Could New Drug Lower Cholesterol in lean people on a Keto diet?

There's a new drug that could be used to treat fatty liver disease that was published in a major new study in the world's highest impact factor journal. Now here's a question: could that same fatty liver drug be used to treat very high cholesterol levels in lean people on ketogenic diets, the so-called lean mass hyper-responder phenotype? And in exploring that question, what might we learn? Welcome to my channel where we navigate the data with nuance. I am going to go over some of the results from the study mentioned and some of our own trial results, blend them, and bring forth some provocative questions. But before I do that, I want to acknowledge that I'm going to assume some background knowledge in terms of lean mass hyperresponders and the lipid energy model. So if those are terms that are completely new to you, I really do suggest you watch the links below first and then come back to this video. But with that, I'll move forward. We've recently demonstrated in our own interventional trials that free thyroid hormone, free T3, is independently predictive of elevated LDL cholesterol, the bad cholesterol in lean people on low carbohydrate diets. This is in addition to lean BMI. So we know that lean people on low carbohydrate diets, they're the ones susceptible to high LDL cholesterol when they go low carb. But in addition to that, thyroid hormone can be a predictor of— specifically free T3— a predictor of high LDL on low carbohydrate diets. And from a 50,000-foot view, this makes sense. The lipid energy model explains the lean mass hyper-responder phenotype— high LDL on low carb diets with high HDL and low triglycerides. Lipid energy model, it's all about energy flux. So wouldn't it make sense that a marker of energy metabolism, thyroid hormone, could be associated or involved. With that, I do want to take a second to provide an interpretive caution. I'm not saying that hypothyroidism, low thyroid, can completely explain the lean mass hyper-responder phenotype. Lean mass hyper-responder patients tend to be euthyroid, normal TSH, have normal or even elevated basal metabolic rates, and generally have absent clinical symptoms of hypothyroidism. So they don't have reduced body temperature, feel cold all the time, constipated, etc., etc. That said, thyroid hormone metabolism is likely involved, as some contributing feature of the lean mass hyper-responder triad, the high LDL, the high HDL, and the low triglycerides. So including the high LDL. Now, delving into the mechanism a little bit, thyroid hormone receptor, it comes in a couple flavors. The thyroid hormone receptor beta is expressed in the liver, and interestingly actually has pathways that intersect with ketosis. I'll give a couple examples. They're not particularly important, but just as examples of overlapping biology. Both ketosis and the thyroid hormone receptor beta pathway, they can converge on epigenetic regulators like histone deacetylases, HDACs. And they can also affect particular histone and DNA epigenetic motifs, things like lysine 27 trimethylation of histone 3. That's a mouthful. You don't need to know what it means. Point being, there's overlapping biology in this thyroid pathway and in the ketosis pathway. With that, let's move on to the trial. A new phase 3 trial published in the highest impact factor journal in the world, the New England Journal of Medicine, found that this new drug, it's called resmetirom, it's a liver-directed thyroid hormone receptor beta selective agonist. That means that it acts on the thyroid hormone receptor beta to activate that pathway, in particular on the liver. And it's a drug that's being used to treat fatty liver disease, or NASH. In the trial, this drug, resmetirol, resolved NASH, fatty liver, in 26 or more percent of patients depending on dose. And it also reduced LDL cholesterol by 13.6% or more depending on dose. It also affected other cardiac risk markers. Resmetirol decreased Lp, ApoC-III, and ApoB. At the 80mg dose, there were significant reductions from baseline versus placebo in Lp by 5%, in ApoC-III by 12%, and in ApoB by 14%. This is actually coming from the October Nature Medicine paper related to this drug, but nonetheless, there are improvements in a broad spectrum of markers and reductions in LDL cholesterol. With that, I do want to note, or at least highlight, that lean mass hyper-responder patients do not have fatty liver. Actually, they tend to have very low levels of liver fat and very low visceral fat, so they wouldn't really be the intended use population for this medication. In fact, in very many ways, they'd be the opposite of the phenotypic profile you generally use this drug in. However, lean mass hyperresponders do have very, very high LDL cholesterol. So I'm curious whether resmetirom would lower LDL cholesterol in lean mass hyperresponders, and if so, by how much? So if free thyroid hormone predicts LDL cholesterol in lean mass hyperresponders, lean people on ketogenic diets, if thyroid hormone impacts LDL receptor expression on the liver, which we know it does, and if liver targeting of thyroid hormone receptor beta activity, this drug, lowers LDL-C in fatty liver, would it do so in lean mass hyperresponders? And because the magnitude of LDL in LMHR is so high, Would it drop the LDL massively? It's a possibility. It's a very interesting possibility for an alternative use of the same drug for an alternative use case. But here's the rub, and here's really why I made this video. There's an alternative possibility, a provocatively alternative possibility. Could it be, maybe, maybe, that by increasing liver fat metabolism, or metabolism in the liver in general, resmetirom could, rather than lower LDL as it does in fatty liver patients, could it actually increase LDL? In lean mass hyper-responder patients. That would be like, okay, if we're saying the lipid energy model is all about energy flux and you're kind of turning up the flywheel, so to speak, with this thyroid hormone receptor beta agonist on liver metabolism, could rather than lowering LDL cholesterol, you increase VLDL export and increase VLDL turnover peripherally and increase LDL? It's actually possible. So we have these two really interesting distinct possibilities. This drug, if given to lean mass hyper-responders, could lower LDL significantly, substantially. It could smash it into the floor or it could raise it. How do we know which would be the case? The only way we would know is to test it. So thus, this findings— or this, not this findings, there haven't been findings— the findings that could arise from a hypothetical trial for this new fatty liver drug in a very different population from fatty liver, lean mass hyperresponders, could provide mechanistic insight into fat metabolism and the lipid energy model. It could, if it lowers LDL, create new creative options for LDL lowering in lean mass hyperresponders beyond carb reintroduction, be it Oreos or sweet potatoes, or standard LDL-lowering drugs like statins or PCSK9 inhibitors. So we could expand the pool of options available for patients. This trial that I'm hypothesizing in my mind that definitely hasn't happened, that I don't have the resources for, the reason I want to highlight it is the same reason I did the Oreo versus statin study, in which I showed I could lower my LDL cholesterol with Oreo cookies by a massive amount. It's because when you take an intervention, Intervention X, be it Oreos or this new drug published in the New England Journal of Medicine, and you take that intervention and you put it in an entirely different metabolic context, What results do you get? There's no way to know until you test it. And the results can be incredibly interesting, like it was for the Oreo versus statin study. And we can learn so much. In my opinion, this shouldn't be something that is polarizing or politicizing in the social media space. This just should be of interest to everyone, everyone with a mind towards nutrition, metabolism, and medicine. So I'm really excited about this new paper for probably a reason other people aren't. I hope you found this video interesting and that maybe it gave you some insight into how I think about these sort of things and why we, why we colleagues studying lean mass hyperresponders are doing what we're doing. It's really fun and really interesting to hypothesize and think about how changing metabolic context can change the way that our environment interacts with our bodies. This was a particularly nerdy one. I hope you followed along. I'd love to get your comments, your thoughts, your hypotheses. Community input, citizen science input is really valuable to us. So thanks for following along. Bye!