Game-Changing Study on Heart Health and Cholesterol: New Insights Revealed

What if I told you that having extremely high cholesterol levels doesn't always mean you're at high risk for heart disease? It sounds crazy, right? Well, data from a brand new study published by our research team has just dropped, and the results, well, they rub up against one of the biggest beliefs in modern cardiology. In this video, I'll explain what these one-of-a-kind groundbreaking new data mean and what they don't, why I'm so excited, and what's to come. But if you want my upfront opinion on whether this study could revolutionize modern cardiology, well, I do. I really do. Now let me make that case, and at the end, you can judge for yourself. Now. For context, colleagues and I have spent the last several years studying what happens to cholesterol levels in people who adopt a very low carbohydrate diet, often called ketogenic diets because they put the body into a state of ketosis. Now, most people do not see increases in cholesterol on a ketogenic diet. Many even see decreases. However, some specific people see their LDL bad cholesterol increase so high most doctors think it's inconceivable. These special individuals are termed lean mass hyperresponders because they are, as a population, generally lean and metabolically healthy, insulin sensitive. In fact, our prior meta-analysis of 41 human randomized controlled trials showed that the leaner a person is, the higher their LDL cholesterol tends to rise on a low-carbohydrate diet. This prior meta-analysis also showed that having a BMI under 25 was 5 times as powerful as being in the top quartile of saturated fat intake for predicting LDL change. So this is certainly far more interesting than a "blame the butter" story. But that's a tangent. Back to the topic at hand. In the current study, we followed 100 lean mass hyperresponders and near-lean mass hyperresponders, having a mean, an average BMI of around 22.5 kg/m² and a mean LDL cholesterol of 254 mg/dL. We followed them with coronary CT angiography., and prospectively over 1 year to see whether and to what degree plaque accumulated in their heart's arteries of these individuals with exorbitantly high LDL cholesterol. Remember, the 254, that was just the average. Now the data I'm about to report— I know the suspense is killing you, just hang in there— they build upon a prior publication where we compared the baseline coronary plaque scores of this lean mass hyper-responder population with a matched population and found in the prior report strikingly that even after having LDL cholesterol levels between 200 and 600 for almost 5 years, the lean mass hyper-responder keto folk did not exhibit any greater total plaque score compared to a matched control population, people with much, much lower LDL cholesterol. And in this prior report, we also found no association between LDL cholesterol and plaque score. But in this study that I'm talking about now, we report on the prospective data, i.e., when we follow these individuals, does plaque accumulate in their arteries? And if so, what predicts plaque accumulation? Finally, the results. The vast majority of participants exhibited no or minimal increase of coronary artery disease. And, I'm sure this will capture headlines, 6 participants showed decreases in total plaque scores over the 1 year. You heard that right, some participants appeared to show regression. That said, the median change in percent atheroma volume, which is a measure of how much of the coronary artery surface is covered in plaque was 0.8%. Pretty small number. This reflects a level of progression that is expected with aging and is comparable to that observed in other cohorts. So to be crystal clear, if you ask the question, are lean mass hyperresponders on a ketogenic diet with very high cholesterol completely protected against heart disease? The answer is no, of course not. But we must then ask, what predicts progression of plaque? Is it the LDL cholesterol or the associated biomarker ApoB? No, neither LDL cholesterol nor ApoB— I'll repeat, neither LDL cholesterol nor ApoB— were associated with plaque changes. By contrast, baseline coronary artery calcium score was positively associated—predictive of—changes in cardiovascular plaque. And I cannot overemphasize how important this is. While some people did see plaque advance, what predicted this advancement had nothing to do with cholesterol, but rather whether they had plaque at baseline. So, simply put in a phrase, in this population, plaque begets plaque, but cholesterol and ApoB does not. This finding will ruffle some feathers, maybe even the whole bird, but these are the data. Now I want to delve even deeper into what this means in a nuanced, and hopefully responsible manner. While both LDL cholesterol and ApoB are independent risk factors for atherosclerosis, the absolute risk associated with high LDL cholesterol or high ApoB is context-dependent, including consideration of the etiology, the underlying physiologic cause of the elevations in these biomarkers, LDL and ApoB, as well as interactions with other risk markers, like markers of insulin resistance. Thus, these data are consistent with the observation that high LDL and ApoB among metabolically healthy populations has a different cardiovascular risk implication than high LDL among those with metabolic dysfunction— overweight, obesity, type 2 diabetes. And it's worth emphasizing that the population at hand here lean mass hyperresponders, and near lean mass hyperresponders on a ketogenic diet, this population is distinct from any previously studied population in several critical ways. First, their elevations in LDL cholesterol and ApoB are dynamic and a result from a metabolic response to carbohydrate restriction rather than as a function of a genetic defect. These people aren't born with high LDL. It is response to carbohydrate restriction. Having to do with energy flux through the body. Also, these people are of normal healthy weight, a BMI under 25 generally, and metabolically healthy as a population rather than living with obesity, prediabetes, or type 2 diabetes, or other insulin resistance disorders. This is really important metabolic context. And again, the high LDL and ApoB in this phenotype It emerges as part of a lipid triad also inclusive of high HDL cholesterol and low triglycerides, representing a metabolic signature, a metabolic fingerprint of a distinct physiologic state having to do with fuel flux around the body. These points are worth emphasizing because unique populations require independent study to properly characterize the risk associated with their metabolic profiles. Furthermore, this is the first and only population in which LDL cholesterol is independently elevated without any clear underlying congenital genetic defect and outside the context of any other notable metabolic dysfunction. Therefore, The lean mass hyper-responder population constitutes a unique and important natural experiment for evaluating the lipid-heart hypothesis in an unprecedented manner. These data presented herein are consistent with the notion that elevated ApoB, even at extreme levels, elevated ApoB and LDL cholesterol does not drive atherosclerosis in a dose-dependent manner. In this population of metabolically healthy individuals with carbohydrate-restricted-induced elevations in LDL cholesterol and ApoB. I know that's a mouthful. Listen back to it. That is a critical, critical point. However, this doesn't mean that the lean mass hyper-responder population is without risk, and it should be emphasized that this risk includes a diversity, a heterogeneity in progression and even regression, quite astonishingly, across the population. However, again, the question that should follow is, what explains this heterogeneity in plaque progression. And here we found that LDL and ApoB exposure was not a significant predictor of changes in plaque, whereas all baseline plaque metrics, including a CAC score, were significant predictors of changes in plaque. At this time, we can only speculate about the lack of association between ApoB LDL and plaque progression, and the mechanisms driving progression in this population. Possible explanations include diet and health-related differences in lipoprotein lipid quality and changes in kinetics, insulin sensitivity, or inflammation profiles as compared to the general population. Future studies will absolutely have to be directed to assess these questions and compare these potential mechanisms. But these insights, they can facilitate personalized treatment and risk mitigation strategies based on modern, cost-effective cardiac imaging. You have questions? Get an image of your own heart. For instance, despite profound elevations in LDL cholesterol and ApoB, based on these data, lean mass hyperresponder subjects with a CAC of 0 at baseline which was a majority of participants, constitutes a low-risk group for plaque progression, even as compared to other cohorts with far, far lower LDL and ApoB. But by contrast, those subjects with elevated baseline CAC scores, possibly from a history of metabolic damage and dysfunction prior to adopting a ketogenic diet, they appear to constitute a relatively higher-risk group —even where their LDL cholesterol and ApoB are equal to their CAC0 counterparts. So again, the practical takeaway for you, for me, is don't guess about your risk profile based on your lipids, get imaging. That makes the most sense. The finding that in this study plaque begets plaque could result from underlying susceptibilities. In those with greater amounts of pre-existing plaque, or could result more directly from the pro-inflammatory state associated with the coronary artery disease pre-existing. And more research will be needed to identify the pathophysiology driving the progression of atherosclerosis in people with higher levels of baseline plaque. There's always more to the story. It's a really interesting story, if I do say so myself. But what does all this mean? Well, after following 100 people with sky-high LDL on a ketogenic diet, we found no association between LDL or ApoB and plaque buildup. Instead, baseline plaque predicted future risk, not ApoB or cholesterol levels, supporting the notion that in this population, plaque begets plaque but cholesterol and ApoB do not. And if you want my CTA— no, no, not that CTA, I mean my call to action, although my coronary CT angiogram actually does look pretty great. Anyway, my CTA, call to action, is to encourage you to share this video and the associated paper linked below widely. Share it to your social media. Link the video or paper in an original post with your take, your two cents,, and tag members of the research team—myself, Dave, Adrienne. Leave a comment. Help us push for more deep discussions that transcend diet dogma. Your contribution really does make a difference. Really. In fact, this entire clinical study was crowdfunded by you, which is a massive testament to the enthusiasm and power of the metabolic health movement. But before we part, let me just say that science is a team sport. In fact, it's only been through the tremendous collective efforts of multiple teams, including my friends Dave and Adrienne, the generosity and support of Bazooki Group and Metabolic Mind, and of course the team at UCLA in the Lundquist Institute, overseen by the principal investigator of this study and cardiac imaging expert Professor Matthew Budoff, that this this pivotal project was completed. And now I want to give you the chance to hear from my team members. So here are some words from Dave, Adrian, and Professor Budoff. Stay curious, and thanks so much.

Hi, I just wanted to highlight from a clinician's point of view why these results are so relevant. Because it can really be harmful if we are confused about what causes plaque progression in a group of patients. If we don't get this simple question right, we may chase the wrong mechanisms and implement the wrong treatments. At the same time, when we think we already found an answer, we stop looking, and this could prevent us from finding the real culprits of the problems in our body. Imagine someone who is coughing a lot, and we believe their cough is caused by an infection when in reality it's caused by an allergy. Well, We may prescribe antibiotics and expose them to the potential adverse effects of a medication that has no chance to help them at all. Ask any clinician. Not getting right your causes and your treatments for an allergy is problematic, but getting them wrong for cardiovascular disease is much, much worse. Another point I wanted to make is that we are confident about the associations we saw and equally confident about the associations we did not see. Because as you know, not because you didn't see something means it doesn't exist. Sometimes scientific studies don't see statistically meaningful differences because there was not enough statistical power. But this is not the case. We are confident that neither ApoB nor LDL were associated with plaque progression. And let me be perfectly clear about this point, because we did see plaque progression in some participants. The thing is that no matter how we sliced it, neither ApoB nor LDL explained this plaque progression. And as a teaser, let me tell you that we have another study in the making that will reinforce how it can be problematic to rely on ApoB or LDL for assessing cardiovascular risk in patients with an LMA phenotype. I also wanted to highlight that the only thing we saw predicts plaque progression is how much plaque there was in the first place. And this is clinically relevant because it emphasizes how important it is to assess cardiovascular risk in patients with an LMA phenotype using modern imaging tools. Finally, I just wanted to say how cool it is that a group of curious patients and citizen scientists found Demings and paid in blood for very clinically relevant insights. To everyone who made this study possible, thank you and congratulations. Stay tuned because, as happens frequently in science, the process of answering a question brings more questions to answer, and the amazing data that has already been collected has much more to give. Stay tuned.

Starting with an idea from a crazy engineer, bolstered by a one-of-a-kind crowdfunded study, and finally rocket-powered by a passionate team of innovators, we finally reached the finish line. If you followed me from the beginning, you know how long I had been asking, even begging, conventional researchers to study lean mass hyperresponders. And indeed, this phenotype I identified 8 years ago continues to defy expectations. Now these new data support it is defying the largest one of all, the expectation of high risk at a population level. These new data show no correlation between coronary plaque progression and LDL cholesterol, even for those at the very highest levels. Is this the end of the discussion? No, there's still so much to do. We need to continue building on these data with our coming study, which is in development right now. But with that said, is this a giant leap forward? I think many will agree it is, especially for low-carb doctors and patients who will rely on these data to better assess individual care. Make no mistake, this victory is as grassroots as it gets, and I couldn't be happier that cameras were there to catch all the ups and downs of the study as it happened in real time for our coming documentary, The Cholesterol Code. Lastly, thank you. To every single person who contributed their time, money, and effort to share and advance this research. We, we couldn't have done it without your support.

In lean, metabolically healthy people on a ketogenic diet, neither total exposure nor changes in baseline levels of either ApoB or LDL cholesterol were associated with changes in plaque. Conversely, baseline plaque was associated with plaque progression, supporting the notion that in this population, plaque begets plaque, but ApoB does not. I think it's important for patients to know whether or not they have underlying plaque, as if they do, we might treat them differently for those patients with KD as compared to those who have clean, coronary arteries.