Cholesterol Balance & Keto Bias

Chapters: 
00:00 The Replication Crisis & Messy Science 
02:11 Why the KETO-CTA Study Was Retracted 
03:25 Mediterranean Keto vs. Standard Keto 
06:14 Cholesterol Balance: Absorption vs. Production 
10:50 The Million-Dollar Question: What Causes Plaque? 
13:07 Small Studies & Statistical Manipulation 
15:03 Addressing Bias, Personalities, and Grifters 
16:56 My Position on ApoB and Personalized Care

In this video, I dive into the "spicy" comments from my recent keto reaction video to address the complexities of heart health, the reality of the scientific replication crisis, and the nuances of personalized medicine. We discuss why a major keto study was retracted, how to think about cholesterol absorption vs. production, and why "testing, not guessing" is the only way to truly understand your own cardiovascular risk.

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Dr. Johnston is a double board-certified vascular and general surgeon in San Diego, specializing in metabolic and cardiovascular prevention. She’s the founder of CorSight Health and a passionate advocate for reimagining how medicine approaches chronic disease.
  
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Transcript

SPEAKER_00 0:00

The comments section for the keto CTA reaction video got a little spicy. We're gonna talk about it. We're gonna talk about cholesterol balance and science versus personalities. If you guys are new here, I am Dr. Lily Johnston, a board certified vascular surgeon. I also specialize in cardiometabolic prevention, so hopefully you will never need me as a surgeon. David says the amount of medical and scientific papers that have been retracted over the past few years is in the tens of thousands. Along with that, it's been found that over the past few years, a huge number of papers' data has never even been attempted to be recreated. And so if it was unable to be replicated, there should be a lot more retractions. Thanks, David, for reminding us that in fact science is super messy and we are in what some people have called a replication crisis, which is two parts really. One is that most of the studies, when they are tried to be replicated, people from other labs go and do the same study again, don't get the same results. That's a first part of the crisis. And the second part is, as you mentioned, most of the studies are not being done over again. And some of that is it's no longer original, there's limited funding. So this is a huge issue. And I bring this up to talk about the state of science as a whole and that we need to respect the findings from one-off studies. And you know, I present them here on this channel and I find them interesting. They are hypothesis generating, and this is always about risks and benefits, right? If the risks for a particular intervention are low, then we are more likely to experiment. But always we are trying to be data driven in our own personal approaches. So we test, we don't guess, we try to measure our own progress going forward, and we wait for a body of literature to speak to a question. And we're going to come back to this later in this video when I talk about how I feel about the keto CTA trial and the lipid hypothesis at large. But let's get to our next question. Rob says, why doesn't anyone say that it was retracted because the Clearly analysis was not blinded? Rob, thank you. Uh, this was a big oversight on my part in the comment video in the reaction video. Absolutely, this was a huge part of why the study was retracted. The authors discovered that the results provided to Clearly had metadata that were suggestive of the timing of the study. So they were unblinded to sequence, and that was a concern. We don't know for sure that it impacted the analysis, but part of a good trial is having this blinded approach. And if you have heard me talk about the CIMT results and the carotid ultrasound plaque results from the nato kinase study that was done in 2022, you understand about the concerns about blinding, right? These are measurements, uh, and ultrasound, of course, is more prone to bias because it's um the sonographer whose imaging can actually adjust both the images and the interpretation. CT is a little less prone to that. Nevertheless, it should have been blinded for sure, and it wasn't, and this is part of the retraction. Thank you for bringing that up. Okay. Frank says, Am I right in my view that a keto diet that removes the cardiovascular gamble is the correct approach? By shifting the focus toward proteins and fats that minimize APOB, you create a powerful dual benefit. You keep the metabolic shield and you avoid the cholesterol spike. In other words, a Mediterranean keto sounds like the best approach given everything I read and assemble. So this is emphasizing uh leaner meats, fish, and egg whites, but not emphasizing a lot of the animal fats and so forth. So, in general, Frank, this is a way to segue into the idea that ketogenic diets are not all the same. There are as many ways to do it as there are ways to do a vegan diet, which is to say you can have a whole lot of processed stuff or you can have a lot of unprocessed stuff. You can emphasize fruits and vegetables, you could emphasize whole grains. I mean, you we can do this a lot of different ways. Um, obviously, that was in reference to a whole food plant-based approach, not a ketogenic approach. Most of us are not doing grains on a lower carb approach. All that to say, I personally have leaned more into this kind of Mediterranean style, uh, ketogenic or low carbohydrate way of eating. That is also something that may or may not be helpful in terms of your APOB situation. I have had patients who, no matter what they do with their nutrition, don't drive APOB down. There are other people who, you know, the minute they eliminate saturated fats or the minute they eliminate animal products, their LDL drops by 50%, which is above and beyond what we typically expect for nutritional approaches. We'll talk about why this might be in one of the future comments. But safe to say, you still need to test. Don't guess. I think that's a great approach. And if it works for you in your household, in your palate, then I think it's great. It has a lot of ancillary benefits, right? We're gonna get some omega-3s from those fatty fish, we're gonna get uh some more antioxidant compounds from our vegetables, all these micronutrients, right? These are great things most of the time for most people. And your APOB might still not budge. So we just need to test, and then we have to figure out if the elevated APOB is a problem. Okay, now again, we'll come back to whether APOB should be at a certain level for everybody or not, but looking for plaque is how in my practice I tend to advise my patients about whether there is an indication to manage the APOB above and beyond a nutritional strategy. So good for you for getting into a whole food approach. And I hope that that is what's working well for you. Mr. DJ Health, what is your opinion on using the cholesterol balance test to decide if one can safely eat foods high in dietary cholesterol? I love this question. So the cholesterol balance test talks about, and this is available only from Boston Heart, and in all honesty, I don't order it most of the time in my patients, but what it does is it helps us understand through some of the metabolites of different types of sterols in the blood, is the liver overproducing cholesterol, or are we hyperabsorbing cholesterol from the gut? Because that both of those things can be true. And some people seem to have a predilection for either overproduction from the liver or hyperabsorbing from the intestine. And it turns out if you only suppress one system, for example, if you suppress hepatic production and increase hepatic recycling by using things like statins, bempadoic acid, you might increase your body might try to compensate by increasing absorption through the transporters in your intestine so that you actually don't get as much lipid lowering from your statins or your other agents that are mostly on the synthetic side as you had hoped. And this means that you might want to add something like azetamib, whose whole mission in life is to block absorption and reabsorption of cholesterol from the intestine, from the bile acids. So, uh, and there are some interesting data from Boston Hart, who runs this test about the fact that leaner women in particular tend to have much more absorption, and women who have excess body fat tend to have more synthesis. I think that is not a commonly accepted phenotype or situation, and nobody titrates or prescribes accordingly. However, it's a pretty interesting thing. And then if you are prescribing these medicines, you will notice that some people have a disproportionately large response to azetomide for um, you know, it's supposed to be maybe 15% reduction in APOB or LDLC, but there are people who actually have a very significant response to acetamide, probably because they are hyperabsorbers. So in my practice, what I tend to do is figure out do people's APOB or LDLC levels respond to reductions in saturated fat and dietary cholesterol? In general, most people can eat dietary cholesterol. It's a saturated fat that seems to be more problematic for folks. And if they don't change a huge amount, then that's one piece of data. Second piece of data is are we going to do monotherapy, either statin monotherapy or azetomide monotherapy for whatever reason? If I had my druthers in many patients, especially if I am advising people who are not necessarily as far along in their metabolic journey as one would like, including, you know, they still have issues with triglycerides or low HDL, and we're still working on things and we need a little bit of stabilization. I will really try to do very low dose statin therapy and acetamide in combination to mitigate that. And most people tolerate azetamide really well. So doing that empirically is an option, right? You measure your APOB levels, you take some azetamide alone for a while, and you see how much of a drop you get. If you get a large drop, then you are probably hyperabsorbing. And either you stay on azetamime or you reduce your intake of those foods. But the cholesterol balance test is available. I think if you want to do that, you don't want to be on any drugs, you just want to have the information, get the test and figure that out and see what happens. Again, I just want to emphasize how important your individual response is. And even though you have a cholesterol balance test that says you're a hyperabsorber, recheck your levels after you've made a change in your diet or your nutrition and make sure that you had the response that you expected. At the end of the day, the cholesterol balance test can't predict what's going to happen as you adjust your intake because we also secrete cholesterol in our bile salts and bile acids, and the body reabsorbs that. And some of that can be mitigated with things like psyllium or the soluble fibers that sort of bulk up and move that stuff through the intestine rather than allowing it contact with the transporters and getting absorbed. But you just don't know exactly what your response is going to be. So, what's the moral of this? Test, don't guess, repeat those labs after you have made an adjustment and move on from there. Mike. So the question is: if you do have plaque, what makes that plaque make you form more plaque? That is the million-dollar question. And um, it's one I like to spend my day trying to answer because, in my opinion, plaque comes from many different places. It comes from inflammation, it comes from dyslipidemia in some people, but not all. It comes from high blood pressure and altered flow dynamics and stiff arteries. It can come from homocysteine or problems with methylation, it can come from uric acid, it can come from polygenic risk issues, LP little A. We have all kinds of reasons that people form plaque, that they're not the same in everybody, toxic exposure, nicotine, tobacco. Uh, so it comes from a lot of places and figuring it out is different, I think, for each individual. But part of what I love doing in my practice is being that detective and trying to understand where is this coming from? Is this undiagnosed periodontal disease that needs to be investigated? Is this inflammation from something else, like excess visceral fat, or sometimes weird things like heavy metals or chronic infections in some people, all kinds of things. Uh, LP little A is another one that isn't checked as often as it should be. So figuring this out and trying to tailor the approach for each individual is where I think this is gonna go in the next 10 years or so. But that's a hard ask. It's a hard lift because there are so many different paths and they're not the same for everybody, and everybody wants one answer, right? We just all eat this way to have this impact, and that's the ad. I wish that were true. Uh, I hope someday this can be formalized in a way that makes it easier for the average primary physician or primary clinician to kind of step through things and help patients get there without just throwing everybody on high doses of all the same, you know, couple of meds that only really target a couple of those pathways, but not all. So my hope is someday we'll figure this out. In the meantime, you're kind of it's it's incumbent on you to ask those questions of your doctor and see if you can get closer to root cause and figure out what are the options to help stop your plaque from progressing. At David Ferry. The problem with studies which are tiny, like keto CTA, is that they are very sensitive to statistical manipulation, especially with post hoc analysis to ensure the favored conclusion can be drawn. So keto CTA is a relatively small study. It's 100 patients, which is not nothing, but it's not enormous. I will say that, you know, I don't know that these were pre-specified analyses. And yes, the smaller the sample size, the bigger the effect has to be to demonstrate a change. But if you think that there is a very strong relationship between APOB and plaque progression, then even a small study should show that with this large range of APOB concentration and this very high APOB concentration. And the, you know, issues with power have a lot to do with funding. They have a lot to do with enrollment criteria. But I appreciate the concept that a bigger trial is absolutely warranted. And this, but this is how you get a grant, right? You have to have a pilot study. You have to have some preliminary data for people to give you millions of dollars to do this at a grand scale. So we have to start somewhere. And I appreciate the effort and cost and dedication that it has taken to get 100 patients scanned twice and flying them across the country and getting the labs done. All of this took a lot. And it's it seems like a small N when you're looking at Mendelian randomization with millions of patients. But if you're looking to answer this question and get more established funding to do so, then we have to start with the pilot. So I don't blame them for going small and getting it started. It's where it's where we can start. That is what we have. And hopefully we'll get bigger trials going forward. Okay. Ricky, I was very disappointed in your analysis of the trial. I have listened before and you seem to be unbiased. However, your relationship with Zay Feldman and Nick Norwitz is getting in the way. Thought Machine can't believe a vascular surgeon is giving oxygen to corrupt charlatans like Norwitz and his fellow grifters. You know atherosclerosis begins with deposits within the arterial wall that CCATA does not see. Used for clinically significant plaque, not early plaque development induced in a single year. At Lars Olsen, Feldman is a charlatan, and you referencing him is bad news. You are not trustworthy. And George, it sounds like you are apologizing for the study author because you know him. Unsubscribe. Okay, I do know Dave Feldman. I have met Nick once, but we he would not remember that, and I don't particularly know him. Um, and Dave and I are acquaintances, but we are not friends. And I think it's important to think about this in terms of the science and not the people. That is not my quote. That was Dr. Budoff uh who said that when he was being interviewed about this study, and I'll say the same thing. Just because I know Dave does not necessarily mean that I completely support the position that he holds about the role of APOB and LDLC. You have heard me on this channel before. You know that I prescribe lipid lowering therapy for many of my patients. And I am not certain that the impact of lipids is universal. I am not convinced that there are people for whom the impact of APOB is the same as others. Um, which is to say, personalization, I think, is important, people's preferences is important, and coming in with data is how I like to manage this because I believe there is still uncertainty here. Now, coming back to the idea of one study versus a plethora of evidence, there is a lot of evidence that supports that in a general population, over time, exposure to atherogenic lipoproteins is not great. Okay. Um, I have read those papers, I have looked at that preponderance of evidence. However, I am still open to the possibility that there are some people for whom this exposure does not result in things, and that is a place to be curious. I am not saying I wouldn't offer medicine, I am not saying I wouldn't offer more intensive surveillance, uh, and I'm not saying that keto CTA has changed my practice. But I have to tell you, I have seen a large number of people who come to me with this particular phenotype who have dramatically elevated levels of APOB that happened as the result of this way of eating. It wasn't like this before, and um, they have been surveilled aggressively over time and they do not seem to be having plaque formation. Now, for those people who do come to meet with plaque, we have a long conversation about what that involves and how they want to manage it. Because I do believe that some of this plaque begets plaque situation is a local inflammatory response that may not be measurable in serum with like HSCRP. But because there is ongoing oxidation at the level of that plaque, lowering the lipoprotein burden may help keep it from progressing. This goes back to the idea that there may be a threshold. And with if we're above the threshold, it doesn't matter that much how much lipoprotein is circulating. It could be an Apo B of 100, it could be an APOB of 200. Past a certain threshold, more there's enough APOB circulating to continue to feed forward this inflammatory effect locally within that plaque. Below the threshold, we may be able to snuff that out and let that fire extinguish, for lack of a better metaphor. That is a little bit of a hypothesis on my part. I don't have a way to prove that, but that is how I offer to manage this for patients. And I don't believe that um I have a you know whole whole hog abandonment of the LDL hypothesis. I I respect what Dave has done and I like him a lot. And I think there's something to what he has to say, at least about this very specific patient population, who behave differently. It is not the same as FH, but I have not abandoned the preponderance of the evidence. And um, that's gonna make lots of people mad, right? Everybody's gonna be mad about this. I know, I get it, I'm sorry, not really. But here we are. And so I just want to emphasize that this is about the data. This is about understanding what happened and trying to remove as much emotion from this as possible because we are all biased, right? I have a bias, but it's not anti-LDLC, it's also not anti-keto. It is some personalized version that meets in the middle, and it looks a little different for every patient, which frustrates a lot of you because I don't have like one blanket recommendation. But unfortunately, that's uh that's the nature of my belief system and my practice. But everybody has bias, and the best we can do is try to acknowledge that, try to stay open-minded and um do our best to think about this from the scientific standpoint. And again, I'm not saying that I believe in the outcome necessarily. I just wanted to be clear about why the paper was retracted, because I don't think it's fair to the authors or to the scientific question to assume that it was this malfeasance or bad behavior or conspiracy, when it was in fact the authors trying, in my opinion, to be as upfront and transparent as possible with what happened in their own analysis. And if they had never retracted the paper, it would have stood and the conclusion would have remained, right? The conclusion was that Apo B didn't correlate with plaque progression in their analysis. So they didn't actually have a lot to gain by pulling the paper. Uh they had a lot to lose, as evidenced by the reaction. So, you know, all that to say, you are welcome to unfollow, unsubscribe, uh, and to believe that that my bias has colored my perspective. That's totally fair. And I appreciate you coming on to give that feedback. I hope that I have it convinced at least some of you that maybe there's um room here for all perspectives. There is room to be critical and to be skeptical, and also to be open to the idea that we don't know everything yet. Until next time. Take really good care.