#255 – Why you might be a lean mass hyper-responder if you go keto but have high cholesterol | Dave Feldman, Dr. Nick Norwitz & Dr. Dominic D’Agostino

A lean mass hyper-responder is someone with high LDL and HDL cholesterol and low triglycerides. They are often lean and healthy people who present with strange and alarming lipid numbers after going on the ketogenic diet. Dave Feldman, Dr. Nick Norwitz & Dr. Dominic D’Agostino discuss the LMHR phenotype, whether it’s a concern, whether it’s rare, the Oreo vs statin study, how exercise levels might play a role, and why more research is needed.

Helpful links

Oreo Cookie Treatment Lowers LDL Cholesterol More Than High-Intensity Statin therapy in a Lean Mass Hyper-Responder on a Ketogenic Diet: A Curious Crossover Experiment: https://pubmed.ncbi.nlm.nih.gov/38276308/

Dave Feldman, CEO of Citizen Science Foundation: https://www.linkedin.com/in/dave-feldman/

Citizen Science Foundation: https://citizensciencefoundation.org/

Dave Feldman on Twitter/X: https://x.com/realDaveFeldman

Dave Feldman on Instagram: https://www.instagram.com/realdavefeldman/

Nick Norwitz, PhD, an MD candidate at Harvard Medical School: https://www.linkedin.com/in/nicholas-norwitz-md-phd/

Nick Norwitz, PhD, on Twitter/X: https://x.com/nicknorwitz

Nick Norwitz, PhD, on Instagram: https://www.instagram.com/nicknorwitzphd/

https://health.usf.edu/medicine/mpp/faculty/ddagosti

Dominic D’Agostino, PhD: https://health.usf.edu/medicine/mpp/faculty/ddagosti

Dominic D’Agostino on Twitter/X: https://x.com/dominicdagosti2

Dominic D’Agostino on Instagram: https://www.instagram.com/dominic.dagostino.kt/

4:29 — What is the lean mass hyper-responder phenotype?

Lean mass hyper-responders, or LMHRs, are a phenotype with a triad of unusual lipid numbers: high low-density lipoprotein (LDL) cholesterol, high high-density lipoprotein cholesterol, and low triglycerides.

I’m Dave Feldman, and many of you probably already know my story by now. I did not at all mean to get into this research. What happened was I went on a low-carb diet in 2015, saw my lipids jump through the roof, and I became obsessed with trying to understand why that happened, particularly given my other first-degree relatives had also gone on a low-carb diet and did not see their cholesterol levels go sky high. I then started doing a number of experiments, was blogging about it; it garnered more and more interest. I started to do presentations on it. And those were the beginnings of what we now call the lipid energy model. And that ultimately then led to recognition of this phenotype that it’s not just about the high LDL; it’s also about the high HDL cholesterol and the low triglycerides, this triad. And that led to identifying this phenotype lean mass hyper-responders that have this triad at extreme levels. And from there, beyond just wanting to develop this model, I wanted to also see if we could study lean mass hyper-responders and that led to the development of the Citizen Science Foundation.

8:32 — Often the LMHR phenotype gets noticed when someone goes low carb

The ketogenic diet is a popular choice for aiding with chronic illnesses. However, some people may experience a surprising shift in lipid numbers after going keto, depending on many factors that researchers are still trying to elucidate.

Along the way, at the end of college and at the beginning of my PhD, I started suffering from inflammatory bowel disease, which ended up being very debilitating—ICU-level care, palliative care. And out of desperation, I started trying things that were outside the scope of Western medicine. I had the greatest admiration for Western medicine; it’s what I wanted to do with my life, but it wasn’t helping so I got desperate. And like a lot of people, when you’re desperate you’re just going to try whatever. And I ended up stumbling across the ketogenic diet, which worked wonders for my inflammatory bowel disease. But lo and behold, something happened—same thing happened to Dave, same thing that’s happened to thousands of other people—which was, to my dismay, my LDL cholesterol went through the roof to absurdly high levels that I didn’t think could exist before.

19:02 — The Oreo cookie study garnered attention for the LMHR phenotype

The Oreo cookie study showed that adding carbohydrates back into the diet of someone who is LMHR lowered LDL cholesterol more so than a statin did.

I tested the lipid energy model publicly and prospectively. So I announced I was doing this before I did it. The test was to test if Oreo cookies could lower my cholesterol. We’ll get into the mechanism of why we thought that would work. But I thought it should work based on understanding of the model and the physiology behind the lean mass hyper-responders. But I wanted to take it a step further than just  eating some Oreos and saying, “Oh, my LDL went down.”  wanted to make it a controlled study, and the control I thought that was appropriate was statin therapy.”

25:32 — Understanding the mechanisms of the LMHR

Why would going on a ketogenic diet potentially lead to lipid numbers consistent with the LMHR phenotype.

The model, which we can go into in a little bit more detail. . . But basically is that when you’re lean, insulin sensitive, and you go low carb, you switch from carb burning to fat burning. And as that process ensues, free fatty acids go up. As your fat cells are spilling out these free fatty acids, some of them get taken up and get repackaged into triglycerides, a stored form of fat, and put into these big spheres, these VLDLs, very low-density lipoprotein. Those get shipped out of the liver and then turned over at your fat cells and your muscle cells by a protein called lipoprotein lipase. This turnover process is what generates the triad we’ve been talking about, the triad that defines lean mass hyper-responders: the high LDL, the high HDL, and low triglycerides.

40:04 — Exercise levels likely play a role in LMHR

In LMHR, exercise seems to drive LDL higher, but more research is needed.

I thought to do a sub study within where I could plant everything and then just change one variable, which is what I went from 10,000 steps per day to 20,000 steps per day. What happened? My LDL jumped by 50 milligrams per deciliter.

51:26 — The alarming LDL levels in LMHR prompted research

More research is needed to determine any concerns with LMHR. On one hand, they are lean and generally healthy, but on the other hand their LDL levels raise red flags.

We’re saying lean mass hyper-responders are unique because they’re healthy and they have this one outstanding variable. And early on in this process, they were like, “But they’re basically going to drop dead . . .”  Our LDLs went up and we’re like, “We’ve got to figure this out or we’re going to go shopping for our headstones.”

59:25 — The “gym hypothesis” will be important for further research

The question is whether LHMR is a rare phenomenon or common under specific diet and exercise conditions.

We know many different people who speculate that this is still a rare oddity and that probably there’s some genetic abnormality about myself and Nick and others who have seen this, because what they would say if they were here in the room is they would say, “But not everybody who goes on a low-carb diet sees this lean mass hyper-responder phenotype. In fact, here’s this friend of mine who’s lean and who tells me that they’re on a ketogenic diet. They don’t see that.” And what I always say is, “Well, give me a group of people who’ve never been lean mass hyper-responders.”

1:10:48 — An open and respectful dialogue is needed on the topic

The LMHR phenotype is a controversial topic but one that needs further research and attention.

Nick and I  have been very proactive. We’ve been getting more and more proactive than ever before, especially coming into this year and wanting to have a productive dialogue with other big names. Like you’re saying, if they’re big names and they can’t fully wrap their head around this physiology and perhaps they want to have a respectful conversation with us on this, we could not be more forthright in our invitation . . . As far as a wealth of data, you can’t get more engrossed in the data than Nick and I. We’re absolutely obsessed and we’re swimming in it.

1:33:47 — The importance of additional research

Ketogenic diets have proven therapeutic for many conditions, including epilepsy. More research is needed to understand LMHR phenotype and any risks or benefits because otherwise the lipid numbers could present a barrier for people who use the ketogenic diet to help manage conditions.

It really is about removing a barrier to implementation of ketogenic diets for a lot of use cases, because this remains the boogeyman. And until we solve it, understand what’s the driver of heterogeneity and what are the actual consequences in terms of risk, it’s going to remain a boogeyman across all fields and all use cases in which ketogenic diets could be therapeutic. So this isn’t just for cardiovascular risk. It’s about epilepsy. It’s about IBD. It’s about kidney disease. It’s about every disease, mental health. It’s about every disease that a ketogenic diet could touch.

Dave Feldman (00:00:06):

However, the lever where they do lots of cardio, go to town. Why? Because lean mass, hyper responders, I believe are especially utilizing a lot of those fatty acids off of the VLDL, at a higher turnover from their cardiomyocytes. So that lever, I want to go ahead and leave up. Right? So if I’ve got all these levers connected on top of them being lean and metabolically healthy, I believe the majority of those people I got from the gym would become lean mass hyper responders, or at least borderline lean mass hyper responders. There might be some that didn’t, because there may be genetic components, but I think that they’re more likely the exception than the rule. That was my hypothesis.

Speaker 1 (00:00:52):

I’m Ben Grynol, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health, and along the way we have conversations with thought leaders about research backed information, so you can take your health into your own hands. This is a whole new level.

(00:01:21):

Does being lean mean that you’re healthy? Well, who knows? It’s kind of impossible to say. We know we’ve talked about it on this podcast before, but our bodies are very much symphonies of biomarkers that don’t necessarily move up and down in unison. We’re still very early in our understanding about how these different biomarkers in our bodies change in real time with things like nutrition, sleep, exercise, stress, and even environmental factors. So picture this, you start eating a lower carb diet and find that it’s working to, air quotes, lean up, and you feel good physically and you look healthier. But internally, there’s a different story going on. You go to your doctor, you get some blood work done, and you find out that your LDL has increased significantly, your HDL has also gone up and your triglycerides have gone down. It’s a bit of a mystery and you’re trying to figure out what exactly is going on.

(00:02:23):

You’re confused, your doctor’s confused, and you just don’t really know what to do about it. Well, it turns out that there’s a whole group of people who are experiencing this and they’ve been identified as lean mass hyper responders or LMHRs, for those of you who like acronyms. And so studies are still pretty early in the space. Researchers are digging into the variables, which may lead to the components of either genetics or phenotypes that lead to this phenomena. You also may have heard about this recent Oreo cookie study, which was published in January of 2024. The synopsis of it was that a researcher, Nick Norwitz, he ran an experiment to see if using statin therapy or consuming Oreo cookies would lower his LDL more. It’s in line with this LMHR model, and so some of the thinking around it. And there’s a much longer research paper on the findings, but the results were that the Oreos ended up lowering his LDL more than the statins did.

(00:03:27):

Now, does this mean that consuming Oreos are a healthy option? Absolutely not. And as you can imagine, in the interconnected or that we live in, the study was totally misinterpreted by people, with headlines floating around the internet that, “Oreos are healthy.” And we know that is not the case, but biomarkers, to reiterate on it, they are an absolute symphony and it really reinforces why it’s integral to monitor more markers than just glucose. We know that’s something that in the world we have to do more in real time, but it’s very much a challenge right now.

(00:04:03):

And so in this episode, Dom D’Agostino, [inaudible 00:04:06] friend, advisor and thought leader in the space, he needs very little to no introduction for those of you who listen regularly. He sat down with two researchers in the space, Dave Feldman, CEO of Citizen Science Foundation, and Nick Norwitz, who has a PhD from Oxford and who’s currently pursuing his MD at Harvard. They explored how diet cholesterol levels and even BMI plan to the LMHR phenomena and why it’s important to keep pursuing research about it. Anyway, it was a great episode where they went deep on a lot of the research in the space and where things are headed. No need to wait. Here’s Dom.

Ben Grynol (00:04:49):

Welcome Dr. Nick Norwitz and Dave Feldman. It is awesome to have you here on the Levels Health podcast. I’m so excited about the research that you’re doing. Let’s just dive right into it. Can you tell us both about how you got into this area of research and a little short bio?

Dave Feldman (00:05:05):

Sure. I’m Dave Feldman, and many of you probably already know my story by now. I did not at all mean to get into this research. What happened was I went on a low-carb diet in 2015, saw my lipids jump through the roof, and I became obsessed with trying to understand why that happened, particularly given my other first degree relatives had also gone on low-carb diet and did not see their cholesterol levels go sky-high. I then started doing a number of [inaudible 00:05:32] experiments, was blogging about it. It garnered more and more interest, started to do presentations on it, and those were the beginnings of what we now call the lipid energy model. And that ultimately then led to recognition of this phenotype, that it’s not just about the high LDL, it’s also about the high HDL cholesterol and the low triglycerides, this triad.

(00:05:54):

And that led to identifying this phenotype, lean mass hyper responders that have this triad at extreme levels. And from there, beyond just going to develop this model, I wanted to also see if we could study lean mass hyper responders. And that led to the development of the Citizen Science Foundation. That’s the public charity that’s right now, the fundraising arm and organizer for doing this research. And that’s what we’re doing today. That study released its first findings. Dr. Budoff announced the preliminary data on December 8th of last year, and that kind of kicked off what I would call a season of lots of papers that we had released. We had the thyroid paper, we had the meta-analysis. And what I’m excited we’re going to be talking about, which is Nick’s very provocative Oreo versus statin experiment that demonstrated some of the principles of the [inaudible 00:06:53] model quite well.

(00:06:54):

And it’s been an exciting journey, because while I’m certainly somebody from outside of this field, I’m so honored to be partnering with, for example, Nick Norwitz, who’s just been such a driving force for helping us get this research moving forward. And that’s what brings us up to today. I will add one more thing. I’m excited that we had our first conference. I say our first, because I guess we’re going to do some more. The Collaborative Science Conference, which happened just a few weeks ago, that featured such amazing speakers. It was Dr. Dom D’Agostino, for example. I don’t know if you’ve heard of him? It was a great event and it was straight up for charity. Everybody who came, came on their own dime and on their own time to make this thing happen and all that money’s going to our next study. So we’re already wrapping up the scope of this first study. We might get an extension more on that later, but at a minimum, we have a sister study that’s being put together right now. And so yeah, it’s been quite a ride, no question.

Ben Grynol (00:07:54):

Yeah. And I’d like to add that the conference was a testament to the public interest and the scientific interest in this area of research. And I don’t know how otherwise it would get done without someone like you, kind of stepping forward. You’re like the ideal person, because you’re out of academia and then you have a certain skillset and qualities about you that are able to pull this off. And of course, Nick here is like your trustee sidekick who is just like a juggernaut when it comes to putting out content on this topic, amazing content. So Nick, maybe share a little bit about your contribution, how you got into this.

Nick Norwitz (00:08:34):

Yeah, I mean, while I was going through my story, it felt very unique. You’ll find out in a minute it wasn’t. But my background was, I grew up in a suburb outside Boston, always wanted to be a doctor, always wanted to be a scientist. My whole family is doctors and scientists. So I studied cell biology and biochemistry in college. And then I went off to the University of Oxford in the UK to do my PhD before planning on coming back to Boston, to Harvard Medical School to do my MD. So very vanilla academician path. Along the way, at the end of college and at the beginning of my PhD, I started suffering from inflammatory bowel disease, which ended up being very debilitating, ICU level care, palliative care. And out of desperation, I started trying with things that were outside the scope of western medicine. I had the greatest admirations for Western medicines, what I want to do with my life, but it wasn’t helping. So I got desperate.

(00:09:34):

And like a lot of people, when you’re desperate, you’re just going to try whatever. And I ended up stumbling across ketogenic diet, which worked wonders for my inflammatory bowelses. But lo and behold, something happened, which same thing that happened to Dave, same thing that’s happened to thousands of other people, which was to my dismay, my LDL cholesterol went through the roof, to absurdly high levels that I didn’t think could exist outside of very rare genetic conditions. Because right now the literature says it doesn’t exist or the literature did say before our papers, it didn’t exist outside of absurdly rare genetic conditions. And being someone with a decent degree of medical background, medical family, I knew, we knew what this meant or what we thought it meant. But it was an interesting phenotype. Again, as Dave mentioned, it wasn’t just high LDL, but there were other facets that went along with it, including very high HDL, low triglycerides, and also the fact, the curious fact that in other circumstances where LDL is this high, it’s a genetic disorder, it’s a congenital disease, you’re born with it.

(00:10:41):

And my cholesterol had been totally normal, but then something had changed. I had taken carbohydrates out of my diet and had this response. So there was something that was different about what was going on in me and I started to do some digging. This was after Dave had actually coined the phenotypes term, but he had written it up in a blog. And being someone in academia, I was just taking to PubMed. So it took a little bit of time for us to converge, but then I said my story wasn’t unique.

(00:11:08):

What I found was there was this pattern of people going on low-carb diets, more and more people going on low-carb diets, they became more popular. And as more people were doing it, more lean people were doing it, including more lean adults. And you were having this emergence of what David named the lean mass hyper responder, where these lean people were seeing these crazy high LDL levels along with high HDL and low triglycerides. And this triad at a population level is very unique. And so I became obsessed like Dave, in trying to understand it. In part, because I was just grossly scientifically curious about it. And also, because I’m a lean mass hyper responder patient and to have skin in the game, as Dave would say.

Ben Grynol (00:11:54):

Were there any other side effects of this super high cholesterol that you had? There’s a condition called xanthelasma, which I actually had when mine was at a 341, I think was the highest number I saw. And I’ve made some adjustments and I don’t experience that now, but in the context of the lean mass hyper responder and a level of cholesterol that completely freaked out my primary care physician and just thought I should start getting my stuff in order if I was going to do anything about these numbers.

(00:12:32):

So it sounds like you had amazing cardiometabolic biomarkers that were maybe even improved on a ketogenic diet. And then with the low triglycerides, the astronomic really high HDL, which really puts you, that makes the lean mass hyper responder a term that was used like a unicorn. But there’s a lot of people who have features of a lean mass hyper responder, that are kind of like borderline. So I think it’s going to be important to talk about those people in the context of this data too. And if anyone in the study that you’re going to talk about and the people that you’ve been in communication with, have any other signs of high cholesterol, having other clinical manifestations, whether it’s overt cholesterol deposits around the eye or otherwise.

Dave Feldman (00:13:26):

As it happens, over the course of the existence of our Facebook group for the lean mass hyper responders, I’ve started, I want to say at least four times threads specific to both xanthelasmas and xanthomas. So xanthelasmas are more specific to around the eyes. It’s usually near the bridge of the nose.

Ben Grynol (00:13:47):

Yeah, [inaudible 00:13:49].

Dave Feldman (00:13:49):

Yeah. And the xanthomas is kind of the tent pole. It’s sort of the larger category for which xanthelasmas are under. But xanthomas are of special interest, because those who have severe monogenetic familial hypercholesterolemia, so they literally have the genetic disease. They tend to manifest these deposits of cholesterol in other areas of the body, such as on tendons, tendons xanthomas are known. Eruptive xanthomas, they can be on the hands or the elbows, sometimes they’re in the glutes. There’s a lot of places that they know to look for. And the first one, xanthalasmas actually are more common than people realize in that they’re about one in 200, one in 300.

(00:14:34):

They do tend to associate with having higher levels of cholesterol, but they also don’t in that, higher levels of cholesterol are one of the possible things that they can associate with. There are many people who don’t have high levels of cholesterol that develop them. And so, they became an area of enormous interest for me, and it’s part of why I started the thread several times.

(00:14:56):

So we’ve had some people in the lean mass hyper responder Facebook group who, when putting these out, will mention if they’ve had them. The problem is that we’ve not been able to find them to be above, at least anecdotally, above the population average. Now that said, that’s not me saying there’s no connection there at all, by any means. Just that what I would have expected is if it wasn’t a dose response level with LDL levels, we would almost certainly see a large preponderance of people experiencing not just xanthomas, but xanthalasmas like you mentioned, in those folks who were in the 500, 600, 700, 800, et cetera. And I am in communication most with those folks. So again, I don’t want to make it sound as if I have a direct answer to that yet, but at least anecdotally, to what you’re saying right now, I haven’t been able to find a direct connection thus far.

Speaker 2 (00:16:00):

This is Dr. Casey Means, co-founder of Levels. If you’ve heard me talk on other podcasts before, you know that I believe that tracking your glucose and optimizing your metabolic health is really the ultimate life hack. We know that cravings, mood instability, and energy levels and weight are all tied to our blood sugar levels. And of course, all the downstream chronic diseases that are related to blood sugar are things that we can really greatly improve our chances of avoiding if we keep our blood sugar in a healthy and stable level throughout our lifetime. So I’ve been using CGM now, on and off for the past four years since we started Levels, and I have learned so much about my diet and my health. I’ve learned the simple swaps that keep my blood sugar stable like flax crackers instead of wheat-based crackers. I’ve learned which fruits work best for my blood sugar.

(00:16:53):

I do really well with pears and apples and oranges and berries, but grapes seem to spike my blood sugar off the chart. I’m also a notorious night owl, and I’ve really learned with using Levels, if I get to bed at a reasonable hour and get good quality sleep, my blood sugar levels are so much better. And that has been so motivating for me on my health journey. It’s also been helpful for me in terms of keeping my weight at a stable level, much more effortlessly than it has been in the past. So you can sign up for Levels at levels.link/podcast. Now, let’s get back to this episode.

Ben Grynol (00:17:37):

I want to add that, because I think it’s maybe relevant to the discussion that this happened at my highest level of LDL, but also my lowest levels of triglycerides, lowest levels of inflammation and lowest levels of insulin that I ever measured. My cardiometabolic biomarkers were the most perfect you could imagine, minus the LDL. And my ApoB was in the upper one hundreds at the time too. So all this occurred during that, as I approached that triad. And it’s interesting, and it went away as I made some adjustments, that I could talk about later. And I mentioned it as a selfish reason, because it happened to me and I just wanted to know with such high levels, if it was a feature that you saw within the lean mass hyper responders? So yeah, I think you answered that. Yeah.

Dave Feldman (00:18:31):

I’ll add one more thing, which is that I’ve also independently connected with xanthelasma support groups and was very upfront in my post that I was very interested in investigating the connection of cholesterol. So coming out from the other direction, those people who had gotten it, how often it was that they had higher cholesterol versus not, I didn’t quite as easily find connections on that, but I did find one common thing that is brought up a lot within those groups that I shared with you, is that there does seem to be a catalyst event of some kind. Typically, a high stress engagement.

(00:19:05):

Sometimes there’s a string of a lack of sleep and sometimes there’s some kind of binging of food or alcohol or something like that. But again, I say all of this with strong emphasis that this is just anecdotal data. It’s relatively loose, but it’s one that I find of enormous interest. And with our study, with our existingly mass hyper responders study, I brought that to the attention of the team in that I wanted to be sure that when they’re doing the workup, if they’re observing anything, or for that matter, to be mindful of it, if that’s something that gets shared. It’s something I would a 100% want to be able to catch.

Ben Grynol (00:19:41):

Interesting you mentioned that. Yeah. Because I did have a little respiratory thing that I think started to irritate to my eye, and that’s why I fasted and went super strict keto, and then it happened after that. So there may be some correlation there. Yeah. So yeah, I didn’t want to bring us off on a tangent, but it was definitely kind of relevant to this. And I was curious. I think we could transition to the Oreo versus statin provocative experiment, which may be obscure to some people, but I think it’s a brilliant experimental design, if you want to call it that, to support the lipid energy model. And maybe Nick, talk a little bit about that. Yeah.

Nick Norwitz (00:20:23):

Sure. You definitely get different reactions to it. It’s either this was absolutely brilliant or this is ridiculous, and this is a joke, which is why right now I might change it. But the video abstract is titled, This Is Not a Joke, because it’s not, it’s physiology. But I did this experiment, even though it was one of our recent papers, really as a conversation starter, to help bring people towards lean mass hyper responders in the lipid energy model, who hadn’t thus far been acquainted with the topic, because I think it’s something that is incredibly fascinating and deserves more discussion. And so, what I was trying to do is conceptualize, okay, with the minimal resources that are available to me currently with my career stage and just financial resources to do studies, what could I do that would turn heads to get people looking at this area?

(00:21:13):

And so I conceptualized an equals one crossover experiment that would be bold and provocative in which I tested the lipid energy model publicly and prospectively. So I announced I was doing this before I did it, and the test was to test if Oreo cookies could lower my cholesterol? We’ll get into the mechanism of why we thought that would work, but I thought it should work based on understanding of the model and the physiology behind the mass hyper responders. But I wanted to take it a step further than just eating some Oreos and saying, “Oh, my LDL went down.” I wanted to make it a controlled study. And the control I thought that was appropriate was statin therapy, since that’s standard therapy, lower LDL, I went for high intensity statin therapy, which was Crestor rosuvastatin at 20 milligrams, recommended by our consultant lipidologist, who became the senior author, Professor William Cromwell, highly esteemed lipidologist, who’s been doing lipidology longer than I have been alive, literally.

(00:22:19):

He recommended Crestor 20 milligrams for six weeks as a very high intensity comparator. So I did a Oreo cookie intervention for about two weeks, it ended up being 16 days, I can explain why in a minute. And then did a three-month washout period to bring my LDL back to similar levels, presuming that the Oreos would work, and then underwent six weeks of a statin therapy. And the results were that the Oreo cookies lowered my LDL from three, what was it, 384 to 111. So from astronomically high levels to the normal range in 16 days. Now, the reason it was 16 days, was because we were getting weekly lipid tests. So day 14 was only the second lipid test and things had dropped so quickly in 14 days. It had gone down from what the high 300s to 140 [inaudible 00:23:14] PCP, who was ordering all my tests, we’re like, “Okay, this is freakish. We probably should just verify it. So let’s do triplicate tests on subsequent days.”

(00:23:22):

Tested again, it went lower. Tested again on day 16, it went even lower. So it was actually trending downward still at day 16. I might have dropped under a 100. On a Western diet, my LDLs in the 90s, but given the protocol, I actually just couldn’t tolerate going any longer than 16 days, so we cut it at 16 days. But there was a 71% drop in my LDL in 16 days, which is stronger than any drug that’s available right now. Then I did the washout and the statin therapy, which lowered my LDL by 32.5%. So the Oreo cookies were twice as potent as the statin in me, a lean mass hyper responder. Now, some could say and some do say, “Oh, it’s an equals one, we don’t even want to entertain it.” It’s an equals one. But I challenge you on a couple fronts, or not you you, but the you saying that, which is, yeah, but I predicted, we predicted this would happen.

(00:24:20):

So what is to say that we had a model. And then I said, “I think Oreo cookies would lower my LDL.” And then that happened. And take that into the context of it actually is consistent with all the other literature. This is the point, this was supposed to be a head turner to get people to look at the literature we have. So people often ask the question, “Nick, why didn’t you use a healthy carb? Are you trying to make a mockery of this?” I’m like, “No. We’ve actually used healthy carbs before.” We’ve used carbohydrate reintroduction in case series, our CDM paper in 2021, we had a 480 milligram per deciliter drop in one patient. Average drop was over 200 milligrams per deciliter with carbohydrate reintroduction, and they were healthy carbs. So the quote healthy carbs was starches and fruits. And the same with the Cooper et al interventional trial with 10 patients, added back carbs, LDL drop.

(00:25:08):

We’d done this before, but people weren’t taking notice. And I think this is a really important discussion to have. This is a fascinating phenomenon and it’s medically important, but just on that point, I’d add for those who are worried that people are going to take away from this, oh, you’re trying to prove statins are ineffective or LDL doesn’t matter, which are not points I ever said or made or intended to make. And if you read the paper, I think that’s very clear. But the response to it has come on several fronts. One has been massive scientific interest, which has been fantastic, and more people becoming aware of that. But along with awareness and hopefully acquisition of resources, which will let us do the crossover trials that I really want to do, but didn’t have the resources for previously, is clinical awareness.

(00:25:57):

So I have been approached by cardiologists, by primary care physicians, by patients, who said-

PART 1 OF 4 ENDS [00:26:04]

Nick Norwitz (00:26:03):

By primary care physicians, by patients who said, “I wasn’t previously aware of this, but I am of this phenotype or I have patients of this phenotype and because of Oreo versus statin. Now I’ve looked at the literature and guess what? Now I’m treating my patients with sweet potato and they’re not on lifelong statin therapy, and their LDL is gone from 450 to 100 and they don’t need to be on medications. We’re very happy.”

(00:26:22):

So this wasn’t about just me trolling cardiology. This was about forcing a conversation is the term I use. I wanted to force a conversation that honestly needs to happen, because I firmly believe that this is an area that we need to explore in order to better understand human physiology, lipidology and advance medical science for patients like me, like Dave, like you, who right now are in a place of frank unknown.

(00:26:52):

So, that was the purpose. I hope people that actually dig into it think it was the legitimate effort.

Ben Grynol (00:26:58):

The lipid energy model, as I understand it, would be completely contingent upon a continuous suppression of insulin and insulin signaling to drive ketosis for one thing and just low levels of insulin. So did you measure insulin? And has this been a biomarker that you’re correlating the lipid energy model to, and also what’s happening at the level of the LDL receptor too?

Nick Norwitz (00:27:26):

So in terms of insulin level, I didn’t measure it weekly. I did get a fasting insulin level even during Oreo, and it was three. My insulin’s always been low. I think people, they ask me also, what happened to your HbA1c? As you would know, in two weeks, my A1c is not going to jump. I’m a pretty metabolically healthy person at baseline, so my fasting insulin is not going to skyrocket over a short period of time.

(00:27:51):

The model, which we can go into in a little bit more detail, but basically is that when you’re lean insulin sensitive and you go low-carb, you switch from carb burning to fat burning. And as that process ensues, free fatty acids go up as your fat cells are spilling out these free fatty acids. Some of them get taken up in the liver and get repackaged onto triglycerides, a stored form of fat, and put into these big spheres, these VLDL, very low density lipoprotein. Those get shipped out of the liver and then turned over at your fat cells and your muscle cells by a protein cell like the protein lipase.

(00:28:27):

And this turnover process is what generates the triad we’ve been talking about, the triad that defines lean mass hyper responders, the high LDL, the high HDL, and low triglycerides, because as the VLDL have the triglycerides suck out of their core, the triglycerides are in the core, they shrink. So your triglycerides drop because the triglycerides are being sucked out of the core very rapidly, so low triglycerides. The VLDL shrinks. What does a VLDL become when it shrinks? An LDL. So your LDL goes up and the LDL has a lot higher residence time than the VLDL. And then as you shrink a sphere, the surface area decreases. Part of the surface area will come off and be picked up by HDL particles, smaller HDL which then become bigger HDL with more cholesterol. That explains the triad we’re seeing. And, again, just to zoom out, if you remove the driving force behind the lipid energy model, this kind of spinning flywheel, you attenuate the phenotype, you slow the flywheel.

(00:29:22):

Now how do you remove the driving force? Well, you put carbs back into the system, you put carbs back into the liver. What you can do is sweet potatoes or banana or honey or your cookies. At least that was the theory or the hypothesis that I wanted to test this experiment and it worked. Oh, and to your question about… So I measured insulin fasting. I didn’t have the resources also bear in mind for a lot of this experiment on surgical services and stuff, so I’m not getting insulin every 30 minutes post prandial. Unfortunately that was not feasible. If I had that freedom, I would’ve loved to. LDL receptor, it’s an interesting question because certain people have claimed that ketosis lowers LDL receptor expression. In fact, I’ll name that person because I’d really like them to come. Thomas Dayspring put out a tweet.

Ben Grynol (00:30:11):

This was a question from a metabolic physiologist that said, “Ask him what’s happening at that level and if he knows.”

Nick Norwitz (00:30:18):

I’d love to dig into that. This came up because I thought this was an interesting claim that people just took for, if he has a tweet where he says, “Ketosis lowers LDL receptors.” Now I’m not aware of any literature to support that claim. Now, there’s a couple separate things that we can talk about here. One is ketosis, the other is ketogenesis. So the state of having high ketones or the process of making ketones. Now, if you want to isolate ketosis, which was the claim that was made, then you can do that with exogenous ketones, which you are well familiar, Dom, with exogenous ketone experiments.

(00:30:54):

I know this has been done in rodents. Interestingly, liver LDL receptors go up with ketone esters in rodents. Not down, they go up. And in terms of the human data, a human RCT, which we can send to you, we brought it up on the Plant Choppers podcast, investigated LDL receptors. I think it was in circulating peripheral blood mononuclear cells because these were healthy patients. And again, it’s a practicality. You’re not going to take a healthy patient and get a liver biopsy. It’s kind of an unpleasant intervention. So it’s a limitation in terms of what is there in the literature. But this was interesting because it was actually a high saturated fat ketogenic diet.

(00:31:37):

So my understanding is lipid energy model is probably the major driver, and we actually have evidence for this now that BMI is as much stronger driver than LDL and lean people who go low-carb. We can talk about the meta in a minute. But even separate from that, it doesn’t mean saturated effect can’t have an effect. So saturated effect can lower LDL receptor expression, which is a mechanism by which, in the general population, saturated fat can increase LDL a little bit. Interestingly though, in this human RCT with a high saturated fat ketogenic diet, LDL receptor did not decrease. So my most honest answer for what happened in my liver LDL receptor expression with the Oreo studies, I don’t know because nobody would do a liver biopsy on me. For that physiologist asking, if they can find a doctor at Harvard who would do a liver biopsy on a compliant medical student, I am volunteering myself. But thus far, nobody’s-

Dave Feldman (00:32:34):

I forbid it.

Nick Norwitz (00:32:34):

[inaudible 00:32:35] test. So those aren’t data I possibly can acquire on myself in the context of say, the Oreo experiment. But in terms of what exists in the literature, ketosis has only been shown to increase LDL receptor expression and ketogenic diets in human subjects have not been shown to decrease LDL receptor expression when tested.

Ben Grynol (00:32:55):

Okay, so another question, and I’m kind of paraphrasing because it comes off of a discussion that they’re insinuating that adding carbohydrates will restore proper cholesterol metabolism by upregulating the LDL receptor and it’s restoring cholesterol homeo in that-

Nick Norwitz (00:33:17):

Right. Right.

Dave Feldman (00:33:18):

Can I apply just some mechanistic common sense here? Sorry, I don’t mean for this to come off as-

Ben Grynol (00:33:25):

In the lean mass hyper responder context, but maybe not so much in a normal.

Dave Feldman (00:33:30):

No, no, no. I’m just talking in all contexts. What’s being proposed would result in a positive feedback loop. So what you’re saying is that there’s less LDL particles being taken out of circulation, relatively speaking, by the LDL receptor expression alone on the liver, on the hepatocytes. And if that were true, then there would be a continuous increase in the concentration gradient in the blood, which goes where exactly? If there’s a lack of endocytosis and we know that that’s where we assume they all go, then the expectation is they’re going somewhere else instead. Otherwise, you would just see a continuous increase in the concentration gradient. This is where I feel like I wish they would think a bit more from an engineering standpoint.

(00:34:23):

It’s not an indefinite pool. There’s not some overage point that it just goes outside the body magically. There actually has to be some place. I’m, by the way, super obsessed with endocytosis and transcytosis, and if you get really bored, there’s some papers I got to read on vacation recently that really got me obsessed with it because I’m interested in what the case is for the stimuli of the concentration gradient forcing more LDL particles either into endocytosis or transcytosis pathways. But at the end of the day, you can’t say whether there’s more or less expression of LDL receptors, can explain a continuous concentration gradient in the lumen of our circulatory system because that suggests a feedback loop that’s dictated only by that one component. And that makes no sense at all mechanistically. Am I articulating that well?

Ben Grynol (00:35:19):

I know what you’re saying, but I can’t mechanistically connect the dots.

Dave Feldman (00:35:25):

Let’s say that you have 10 faucets that are pouring water at the same rate, and there are 10 drains that are taking water out of the… Let’s say it’s into a tub. And let’s say that we arrange it so that the water remains level, and then what do I do? I take out five of the drains. What would you expect to happen? Would you expect that the water would continue to increase? I think that if we saw a receptor expression being the sole component to LDL… Let me be more specific. If hepatic liver cell, hepatic receptor expression was the sole component on increase in decrease of levels with no further modulation of any other component such as lipoprotein lipase, then there should be a positive feedback loop or a negative feedback loop, by the way, that would take LDL particles down to zero, right? If you could with something that expresses such as a PCSK nine loss of [inaudible 00:36:33], that should take you down to zero.

(00:36:35):

It shouldn’t be at 30. It should be at none, right? Like zero. Because you have a thousand drains and 10 faucets, but they disappear almost as fast as they come into play. And so I, myself, I’m not convinced by any version of the LDL receptor expression being the… I believe it’s a component, but being the sole component of driving those concentrations. So again, just to reiterate what Nick was saying, and to take it back to the top, we do not dispute that saturated fat has an impact on LDL levels and we never have. And in our meta-analysis, Adrian went so far as to do a simulation and emphasized as best as he could, what he could model was the expected differential between how much saturated fat made a difference versus BMI. It’s just it can’t be turned into a false choice and then you can pull up anything with saturated fat. BMI clearly and demonstrably has an enormous impact in this context.

Ben Grynol (00:37:42):

That’s interesting. Yeah. Any thoughts, Nick?

Nick Norwitz (00:37:44):

Yeah, so just to get back to your… How did you put it exactly? It was something about dysfunctional cholesterol metabolism. There was a phrase you used.

Dave Feldman (00:37:53):

I like dysfunctional lipid metabolism. I like-

Nick Norwitz (00:37:57):

But Dom was referring to the lean mass hyper responder phenotype and postulating whatever this physiologist is who was talking to him that the return of carbs increases insulin to restore normal cholesterol physiology. It was something like that. I forget what term you used. I mean, first I pushed back on whether or not this is abnormal or normal metabolic response because I don’t think that’s been established. Second, I’d reemphasize that I’m citing what data we have available for whether or not LDL receptors would be expected to go down, and it doesn’t appear to be the case. So that’s not necessarily a deficit that needs to be corrected. And then in terms of the insulin-

Ben Grynol (00:38:34):

Well, I think what I was getting… Just to clarify, a carbohydrate induced restoration of LDL receptor sensitivity function and translocation to the tissues to enhance uptake. I’m paraphrasing the discussion, but it was therefore returning to proper normal from their context.

Nick Norwitz (00:39:01):

From their opinion. First of all, I think you want to… The presumption that there is insufficient insulin signaling is, I think, quite a leap, but it’s an okay hypothesis. However, with any hypothesis in any model, if that’s their alternative model, we have a model and it explains a lot of things, not just the LDL level. And let’s investigate that model, insulin insufficiency. How does that explain the lean mass hyper responder triad, because if there’s insufficient insulin signaling, isn’t lipoprotein lipase going to be understimulated? So how do you end up with triad? There are a lot of elements here that aren’t explained by that hypothesis that LMA charges have insufficient insulin signaling at some level. Additionally, I’m not aware of any literature suggesting that, for example, insulin can have or insulin insufficiency can have this sort of effect. We don’t have type one diabetics with this phenotype, and you don’t give insulin to a type one diabetic and see their LDL plummet by 71%. So it seems tunnel vision hypothesis that might have a contribution, but as compared to existing models, I think is inferior and insufficient.

Dave Feldman (00:40:23):

And how can we take their model and apply to somebody with a BMI of 30? Why aren’t we seeing people with a BMI of 30 or 35 also exhibiting in ketosis this lower expression of LDL receptors and therefore the higher LDL?

Ben Grynol (00:40:39):

And the fact that in most cases they have lower BMI and they’re probably on the spectrum of more advanced athletes or just having athletic phenotype which leads to another provocative question here. One way to validate the lipid energy model would be to acutely lower LDL and Apo B and look at the effects on exercise. So clamping macronutrients, maintaining that, and then lowering LDL, Apo B in half theoretically, and then doing an exercise study before, during, and after, and seeing would this impair lipid trafficking to the muscles and exercise performance.

Dave Feldman (00:41:23):

A great idea, Dom. What do you think, Nick?

Nick Norwitz (00:41:27):

Well, I mean, I don’t know why the lowering is… Oh, you mean would it impair? Okay, that’s what you’re saying.

Ben Grynol (00:41:33):

Yeah. Acutely lowering. Yeah, and just simple like probably two week study that you could do to test this hypothesis.

Nick Norwitz (00:41:41):

In terms of energy changing it, what I’ll say is this has been reported by others, but I’ve definitely seen it in myself because as a medical student you have variations in your activity level. When I’m less active, my LDL drops. And if you look at the Oreo study, I think you saw this, Dom, because I presented on it and pointed it out, what happens at week five to six? Either you want to tell me? What happened at week five to six to my LDL on the statin arm?

Dave Feldman (00:42:06):

You’re talking about when you intentionally brought up your exercise level as that last little stent, is that actually your LDL increased.

Nick Norwitz (00:42:14):

By 50. So what happened was the LDL had plateaued on Rosuvastatin at weeks three, weeks, three, four, and five were within three or 4% of each other. So I thought to do a substudy within where I did as you said, plant everything and then just change one variable, which is what I went from 10,000 steps per day to 20,000 steps per day. What happened? My LDL jumped by 50 milligrams per deciliter. Now, in terms of proposed study, I think your saying, would dropping LDL acutely, probably with pharmacotherapy, impair physical performance because there’s insufficient fuel trafficking? We’ve wanted to do that study for a while now. To do that properly, we’d want to do it as a double blinded placebo controlled trial. I want to take a bunch of lean mass hyper responders, give them a statin, probably high dose versus a placebo and see how it impacts exercise physiology.

Dave Feldman (00:43:13):

I want to emphasize this. It’s important that we bring it down a lot. So, the problem is you can get a lot of effect size that-

Ben Grynol (00:43:22):

I 40 or 50 from 400. Yeah.

Dave Feldman (00:43:25):

Right. If you bring it down to 40 or 50, I think that we’ll see an effect. But let’s say somebody’s a lean mass hyper spotter and they have some pharmacotherapy that brings them down to say, 120 or even 100. I wouldn’t be surprised if you don’t necessarily see the effect because it doesn’t take much to just offset it by that much. You’d want to bring it down to where there would be, in fact, an induced rate limitation of that turnover that we’re describing in the lipid energy model of the triglyceride delivery. And yeah, I would speculate that there’s a decent chance we might actually see that, and I would love to do this double-blind. That would be the exciting part about it, is nobody knowing for sure they’re on it. Go ahead.

Nick Norwitz (00:44:08):

A couple of things I want to add. One is, it’s important also to emphasize that blood levels don’t necessarily imply flux. So if you give an LDL lowering medication levels can go down because you do. I mean, even if there isn’t a deficiency in LDL receptor, LDL receptor will still go up. If I take a statin, my liver LDL receptor will go up. And so you could actually-

Ben Grynol (00:44:27):

That’s my next question.

Nick Norwitz (00:44:28):

[inaudible 00:44:28] more of the LDL export and turnover and the reduction in the LDL level won’t necessarily correspond to a reduction in flux. But, like Dave said, if you lowered it enough, I would speculate that you would see an effect on performance. Now, that said, could it be detectable? Well, you’d need to power the study right. To power a study for physical outcome metrics and to do it properly in a double-blinded randomized trial, I’d love to do that, but that is a multimillion dollar study, and I don’t have that money. If you know someone with that money that will give me that money, let’s do that study. If somebody’s really interested in that and have those resources, they’ll race to do it. But right now it’s just we haven’t been able to do it. But yeah, I’d hypothesize that you would see an impairment and [inaudible 00:45:15].

Ben Grynol (00:45:15):

Yeah, even a case report from 400 to 40 and do time to exhaustion, you could do a whole battery of tests like we do in our exercise studies, and I think it could be a two week. I think it could be a pretty-

Nick Norwitz (00:45:29):

You couldn’t blind it very easily though. If I volunteered… Let’s say I did this on myself and we publish it, and I actually had an impairment in exercise performance, do you think anybody who wasn’t inclined to want to believe it would believe it, or would they say, “Nick, you just quit early?”

Ben Grynol (00:45:49):

Yeah, well, you would not be the ideal person to do this. So we need someone who’s kind of naive to the lipid energy model and say, “We’re going to give you…”

Dave Feldman (00:45:57):

Believe it or not, I’d like to find a lot of people just like Nick. I would like to find a lot of very lean, very athletic, especially on the cardio side, who ideally had very high levels of-

Ben Grynol (00:46:09):

But he knows his body way too well.

Nick Norwitz (00:46:10):

Yeah.

Ben Grynol (00:46:10):

If you want someone who’s just more naive with their self-awareness of their body and their physio, yeah.

Nick Norwitz (00:46:17):

If you can pluck my brain out for a few weeks, but yeah. I mean, if we can find that subject, I’m not aware of that human being, but I think that’d be fantastic. I think it’s a good question. I think it’s putting us on the spot to make a bold prediction, but I’m very comfortable making that prediction, and I think that if it were an enough of a reduction, I do think we’d see impairments in exercise performance, and if we’re ever able to do this test and I’m wrong, then there’s some thinking to do. So that’s how science works.

Dave Feldman (00:46:48):

Stated plainly, we need to induce a rate limitation, and we don’t know what that threshold exactly is. It’s just that we would speculate. I would certainly speculate that it probably is somewhere in the range of forties or fifties, roughly at least.

Nick Norwitz (00:47:06):

Not only is there a rate limitation, but you can’t have other compensatory processes. So you could do it and there could be the same performance, but there’s an increase in RAR because they’re just upregulating gluconeogenesis. It has to be an endurance activity with the rates patient and blockage of compensatory mechanisms.

Ben Grynol (00:47:28):

That’s why the acute lowering with intensive therapy, statin therapy and the testing… you know… I mean.

Nick Norwitz (00:47:37):

But you can still do gluconeogenesis, you still have muscle glycogen. In the faster trial they had normal levels of muscle glycogen, the athletes that were low-carb. They’d burn through all that glycogen, somehow make sure that gluconeogenesis isn’t compensating. It’s a really good thought puzzle. Doing it in practice, doing it correctly in order to not get a false negative, is also difficult.

Ben Grynol (00:48:02):

But the RER would give you a lot of-

Nick Norwitz (00:48:04):

It would.

Ben Grynol (00:48:04):

… information too. I think that [inaudible 00:48:07].

Nick Norwitz (00:48:09):

[inaudible 00:48:09] RER. That would be very cool. But again, I’m just saying there’s more variables here. So as I’m thinking through it, it’s like, “Oh, what if the exercise performance was the same but the RAR jumped?”

Dave Feldman (00:48:16):

I think that I doubt you’re going to get enough compensatory gluconeogenesis. I mean, it accounts for around 10% of the ATP of a triglyceride. I really do think that with intensive enough exercise, we’ll get to that rate limitation pretty quickly. So it’s a matter of getting, people really can do it, to the extent that we can and who already started high enough LDLs that we have the expectation they must have that level of turnover, particularly with the cardiomyocytes. I think it can be done. And you know what? I’m going to go ahead and float something. I haven’t even talked to Nick about this so I’m going to mention this here, and by no means hold me to this, but one of the things that I had floated as an idea to Sharon is on the next co side to actually have an experiment piggyback on the back end of the conference.

(00:49:11):

It would have a reason for a lot of lean mass hyper responders to come out to our conference and then see if we can heal in, since they’re coming out here anyway, to have some kind of experiment to take place either before or after.

Ben Grynol (00:49:24):

Yeah, I love that idea.

Dave Feldman (00:49:27):

Don’t hold me to that. Don’t hold me to that, but that would be fun if that were the case.

Ben Grynol (00:49:31):

Yeah. Well, what we’re talking about here is most people may think this is really down in the weeds, but it’s very fundamental and it’s very central to what you guys are proposing, the lipid energy model. Maybe let’s take a step back a little bit and just talk about what kind of pushback… Let’s talk about what kind of pushback are you getting from other people in this field, and what are some questions that, I guess, stated another way, the pushback that you’re getting, what kind of experiments would help appease some of their concerns, especially from the context of the cardiovascular risk territory?

Dave Feldman (00:50:14):

I say this with love in my heart because I do think it’s just the nature of us as humans, but I sort of feel like those goalposts move over time. Look, Dom, you’ve been in this field for a long time. If we were to go back eight years and we were to walk into a lipidology conference at the bar, and we were to say, “Hey, we’re about to do a study where the average LDL per this participant group of average 55-year olds, mostly males, their LDL is 272, and they’ve been at these levels for about 4.7 years, and we’re going to check in to see how much plaque they have compared to a control group who’s had an average LDL of 123 of about the same age and otherwise mat.” You and I both know, eight years ago, we could bet them that, “Oh, we actually think that, that group will be statistically no different. In fact, they’ll even possibly trend in the other direction.”

(00:51:21):

Almost everybody would take us up on that bet. But today, there are a lot of folks who say that actually may not be enough time, and actually metabolic health, this is the most fascinating thing, that the good metabolic health of our cohort with our lean mass hyper responder group… By the way, for those who didn’t actually pick that up, I am mentioning the match study data that Dr. Budoff shared on December 8th and that we’ll have published here pretty soon. But getting back to what I was saying, the fact that there’s such a recognition that metabolic health is itself from cardiologist’s perspective, a massive confounder because it’s that relevant to cardiovascular risk, is already a…

PART 2 OF 4 ENDS [00:52:04]

Dave Feldman (00:52:03):

… to cardiovascular risk is already a, I think, a significant shift in the field. And that’s not me putting words in their mouth that now that’s all that matters in LDL, doesn’t matter by any means. It’s just that I do think that there is a stronger recognition that there’s possibly something different with this population that we’re studying with lean mass hyper responders, that they may not be as higher risk at a population level as was first expected. Now to steal man, their position, I think they would still say, “Look, all things considered, they had all the same metrics.” If people like myself and Nick had all the same metabolic markers, but we also had low LDL, then that would be optimal. And what we’re at right now is at least suboptimal and will be relevant. But that’s already a big difference between now and the eight-year hypothetical that I just mentioned, right?

Ben Grynol (00:52:58):

Yeah. One confounding variable that was also brought up in a recent conversation with someone is did exercise. So presumably the lean mass hyper responders engaged in more exercise. So could this be the lack of atherogenicity of the elevated LDL, could that simply be due to, did you control for exercise? I guess is another question because exercise is a pretty big hammer, I mean, not a hammer, but equalizer in improving metabolic health overall. So that was another question I was supposed to ask you.

Nick Norwitz (00:53:37):

Can I make this point? Because I feel like Dave has already made it, [inaudible 00:53:43].

Ben Grynol (00:53:43):

I know. Metabolic health. Yeah.

Nick Norwitz (00:53:45):

It’s like we’re saying lean mass hyper responders are unique because they’re healthy-

Ben Grynol (00:53:50):

Yeah.

Nick Norwitz (00:53:50):

… and they have this one outstanding variable, and early on in this process they were like, but they’re basically going to drop dead. We used that terminology. I don’t even remember if it was this recording, because we had to have a bunch of takes as there was technology failing, but basically saying, we all had the reaction. Our LDLs went up and we’re like, we got to figure this out, or we’re going to go shopping for our headstones, right?

Ben Grynol (00:54:12):

Yeah.

Nick Norwitz (00:54:12):

So that was the original place we were starting, and now we’re at the place of saying, or people are criticizing, well, that LDL of 300 or LDL of 400, it’s confounded by you’re exercising a bit more, or your BMI is a few points lower, or you’re not 0.8 kilograms per meter squared over the… it’s an order of magnitude thing [inaudible 00:54:36].

Ben Grynol (00:54:35):

But it’s also a feature of the exercise. So I mean, what you guys are saying-

Nick Norwitz (00:54:40):

But I’m saying-

Ben Grynol (00:54:41):

… I mean I understand their perspective and I understand their criticism that you have to control for exercise or it doesn’t mean anything.

Nick Norwitz (00:54:47):

You can’t though.

Ben Grynol (00:54:48):

But it’s a feature of lean mass. Well, I guess you can, yeah.

Nick Norwitz (00:54:51):

But practically speaking, in certain experiments you can’t control for every single variable. So in terms of the matching, you can’t match lean mass hyper responders to Miami Heart based on HDL, because lean mass hyper responders have such a high HDL.

Ben Grynol (00:55:04):

Yeah.

Nick Norwitz (00:55:05):

You actually can’t do it in practical reality. As a non-researcher, maybe Monday couch quarterback and saying “It would be ideal to XYZ,” but in practical research, it’s not feasible. You only do the best that you can. And so what you’re effectively saying with this challenge is, oh, this is a confounder, but it’s a confounder that’s enough to wipe out the risk associated, like the delta. The risk delta of the high LDL you’re saying is wiped out by exercise. So I can have an LDL, this is not me arguing this, this is the implication of the criticism that I can have an LDL of 300 if I exercise more, oh, maybe I can have an LDL of 500 if I exercise even more.

(00:55:49):

I know they’re not meaning to make that claim, but as Dave said, the goalposts move, the original point was this is a high risk phenotype because LDL is so high and this is so important, and now it’s, oh, well this study was confounded because not all the variables were matched. When that’s not a bar you can set that is a reasonable bar because it’s impossible to match for all of these variables. It’s just never going to happen.

Dave Feldman (00:56:17):

First of all, exercise is not in our eligibility criteria, and it’s not a metric that we were looking at. Now, do we find, in general, people perhaps-

Ben Grynol (00:56:26):

But do you think it’s important to look at that and just get in hindsight, so in hindsight, would you, yeah, I mean activity trackers or something, or just some self-reported exercise.

Dave Feldman (00:56:38):

I’m interested in all data.

Ben Grynol (00:56:39):

Yeah.

Dave Feldman (00:56:40):

And this is why I’ve joked about it whenever the challenges come forward, challenges like these where it’s sort of post hoc. Well, what if there was this? I’ve said, and believe me, I have a track record of doing this with myself. I love it all. If I had the money, I would have tracked every single possible thing that I could with all of our participants. It might’ve meant a tougher time recruiting because of just how many things we were collecting, but of course I would be interested in that. But yes, Nick’s making the point that I’ve made umpteen times, which is, for example, the exercise was not what was brought up in the course of starting this study. So for all of us that were coming together and designing this protocol together, part of the reason we had a mixed team was so that we could decide amongst ourselves what this starting point was and then stick to those rules as we kind of headed into it.

(00:57:33):

Well, in the case of something like exercise, I mean, of course I assume lean mass hyper responders are probably more athletic than non lean mass hyper responders, but once we did the match, those folks who had likewise high HDL, low triglycerides, not as high as ours, not as low, but they also, I want to say the average in the match group was still an HDL of 60, and I think that their triglycerides were like 90. That’s almost certainly a group that does a lot of exercise. Now, is it exercise matched? No. Would that have made a significant difference? Possibly a difference that could be found to be a significant, but the catch is that we’re still talking about a difference of magnitude. The difference in milligram years of 4.7 years times the 272 minus the 123, 700. We have around 700 milligram years. So what if your claim is that the eligibility of our study participants makes them low risk? Then you’re implicitly saying, if we landed at that average of 272-

Ben Grynol (00:58:42):

Not my claim, but I’m just the messenger of the [inaudible 00:58:45].

Dave Feldman (00:58:44):

Of course, of course [inaudible 00:58:45].

Ben Grynol (00:58:45):

Yeah, I thought it was a relevant, I thought it was a reasonable question, yeah.

Dave Feldman (00:58:49):

No, and for what it’s worth, that’s what I’m saying is the difference.

Ben Grynol (00:58:53):

Yeah.

Dave Feldman (00:58:53):

If we went back eight years ago and we said all these same things, imagine we were having this conversation with a lipidologist or cardiologist and we said, “Hey, but what about this? What if this group exercised more? What if they exercised more, but also they were eating red meat, high saturated fat diet, et cetera.” They had really high HDL, really low triglycerides. Would that mean that they couldn’t be as concerned about their 272 LDL? There’s no way. There’s no way. And if we told them in advance, this is how that group landed as far as what their mean averages were before reporting on what the CCTV data is, I believe they would’ve predicted then that no, there’s still going to be a high risk population 4.7 years. It’s plenty of time because like I said, the delta of 700 milligram years between the two groups should have provided a strong signal.

(00:59:50):

Now that it hasn’t provided a strong signal, I think there’s a lot more interest in discussing that perhaps they’re not as high a risk, but again, again, I want to steal man, I’m sure the current position is, well, it will take more time. Maybe they will develop as much because sure, maybe things like exercise are relevant. It’s just is it as relevant as making a difference between people who have the highest LDL, like in the top 10% of the top 1% of the population? That’s a very different goalpost than where we started.

Nick Norwitz (01:00:23):

Can I also just address a little bit of an elephant in the room with this question? I don’t know if it was the same person that asked the prior question about exercise. We’re talking about between groups right now, but if we are going with the presumption that exercise is cardio protective, we have the prior question about the lipid energy model and lean mass hyper responders, then as a thought puzzle, what happens when a lean mass hyper responder does more exercise? Or is the exercise more cardio protective, but their LDL goes up and how do those factors offset? In other words, if I’m relatively sedentary, maybe my LDL will be 280, then I just go crank on the rower for two and a half hours a day for a few weeks, I better get my LDL to 600.

(01:01:02):

Is that protective or harmful? If you’re saying exercise is protective. That’s more of a provocative thought puzzle, but it’s again, an order of magnitude. I think pose like that, most people would say, okay, 600 is scary. The exercise is not offsetting. Now you’re delta in this thought puzzle, what 320 or whatever.

Ben Grynol (01:01:23):

So let’s jump to, because I’m very interested in the gym hypothesis that you guys kind of talked about a little bit. So give me your thoughts on, are we talking about activity induced glycolysis or glycolytic activity sort of offsetting or negating?

Nick Norwitz (01:01:41):

No, that’s not the [inaudible 01:01:43]. Dave explained it [inaudible 01:01:44].

Dave Feldman (01:01:44):

Yeah. The origin of this is as the lean mass hyper responder phenotype is emerged as you know, Dom, between us, we know many different people who speculate that this is still a rare oddity and that probably there’s some genetic abnormality about myself and Nick and others who have seen this because what they would say if they were here in the room is they would say, but not everybody who goes on a low carb diet sees this lean mass hyper responder phenotype. In fact, here’s this friend of mine who’s lean and who tells me that they’re on a ketogenic diet. They don’t see that. And what I always say is, well, give me a group of people who’ve never been lean mass hyper responders, and often I choose a fictional gym, that’s how it came about. It’s actually our colleague, Adrian Sodamoda who coined this term.

(01:02:35):

I’d say, give me a gym down the street. Let me be able to select the people. What I would select are runners. I would select people like Michelle Hearn who are more into the running and the cardio less so than into the lifting. So not the Don D’Agostino’s, although you actually do a lot of cardio now too, right? Anyway, but I would get a group of those folks who are fairly lean and then I control their diet because unfortunately, as you well know, the term keto has kind of become a broad term. So what I would do is I would be feeding them effectively a carnivore diet. When we were putting together the Lipid Energy Model paper, so much credit I’ve got to give to Nick, it was his idea to make a checklist. We had only so many words, but he correctly pointed out it was great for us to have a checklist on things to directly challenge the Lipid Energy Model. It’s making these predictions, and we put the gym hypothesis right in there, and it’s great because yeah, that’s something we would like to do. It’s something we’re still trying to get put together, but we know it’s a bit ancillary. Things like the risk. We know that it’s kind of front and center. That’s part of what’s going to feed interest in studying this group further, is if it can be determined that they’re not at higher risk, especially when you’re talking about this gym hypothesis experiment. You’re saying, I want to turn people into folks who would have the equivalent of FH, but I think that this will help grease the wheels for us to get there, and with the amount of interest that’s going up, we might be able to do this and test that gym hypothesis.

Ben Grynol (01:04:11):

Well, I was talking to a researcher, I’m not going to mention him, everybody knows him, but just mention that the lean mass hyper responder phenotype and the people that he saw were essentially like hypogonadal, so lower testosterone, and I saw, just kind of gets back to your studies, blood work on people who then used an anabolic agent, whether testosterone and other anabolics and then LDL sharply goes down. So that may lend to the gym hypothesis and anabolic-induced endocytosis of cholesterol being put into biosynthetic pathways and a greater uptake of that. But I think moving forward with some of your research, it would be important to, and I know you guys already do this with the thyroid and the T3 being low, which is kind of another discussion with the women, but looking at hormone levels, so does a lean mass hyper responder have a particular hormone profile that is consistent with that, especially in regards to metabolic hormones, anabolic hormones? So just something to look at if you’re not already doing that.

Dave Feldman (01:05:23):

My own testosterone when I last tested was like 700 or something like that, and I have no business having that number by the way. I’m not nearly as athletic as the two of you.

Ben Grynol (01:05:32):

I sense that-

Nick Norwitz (01:05:34):

[inaudible 01:05:34] were just over 1100 and 1007.

Ben Grynol (01:05:39):

Oh my, okay.

Nick Norwitz (01:05:40):

I can send them to you, but actually it was interesting. I got them measured. I won’t give the detail backstory, but my testosterone usually does not run that high. That is a high testosterone. This is just completely natural. I didn’t take anything, but it actually went over a couple months from 400 to 1100. There were a few things going on. Part of it actually might’ve had to be stress levels. I was on a surgical rotation. It was 400. I came off, I was on vacation, jumped to 1100, but there wasn’t a change in my LDL.

Ben Grynol (01:06:10):

Okay.

Nick Norwitz (01:06:11):

Maybe we’re getting them for the LMHR study with Match to Miami Heart, but my testosterone for various reasons has bounced around as a function of natural variation and it’s never really affected my LDL. And I can tell you I’m not hypo [inaudible 01:06:29].

Ben Grynol (01:06:29):

I know it’s super important to get it measured first thing in the morning ’cause I’ve done maybe two or three times I’ve taken it in the afternoon and it’s always half of what I have in the morning so ’cause you have that [inaudible 01:06:40]-

Nick Norwitz (01:06:39):

They were 730s.

Ben Grynol (01:06:40):

… fluctuation.

Nick Norwitz (01:06:40):

They’re all 730s, 830s.

Ben Grynol (01:06:42):

730s, okay. Yeah. Well, I think it’s, as you guys found with the women, lean mass hyper responders the T3 levels, which trended kind of low. And I’m sure you guys may get some questions on that, but…

Nick Norwitz (01:06:59):

Kevin, can I point out-

Ben Grynol (01:07:01):

I think there’s higher sensitivity receptor sensitivity in people who…

Nick Norwitz (01:07:07):

Yeah, so their TSH was normal. Also-

Ben Grynol (01:07:10):

Yeah.

Nick Norwitz (01:07:10):

… there’s decreased demand because there’s fewer carbs and their basal metabolic rate did not change.

Ben Grynol (01:07:18):

Yeah, that’s the key. Yep.

Nick Norwitz (01:07:20):

So they’re not clinically hypothyroid in any way, shape or form.

Dave Feldman (01:07:26):

And there’s not the symptoms. This is what it gets a bit frustrating to me because-

Ben Grynol (01:07:30):

It gets so many questions about this. So I think we should talk a little bit about this, multiple questions a week about thyroid, especially women, keto affecting thyroid levels.

Dave Feldman (01:07:41):

Yeah. Look, there are symptoms-

Ben Grynol (01:07:43):

Now they’re referencing that study.

Dave Feldman (01:07:44):

Hypothyroidism.

Ben Grynol (01:07:47):

Yeah.

Dave Feldman (01:07:47):

Do you have symptoms of that? No. Well, guess what? We have a huge number, including this published study that shows especially with lower free T3, that’s very predictive of your LDL levels. And even before we had done this thyroid study, we already had this in Lipid Energy Model paper because, while we hadn’t elucidated all aspects of the cascade, and we still haven’t with regard to the lower liver glycogen stores, impacts downstream to what is ultimately going to be this profile. We do know the thyroid is extraordinarily important. It makes total sense, of course, because you’re talking about whole body fatty acid turnover, and so yes, whenever people were talking about using terms like underperforming thyroid, I’m always wanting to say, how do you know? What are the symptoms that you’re experiencing? If the only symptom is the number that’s coming back on the lab report, and especially when so many other people are sharing this symptomless lower T3, particularly free T3, I think that’s a huge clue of course.

Nick Norwitz (01:08:52):

If anybody ever takes an endocrinology course, the number one thing any endocrinologist would tell you is do not use the term normal. There’s a garbage term in endocrinology, it’s is it appropriate? Is it appropriately normal? Is it appropriately suppressed? Is there an appropriate response? So if you’re say hypocalcemic, then your PTH should be up because you should have that physiologic response. It’s always in context. So in a low carb context, it’s fine. I mean, I’m not going to say it’s fine in all [inaudible 01:09:29], in all circumstances, but a T3 that’s low isn’t necessarily abnormal. You need to manifest in some way, shape or form a sign of hypothyroidism or have associated changes in markers, things that suggest sick euthyroid, which happens in critically ill patients where they can have a normal TSH, but these women had normal TSHs and they had normal basal metabolic rates. They’re not feeling cold, they’re not losing their hair, and we see this all the time in low carb.

(01:09:56):

I mean, you can take me as an example. My T3 runs low. My TSH is 1. O, my reverse T3 is normal. Do I have a basal metabolic, like decreased basal metabolic rate? Well, I mean, I can overfeed with over 4,000 calories and 2,000 calories in butter and somehow lose weight over a week so I’m not that. I don’t have a produced basal metabolic rate. I’m not exactly a low energy person, and I don’t run cold. I never get cold. I’m only hot, and yet my T3 is low. Am I hypothyroid? No, I’m just not eating carbs. So I don’t have a demand, and I probably have a lot of, as you said, thyroid sensitivity. It’s the same with insulin. If your insulin levels are high, does it mean you have more insulin signaling? No, probably you’re insulin resistant, so your body’s trying to compensate. So yeah, no, I definitely do not think the women in this study were hypothyroid.

Ben Grynol (01:10:45):

Yeah. So the next hormone that I got to talk to you about, ’cause I’ve gotten a lot of questions and a couple podcasts that were sent to me, that being low carb to the point of lean mass hyper responder is inducing a chronic condition of chronic hyper cortisolemia that this is basically putting your body in a protracted stress response. And I know, well, I’m not going to mention the podcast. Some big names kind of threw out some podcasts recently, and that sparked a discussion and somehow I always get tied to these things, but maybe a little bit of discussion about cortisol levels on low carb, especially in the context of lean mass hyper responder.

Nick Norwitz (01:11:32):

Can I just pause and take a step back and ask a couple questions? One-

Ben Grynol (01:11:35):

Yep.

Nick Norwitz (01:11:36):

… what was their proposal for how this is inducing lean mass hyper responder physiology?

Ben Grynol (01:11:44):

Well, not necessarily inducing, but just in keto diets in general. That was the context, and then a lean mass hyper responder, and then it was kind of thrown in with the discussion of also elevated cholesterol is another feature of this phenotype that is potentially pathological. It’s just more evidence of a biomarker going out of range. So you have thyroid out of range, cortisol out of range, cholesterol out of range. It’s just this is all pathological, not in the, it was very carefully put, not in the acute sense that this could be very therapeutic acutely, but from a long-term sense, it’s a recipe for death essentially.

Nick Norwitz (01:12:28):

You know, I’m trying not to be disrespectful in what I wanted [inaudible 01:12:31]-

Ben Grynol (01:12:31):

A lot of these people, we kind of live in an echo chamber, so these numbers, I was even talking about these LDL numbers to a metabolic physiologist who’s world renowned and they just could not get their head around-

Nick Norwitz (01:12:43):

What are they?

Ben Grynol (01:12:43):

[inaudible 01:12:44]

Dave Feldman (01:12:44):

Well, he may. Yeah-

Nick Norwitz (01:12:46):

[inaudible 01:12:47]

Ben Grynol (01:12:47):

One’s your colleague, and I don’t want to mention their name.

Nick Norwitz (01:12:50):

I know you don’t. I’m sorry to put you on the spot-

Ben Grynol (01:12:51):

But you guys know this too, but there are metabolic physiologist cardiologists that if you just, and they’re teaching at a high level university and you talk about these numbers in a lean mass hyper responder, they just cannot get their head around it.

Dave Feldman (01:13:05):

Can I say this?

Ben Grynol (01:13:06):

Yeah.

Dave Feldman (01:13:08):

Nick and I have been very proactive. We’ve been getting more and more proactive than ever before, especially coming into this year at wanting to have a product of dialogue with other big names. Like you’re saying, if they’re big names, and they can’t fully wrap their head around this physiology, and perhaps they want to have a respectful conversation with us on this, we could not be more forthright in our invitation to, I don’t know if I want to say cross the aisle like there’s different sides, but as far as a wealth of data, you can’t get more engrossed in the data than Nick and I. We’re absolutely obsessed and we’re swimming in it. And so things like if there’s a hypothesis such as I believe that there’s a high level of cortisol leading to a stress response, such as having elevated HSCRP, such as having elevated TNF Alpha, right? I could quite literally go to the lean mass hyper responder Facebook group right now and post this up as a question.

(01:14:14):

And what I’m proud of with our social media groups is that they know I champion the minority voices in that group because I want it to be the opposite of an echo chamber. I want it to be something where, even if there’s a kind of a predominance of one sort of side, if you will, you can see my messaging inside that group, including videos that I posted, that I want everyone to just maintain a respectful dialogue and to appreciate the importance of sharing data. And so in that regard, it’s not just that Nick and I have learned a lot, it’s that we’re a great resource to test other people’s hypotheses. And I mean this sincerely when I say this next thing, it may well be that lean mass hyper responders do have other problems that they’re prone to, even if it turns out that cardiovascular disease is not one of them. That’s possible. To be good scientists, we’ve got to appreciate that we’ve identified this phenotype and that it may be that we find that there are some things that can be problematic about it.

(01:15:15):

I couldn’t be more interested in coming to understand what those problems might be. But if there’s speculation without an interest in even using us as a resource because they’re remaining in their own echo chamber, then I don’t have as much to say about that. We can only do the best that we can to reach out our hand to try to shake it. Nick and I have had various ways by which we’ve tried to connect with bigger names in the space who’ve come to look at this, but it couldn’t be more emphatically stated by both of us that we want this dialogue to happen more than ever. So let’s do it.

Ben Grynol (01:15:52):

I’ll connect you guys. Yeah-

Dave Feldman (01:15:53):

Yeah.

Ben Grynol (01:15:53):

… I mean, my testosterone, cortisol and thyroid are boringly normal, so I use that in my, but yeah, yeah, I’ll connect you guys with some people and yeah, because of the discussion, even there’s a guy, I don’t even know this guy, but Ray Pete, there’s Ray Pete, do you know that name? Or something? So a couple of people have brought him up to me and his whole dietary philosophy on low carb diets, also elevating cortisol. Sometimes that name gets thrown out to me, but I believe he may have passed away recently. But there’s a lot of practitioners of his approach just comes to mind because it had some messages today-

Nick Norwitz (01:16:33):

Yeah.

Ben Grynol (01:16:33):

… about this.

Nick Norwitz (01:16:34):

I don’t mean to obviously express any frustration to you, Dom, you’re-

Ben Grynol (01:16:39):

Yep.

Nick Norwitz (01:16:40):

… exceptionally gracious all the time. It’s the background of sometimes we want so hard to push these conversations forward. We want to be challenged. We want to have the hard questions asked, and we want to have conversations with people who don’t share our opinions. But it sometimes feels like despite our best efforts, they evade, and I don’t know who’s passing questions to you, but sometimes I feel like they do try to hide behind [inaudible 01:17:04].

Ben Grynol (01:17:03):

It’s a bunch of people actually.

Nick Norwitz (01:17:05):

Yeah, and so I’m not targeting anybody.

Ben Grynol (01:17:07):

Yeah.

Nick Norwitz (01:17:07):

I don’t know who’s asking these questions, I genuinely don’t. But I do know other people.

Ben Grynol (01:17:10):

Yeah.

Nick Norwitz (01:17:11):

You can imagine who they are, ’cause I’ve even said who they are publicly, who will be, who will make very public statements. These are big names. They’ll go on a podcast and say, “I’ve tried so hard to understand this perspective,” and I’m like, “We’ve asked you a hundred times to have a conversation and you’ve never, somebody has offered to pay you $10,000 to a charity of your choice to have a conversation.” Now I’m kind of revealing who that person is, but if you really want to understand this, sit down and have a conversation with us and stop evading that conversation or get out of our way. But don’t pretend to virtue signal that you’re really trying to understand this physiology and then not be willing to have a conversation. What I will say, that I’m positively taken by is the number of people willing to sit down and converse with us is growing. So it started with Chris McCaskill, who is a fantastic bridge. Simon Hill has been quite solicitous.

Ben Grynol (01:18:03):

Yeah.

PART 3 OF 4 ENDS [01:18:04]

Nick Norwitz (01:18:00):

[inaudible 01:18:01] Bridge. Simon Hill has been quite solicitous.

Ben Grynol (01:18:06):

My favorite is Bill Cromwell.

Nick Norwitz (01:18:07):

[inaudible 01:18:08] Bill Cromwell. I just assumed him now in the whole, our team. But yes, no more and more people like Ronald Prouse, Anatul Kontush. The list is growing with people also that were perceived from “across the aisle”. And the difficulty for me is continually having our position grossly misrepresented.

(01:18:33):

So people saying things like, you’re promoting high LDL as safe. And then I will throw at them that I went out of my way to do an editorial in the Journal of Clinical Lipidology with nine other coauthors. Please promote this. The title is Urgent Clinical Caution and More Research Needed, something like that, and it just gets swept under the rug.

(01:18:53):

It just continually gets swept into the rug but they’re trying to strum at it. This is what happened with Lane. I sent him an email. This is the one thing I highlighted. I’m like, if you’re going to share one thing, highlight our position that we want more research and that we want to urge clinical caution, and then let’s talk about the lipid energy model, this, that or the other.

(01:19:09):

And then he does a hatchet job, misrepresenting the physiology, not representing our points of view, and then pointing to randos who are fear mongering or anti-fear mongering.

Ben Grynol (01:19:19):

That’s a shame because in a sit down conversation, I know Lane is very capable of having a very nuanced, educated discussion. So I can work to facilitate that.

Nick Norwitz (01:19:29):

But that’s the question then why, okay, we opened up a group chat. I’m fine to be public about this. People can call me an asshole if they want, but this is a sore point. He was asking about Adrian’s meta analysis. Now, Adrian being a very busy clinician scientist. We have a meta analysis of RCTs. Bearing in mind, he always likes to flex that he likes to cite the RCTs.

(01:19:48):

He’s asking continuous questions about it. We’re taking it as his best faith and Adrian’s spending his time between clinics answering questions. Then we’re answering questions about the lipid energy model and physiology. And we’re continuously saying, let’s have a conversation on your platform. This would actually save all of us time and if for whatever reason you’re not comfortable having us, platforming us on because it affects your reputation, Bill Cromwell will come on.

(01:20:14):

So we’re offering you all these opportunities. We’re talking to you about the meta analysis of RCTs. Then you go on and just talk about how it’s one person, one person, and emphasize that as the Oreo versus Statin. Completely ignore the meta analysis and our opinions on risk. That is just a shitty thing to do.

(01:20:30):

And then you don’t cite the studies and you sell your data over feelings and then feel sore because we come after you. I come after you for misrepresenting the data. Well, I mean you can see why this is frustrating. I’m using Lane as a case in point because I think he’s made an example of himself and I am the one being the “provocative, rude person” here. I’m fine with that. Dave and I play good cop, bad cop, and I love being the bad cop. I have no problem [inaudible 01:21:00].

Ben Grynol (01:21:00):

This controversy is great. I think it brings more attention and I think the personalities, and people, a lot is on the line here because I mean people are very concerned about their health and I think it’s just going to draw more attention to this. And I think it’s important to debate this and I think once you guys reach the-

Nick Norwitz (01:21:20):

I’m happy to [inaudible 01:21:21]-

Ben Grynol (01:21:21):

The doubting Thomas, it’s just going to draw more attention to it. So genetics is another thing I didn’t want. I thought we should talk about our lean mass, hyper-responders, genetic anomalies for example.

Dave Feldman (01:21:36):

That’s where the gym hypothesis comes into play because basically the gym hypothesis is suggestive. If I’m grabbing a random assortment of people and the majority of them turn into lean mass hyper-responders, then almost certainly that can’t be the case, right? Unless it’s the majority genetic abnormality, it’s not an abnormality, it’s a normality. We’re making the case. This is we believe physiologic, but we don’t know for sure until we do this.

Nick Norwitz (01:22:03):

Would add, I would very much distinguish between a genetic phenotype like FH and a metabolic phenotype like lean mass, hyper-responders, which might have permissive genetics. So my genetics don’t change if I gain weight, but my LDL will go down. So there’s physiology here, but it doesn’t mean there can’t be a underlying core set of permissive genetics that need to be there in order for the metabolic phenotype to express itself.

(01:22:35):

So that’s what we mean by permissive genetics, which is very feasible now in terms of the penetrability, I guess, of the phenotype. That’s why we need the gym hypothesis because we don’t know and we can’t really do a genetic test to figure that out. We can look for monogenetic FH, which is screened out of the lean mass hyper-responder study. I have my VCF file of my exome. So any gene you want me to test, I can go look. But we haven’t really fully annotated the genome. So it’s not actually possible to do just via genetic testing very… you just can’t do it. That’s why you need the gym hypothesis.

Ben Grynol (01:23:11):

So looking at, well, I looked at the, as you know Nick, the NPC1L1 receptor. I have a missense mutation potentially gain a function mutation there, and then maybe that’s why it had such a robust effect to Ezetimibe. So like a crazy just cutting in half.

Dave Feldman (01:23:26):

No, but that’s very common with lean mass hyper-responders. Ezetimibe is probably the favorite of weights to lower LDL within the LMHR group.

Nick Norwitz (01:23:34):

Yeah, I’ve actually seen, there’s one case series going on. I was approached by a cardiologist who’s writing it up. We may be contributing it. They’re taking a little while to do it. But I’ve seen LDLPs on 10 MIGS monotherapy go from 3,500 to 500, and they didn’t have genetic testing.

(01:23:55):

I’ve checked for the Neimann-Pick and I don’t have any. Lean mass hyper-responders are a phenotype. Within there, there’s probably heterogeneity. Again, one of my key trials that I’d love to do, we have a whole wish list, but a crossover of carbs to statin to Ezetimibe. I do think Ezetimibe’s going to punch above its weight in this phenotype, but it’s possible that you would even punch us higher because of a missense mutation.

Ben Grynol (01:24:21):

If you dig into the research of Ezetimibe and see that basically when they combine it with a statin, it makes it a much more potent- it’s almost like there’s forces at work to prevent Ezetimibe monotherapy because statins are maybe more profitable from a patent perspective or something like that. Just because, I mean, it was just so mind-bogglingly effective for me in lowering my LDL. I posted my numbers and so many people reached out to me, telling me their numbers had the same response to monotherapy.

Nick Norwitz (01:24:55):

No, I think what it is it’s just because it’s a feature of how research was done historically, which was statins were first, so there were trials on them, showed benefit, and so it then became unethical to do RCTs with Ezetimibe alone, in high-risk patients. So there isn’t the evidence base, even if people are saying ApoB is the thing, there isn’t the evidence base in order to prescribe it as monotherapy.

(01:25:24):

And you see this all the time actually. I’m seeing it now with the GLP-1’s because I’ve been in weight clinics and if a person’s in a weight clinic, in a cardio clinic, what’ll inevitably happen is maybe their weight doctor will want them to go on the new combination GLP GIPs, which are a little bit more potent of weight loss therapy. But they haven’t actually yet shown benefits for cardiovascular risk. So the cardiologist will want them to stay on the semaglutide or a particular form.

(01:25:58):

So the injectable and the oral have different results for cardiovascular health. So until the outcome is proven, people don’t generally feel as comfortable prescribing it. The same thing with the statin. Logically you’d think, okay, the drug that’s going to cause more potent weight loss, the GLP combo probably will be better overall, but it yet hasn’t been proven for the cardiovascular outcome, so they stick with the first drug. Same with statins and Ezetimibe as monotherapy. Just is what it is with what evidence base is available. Practicing “evidence-based medicine”. We had a talk about that the other day. Topic for another time.

Ben Grynol (01:26:30):

I got so many more things to talk about, but would love to cover any other topics that we should be covering or missing here.

Nick Norwitz (01:26:38):

I had one other thing I wanted to talk about that wasn’t LMHR. I guess I’ll probably table that. I think it’d be the best to table that right now, as much as I want to talk about it, and people will know when it drops. This podcast is going to drop after that, but today is what? April 8th?

Ben Grynol (01:26:55):

Eighth.

Nick Norwitz (01:26:57):

Yeah, April 8th. There’s going to be some things happening this week on X. so you’ll know what I mean when this drops. So anyway, it’s going to be an exciting-

Dave Feldman (01:27:04):

By the time you’re listening to it will have already happened.

Nick Norwitz (01:27:07):

It will have happened. It will have happened. Anyway, it’s been-

Ben Grynol (01:27:10):

Real quick. I want to ask the last question because it intrigues me. Tracer studies. Are there any kind of tracer studies that you guys have on the table that would support, I mean, I don’t mean for this to be a long, because I know tracer studies can be pretty in depth, but maybe a simple concise explanation of some tracers-

Dave Feldman (01:27:30):

We were surprised at how cheap they are, right, Nick?

Nick Norwitz (01:27:33):

I got a quote. I actually got a quote for one we wanted to do, and it was 2 million. So with any of these studies, if you’re going to do it, do it right. And yeah, we want to actually look at flux, 2 million was the price tag we got. It was to do that equals 30.

Dave Feldman (01:27:51):

[inaudible 01:27:51] million dollars.

Ben Grynol (01:27:52):

You’ve got to be on site and everything where the cyclotron is. Yeah, you got it. Yeah, it’s very in depth.

Dave Feldman (01:27:58):

There’s another problem that I had talked about with Nick from the get-go that’s not necessarily going to be relevant, but is something to just always bear in mind. There still is a lot of multi-compartmental calculating. So there’s some degree with which there has to be some baseline assumptions made, but I think that we overcome that with our core hypotheses and what would be interplaying.

(01:28:24):

Now that said, I am hopeful that the most robust data we’ll get is next tranche, I guess you could say, on the mechanistic side, will be with this assay out of Finland called Nightingale, which is already baked into the existing study we are doing right now. In fact, I’m going to be meeting with Dr Budoff and his team on how we’re going to get that blood work over to Finland. I’ll admit here on camera that I’ve quite literally volunteered to walk it over myself, just literally handcuff the case to my body until I’ve made my way all the way over to their labs in Finland because I am so obsessively…

(01:29:09):

Those are frozen samples minus 80, and they are extraordinarily important to the research. But that assay, the Nightingale assay has enormous capability if true, to really get down to the compositional level of the lipoproteins of our lean mass hyper responder phenotype, the samples. And I think from that we’ll be able to test one of my longest ongoing hypotheses, which is I think pretty easy to make, which is that we’re going to find that there is a lower triglyceride, higher cholesterol ester content per lipoprotein per these LDL particles. And that’s going to be highly relevant because there’s not a lot of research on folks like those versus those who are severely diabetic. As you know, they tend to have a higher triglyceride per LDL particle. So same size LDL particle for somebody with severe diabetes versus somebody who is a lean mass hyper-responder, one of our participants, and the composition being different is a manifest.

(01:30:19):

It’s telling a story about what happened before it. And so while it’s not as good as the tracer study, I think it may go a long way to testing a lot of these core components of the lipid energy model. And that’s why I’m hoping this works. And that might be data we have fairly soon. Unfortunately it’ll be months until we publish it, but we’re close because now all of those blood samples are in, now it’s possible for it to happen. I just don’t want it to get lost in shipping or any kind of mishandling or anything.

Ben Grynol (01:30:48):

Oh god, that would be tragic.

Dave Feldman (01:30:53):

I joke, but I’ll probably be holding it like this even when I’m sleeping in my airplane chair. Anyway, I’m so excited to finally get that data in hand.

Ben Grynol (01:31:01):

That’s exciting. Well, I commend both of you for what you’re doing. Is there anything else to add? Please do, Nick, if you have any final thoughts.

Nick Norwitz (01:31:11):

This is more of a selfish commentary, but as this went on and it’s gotten on in the day and my self-control evidently has gone a little bit, I’m feeling not guilty, but need a further explanation. I think I’m feeling emotions right now because, or expressing emotions that I feel all the time, not only because I feel like on some people’s parts, I’ve named two people, there’s a disingenuous effort to really understand something that’s incredibly important with incredible scientific and clinical relevance, but that when I get frustrated with people, there are some idiots, I’ll just use the term idiots that I don’t bother with. I do get frustrated with people when I think they are capable of being helpful and that I think greater of them and that they’re not matching what I would want for them. And I think what they want for themselves as their standard, and especially I have a very, very low threshold for bullying, which has been a common feature of both people I’ve named. Very vitriolic.

(01:32:16):

I won’t even use the terminology that’s been used, but pretending to be an expert in telling other people basically to shut the, and I won’t put the expletive there, up. That I’m not cool with because I want science in general to be a safe space where people can ask genuine questions and we can have an open dialogue. So the combination of not doing their due diligence on a topic, pretending to be an expert and then telling other people to get in their place when they dare to ask questions. And that level of cyber bullying I have little tolerance for, but, this is my last comment, then I’m going to shut up. I’m not a person who holds a grudge whatsoever.

(01:32:57):

I could very easily get over basically anything with anyone and give a hug, sing kumbaya and move forward if somebody genuinely wants to move forward with the research and expresses interest. And I mean that authentically, 100%. I can bend or hold grudges. So I can punch back, but I can also be your friend if you’re willing to be my friend and you’re a co-collaborator on whatever scientific efforts, if somebody wants to partner up.

Ben Grynol (01:33:25):

Your passion for this, Nick and Dave, just is very inspiring. Thank you for giving your time so late in the day on all this and keep doing what you’re doing. And I love being a connector and a facilitator of you guys doing more podcasts.

(01:33:41):

So I’m going to reach out to people who just… usually it’s people in the anti-keto space too, but they’re usually very, they can be open-minded, and I think you guys are the best team working together to advance this and just based on your education outreach that you’re doing, Nick, through the channel, YouTube channel, that’s great. Been catching up on all your YouTubes and Dave with Citizen Science Foundation. It’s such a novel concept and project to spearhead. So man, props to what you’re doing and if I can help in any way, well just feel free to reach out. But I’m excited for the next event, so I can’t wait.

Dave Feldman (01:34:28):

Yeah, it’s been great. And yeah, thanks again of course for participating in this last one, but look, maybe that’s a good last thing to leave on, which is that I’m humbled at just how much support there is for making it happen regardless. You were opening with how else would we get this done? And that really is the nature behind this movement and our research overall is it’s been through the generous support of people watching this right now who have donated their time or their money or just for that matter, their sharing of our research of making it happen.

(01:35:11):

I’ll mention just real quick that the most amount of effort I think I’ve ever seen from anyone in such a short amount of time was Nick with the Oreo versus Statin experiment. I mean, he took that on seriously. I think you did something like 14 interviews in a span of eight days or something ridiculous like that.

(01:35:33):

And it was across the gamut. It wasn’t just the big channels, it was small channels, it was all the channels, etc. And he watches closely this Altmetric score, which you’re probably familiar with Dom, but a lot of people aren’t. And it shows the composition of all the different channels of media, whether it’s social media or whether it’s traditional media, like mainstream media. And it’s almost exclusively social media, which is also kind of dark when you think about it, because mainstream media just was not getting tracked for this Altmetric score. The reason I bring that up in this context of the Citizen Science is this further emphasizes why this is truly a grassroots movement and that it really does take the elbow grease of every single person for all of us to help push it forward because those on the anti-low carb side, they’ve got the wind at their back on this if that’s what they’re wanting to push back on. And so yes, this is what it takes and thank goodness we’re making it happen.

Ben Grynol (01:36:34):

And whatever the science says, I mean, you’re elucidating this phenomenon and the truth behind LDL in this context at least. But I think it’s important even for, you guys may not know this, but from the epilepsy world that I’m from, just going to American Epilepsy Society, I mean this comes up. The elevated LDL in kids or adults or the metabolic psychiatry that’s being spearheaded by the Baszucki’s.

(01:37:02):

I mean, there’s probably pushback from institutions and they’re gracious funders of your research and others and just spearheading this movement where they go to an institution or a scientist and they’re probably going to get pushback on people who are presenting as lean mass hyper-responders. And we thought they were unicorns, but I think there’s so many more out there, it’s not as unique as we think. And there’s also, we didn’t discuss this, but there’s a spectrum of LMHRs, right? Where you may not meet all the criteria, but these borderline, and that’s maybe a topic of another discussion.

Dave Feldman (01:37:38):

Can I fit in though? That seems to be the new goalposts if I can. There seems to be now an acknowledgement that lean mass hyper-responders may in fact be lower risk, but that’s shifted now to, but they’re so super rare and that they’re unicorns that this research that we’re doing doesn’t apply to the average people because they’re just so extraordinarily rare. But again, that’s already important information because it signals how much, there’s at least a greater awareness that that’s possible. That that’s possible. Whether or not we need more or not, that’s a big deal. That’s a change.

Nick Norwitz (01:38:22):

It was rare. Almost like FH.

Dave Feldman (01:38:25):

Yeah, exactly. And there were no RCs on that.

Ben Grynol (01:38:30):

Yeah, great.

Dave Feldman (01:38:32):

When they were looking at that in the seventies, I’ll bet we have more people in our lean mass hyper-responder Facebook group than all of the homozygous FH that Brown and Goldstein have ever looked at.

Nick Norwitz (01:38:43):

And just to Dom’s point about this touching on other fields, we were actually talking to Jan, was it yesterday? It might’ve been yesterday in his spaces about exactly that. This research is interesting for lipids, but it really is about removing a barrier to implementation of ketogenic diets for a lot of use cases because this remains the boogeyman, and until we solve it, understand what’s the driver of heterogeneity and what are the actual consequences in terms of risk. It’s going to remain a boogeyman across all fields and all use cases in which ketogenic diets could be therapeutic. So this isn’t just for cardiovascular risk, it’s about epilepsy, it’s about IBD, it’s about kidney disease, it’s about mental health. It’s about every disease that a ketogenic diet could touch.

Ben Grynol (01:39:32):

I looked on clinicaltrials.gov, to your point, I think there was about four dozen different use cases, alcohol use disorder. I mean, there’s so many different things. This research is so important for all those different applications.

Nick Norwitz (01:39:45):

It’s not about just the average. People have asked me if I were just otherwise it didn’t have an IBD history, would I lower my LDL with sweet potato? I’m like, all things being equal right now, if I was in that position and it was just like, yeah, I can have a sweet potato or not, I’d just eat some sweet potatoes. I don’t care. It’s not for those people, it’s for people like me or kids with epilepsy or people who if they add back carbs, their schizophrenia flares up. It’s for those people that we need to understand this.

PART 4 OF 4 ENDS [01:40:23]