Sky High LDL and No Heart Disease? Results from Dave Feldman’s New Study

Dave: 
Hard to distinguish between the arsonists and the firefighters, and we shouldn’t be afraid of that as an interesting question to tackle. We should welcome the discovery process itself.

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only. And we aren’t giving medical advice, we hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

Let’s set the stage. You start a keto diet and ketogenic therapy to treat some medical condition, and results better than you’ve ever seen with any other treatment modality, but your LDL cholesterol goes up and your doctor tells you have to get off that keto diet and you have to start a lipid lowering medication.

Do you? We’ve never had any data on this specific population. The lean mass hyper-responders, the people who are lean metabolically healthy on a ketogenic diet, who seem, who see dramatic rises in their LDL. But all that has now changed thanks to engineer Dave Feldman and the team of researchers and physicians that he’s built, we now have data on this topic. Now, it may not answer every question, and like a lot of research it, it probably asks more questions than it answers, but it is an amazing start and amazing feat. So here’s the interview with Dave Feldman.

Dave Feldman. Welcome back to Metabolic Mind. 

Dave: 
Thank you for having me on, Bret. It’s been a journey. 

Bret: 
It’s been a journey and I don’t think your journey’s ever going to end, but this phase of the journey is now reached a conclusion because now your keto trial that you’ve spent so many years dreaming about designing, starting, concluding is now published. So first congratulations. It’s been a long road but congratulations. 

Dave: 
Thank you. Thank you. I have some high school teachers I want to get back to and be like, hey. 

Bret: 
Yeah, yeah. 

Dave: 
Bret, you know this about me. I could spend all day long just on the thank yous. And I have to extend a thank you to you, Bret, to you in particular.

You’ve been a big champion of this whole process going forward and on the research itself. But yeah, it’s been a collaboration of lots of people. Including, of course, I’ve got to give a big shout out to the team, the protocol team, to the publishing team with Nick Norwitz and Adrian Soto-Mota, and of course, Dr. Matthew Budoff, himself, the principal investigator. It’s been a long journey, but we’re here. Yeah, we’re actually here. It’s cool. 

Bret: 
Yeah. So let’s get into the details, and I will do my best to be an objective interviewer here rather than fanboy out because I’m super impressed and proud and just in awe of what you’ve done as an engineer, as an outsider, to come in and ask questions that nobody within medicine really wanted to ask. And to build the team to be able to design the trial, crowdfund the trial, and complete the trial and get it published. It’s just a remarkable feat.

But all right, I’ll put that away and turn into objective of interviewer here. The trial, why don’t you go through sort of the basics of the trial setup and then we’ll jump to the results and then talk about the implications of those results because I think that’s the most important part is the implications of the results.

But tell us about the trial setup. 

Dave: 
The trial setup was we wanted to look at folks who were metabolically healthy. On a ketogenic diet, and like myself and many of your patients saw their cholesterol skyrocket, the hyper-responders. And in particular, we were interested in lean mass hyper-responders, or at least near lean mass hyper-responders, people with extraordinarily high LDL, but also matched with high HDL cholesterol and low triglycerides.

And we were flying 100 of them to The Lundquist Institute at UCLA to get what’s known as a CT angiogram. It’s an advanced heart scan that can pick up at extremely high resolution, what’s known as plaque volume. You as a cardiologist are already more than familiar with this. There’s the development of plaque, which of course, is very relevant to the outcome of cardiovascular disease and especially to things like heart attacks.

So we wanted to scan their plaque levels, particularly to see how much plaque they started with. But in particular, we were very interested in capturing a second scan, which we flew them all back for about a year after they started their first scan, or got their first scan, and then have that for comparison to actually be able to look at a population level of the hundred first scans against the hundred second scans, and in particular, see how much LDL cholesterol or ApoB, for that matter, associates with the outcome of plaque progression, particularly non-calcified plaque. That’s the major endpoint we were especially interested in. 

Bret: 
Yeah, so a lot of really important points to emphasize. And the first is that these were individuals with remarkably elevated LDL levels so high that most doctors would say, or I shouldn’t say, most many doctors would say there’s no point in even studying it.

We know this is high-risk and absolutely needs to be treated. Patients will report that their doctor told them they were a quote unquote ticking time bomb, which I think is just a terrible thing to ever say to a patient. But we hear that a lot and because the assumption is they’re incredibly high-risk.

So that I, that’s one really important part to bring up. And the second important part for clarity is that the scan that you’re doing, the CT angiogram with the plaque analysis, can really detect very low levels of plaque buildup and low levels of plaque change. So it’s not a blunt instrument like a calcium score, although still a very good test, but it’s a much more fine tuned instrument. And I think that’s two really important points to to bring up about this.

And then, of course, that they, the LDL went up for a reason because they were in ketosis. So you scan them at the baseline. And we’ve already talked about the baseline data, but there were some surprises in the baseline data, weren’t there, with people who were average age 55 who’d been keto for almost five years, average LDL 270 or something.

And what was remarkable about their baseline data? 

Dave: 
Yeah, so this first, when you say baseline, you’re talking that first set of scans. We already could look at what their LDL cholesterol was in the association of existing plaque that they had. And bottom line was, there was no association.

There was no association, even a weak one, between the levels of LDL cholesterol that they had and the plaque that they presented with as it’s called, commonly it’s cross-sectional, it’s just a single point in time that many might say, that may not tell us enough. But importantly, as you and I discussed before, we also got to do an additional analysis where we could grab other metabolically healthy folks from this other study called Miami Heart and do a comparison when they had much lower average LDL cholesterol. In fact, less than half of our cohort.

And sure enough, they didn’t have an association between LDL and their plaque at baseline. On top of that, there was no statistically significant difference between both groups. Our group with sky high LDL, and their group with average levels of LDL. Even though our group with sky high LDL had maintained those levels at almost half a decade.

So we already had quite a lot of exciting data even before coming to this final endpoint where we’d have the second set of scans to do an internal comparison from the first set of scans. 

Bret: 
Right? So then you have a year later for each individual, a second set of scans to compare their total plaque volume, their non-calcified plaque volume, their calcium score, and see how it correlates to their degree of LDL elevation.

For example, do those with an LDL of 500 see much more rapid plaque progression than someone with an LDL of 200? The LDL hypothesis, if LDL is what drives vascular disease, would make sense that for a very high resolution scan you would see that degree of correlation. 

But did you? 

Dave: 
We didn’t. That’s the bottom line. The bottom line is we went through lots of variations of not just LDL. As the title of the paper emphasizes ApoB. 

Bret: 
So actually, yeah, let’s take time out and so I apologize to disrupt you, but for those who don’t know the difference between LDL and ApoB, please give a, a quick update and then continue.

I’m sorry to interrupt. 

Dave: 
No worries. That’s, and it’s important because I think it’s worth emphasizing that when we were starting this research and getting into the study design and so forth. LDL cholesterol is, of course, the major target of treatment. But more and more of the literature and definitely more of the lipidologists would point to it’s not as good of a marker as ApoB, and fortunately we were getting ApoB metrics as well as LDL cholesterol. And therefore of, course, because it was the major endpoint of interest we wanted to bring forward that.

You can see it in the paper, we discuss LDL cholesterol as well, but ApoB is considered by many in the world of lipidology, of cardiology to be the more relevant marker. Now, to get geeky for just a second, if you’ll bear with me, I’m going to explain the difference between the two. LDL cholesterol is the major cholesterol found on a particle, known as low density lipoproteins, that’s where LDL comes from, low density lipoproteins. And low density lipoproteins, and the cholesterol found on them have been thought to be the major driver of atherosclerosis. But more and more recently, there’s been a lot of interest in looking at those a alongside other things known as remnants, which are, for example, precursors to LDL, like VLDL.

The one thing they all have in common is one major protein for which they all have one copy of, and that’s ApoB. So for a lot of folks, like Thomas Dayspring, like Alice Snyderman for example, they would say, look to ApoB. That should be the strongest predictor in concentration levels with the outcome of atherosclerosis, which is this buildup of plaque.

This is why we knew that there would be a lot of interest in, and we wanted to draw attention to how would this compare with lean mass hypers-responders. Because spoiler alert, if you have high LDL cholesterol, you almost certainly have high ApoB. There is a profile which you can have low LDL cholesterol, but also high ApoB, called atherogenic dyslipidemia.

But there’s almost no circumstance in which you’re going to have high LDL cholesterol and not have high ApoB. So we knew lean mass hyper-responders, we knew our study cohort would likely have high ApoB anyway, and therefore, we knew people would be interested in that metric, which is why I’m glad that’s, it’s not just a essential metric, it’s actually part of the title of our paper and so yes, with there not being a correlation, what did have a correlation? 

Bret: 
All right. So as we’re talking about the non-correlation, I think, a picture says a thousand words. A graph really helps show this, and you have some really impressive looking graphs in the paper starting with Figure 2A. And we have the change in non-calcified plaque volume, so the delta NCPV on the vertical axis, and the horizontal axis is the change in ApoB. And for someone who’s not looked at, used to looking at these, you just see like a whole bunch of ants like scattered around. How would you direct someone to interpret this graph? 

Dave: 
Yes, and for the novices out there, and I consider myself one, it’s really important to notice that triangle.

You called it out, but I’ll mention it again myself. The triangle to the left of those titles, so to the left of NCPV, that’s non-calcified plaque volume, and it’s measured in millimeters cubed versus the change in ApoB. That’s the triangle to the left. We’re now looking at these changes and how they compare and each of those dots is a plot.

That looks at both of those metrics for each of the individuals. So all 100 people are represented here in a dot, but as you can see, it’s all over the place. There’s not a pattern that we can statistically find. Or if there was, then the left axis and the right axis would give us more of a direction that wasn’t left to right, that wasn’t as flat and as horizontal as this one is.

So this graph is very indicative of a lack of correlation when plotting all of these dots together. 

Bret: 
Yeah, and then for comparison, you can look at, C of Figure 2, which looks at baseline calcium score compared to the change in non-calcified plaque volume. And there you see something a little different.

Now this is interesting because the majority of the people had a zero calcium score, so a lot of them are over on that left side. But as you see the dots towards the right with higher calcium scores, that’s where you start to see the higher levels of change in non-calcified plaque volume. 

Dave: 
That’s exactly right.

And even if we didn’t have that line there, you would probably start to see it yourself already. You’d see that as you move to the right and as the baseline CAC, that is to say the calcification score of the first scan, the higher it was. So the higher you started, the more likely there was a change in the non-calcified plaque volume that’s given on the axis, on the y axis on the left side.

And so from that, you can see there is a loose correlation and it’s fairly predictive that you know where wherever your CAC starts, it’s pretty likely you’ll see an increase in your non-calcified plaque volume based on that alone. 

Bret: 
And, but as this graph also shows, it’s not perfect, right? It’s not a hundred percent of the people saw it.

It’s a trend, it’s a population based trend, I guess you could say. This is how research is done now for an individual. You can still test it for yourself, see for yourself. But it’s certainly in informative to have the population trend. And then the lower, the second line of this figure has the total plaque score.

So, whereas, the top was the change in the non-calcified plaque volume. Now as we look at D, E and F we see the change in the total plaque score. And there, that’s even more dramatic for the change in ApoB, or the baseline ApoB, just those flat lines like absolutely showing no correlation.

And then the baseline calcium score showing a slight increase correlation. So how do you relate that as it’s different from the non-calcified plaque volume? 

Dave: 
The special advantage here is that the non, is that the total plaque score, you could think of it as almost a second set of eyes.

So on the top set that we just looked at, the non-calcified plaque volume, that was through clearly interpreting scans. The total plaque score is from human readers making these scores, and the catch with these scores is that they are discreet, so a 0, 1, 2, 3, 4, that’s total plaque after they’ve added them all together.

But they don’t, they don’t go on decimals. That’s why they look like steps as they go up. But as you can see, they’re in agreement with each other that the total plaque score and the change in ApoB or the ApoB itself, there just is no correlation with the with the plaque score itself, it’s quite impressive just how much of a lack of correlation there is.

Given the enormous, It can’t be emphasized enough, Bret, I know you and I swim in this data all the time, and we’re used to people presenting with levels of LDL that are extremely high as being common, but it’s worth re-emphasizing that our population, average LDL cholesterol is in the top 1% of the general population. So by the same token with the ApoB being as high as it is, if there was a correlation, it would follow that likely it would present itself.

It’d be more likely to present itself for the sheer degree of concentration that’s involved with our patient pool. Yeah. 

Bret: 
Very good. Now, another one that I think deserves a lot of attention is H. So the correlation between saturated fat intake on the horizontal axis and ApoB on the vertical axis, because a big argument or comments that we frequently see is your, someone’s LDL goes up on a keto diet because they’re eating all that saturated fat. That’s why the LD on the ApoB go up, whereas looking at this graph says, actually no, they don’t appear to be correlated at all, do they? 

Dave: 
No. And this is one of the benefits of us having diet data is we had three 24 hour recalls at different points in the course of the study.

One at the beginning, one at the midpoint, and one at the end. And from that, we were able to get assessments of saturated fat intake, and this met with our predictions. We’ve, I’ve been predicting this for a long time and it’s not, I’ll reiterate, it’s not because there is no association that I would expect there to be with saturated fat in ApoB or LDL levels.

It’s just by comparison to the lipid energy model. I would put the lipid energy model against saturated fat intake with regard to the outcome of LDL and ApoB all day long. I would make a sizable bet that I’m pretty sure, Bret, you wouldn’t take me up on. But yes, we knew this would be of special interest because we know a lot of people predict the lean mass hyper-responder phenotype is really mostly being determined by just the intake of saturated fat.

And so we wanted to be sure this graph got in there as well. 

Bret: 
Yeah. And then last one, I know, I apologize, we’re going through a lot of graphs here, but I think it’s really important. And if someone’s listening to the podcast of this, I recommend you check out the YouTube version to see these graphs.

But the last one is maybe one people aren’t very familiar with on diet cumulative LDLC exposure in milligrams per deciliter years and correlating that to non-calcified plaque volume. So tell us about that one. 

Dave: 
Yeah, this was actually one I fought for myself because as a common heuristic, in the world of cardiology, is this concept of cumulative LDL cholesterol exposure.

So the greater the exposure over time, the more that you might expect there to be a change in plaque volume. And there are many different studies that kind of graph this out in different ways. And so sure enough, we have specifically the on diet cumulative LDL exposure based on what they report to be on diet.

And you can actually see that for many people it gets up there in to say the 2,500 realm, a couple that are in the 5,000. Even somebody is well above 7,500, whereas, it is under most of these heuristics assumed to be lifetime LDL cholesterol exposure of 5,000 or more is the point at which risk starts to increase longitudinally, or log-linear, I should say.

And bear in mind that the reason this graph is so powerful is you take the average age of our participants, right? They’re in their mid fifties. You can add their prior five decades of cumulative LDL cholesterol exposure to this. It would stand to follow that if LDL cholesterol was the central driver for this population, we should see the final non-calcified plaque volume being substantially higher.

And that’s not what this suggests so far. 

Bret: 
Yeah. I know that the, that those are very detailed analyses in these graphs, but I think it’s so helpful to see them see the image and really understand the impact or the results of this study. 

Dave: 
Absolutely. 

Bret: 
So, no correlation, meaning it didn’t matter. Actually first, so it’s interesting that the, a lot of the focus of the results are the correlation, but one question is, did plaque go up? Did they, did most people see an increase in their plaque volume? Is it what you would expect? Could anybody possibly see a regression in their plaque volume at this level of LDL?

So first, give us that data and then we’ll talk about the correlations. 

Dave: 
Yeah. the first thing I should emphasize is what I’ve actually said to you even before we ever had all the second scans, several times, which is that once I knew we had a middle age group of people, we knew that it was almost certain that there would be an increase in plaque on net.

In other words, even if it’s a very low level of an increase of plaque at a population level that would be expected because every middle age group at a sizable enough amount is going to have some level of plaque progression. The bigger question is it rapid? Which is why I’ve always phrased it that way when even we hadn’t had the study yet, was that would there be a rapid progression of plaque at a population level.

And no, not only was not a rapid progression of plaque at a population level, but we didn’t really have a good comparator for longitudinal data. We did have a good comparator for the cross-sectional data with Miami Heart, but unfortunately, Bret, as you probably well know, there’s just not normally longitudinal data acquired on metabolically healthy populations.

We hope that changes over time, but that’s an important part of this larger question. But getting back to the scans themselves, the initial data that we had was through readers who themselves have trained eyes to be able to look through and assess what’s known as a total plaque score.

And that’s what we reported on before, before we had Cleerly analysis on top of that. And the total plaque score, indeed, please don’t spoil this for other people, we’re going to see the movie. Indeed, we did have six folks who actually had a lower total plaque score in their second scan than they did in their first.

So technically they were regressors in the total plaque score. Now in the.. 

Bret: 
So a regression of their total plaque score, despite LDL levels that are deemed so high that they’re immediately dangerous and at risk of forming atherosclerosis. Important context. Yes. So, please continue.

Dave: 
Yes. Now I want to qualify the Cleerly analysis also looks at a different version of the metric called a plaque. there’s a few different, there’s a few different variations of this, but plaque volume, which is something we report on, and then there’s one that’s like the total area of plaque.

Those yielded different metrics, but otherwise agreed with the lack of correlation. LDL and this again, it should it’s worth emphasizing what you just said, this includes folks with extremely high levels of LDL. In fact, our biggest outlier in their initial scan had zero added. A zero total plaque score.

Now with the Cleerly analysis, we have plaque detected with every scan. AI guided reading is so granular that there’s a number for everyone. And that’s helpful because then you can do a little bit more of an assessment between the two values. But I want to be a good scientist and say it’s possible there’s some amount of it that when you get so low that is within range of error or something.

But that said, it’s so low. it’s still below anything that’s detectable in, or with the degree of change relative to many of these other studies on metabolically unhealthy folks. Once again, if there’s anything that can be reemphasized that you and I have discussed so many times before, it’s that crucial component of metabolic health as it relates, especially to LDL cholesterol in particular in this population.

Now not to bury the lead. You know that there was one thing that was of enormous correlation with this study, which is their end title plaque begets plaque. So what is the biggest corollary? Existing plaque, if any of the patients already had plaque, how much plaque they started with had a big association with future plaque progression with the second scan. And I’m going to guess that doesn’t surprise you, Brad. Does it? 

Bret: 
It doesn’t surprise me, no. But I think it’s going to surprise a lot of people that it correlated with preexisting plaque and did not correlate with LDL or ApoB that is, that’s the title.

And that’s the shock factor too, that despite these high values. So, why? Because people want to say okay, then what caused the plaque? People always ask me what caused my plaque? And I want to say, it’s not ApoB as the only cause and you can’t say there’s one cause.

And I guess that’s maybe the frustrating part of this study, right? It’s great when you have a boogeyman, when you’ve got the villain, you’ve got the one thing that causes it. So this isn’t going to tell us what causes plaque, but this does tell us if you have plaque, that’s what makes somebody more likely to develop future plaque and not ApoB.

You would you agree with that? 

Dave: 
Yes. I don’t know how many times I’ve had this discussion. My, I’ve continually had a frustration with the, I think, oversimplification of this whole process. We can’t say we know enough about atherosclerosis to boil it down to a marker, any marker, of interest to be the end all, be all, and that’s the one you have to look toward.

But I can say this with a lot of confidence and our study is supporting existing prior data in this regard, which is that nothing beats the existing disease itself because these scans are becoming more and more available, such as the CAC. They’re extremely prognostic. They’re extremely predictable as to what the likelihood of a future event is.

None of them are perfect, but by comparison to a blood marker, they’re actually incredibly impressive if you compare the data to each other right now. Now I’m going to say myself this next piece is very speculative, but I’m going to be upfront about that. I think whatever diet you went on, whether it’s on a keto diet or so forth, if you improved your metabolic health, I suspect that plaque progression doesn’t just halt on day one of whatever you did for your improvements.

I think so many other aspects of the immune response, there’s some difficult to determine span of time, a backlog if you will, let’s call it sites of construction for which there’s some rate limitation as to how much the city can get out there and deal with those construction sites to deal with, to begin with.

That is an unknown and may take us some time to figure out. So for me, personally, and for family members who are in the process of improving their health. Even if they do find out that they have existing disease, I don’t want them to give up on the process of improving and getting to a better place.

So even if you find that you’ve got work to do by the scan that you have, then I think that you’re at least into that first step of trying to see what you can do about it. 

Bret: 
Yeah. And that, that breaks up, brings up a crucial point. One of the things that has highlighted so well in the documentary that you’re working on and just in this, in the whole keto as medicine movement, is that people are changing their lives with ketosis.

They’re putting their bipolar disorder, their schizophrenia, their depression into remission. They’re putting their ulcerative colitis into remission, their treatment resistant medical conditions, their type 2 diabetes, their PCOS, you name it.

They’re putting them into remission with ketogenic therapy in ways that they tried and failed many other interventions. So then for someone to have a high LDL and to be told, now you have to come off that diet, is life changing potentially for that individual in the wrong way. Undoing all the benefits. So what this study shows is that well look, even if you have plaque and you have high LDL from being on a ketogenic diet, that doesn’t mean that is going to cause more plaque. Now there are lots of caveats around that, but I think that is the key take home for that individual, that patient population who’s often told to come off their diet.

So do you think that they should, that they could walk into their doctor’s office with this paper and say, okay, we need to reexamine this. 

Dave: 
I definitely think so if, especially if, that context applies to them, right? It’s, we’ll continue to emphasize as we should, that this is population level data and what your individual circumstances are, or between you and your doctor.

But that said, we didn’t have this data before. We just, it wasn’t there. And yes, part of a deliberate intention that we had with the movie that I’m so proud of is it’s not covering a bunch of people who are just looking at weight loss. We have story after story of people improving their health in a way that’s very efficacious being accomplished with a ketogenic diet.

Again, as I say in the movie, it’s not for everybody. It’s not for every disease. That’s true. But is there like a revolution taking place right now? I think there’s no question that we’re seeing, and thanks to Metabolic Mind for bringing so much of this to the forefront and supporting so much of the research behind it.

Of course, I care about people like Robin Dobbins or Jen Unwin who would be facing this central conflict that they’re getting a new lease on life in adopting ketogenic diet for their unique circumstances, but now they’re concerned about their cholesterol going through the. This is why we need to get these data and why it can better inform their decision because for many people it’s just not as simple as, I’m going to go ahead and take on a few more carbs so that I can reverse this profile.

If you can, that’s great, especially if that’s a concern you have in having high LDL. If you can’t, I’m sure you’re going to be very interested in these data to better inform yourself and your doctor. 

Bret: 
Yeah, and that’s a good point. And there have been public case series and a lot of clinical experience of people saying, okay, you fit this profile for lean mass hyper-responder, add a potato, add a sweet potato, add another 30 grams of carbs, and actually LDL goes down.

But not everybody has that luxury based on the medical condition that they’re using ketogenic therapy to treat, but there are limitations, right? There are definite limitations to this study, and limitations to the interpretation and one interpretation that I think, speak if I can put words in your mouth, that we are both very cautious of is for someone to say, see, LDL doesn’t matter, and I can forget about it and not worry about it at all, as opposed to the interpretation of see LDL doesn’t matter quite as much as we think it does. So with added testing and added evaluation and continued follow up, I can ensure that I’m not at increased risk. So different between putting your head in the sand and forgetting about it versus reframing how you see it with continued follow up.

Now, I’m totally leading the witness here, but do you agree? 

Dave: 
Yes, I’ll put it this way. I’ll say that coming into this space, there definitely was an opinion that LDL is effectively a toxin. It’s effectively a pathogen, it’s, it has only detriment to bear, and that gets worse the higher the levels.

It is now just opening up the question saying, I’m not sure if that’s true. I’m not sure if always lowering it is always the best option, especially if there are trade-offs with how it is you accomplish lowering it, which you just mentioned and that I’ll mention again if, for example, adding bad carbohydrates might succeed at lowering LDL, but it alters the efficacious that you were making use of with the ketogenic diet.

That’s one thing, but I think it’s also fair to say there are other things that may not be as obvious for however you take steps to lower your LDL that could be a detriment beyond what’s inconvenient. At the end of the day, we want to at least have a strong sense of what the benefits would be for any intervention.

That’s related to health and in the case of LDL, just being able to say, hey, I think there’s more to the story. I know might be considered a controversial position, but I think we have more than enough data to at least say that much. So do I think we can broadly state to everybody out there, hey, lowering LDL is a net benefit no matter what the circumstances?

I just don’t feel like that’s an evidence-based position. And, unfortunately, we don’t have enough evidence to say the opposite as well. Like it’s a process of discovering more and building on the existing data. We have to better understand it. 

Bret: 
Yeah. And for those with existing plaque, there can be some benefits to lowering LDL even in this population.

We obviously need more research in this population, whether it’s changing non-calcified plaque to calcified plaque or even low density non-calcified plaque or the more necrotic core type of plaque. Studies have shown in general populations that LDL reducing therapy can beneficially change the plaque characteristics.

Is that the same in this very metabolically healthy population of lean mass hyper-responders? We don’t know. But sometimes you have to make that assumption. But like you said, we absolutely, in my opinion, now have enough evidence to say, wait a second, we need to take a step back and see this differently than the general population, and understand that this is a completely different phenotype of individual.

Dave: 
And to be fair, that’s a difference between us, right? Like I’m, I am more in the role of a scientist slash engineer. I don’t have to make those determinations in the same way that you do. You’re a clinician, you’re treating patients, and therefore you’re to some degree, you have to work with the data you have on hand in your best assessment of where it stands. 

Bret: 
Right. Now, so we were, I was starting to talk about some of the limitations of the study. Because look, it’s a first of its kind study when expected to answer every question, and one of which is the lack of a control group, which you have already mentioned. So we can say, all right, there was some plaque progression on average, but what is the standard of plaque progression?

What would a control group with LDLs of 120 or 110, how would they progress? So we don’t know that answer. How do you respond to that? 

Dave: 
No, it’s a completely valid statement. it’s why the next study that we’re intending to do, we’ll have an attached control group as well.

There are many who feel that you can be metabolically healthy, have extremely low levels of LDL, and then you get the best of both worlds. That if you had our cohort with half of them randomized to some lipid lowering therapy, that there would be a difference between with regard to the progression.

And I want to be a good scientist to say anything’s possible. You just, you don’t know until you observe that. All of that said, I will say that having the match control with Miami Heart was maybe one of the best moments for me. That was a surprise in the course of this whole science journey because I didn’t know we would have that.

So even though it’s cross-sectional and it’s not actually picking up progression with regard to the incidents the appearance of plaque, I think that says a lot, at least with regard to the baseline, with regard to how it starts out. Do I speculate a lot? Sure, I do. But again, I want to be a good scientist. I want to say I’d rather get the data, however anguishing it is. However much blood we have to sweat together to make it happen.

Let’s keep the revolution going. 

Bret: 
Yeah, and referencing being a good scientist, it’s interpreting a study in a way that probably creates more questions and answers. And to address those questions, you need more studies. So you are already working on more studies. What do you hope a cardiovascular researcher would read this paper and then start to think?

Dave: 
I certainly hope that there’s just a greater awareness of how non-correlative this is for this population and how I think that should prompt some rethinking as far as at least ApoB containing lipoproteins being the driver of atherosclerosis with everybody. Is it possible that those who are in a worse metabolic state, those with severe existing disease, that it is a essential driver?

It’s possible. Part of the problem that I hope everybody’s bearing in mind, and something that I’ve said from the get go is. Unfortunately, a lot of these same diseases that associate ApoB with the outcome of atherosclerosis have a cluster of other things that impact the lipid profile. So it’s hard to disentangle that causal directionality.

I know it’s a mouthful, but basically how much can we feel confident ApoB lipoproteins are independently driving the development of plaque versus something that changes both the ApoB levels and the plaque development? It’s hard to say. We can say that, while at the same time conceding that they are a part of the process of atherosclerosis itself, but just doesn’t quite tell us enough.

It’s just like things such as inflammasome, such as C-reactive protein and so forth. It’s hard to distinguish between the arsonists and the firefighters. And that’s, we shouldn’t be afraid of that as an interesting question to tackle, we should welcome the discovery process itself.

Bret: 
Yeah. Now that is a completely reasonable statement and makes a lot of sense. And despite that, a lot of fairly reasonable, you, generally reasonable and well-meaning doctors are going to look at this and completely dismiss it and say, we know enough about LDL, this isn’t strong enough data. I’m not going to change a thing.

How do you think about people like that who are just going to dismiss it out of hand because of what they’ve thought and been told for decades? 

Dave: 
I respectfully say, rethink doing that because unfortunately, if you are looking as though you don’t want to be informed by new data that doesn’t bolster that position. What bolsters the position the best is that you’re taking into account all the data, all the spectrum.

You want to have good answers to tough questions, and I have emphasized this throughout. I’ll say it again, I believe that there’s an important difference, as I mentioned just a moment ago, with regard to these other things that affect lipid levels that are based on the disease and the lipid levels themselves driving the disease.

Now that we actually have a spectrum where we only had it on one side, now we have this other side where we’re getting a cleaner signal that’s worth examining. And even for those scientists in this space who feel that they have enough data, they don’t need to know more. They’re basically saying, I’m not as interested in this clean signal version of the data to the same degree.

And, yeah, I’ve said this a million times over, Bret. Our door is open. Whoever would like to have a real intelligent conversation about this, we welcome it because we know that’s what’s important is to continue moving this conversation forward. 

Bret: 
Yeah. Great. Great. I, as usual, you portray things with a very nuanced and reasonable voice that I think a lot of people should listen to. it’s a breath of fresh air within the scientific community and you really do deserve a lot of recognition for what you’ve accomplished and the team you’ve put together to help study this and publish it.

And on the one hand, we say it’s the end of the road for this one study. But it’s really just the beginning because you’re already doing new studies. Hopefully there’ll be many others doing new studies. It’s really just the beginning of a sort of a new era in terms of how we look at ApoB and lipidology and metabolic health and put all those together.

Thank you for your work, and where can people find out more about you and all the work you have coming down the pike? 

Dave: 
Naturally, I’ve got to pitch the coming study we have. So you could find us at cholesterol or sorry, at citizensciencefoundation.org, where you can also donate if you want to help us make this new study happen.

But we have a new site to pitch, which is cholesterolcodemovie.com. We hope a lot of people are watching this now will consider going there and signing up. We’ve got a new newsletter that we’re excited about and it’s also going to be where a lot of these updates are being dropped. So I would definitely want to suggest a lot of people go there.

The third and last one that I’ll mention is I am fairly active on Twitter slash X, realDaveFeldman, and so they could find me there as well. And yeah, I’m hoping that these next few announcements will further illuminate exactly where we’re going next with the research beyond this new study.

I have something else in the works that hopefully I’ll be, mentioning in the next few weeks. We’ll see. 

Bret: 
Great. Thanks, Dave. I want to take a brief moment to let our practitioners know about a couple of fantastic free CME courses developed in partnership with Baszucki Group by Dr. Georgia Ede and Dr. Chris Palmer.

Both of these free CME sessions provide excellent insight on incorporating metabolic therapies for mental illness into your practice. They’re approved for a MA category one credits, CNE nursing credit hours, and continuing education credits for psychologists, and they’re completely free of charge on mycme.com.

There’s a link in the description. I highly recommend you check them both out. Thanks for listening to the Metabolic Mind Podcast. If you found this episode helpful, please leave a rating and comment as we’d love to hear from you. And please click the subscribe button so you won’t miss any of our future episodes.

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