now, it'll be it'll just be kicking ass and it'll blow everything else out of the water. And I don't know. I'm skeptical about most things, but we'll see what happens. I don't Dave, do you want to share? I'll chime in a little bit. Nick knows this pretty well. You probably know this pretty well. I all concede. There's a little bit of the... Let me just be upfront that there's a little bit of an emotional component to me because I was very attached to diet doctor in its original form because it was a major pillar of the low-carb community. It was a great site to send beginners to because it had a lot of great guides. And I shouldn't say had as in it's entirely gone per se. It's just a subsection now. It's the diet doctor overall is now mostly pitching the satiety per calorie and then low-carb and keto is one other thing that you can look at. But it starts you in this sort of guided, almost wizard that seems to cater a bit towards the satiety per calorie. So I bring this up because I'll concede there's a little bit of an emotional component to me and that I feel a little bit sad because of how strong it was for me to send especially a lot of my family, diabetes is a major problem in my family and diet. Doctors was a great solution for me not needing to instruct them but to send them there. But to Nick's point into what you were just saying now, Sean, yeah there's a lot of science around individual components such as protein, such as fiber and there may be a lot of science towards specific diet types. But to Nick's point, if you have a recipe, if you're saying we're going to put 30% of the weight into protein, we're going to put 22% of the weight into fiber, we're going to have this other component that's 18% towards hedonic and the hedonic is based on this component or something like that, something that can be validated. Then I think that there's more of a case, even then it's still a hypothesis, right? You're still saying this is some new methodology we're going to apply, maybe cures the data that we're getting and maybe it's just a convenient sample currently by the people who are actually making use of it and here's what we've gotten. I think the main objection that a lot of people have and I can understand why they would have it is if you want to say this is something we're trying, something we're doing, we're learning about it, we're finding out about it, that's one thing. What I've felt a bit strongly about is how low carb has been getting often, it just feels like it's been getting thrown under the bus as part of the pitch towards a tidy per calorie, that's tidy per calorie absolutely is a better methodology than low carb. And coming from the originators of diet doctor, I'll concede that's been a bit tough because the tidy per calorie has not been validated, at least not in a form that I understand it to be. If there's a study that's underway right now, that's great. But in the meantime, I would love if it just wasn't claimed currently to just be a better methodology than low carb on the overall and that especially that it's based on the best science when as Nick pointed out, it's neither transparent nor has it been validated as of yet. Yeah, so I approach would say, hey guys, we've got this theory. Would you like to participate to help us validate this theory? And I think that's a fair way to do it because it could be. I offered at the beginning of the process, I'm like, I help you design a study or I will help you publish a perspective's paper, even at my own expense, that I can figure out how to get the open access he's covered. And to a couple of things that have been like brought up, the whole, if you combine these components, it's better concept falls apart if you're not considering other factors. They also don't consider things like metabolic meditation. And on top of all that, Dave's point, and the way I think it circles back to this conversation as a whole is there is definitely an anti low carb, anti keto, let's say, aura or halo on social media. It's a very easy way to get points, social media. When we see people use this all the time, Lane Norton will just attack you know, people just for being cute. And now like I see Ted and Andreas falling into that pattern. And I can find these tweets where Ted is I used to be an XYZ and now I'm more evolved, or the low carb keto cultists or zealots. And these are words that they choose to use selectively, we'll say XY and Z. And he then says something like low carb zealot keto cultists, and then goes on to say, and he's I can find this tweet. So this is me paraphrasing, but basically exactly what he said. Maybe I'm the only unbiased low carbber to a rental literature, and then make claims like these data about say post-prandial energy deficit in the blood are mythical, these profound claims. And then I'm like, here's a random estimate role trial that shows that they are not mythical, they're right here, you shouldn't read the literature. So please don't claim to have something that's better, that you have no real science on, and then try to attack low carb with name calling cultists and pretend you're evolved when you clearly don't know the literature. It's all very, I think, disingenuous and dishonest. And there's so many ways that they can go about doing this better, either from an intellectual honesty standpoint or from a scientific standpoint. The fact that they're unwilling to do so makes me highly suspicious that they're in it to make a buck for their proprietary algorithm without any validation or any genuine science behind it that's behind a paywall. And the cynic in me has to ask the question, these techniques, the easy playbook things that if you look for, you can see like shifting the burden of proof or virtue-signaling about diet agnosticism that do work to sell a product, companies like Weight Watchers use it, it's a pretty classic playbook, it will work for the company. I think it will be a successful company. So when you're saying you wish them all the best with respect to their bottom line, I think they're going to do fine. So that begs the question, what is their incentive financially to do the right thing? Yeah, fair enough. You can do a white paper and so on and so forth, which use proprietary data and so on and so forth and get your contracts. Let me just, we've just got a few minutes left. I want to shift back to where we can and talk about the future data. So you've got, we've got the baseline study published. So one year data is collected and whenever Matt Rudolph decides he's going to let people know about it, who knows, I think you got more funding to extend out the study correctly if I'm wrong. What are the next evolutions in this? Because now we have the first, I will call it an intervention trial. Well, I guess we can't after a year, you can call it an intervention trial. We've got the toehold is there now. So where do we go from here? Yeah, so I'm sure Dr. Budoff would want me to correct it isn't an intervention trial. It is observational, at least with regard to the longitudinal study that we currently have underway. The lean mass hyper-sponder study, as I've called it on social media, but as it's as Lundquist would put it, as is in the paper, the keto trial. I'm hoping to get an extension in the process of securing that right now. Look for an announcement on that soon. But on top of that, we've had a recent conference, the collaborative science conference, which we just call cosi recently, which is basically just a fundraiser dressed up as a conference. And this may be the first podcast I'm mentioning this, but we're going to have a second one. We're actually very close to signatures and that will be coming up next year, early next year. So Sean, and maybe tap and yes, effectively what we're doing is we're raising the money for what's going to be a much costlier study. But this time around, we're going to have more permissive criteria. We needed this first study to potentially showcase that these are in fact a lower risk at a population level, such that it could clear the way for a modestly higher risk population. And additionally to that, we'll have a control group. And it'll be anywhere between 40 in each arm to 100 in each arm, and naturally I'm wanting to shoot for 100 in each arm. But that's really expensive once you count the longitudinal data travel and everything else that's involved. But we're really excited because as science is also built on replication, so we wouldn't just be stopping right here on the first study. We were excited to get that much more data on a brand new one as well. Just we've all levy criticisms at the FFQs, a food frequency questionnaires. How do we ensure we know what the hell these people are eating and do you have like they've taken pictures of their food? Is there some level of concern about validating what people are actually eating or is it just we just care about the numbers? And because that's easier to assess. It's either when you take a blood test, it's not subject to recall bias. It's pretty much it is what it is. Yeah, we had three points of a 24 hour food frequency question year, which was the one version that I was going to be the happiest with, which is that it's taken on in their first workout. It's taken at the midpoint, so six months after they've had their first scan and work up. And then at the final point, at the last scan to work up. Now, to be fair, my same opinion of food frequency questionnaires still holds to where I don't put, in my opinion, a lot of stock on the granularity of, for example, parsing out the exact calories for recall. However, I, and I'm sure you, Sean, are interested in the composition. The composition is probably going to be relatively accurate. And we're pretty sure we already know what it is from the lean mass hypersponder Facebook groups. Generally speaking, it's going to be a lot of people on extremely low carb, probably very animal based diets. There's already a number of people who've outed themselves as being participants who are well known carnivores. And yes, this is the one place that a lot of people don't realize our research kind of has a little more data to it, in that we're not just looking at people with high LDL, but technically they're checking all the boxes for the diets that are not recommended. They're going to be high in red meat, high in animal protein, high in saturated fat and low in fiber, generally. And that's, but to be fair, I'm blinded from the data. I could be wrong. They could all turn out to be vegan lean mass hypersponder as that's possible. But that's, that would be my expectation is that's probably what the food frequency questionnaires would be looking like. Yeah, I'm probably one of the few people that could accurately do a food frequency question, you're going back a year and be pretty damn accurate. Because I used to say stuff every day. So there's a mall done today. I'll take both you on on accuracy. I still take a picture of every single thing I consume. So I can do it. I'm not far off of that. Yeah. So there. All right, guys, I got, man, I got literally three minutes before I got to run my kids somewhere, but any last words from either you guys? Just a quick set of thank yous to everybody who's been able to make this happen, not just for the study that we've had right now, but of course, another big thank you to Nick himself for being able to also help out, including with this research with the Jack advances paper that's coming out here shortly. And lastly, a big thank you to all of our participants who are making this happen. Sean, if it if we didn't have the people jumping in to literally help us do this research, there'd be no research. So it's a group effort. And that's what's great about it. Yeah, this just really is a grassroots type of thing. And I'll echo Nick has been helpful, but some behind the scenes with some of the carnivore stuff as well. And I certainly appreciate you because I don't have like you. I don't have the research credentials or chops or know-how. And so just because we're talking about like weird barriers, I apologize for how slow things are going because so we want more not just me, but who are like well established researchers and we're all like jaw to the floor because some of the projects we're doing are like even retrospective analyses and the bar to just get like these approvals for completely safe, like equitably safe things that have even already happened as a retrospective. The questions we're being asked just observe are both like, is this really happening right now? I feel like we claimed 5 plus 5 equals 10. And they're like, but really let's go into this and spend two years trying to give you approval for this. It's still baffling me how much problems there are to even study it. And it's what I even making claims were just like in a particular case. So one thing we want to do is look at it in the context of a severe inflammatory bowel disease, even retrospectively. And we're just trying to doubt our eyes and cross our T's and they're like, we shouldn't give this x, y and z. This is a very legitimate question for a very particular use case. We're not making extreme claims. So I wish people would just get out of the way of like metabolic health interventions. Speaking of which, people should go sign that petition by Chris Palmer for the trial that we can shut down. Curlins, but it's talking about obstruction. There just does seem to be like an absurd amount of obstruction to even studying these things. I hope it's back on because that's one of the most egregious things I've ever heard of. And it's one thing to literally hold up the progression towards getting a trial started. It's quite another to really stop one. That's IRB approved in the middle that it wasn't a decision by the IRB itself that I've never heard of before. Yeah. Well, it's time before another time and we're gobbling up Sean's time. I'm hoping all of the can of worms here, but trailer. I'm sure we'll talk again, see each other again some point good job guys and keep up the good work. You guys have a great rest of your day. Bye-bye guys.
