44: Drugs for Cardiovascular Health with Dr. Ben Bikman

Welcome to this week's episode of the Metabolic Classroom. Thank you for tuning in today. As usual, I am your host or teacher or professor. I'm Professor Ben Bickman and I am going to be taking us through the lesson, if you will, for the day in this week's Metabolic Classroom. The topic for the day is the final in this four part series discussing the most commonly used cardiometabolic and weight loss drugs. That's been the theme for the previous four episodes, this one included. I some I put this one at the end in part because of the controversy that surrounds it. It's one thing to criticize weight loss drugs, it's one thing to criticize diabetes drugs. It's an entirely extra or other matter to criticize cardiovascular drugs. The reasons for this are myriad I would imagine. But the two that come to my mind are the fact that heart disease is the leading killer. So more people die from heart disease than any other chronic disease. And then second, it's the one with the strongest advocates with regards to the drug use. When you start commenting on pharmacology or the use of drug therapies for disease, this is the one that just elicits the strongest reaction. So I have come to this topic carefully now. There are a lot of drugs, not surprising give that have been marketed or presented to improve heart disease. That again, isn't overly surprising given the statistics where this is the disease that most people are dying from. So again, let's get into just the most common. This is always overview level stuff, always intended to be very accessible and usable information that you can not only digest on your own and use it to have your own conversations or make informed decisions, but also share information with others. As we get into these specific drugs, there really are two broad categories for these drugs, namely those that address blood pressure and those that control cholesterol. Now the blood pressure side is the justification for that is that high blood pressure appears to be one of the most consistent variables that goes along with people who have a heart attack and, and even heart disease itself, as I've been invoking, that term is a very broad term. There is a lot that goes into that, including just hypertension itself, just considered part of heart disease. But usually there's the hard outcome being did you have an infarction or a heart attack? In other words. So blood pressure is thought to be relevant because of this idea that as you have a higher blood pressure and you are pushing against the blood vessel wall, you know, it's like you are over inflating a balloon. You can create this stress and even tears and damage to the inner lining or the endothelium. And that's an important term to be familiar with, that inner lining of the blood vessel wall. That term is important because that's thought to be, you know, that is the first layer of the blood vessel. And then anything that's creating the, the plaque, the dreaded plaque that we'll come back to when we start talking more about cholesterol. Well, in fact, in just a moment, just to tee things up, a lot of it has to get through the endothelium. So the damage is starting at the level of the endothelium. And then you would have stuff accumulating in the deeper layers of the blood vessel wall, in particular in the arteries of the heart, the arteries that feed the heart. It's when those arteries are blocked that we have the dreaded heart attack. All right, so the first class of drug, as I mentioned, is to control blood pressure. And the second one is to control cholesterol. And this is deeply controversial because even the very idea of controlling cholesterol assumes that cholesterol is simply a villain, that it is purely a villain in this story of why we are dying from heart disease, why it's the leading killer. It's all to be blamed on cholesterol. Thus, cholesterol levels must be pushed as low as possible. So no surprise that we will talk about a couple drug classes that fall into that anti cholesterol production category. All right, now let's start with drugs that control cholesterol, blood pressure. Now, as I get into these, I've made an effort, not surprising, giving, given my background and my focus, to highlight the effects, the specific effects that these, that these drugs may have on insulin resistance and mitochondrial bioenergetics. So in particular, again, I've wanted to focus on the degree to which these drugs may improve or exacerbate, make worse insulin resistance. Now that is very relevant because insulin resistance is one of the, if not the most common and strongest risk factor for heart disease. So if there is someone citing justification for the use of these drugs as a preventative mechanism or intervention for heart disease, but they increase the risk of insulin resistance, you can see that there's obviously a, a conflict here. And as goes with all of these drugs, we need to just appreciate the inherent limitations with these studies, that it is very difficult to the point of often impossible. It is really impossible to perfectly conduct these studies. You just simply cannot perfectly control the environment of a human, let alone hundreds or thousands of humans, to account for every variable going on in their life, you may know they were on the drug, you may know who was dying from what. But even then there's some subjectivity as to, and even unknowns as to what actually killed the person. So there, all of these are very big, long studies. It's difficult, it's expensive to actually track people for decades. How do you know whether they're taking medications? How have you perfectly accounted for all of the other changes in their life with regards to their diet or their exercise or their sleep or their alcohol consumption or their tobacco consumption? All of that is just based on questionnaires, it's surveys, and they're deeply flawed. So for me, as a basic scientist, as a guy who actually does experiments in my lab, and I do one thing and I see the effect of that one thing, I can't help but look at all of these kinds of studies with a tremendous degree of cynicism and even a little disrespect, if you will. If you'll allow me. All right, so let's get started then. So the first several drugs we're going to mention are all related to blood pressure changes. The first four we're going to go over beta blockers, ACE inhibitors, calcium channel blockers and diuretics. And then we'll get into two of the more common families of anti cholesterol medications. So the first one is the beta blockers. Now, that class of drug automatically invites us to consider the nervous system and in particular the sympathetic nervous system. You've heard of the sympathetic nervous system and it is often aptly so described as the flight, the fight or flight mechanism or system within the body. One of the effects of the sympathetic nervous system is some substantial changes of hemodynamics or the way the body is handling or moving blood. And it makes sense if this is the part of the nervous system that is helping us defend ourselves or flee from danger or react to a situation. One of the things we would want would be to move blood more rapidly through the body. By moving the blood more rapidly, we are able to exchange metabolites at cells. We are able to feed oxygen and take away metabolites and waste products like CO2 to enable the body to react and to continue to react as long as needed, as long as this stimulus lasts that turned this nervous system on. With that in mind and the need for more rapid movement of blood, it wouldn't surprise you to learn that when the sympathetic nervous system is. We have within the cardiovascular system a combination of events that collectively result in blood pressure Going up quite a bit. This includes not only the heart beating harder and faster, but it also includes the blood vessels, the systemic blood vessels. So the blood vessels that are going throughout the body, like for example, to our muscles, they constrict. And as they get narrower, it does facilitate the blood moving faster. But of course, there is a much higher blood pressure from this. Now, the term beta blocker refers to some specific receptors throughout the body that mediate all of what I've just been talking about. The heart rate beating harder and faster, the blood vessels constricting. The beta receptors are these cell receptors that are responding to epinephrine, or also known as adrenaline, and that is the ultimate hormone of the sympathetic nervous response, epinephrine. And as they bind and activate these beta receptors, we have this systemic response with regards to the cardiovascular system, all in an effort to move blood more quickly. Now, however, this is something that could theoretically be turned on a little too high chronically in someone who suffers from high blood pressure. Now, as a brief aside, but relevant to insulin resistance when, when the body is insulin resistant, it increases epinephrine, it is activating the sympathetic nervous system. This is one of the reasons why I'm such an advocate of not going to bed just having spiked your glucose and insulin because you're turning on your sympathetic nervous system. And of all the times you want your heart to be racing, it's not when you're trying to go to bed. So that again, becomes relevant with regards to the drugs that make insulin resistance a little worse. Now, the most common beta blockers, they're going to end in a, the, the drug family. The name names of the drugs here are going to end with an ol. They're going to have that suffix like metoprolol or atenolol. Anything that has an allol at the ending is generally going to be in this beta blocker family. Some of the more general side effects can be fatigue, sleep disturbances, not surprising a little bit here, depressive symptoms, but also cold extremities. As you have the narrowing of the blood vessel, circulation can become a little compromised. So it wouldn't be shocking or unexpected to find that the hands and feet are a little colder than normal. Now, with regards to insulin resistance, there are studies to suggest the beta blockers can make insulin resistance worse. They can also affect insulin secretion and affect just general glucose levels. This becomes a particular problem in people with type 2 diabetes, where you already have an increased risk of heart disease. So ironically, these are going to be the very people who are often put on, on say, a beta blocker to control their blood pressure. So there isn't slight evidence of an increased risk of insulin resistance. And with regards to mitochondrial function, not much really is there. There's no evidence of damage to the mitochondria, unlike some of the other drugs we get to. So there's nothing really much to mention there. Now, you would be changing some degree of the mitochondria's burning of fat. So there may be some influence on ketogenesis, but that's some speculation on my part. All right, those are the beta blockers, a pretty common class of anti hypertensive, kind of, thus heart protective class of drug. Now the next one is called the ACE inhibitors. Ace, ace, now that's an abbreviation for angiotensin converting enzyme. And as the name implies, this is an enzyme that will take one form of angiotensin, namely angiotensin I, and convert it to angiotensin ii. Now, there's a lot going on here, even here, and then there's more that goes on later, because if you are inhibiting the conversion of angiotensin I to angiotensin ii, that has one direct effect. Because angiotensin II does have a vasoconstrictive effect, it will have its own ability to influence the constriction of the blood vessels systemically. And no surprise if you are attempting to compress, compress the blood vessel into all of its blood. The blood is, if you will, pushing back and so you have that higher pressure. But also angiotensin 2 then goes on to induce the increase in another hormone called aldosterone. So that's the downstream phenomenon that I was referring to. And aldosterone has its own effect, not so much on blood vessel constriction like angiotensin II does, but more so on forcing the kidneys to retain water to hold on to water. So with the ACE inhibitor, the person ends up reducing their blood pressure through two different mechanisms, but of course sequential. By stopping the process at one, you end up preventing two subsequent actions that would be increasing blood pressure. Again, you're blocking the vasoconstriction of angiotensin II because you're getting less angiotensin ii, and by getting less angiotensin ii, you're getting less aldosterone. And less aldosterone means the kidneys are dumping water more readily and thus you have lower blood volume. And within this closed system of the human body, if you have a reduction in the volume, you have a reduction in the pressure. So all of this combines to lower blood pressure pretty substantially. Now, of course, a consequence of this could be some degree of dehydration, and it could be that they end up getting dangerously high levels of potassium, because one of the consequences of futzing around or messing around with aldosterone is that you don't excrete potassium like you should. The body's holding on to too much of its potassium while selectively dumping its sodium in the water, going with the sodium. And so you may get a potentially problematic level of potassium, a condition called hyperkalemia. Not to be taken lightly, hyperkalemia can be lethal. Now, with regards to insulin sensitivity in general, there's not much to suggest that ACE inhibitors are going to hurt insulin sensitivity. And there might even be some evidence to suggest that it helps. That's. That's somewhat unclear. And in fact, similar phenomenon seen with mitochondrial function that the ACE inhibitors are generally inert. They're not really doing much to mitochondrial function. Okay, now let's move on to another antihypertensive. So another class of drug that is controlling blood pressure and that is calcium channel blockers. These are drugs like amlodipine and diltiazem. So those are not really following into falling into a consistent name of drug. And they work by preventing calcium from moving into the cells of the heart or blood vessel walls. Now, why does that matter? If you. Typically, when you think about calcium, you're only thinking about things like bone health. And appropriately, because calcium is so relevant to the matrix of the bone. However, calcium is completely essential to the normal process of muscle contraction and relaxation. Now what happens? Well, very briefly, within muscle cells, you have this phenomenon referred to as cross bridge cycling. And as I kind of try to act it out here, those of you watching this, rather than just listening to it, it. You have these molecules, these proteins within the cell. In fact, you have a lot of them. And I'm just presenting the most general version of this. You have an actin, which is like an arm. And then you have like, you know, my arm here in this action, it's something that's reaching out to grab a myosin, these long stringy filaments. And as they grab each other, they're kind of cranking, they're cranking and releasing, you know, grabbing it and pulling it and then releasing and grabbing it and pulling it and releasing. And the collective effect of this is the contraction and relax. In order for this to happen, we need to flood the cal, the cell, the muscle cell, heart, for example, and blood Vessel the, the muscle around blood vessels with calcium. To varying degrees, the same thing's happening in the muscle, although it's slightly adjusted in skeletal muscle compared to these muscles. But regardless, we need a big rush of calcium in order to induce normal contractions. If we start blocking now, now there's always not a bunch of calcium in the cell. We let the calcium. The calcium gets dumped out and pulled back out of. Dumped into the cell and then pulled back out of the cytosol or the general area of the cell. And there are particular organelles or these little substructures within the cell that are basically like little calcium bladders. They will squeeze the calcium out and suck it back in. And the calcium channel blocker is just preventing all of the calcium from getting out. And so the heart and the blood vessels can't contract as much as they would have normally. So this makes it, of course, a very obvious effect or obvious mechanism to reduce blood pressure. Now, unfortunately, you're messing with some pretty powerful stuff here. And so it's no surprise that the person can have some changes, particularly with headaches, but also some degree of edema and dizziness. Those are all fairly common general side effects. Now, specifically with regards to insulin resistance and mitochondrial function, there's not a lot there, not a lot with regards to insulin sensitivity with the mitochondrial function, there's a little bit of evidence, but it's conflicting. But by, by modulating calcium influx, the calcium channel blockers could influence insulin mitochondrial calcium levels, which would. Which would be problematic. But again, and there's a little evidence to suggest this, that the calcium channel blockers are affecting the mitochondria's ability to make ATP, which is the main work molecule that is produced by the mitochondria. But again, it's not totally clear. All right, now, just general. So as we've been talking about, some of these drugs, like the ACE inhibitors. ACE inhibitors would fall into the general family by, by increasing urine production because of the reduction in aldosterone. You would. That could fall into a class called a diuretic. Now, there is a separate kind of class of drugs that are really diuretic or also known as water pills like furosemide is one that's generally, I think, the most common one. And these simply act by basically forcing the kidneys to expel to. To dump any excess salt and water. And where the salt and the water goes, of course, you have this reduction in blood volume and then blood pressure. Now, not now. This does mess with electrolytes. Salt is an electrolyte and so it's no surprise that these can result in electrolyte imbalances and dehydration. And if the electrolyte imbalance gets too bad or too extreme, it's no surprise that you can start to get neurological problems and cramping or tremors and even the heart starting to spasm. Now this is relevant to insulin resistance. Thiazide diuretics have been associated with worsening insulin resistance and an increased risk of type 2 diabetes, particularly at the higher doses. What's interesting to note here is in a way harkening back to a point I made earlier with regards to aldosterone, one of insulin's oft overlooked effects is to control blood pressure. Now we really do. This is something I've harped on before. We do insulin a disservice by only viewing it through the lens of glucose. That is not fair. Insulin does a lot, including influencing electrolyte balance. In particular, insulin will seek to increase generally electrolytes within the blood, particularly sodium, and it does so through its actions on aldosterone production. So if insulin is, if there is a reduction in sodium, the body wants to try to correct that and, and force the kidneys to start reabsorbing sodium and not letting the sodium out. That not only will turn on, that will be the feedback will turn on the aldosterone pathway through angiotensins, but it'll also increase insulin, which further increases the activity of that particular pathway, the angiotensin aldosterone pathway. And so if you are forcing salt down in the blood, it's no surprise that one of the responses to that will be insulin going up higher. And as insulin goes up higher, as you know from previous metabolic classrooms, the body becomes ever more insulin resistant. So again, pretty clear evidence that these diuretics do cause insulin resistance directly. Mind you, brief tangent, the same thing happens with just general salt restriction. If you take people and force them onto a low salt diet, or they willingly do it as an act of self or lack of self respect or lack of appreciation for feeling good, then they will increase their own insulin resistance. This is very well documented. Now, mitochondrial function, not a lot there, not a lot there. Just as you start messing with electrolytes, you may be messing with some of the movement of electrolyte of molecules at the mitochondria, but it's pretty unclear. So we'll just pass by that one. Now that is the end of the heart disease drugs that focus or are built or designed to address blood pressure. One of the leading risk factors of heart Disease. Now let's get into the bigger one, namely cholesterol. We'll just go through two families of anti cholesterol medications. Now they act through different ways and These are the PCSK9 inhibitors and the statins. They act through different mechanisms and we'll get into each of them. But. But again, they're built on the idea that cholesterol is synonymous with heart disease. I just feel inclined to mention that as a biomedical scientist. The precise series of steps that takes a person from cholesterol, or to be more specific, ldl, the lipoprotein that is carrying cholesterol and other things, the precise series of events that takes us from LDL to plaque formation is very unclear. It is not known that this step leads to next step two, which leads to step three, which leads to step four. The general view is, which is ridiculously oversimplified and I would say very problematic and incorrect, is that you have a high level of LDL and then the LDL penetrates the blood vessel wall. Why? Who knows? Let's not ask that question. And then as the LDL penetrates the blood vessel wall, it then gets engulfed by a macrophage. Why does the macrophage do this? Well, don't ask that question. We don't know. And then the macrophages get really loaded with all of this fat from the LDL cholesterol and they become very pro inflammatory foam cells and they keep recruiting more and more macrophages and all of this begins to constitute the core of a PL plaque. And then the plaque grows and eventually occludes a coronary artery. And now the person has a heart attack. That is the general view. And yet there's significant evidence just to find one flaw in this description, that if you take an LDL particle and incubate it in a culture of of cells, incubate it with a macrophage, the macrophage will do nothing to it. This is work in fact from Nobel prize winning fellows at the University of Texas San Antonio, last names Brown and Goldstein, they're legends. They found that native or unchanged LDL elicited no effect. The macrophage ignored it completely. But the moment the LDL molecule was somehow altered, like for example, through peroxidation, which is, sometimes people refer to it as just oxidation, but I like to use the term peroxidation. Then all of a sudden the macrophage sensed the LDL as problematic and engulfed it. Now what gets peroxidized? Well, fats can get peroxidized, but not all of Them to the same degree. For example, saturated fats do not undergo peroxidation. Omega 6 polyunsaturated fats undergo peroxidation so readily that you actually have to try to mask the smell of that peroxidation, the rancidity of it when you buy a bottle of it, so called vegetable oil, more accurately called refined seed oils, like soybean oil or canola oil, et cetera, those are enriched with this omega 6 polyunsaturated fatty acid, linoleic acid. So in other words, what I'm implying here and now stating explicitly the composition of the fats within the LDL molecule itself are very, very relevant. Now, another feature here, and that actually becomes relevant in one of these drugs that we're going to discuss, another aspect to this is why the LDL is even within the wall of the blood vessel in the first place. Now, I'm not arguing that if you go in and root out a plaque, you'll find LDL particles there, but why are they there? And to explain this, let me just ask you if you were un, if you were naive, unfamiliar to the world, you were. An alien comes down, let's not address it to you, second person. Let's say an alien comes down from, from space and they see, among all of the things they observe, that anytime there is a house on fire, there's a big red truck parked out front with flashing lights. What might the alien conclude if every time they see a burning home and they see the same type of big red truck with big flashing lights out in front of it? Well, they may conclude that that big red truck is causing the fire every time. But you obviously see the problem with this because you know the cause and consequence and you know that the burning fire is actually what's bringing the big red truck with its flashing lights to the home in the first place. But it didn't start it, it's reacting to it. Now let's bring that back. Perhaps a poor metaphor to the blood vessel in the plaque and the ldl. Why is the LDL there? The assumption is it caused it. And so we have to wage war on LDL cholesterol in the form of these two drugs. That I'll get to. However, what if an alternative paradigm is that the LDL is there because of an injury to the blood vessel wall? Now, why would I say that if you were to go in and root out that plaque, yes, you could detect some ldl, but you would also find likely multiple infectious pathogens, bacteria. And so another view of plaque formation Is that it is simply an immune response, that you basically have an infection in that particular spot. It's like a scab of an infected wound. So again, there's very strong evidence to suggest that when you go into a plaque, there are numerous, often numerous infectious bacteria there. So you have an infection. Now what does that have to do with ldl? LDL is known to have the ability to bind bacteria and remove them from the blood and dump them through the liver out of the body. This is important and we see this at a, at a whole body population level. The people with the lowest LDL levels are multiple, even 10 to 20 times more likely to have serious infections, sepsis, which is a life threatening level of infection. That's because ldl, as much as we have talked about it in the context of heart disease, it is perhaps more relevant in the context of the immune system and again, its ability to bind and clear bacteria. So perhaps again, to finish this discussion and get onto the drugs, my original point, perhaps the LDL is at the plaque in order to try to remove the infectious bacteria, the pathogens, rather than causing the problem. Anyway, that's just an alternative paradigm. As we get into the interventions to wage war on ldl, perhaps we shouldn't. All right, now the neck. The first of these two classes of kind of anti LDL drugs is the PCSK9 inhibitors. This involves a handful of drugs and they typically end with the suffix qmab, like aliroqumab. If you see that suffix qmab, it's generally going to be a PCSK9 inhibitor. And they are a class of drug to lower LDL cholesterol. And the specific PCSK9 is a protein that plays a role in cholesterol metabolism. It will bind LDL receptors on the liver and by binding the LDL receptor on the liver, it forces the LDL particles to stay longer in the blood. So normally the LDL receptor on the liver will bind LDL and pull it in, removing it from the blood. That's, that's normal. Rather that's with PC SK9. That's what it wants to do. PCSK9 wants to help that receptor work, so it binds to it and promotes the degradation. Sorry, PCSK9 will promote the degradation of the receptor. And so if you have more PCSK9, you have fewer receptors and then LDL levels would be higher. If you have a PCSK9 inhibitor, you're blocking the function of the PCSK9 protein. And by inhibiting PCSK9, the drugs will increase the number of LDL receptors. So you're freeing up the LDL receptors. Now, it can do what I erroneously alluded to a moment ago, which is now it can bind the LDL and pull it in more readily, thereby lowering or enhancing the clearance of the LDL from the bloodstream. So overall LDL would go down. So it works in that regard. It is effective at lowering LDL cholesterol levels. Now, interestingly, as the, as is the case here with all the other drugs, any studies you see that report an improvement in heart disease risk, look at who they're funded by, and look at the absolute risk reduction rather than the relative risk. If they say the use of these drugs reduced the risk of heart disease or myocardial infarction by 40%, that probably means it took it from a 0.6% chance to a 0.4% chance or something like that. So it might have reached a point of statistical significance. But as my mentor taught me many, many years ago, significance is not always the same as meaningfulness. Nevertheless, that's how the drug worked. Now, the side effects with regards to insulin resistance, there's a little bit of evidence. There was a paper published in 2017 that was a meta analysis. So that's powerful because that means it's reviewed every study and it looked at the effect of the PCSK9 inhibitors versus placebo on insulin resistance, and they found or markers of that. And they found that the use of these drugs did result in a significant increase in plasma glucose and HbA1c. Now, they of course, had to emphasize that it was small, but it was statistically significant. And so we are obligated to note it, just like I noted the relative risk reduction earlier, where it's often significant. So there is evidence that it's not great, that it is making some degree of measurement of insulin resistance and diabetes risk worse. Now, unfortunately, there's also a complication with mitochondrial function. By altering mitochondrial function somewhat, it's actually these drugs appear to increase the production of reactive oxygen species, and these then are enabling the ox. The production of oxidized LDL. And so there are some reports to find that PCSK9 blocking can increase oxidized LDL levels and in, in fact, in one particular study, directly contribute to some damage to the heart muscle, the myocardium. So pretty pretty risky trade off. You're doing all of this to reduce LDL cholesterol levels, and you may be, in fact, hurting the heart muscle itself. Now, the last, the biggest one, the one with the most vested interests are the statins. These are drugs that are Easy to identify because the term of the drug will end with the word statin, like atorvastatin or simvastatin. Those are two of the most common. These drugs work by inhibiting an enzyme called HMG CoA reductase. This is an enzyme that, in fact, every cell that has. That has mitochondria, because every cell makes cholesterol. But it's mostly relevant in the liver because the liver is making cholesterol and releasing it, whereas most cells are making cholesterol and keeping it for their own use. So here we are. By inhibiting HMG CoA Reductase, this enzyme that is essential for cholesterol production, we are reducing cholesterol production. Now, PCSK9 inhibitors, you'll recall, are specific to reducing LDL levels by increasing LDL receptor expression at the liver. Statins are not the same. Statins are inhibiting just the general production of cholesterol, again mostly by the liver. Now, that results in a reduction in ldl, because as the liver is making cholesterol, it's packaging it and releasing it on vldl, which becomes ldl. And so if you're just making less of the contents of these lipoproteins, you don't need as many lipoproteins to carry the contents throughout the body, again because there are fewer or less of the content. Now, of course, these drugs are not without controversy, and that's of course, because cholesterol is an absolute essential molecule. It is a molecule of life for every cell, for every animal. You need it. Now, there's some evidence to suggest statins increase the risk of developing type 2 diabetes, particularly in women, in that it does so by affecting insulin resistance. And there's also some debate with regards to its effects on Alzheimer's disease. Some studies indicate statins lower the risk due to cholesterol lowering, while others say it increases the risk by affecting the nervous system's ability to produce cholesterol. Because cholesterol, the nervous system in the brain especially, is very fat, it's very fatty. And even the conductance of signals from brain to the rest of the body requires these fatty little molecules along neurons to conduct signals as rapidly as we need. Now, the specific side effects, they are in fact, myriad. And so just we'll end with this doozy of a drug. And I'll go a little further than I have on the other. As I already noted, there is evidence, in fact, a lot of evidence, to suggest that people on statins have a higher risk of type 2 diabetes and insulin resistance. There is a known effect at the mitochondria because among the many things we use cholesterol for, one of them is to produce a molecule called ubiquinone or coenzyme Q10. CoQ10. This is, this is something that can be taken as a supplement and very often someone who's on a statin will, will take this and to try to offset this negative effect. But CoQ10 will carry the electrons across the electron transport system, which is the kind business part of the mitochondria. And it's the end result of which is being the production of ATP that I mentioned earlier. As you affect ubiquinone production, you're blocking the ability to move the electrons and you can, that can result in greater oxidative stress. And in these mitochondria, reliant tissues like nerves and muscles, it can compromise their ability to work. So it might be this mitochondrial specific damage by reducing CoQ10 that results in one of the more common side effects, which is the muscle pain. Also there was a new paper just published weeks ago finding that statin use significantly, it was like by half, reduces GLP1 levels. Now that's relevant because of all of the weight loss drugs that are focused on GLP1. But GLP1 does have favorable metabolic effects like inhibiting glucagon to reduce blood glucose and delaying gastric emptying to help with satiety and reducing hunger. Also, it's not a surprise insofar as statins wage war on cholesterol, anything else that comes from cholesterol is reduced. Like all of the sex hormones, all of the sex hormones are built on a cholesterol. This, this nucleus molecule, this what's called a steroid nucleus, it's built from cholesterol. And if you can't make much cholesterol, you can't make sex hormones. So no surprise to find that there are consequences in men and women with regards to fertil or even libido. Now my final comment about cholesterol is simply to poke a hole in the whole idea that we need to attack it. There are multiple population wide studies that have been published over the years, including one that was just published a few months ago, a very, very good one based out of Sweden that meticulously followed people for 35 years. This study found the same thing, which is that one of the features of the longest lived people is that they have the highest cholesterol levels, highest total cholesterol, that includes ldl. And so right here I have pulled up the findings of this study that was just published in September 2023. The title of the study is Blood Biomarker Profiles and Exceptional Longevity. That's the first part of the title. So if you just use that and do a search for it, you'll find it. Blood Biomarker Profiles and Exceptional Longevity. And in the abstract they say, and I quote, higher levels of total cholesterol and iron and lower levels of glucose, creatinine, uric acid, and then some other markers of liver health were associated with reaching 100 years. So isn't that interesting, they say that higher levels of total cholesterol was associated with living exceptionally long and lower levels of glucose. In other words, some sign of insulin resistance and prediabetes. And this is again reflected or identified in many studies. Looking at the longest lived people, one of the most consistent themes is they have some degree of insulin sensitivity, if it's been measured, high insulin sensitivity, and they have high cholesterol. Just something to keep in mind as we are told often that cholesterol is the. Is the enemy and we need to address it as much as possible and lower it as much as possible. Now I am. Thank you for listening. Thank you for tuning in. That is the end of the metabolic classroom itself. The lesson part. Now let's, let's transition to the Q A for those who were joining me live. We've got a lot of great questions here and let's get into them. And remember, of course, I'm just your friendly neighborhood professor and scientist. I'm not your clinician and I'm not a cardiologist. So I'm not giving you medical advice. So thanks for always keeping that in mind. It's just my own thoughts.