Peter: So it really wasn't until the mid to late eighties, probably I think 1987 if my memory serves me correctly, that the first statin came to be developed. And that was the real turning point in basically the pharmacologic tool that became valuable against ASCVD. Now the first, second and third generation statins of that era are no longer in use today because their side effect profile was very harsh relative to what we can do today. So there are currently seven statins in existence. And each of them offers some strengths and advantages over others. And they're not a benign class of drugs. So to be clear, they're an effective class of drug. They're very effective at lowering LDL cholesterol. They work by inhibiting the first committed step of cholesterol synthesis. They do that everywhere, but primarily in the liver and their response of the liver when cholesterol synthesis is being shut down, the liver says, I got to get more cholesterol in here. And what does it do? It puts a whole bunch more LDL receptors all over the liver. And that's what's primarily driving down LDL in the presence of a statin. But the side effects are what? Well, about 7% of people develop muscle aches on statins. So that's if you think about how many people are on those drugs or how many people are prescribed those drugs, that's a huge number of people. The good news is that's a completely reversible side effect. So you put a person on a statin, they experience muscle soreness, you take them off, it's gone within a week or two. The other big side effect, the one that I probably think about the most is insulin resistance. So a very small set of subset of people, about 0.4% of people put on a statin might go on to develop type two diabetes as a result of it. Now, I think any doctor who lets a patient get to the point where they get type two diabetes because of their statin hasn't been paying attention. We want to know the minute you're becoming insulin resistant in response to the statin. And those data are less clear. You don't know exactly how many people are getting insulin resistant, but this is a reason to be paying attention to bigger markers and more important markers than just hemoglobin A1C trips over the threshold of 6.5%. You have type two diabetes here. You want to be able to say, is the hemoglobin A1C moving? What's happening to the fasting insulin and glucose and these other markers? Does a patient wear a CGM? One of the reasons we like CGMs on patients when we put them on statins is we have a historical level of what their glucose control looks like. And if all of a sudden their baseline average glucose goes up by 10 milligrams per deciliter, which I've seen in patients on a statin, I know it's, you know, that's not just a quick dietary trigger, especially when you take them off the statin and it comes right back down to normal. So even though they haven't become, you know, they haven't gone to the level of being diabetic, they're clearly becoming insulin resistant. And the third thing we see with statins is a change in, or an increase in the transaminases or the liver function tests. Liver function test is a bit of a misnomer because the transaminases really tell us more about inflammation than function. So all that said, statins are still kind of, you know, they're doing the lion's share of the work in this area, but by no means should we say that that's the only thing that we have at our disposal. About 20 years ago, another drug called azetamide. Can I interrupt for a second and ask you about statins?

Rhonda: Yeah, of course. Cause I have a lot, I have some questions about them. So, and I'll never forget this conversation that again, I had with our mutual friend, Ron Krauss, because he worked down the hall. I worked down the hall from him and I collaborated with some of his postdocs and you know, they would come over and show me data and we would talk because, you know, I had a lot of experience in assaying mitochondrial function and mitochondrial biology during graduate school. And I remember saying this to Ron, I'm like, you know, so statins are affecting the HMG-CoA pathway that you mentioned, the cholesterol synthesis, which also is important for the synthesis of ubiquinol, right? This is an important or co-Q10 as I should probably call it. This is important for mitochondrial function. I mean, it's necessary for mitochondrial function, for transferring electron, electrons across the electron transport chain, which is essentially coupling the oxygen we breathe with the food that we eat to make energy. And I remember saying, oh, so statins have a side effect of targeting mitochondria. And he said to me, no, it's a direct effect. So what are your thoughts on how statins are affecting mitochondria and through this pathway? And obviously you might mention supplementation with a, you know, reduced form ubiquinol, right? Measuring mitochondrial function in terms of VO2 max, something.

Peter: So it's a great question actually. And something I have thought a lot about. So the literature has nothing to offer here, unfortunately. So I wish I could say, you know, Rhonda, the answer is this because here's what the literature says. Here's what I can tell you. And this is not going to be a satisfying answer. If there is an impact on mitochondrial function with statin use, it's very small based on what I consider to be the single best measurement we have to measure mitochondrial function, which is zone two testing with lactate production. So I know you know what this is because we talk about this stuff all day long, but just for folks listening this requires a little bit of explanation, but it's very important. And I think it's, I'm glad you brought this up. So everybody understands what the mitochondria do. If they're, if they're, you know, listeners of your podcast, we don't need to explain the mitochondria, but it's important to understand that a functional test is a very important test in medicine. We don't have many functional tests, right? Most of the things we talk about are biomarkers and by themselves, they don't tell you a huge amount of information. They tend to be quite static and not dynamic, but we understand that the healthier an individual is, the more they can rely on their mitochondria for ATP generation under increasing demands of the cell. This is one of the hallmarks of health. And by extension, one of the hallmarks of aging and one of the hallmarks of disease is an inability to do that. Meaning as the ATP demand on a cell goes up, there is an earlier and earlier shift to glycolysis as opposed to oxidative phosphorylation. So how do we, how can we measure that clinically? Well, we can put a person in because we can't, you know, rather than test a cell, let's test the whole organism, right? So we put a person in sort of an ergometer, right? So on a treadmill or on a bike or under some sort of demand where we can control the work that they have to do and we can drive up the amount of work they do while sampling lactate. And why does that, what does that tell us? Well, just to remind everybody, you know, glucose enters a cell and it basically has two fates, right? So glucose will be converted into pyruvate regardless. It has the fate at which oxygen is plentiful and the body has the time to make a lot of ATP where it goes into the mitochondria and it has the less efficient, but quicker way to get ATP, which is converting lactate, pardon me, pyruvate into lactate. So this is the glycolytic pathway versus the oxidative phosphorylatic pathway. The longer a cell can stay in that mitochondrial space, the better it is. It makes way more ATP and it accumulates less lactate and hydrogen ion. And the more lactate and hydrogen ion you accumulate, eventually the cell becomes effectively poisoned by that hydrogen ion and it becomes very difficult for a muscular cell to contract. So we use this test with patients. This is one of the most important metrics we care about. Literally it would be in the top 10 things we care about for our patients, which is how many Watts can you produce on a bike or how many Mets can you exercise at on a treadmill or whatever vehicle you're using while keeping lactate below about two millimole. Two millimole is about the threshold beyond which you are now shifting away from the maximum capacity of the mitochondria to, to undergo this process. Okay. All of this is to say I have clearly seen the effect of a drug like metformin at impacting that. Metformin, which is a mitochondrial toxin, right? Metformin impairs complex one of the mitochondria. We immediately see a change in the lactate performance curve of an individual on metformin. We see a complete reduction in their zone two output. They hit that lactate of two much sooner. We also see an increase, not big, but significant, meaning clinically significant in their fasting resting lactate level. So all things equal, their lactate is just getting higher. To me, by the way, I don't know if that's necessarily harmful. I don't think it's a good idea, which is why I don't believe in metformin as a geroprotective agent. I think metformin is a good drug for someone who's diabetic if they can't exercise enough and they can't get into energy balance. Um, but I don't think metformin is a great drug for someone like you or someone like me. We don't see this with statins. So if it's happening, dose dependent or no, just don't see it. Yeah. Just don't, just don't see it. So it could be happening, but we don't have the resolution to measure it. So that's why I'm saying like, I think one always has to have the humility, which I hope I have to say, look, I don't know. But what I do know is if there's an effect there, it's, it's really small. Now you mentioned ubiquinol or CoQ10. Um, and there are two states of it ubiquinol and ubiquinone, but ubiquinol would be the state we would want to consider here. There have been a number of clinical trials looked looking at using or supplementing ubiquinol with patients taking statins. They have mostly done this to assess, uh, the muscle soreness issue. So they've mostly done this as a way to ask the question, can you reduce the insolence, the, the incidence rather of muscle soreness with statins? I haven't looked at those literature in a couple of years. The last I looked at them, there was still no difference. Um, that said, we have patients that really feel strongly about taking ubiquinol when they're on a statin and I don't have any issue with that. I, I, I don't think there's any harm in taking it. I really don't think there is. Um, and if there's a chance of benefit, then I would say let's take it. But again, I, I, unless something has happened in the last couple of years that I'm unaware of, I don't think we have great data that ubiquinol offsets that. And more importantly, to your point, it's not clear to me that that effect translates to a functional deficit in the mitochondria.

Rhonda: When you're measuring, so, uh, the, the, using the zone to, you know, lactate threshold training to kind of measure mitochondrial function. Um, how, so buying the lactate meter Nova diagnostic, Nova biomedical or something like that.

Peter: It's like a yellow purple one.

Rhonda: I got it per your like recommendation, but, uh, for people listening, uh, if they want to, to get one, but also knowing like how, you know, because there's, when you, when you go to like any sort of, if you were to go talk to an exercise physiologist and you say lactate threshold, like they kind of know.

Peter: They're going to push you up. They're going to lactate threshold is a different number.

Rhonda: Right? So this is like lower level. This is lower. So, um, how do people know, like, like let's say they have a Peloton at home and they get on their Peloton and they want to do a zone two test. Okay. Do you, can you somehow use a, you know, percent max rate, a heart rate, sorry, max heart rate, uh, like proxy to kind of know, like,

Peter: yeah, there are lots of different ways to estimate this. And to be clear, like I'm one of the very few people that is checking his lactate every, you know, every day that he's on his bike, which is four days a week for me. And by the way, I'm also doing it while using all the other metrics that I'll explain in a moment, mostly just in an ever never ending quest to just have as much data as possible to understand when is lactate the best predictor? When was RPE the best predictor? When was heart rate the best predictor? When was absolute wattage the best predictor? Like there's a lot of stuff going on here. So first thing I always say to people, namely my patients, when they say, I don't want to get that lactate meter. I don't want to be poking myself in the finger. I'm like, great, don't, you don't have to. There are like other ways that you can pretty much approximate your zone two output. And the only reason I brought up the whole lactate testing is it is the gold standard and it is the most objective way to do this. And therefore, if I'm trying to really understand the impact of say metformin or a statin, that's what I want to do. But let's put that aside for a moment and answer the relevant question, which is, hey, how does someone exercise in this zone? I think the most important tool for virtually anybody is rate of perceived exertion. I think that will almost never let you down. In fact, I would argue that for a really, really out of shape individual, rate of perceived exertion is even better than lactate. And the reason for that is you take somebody who's got, for example, type two diabetes, their resting lactate may already be at two. So in those patients, we actually never use lactate until you get somebody to a certain level of fitness. We only use rate of perceived exertion and we will provide heart rate guidance. So here's two ways to think about it. RPE, rate of perceived exertion, we give people the test, which is the talk test. So when you are in zone two, you should be able to speak to somebody, but it should be uncomfortable and not something you want to do. If you can't speak, you're out of zone two. If it's really, if you can't speak in a full sentence, you're not in zone two anymore. You're, you're, you're North of zone two. If you can speak the way you and I are speaking now, you're, you're not working hard enough. You're too far below it. So there is that sweet spot where if you're on that Peloton and the phone rings and you answer it, the person knows you're exercising and you're going to let them do most of the talking. But if they ask you a question and you have to answer it, you'll, you'll answer it and you can speak in a full sentence, but you're not that comfortable. That's the single most important thing people need to understand about it. As far as what heart rate guidance comes with it, Phil Maffetone uses a test that I think is a pretty good starting place, which is 180 minus your age. Now, the fitter you are, the less relevant that becomes. So I'm 51, so that would put me at one 30, but I can tell you my zone two is above one 30. So if you're fitter, you may add five to 10 to that. I, uh, my, my, I use another app that checks my HRV every single morning and it predicts my zone two as a result of my HRV. And so every day what I'm doing is I'm looking at the heart rate predicted by the app, which can vary by as much as 10 beats per minute based on how much I slept, the quality of my sleep, how sore I am, a subjective measurement of how much I want to train that day and my HRV. So it, it's a, it's called Morpheus. Yeah. Um, so I have no affiliation with or anything like that. So, so basically this morning I got up, my HRV was, I don't even remember, 78 milliseconds, slept seven hours, 15 minutes, good quality sleep, not sore, felt good. So I actually had a pretty high target today. My target today was 141 was the heart rate on a day. That's about as high as it will predict me to be on a, on a day when everything sucks. It might tell me as low as 129. Usually it's about 136, 137, 138 is where it's predicting. And that's generally aligning with where my lactate is, where what that'll generally put me in a lactate about 1.9. Um, and then on top of that, I'm paying attention to the wattage. So I kind of know where to be. But again, for somebody just starting out, RPE is all you need to know, 180 minus your age is good. And then the, if a person is fit enough that they truly know their maximum heart rate, we tell them to start at somewhere between 75 and 80% of that number.

Rhonda: Great recommendations. If so, if a person is specifically trying to do this functional mitochondrial test, how long should they be in that zone 2, before they can measure their lactate?

Peter: We like to see people there for 30 to 45 minutes before we do it. Yeah. So a true, true steady state.

Rhonda: Awesome. Um, so I kind of want to, the, the other, going back, circling back to the statins and, um, here's, here, here's my question to you. Okay. What questions do you think I should be asking and looking in the literature to convince myself that, let's say a lipophilic statin that could, uh, you know, cross the blood brain barrier, get into the brain, inhibit, you know, HMGCoA in the brain, um, particularly at higher doses. Uh, but generally speaking, what can, what questions should I be asking myself to convince myself that it's not going to put me at a higher risk for both of the neurodegenerative disease that I'm terrified about? Uh, one Alzheimer's disease, I have a genetic, it's family history, genetic risk factor and Parkinson's disease, family history. Um, both of those diseases have been associated with statin use. They've also been, it, the, the literature, as you know, is, you know, you can find what you want, right? So do you have any, you know, advice for me?

Peter: Yeah, I did, I did a recent AMA on this. Um, although it might not be out yet. I lose track of when I record them and when they come out. So I apologize if it hasn't come out yet. Um, but I did an entire AMA on this topic because it is so, uh, important. And I think it's, as you said, it's, it's so confusing. Um, so I was actually surprised to learn this. Um, I was surprised to learn that there has never, I shouldn't have been surprised, but forgot this, here's what it is. There has never been a study done that has looked at the use of statins and the incidence of Alzheimer's disease or dementia as a primary outcome. Why is that important? It's important because in clinical research, the primary outcome is the only thing you can really take to the bank because that's what the study is powered to detect. There are more than a dozen, probably less than 25. So a big number of studies call it 15, 16 that have used statins have had a primary outcome of ASCVD, but a secondary outcome of dementia or Alzheimer's disease. And I looked at every single one of those. And I can tell you that every single one of those found neutral to benefit of statin use on the incidence of dementia and the incidence of, um, Alzheimer's disease. So that includes vascular dementia.

Rhonda: Vascular health is, I mean, I, that sort of makes more sense. Yeah. Parkinson's disease. Have you seen, have you looked at the literature on that?

Peter: So Parkinson's is a little bit more confusing because the literature is way more sparse. Um, but I do want to go back and talk about Alzheimer's disease because I think there's an important caveat to everything I just said. What I basically, Oh, the other point I want to make Rhonda, this actually surprised me. There was no difference between, uh, hydrophobic and hydrophilic statins. With respect to the. To these outcomes. Okay. So counterintuitive, um, but no difference whatsoever. Um, so even though, again, you might think, well, gosh, you know, a statin that gets in the brain should have more of an impact, but it didn't, it didn't seem to have.

Rhonda: Is there a difference in those two types of statins with respect to the diabetes, uh, increased, uh, diabetes risk that you're talking about? Or is that not enough?

Peter: Uh, that's a really good question. I, I didn't look at that in, and that wasn't looked at in this. Or maybe it's not. Yeah. That's what I can tell you. The highest incidence of diabetes is probably with atorvastatin. Um, but that might also be because atorvastatin is the most widely used. Like I don't, we, we basically, first of all, there's only four statins that I think are even worth prescribing these days, maybe only three. And I treat them all equally in terms of risk. In other words, I would assume anytime you put somebody on a stat and you should be looking for any of the side effects. And I don't particularly, because again, at the, you might say at the population level, it's different, but at the individual level, who cares? You, it's, it's either one or zero, you're going to get it or you're not. What's what statins are those? What three? The ones that we would prescribe would be rosuvastatin or Crestor, uh, Crestor, atorvastatin or Lipitor, uh, pitavastatin, Livalo, and sometimes we use pravastatin or Pravachol, but pretty rarely. Uh, but so, so usually those, those would be a big four. Now, here's what, um, I would say, and, um, this is something that we spend an awful lot of time looking at in our practice. And actually just last week, Tom Dayspring, um, gave us an internal presentation that was so incredible. Um, it was months in the making, uh, looking at the relationship between statin use and desmosterol levels and dementia risk. So you may recall a moment ago, I mentioned desmosterol. So desmosterol is, well, let's back up. Remember how I said there were two cholesterol synthesis pathways? Well, in the CNS really only you have one pathway and it's the pathway that goes through desmosterol to cholesterol. So desmosterol levels are actually a decent proxy for brain cholesterol synthesis. Lathosterol, which is the penultimate molecule in the other pathway, is more of a proxy for peripheral cholesterol synthesis.

Rhonda: Are these measured, you can measure these on a, like...

Peter: They're very difficult to measure in most labs. We use a lab that measures them. So we measure desmosterol and lathosterol in every patient with every blood draw. Unfortunately, this is not standard of care. Most labs can't measure this. Boston Heart does this. That's why we use Boston Heart. There are enough data suggesting that if desmosterol levels are very low, the risk of AD does indeed go up and the risk of dementia beyond AD goes up. So this is, you know, kind of what I would describe as personalized medicine slash medicine 3.0 at its finest, which is you have to treat every patient individually and we're doubly careful in patients with an APOE4 gene and or a family history. And in those patients, based on the literature, and I'd be happy to send you Tom's presentation. He would not have a hard time with me sharing that, even though it was kind of an internal presentation. In fact, I could share with you the recording Tom made because we recorded the internal meeting because it was so valuable. But basically the cutoff we use is 0.8. So if desmosterol falls below 0.8 milligrams per deciliter, we think the risk of dementia is sufficiently high enough that we would abort the use of the statin.

Rhonda: Very good information. And you think there is a correlation with APOE status on that?

Peter: No one has done that study yet. In your clinical. But in our clinical practice, we just decided like, why would we take the risk? But yes, no one has done the study to show our desmosterol levels lower in APOE4 individuals. That's actually a very testable hypothesis and it makes a lot of sense because we know APOE is heavily involved in cholesterol activity in the brain. And so it wouldn't be surprising to me if, you know, if you put people into three buckets, zero alleles, one allele, or two alleles, E4 alleles, and then just looked at desmosterol levels, like that would be a very easy, mindless study to do. Just a survey, like just a quick, is there a correlation? Yes or no? So that's one thing I'd love to know the answer to. But even absent that knowledge, our view is there's simply no reason to take the risk. You know, earlier I said it makes no sense to go on some crazy obscure diet that has a whole bunch of unintensive consequences just to control your lipids. Well, I would make the exact same statement here. It makes no sense to get all, to take unnecessary risks with statins in a higher risk individual when we have these other tools. We have, as we talked about, or we will talk about, ezetimibe, PCSK9 inhibitors, bempedoic acid. These are unbelievable tools that have no bearing on brain cholesterol synthesis.

Rhonda: But Peter, aren't people that have an ApoE4 allele more likely to be prescribed statins based on their LDL particle number by their physician? Because a physician doesn't look at their, none of this. This isn't personalized. It's not medicine 3.0, right?

Peter: That's right. Yep. No, it's very frustrating. And it's also frustrating that of those three drugs that are an alternative to statins, two of them are still very expensive.

Rhonda: Okay. So the three drugs, I know the PCSK9 inhibitor. Yep.

Peter: Highly effective, insanely safe, zero side effects, cheaper than when they came out. So they were approved in 2015.

Rhonda: And we have long-term data with the people walking around with a natural mutation, right?

Peter: Just amazing. Yeah, exactly. We have the natural experiment. We have all of the data from these drugs. And these drugs have been tested in really good trials, and they've gone head to head with every drug, and they always win, and there's no side effects. But they're expensive, right? It's a $500 a month drug in the United States. It's cheaper outside of this country, so everything's better out of the US when it comes to drug pricing. But in the US, you're talking about 500 bucks a month for that drug if it's not covered by your insurance company. Right.

Rhonda: And if you can get a doctor to say, I'm going to prescribe it to you. I mean, like...

Peter: I mean, at this point, a doctor who's not willing to prescribe a PCSK9 inhibitor just is a fool. So it's just a question of the cost. Because unfortunately, most insurance companies will not cover it unless you meet certain criteria, such as having familial hypercholesterolemia, or having already had a cardiac event, like a heart attack, and not being able to tolerate a statin.

Rhonda: Oh, what about myopathy? Like if you have muscle?

Peter: Yes, significant myopathy on multiple statins, but you'd also have to be at high enough risk to justify it. So insurance companies are gonna go out of their way to not pay for this. Okay. Then you have ezetimibe. Now, ezetimibe is relatively inexpensive. It's just not as potent. So ezetimibe also effectively serves to increase the LDL receptors on the liver, but it does so by impairing cholesterol reabsorption. So it blocks one of those two transporters I was talking about in the gut, the first one. And by blocking that, the body is absorbing way less of its own cholesterol, and the liver senses that, and the liver says, hey, I gotta get more cholesterol, puts more LDL receptors on, pulls it out of circulation. It's not as potent, and as a monotherapy, the only times we see really head-over-heels responses are in patients who have defective ATP-binding cassettes in their gut. And we measure that by looking at phytosterol levels. So we measure two things. One is called cytosterol. One is called compesterol. Those are phytosterols. So these are cholesterol we don't make. It's zoosterol. Pardon me, it's phytosterol, not zoosterol. And so when we measure those levels, we know that it speaks to how much plant sterol is being absorbed and not being excreted. And so when patients have really, really high levels of phytosterols, you know they have a defective ATP-binding cassette, and those patients respond really well to ezetimibe. It's like a blockbuster in those people.

Rhonda: Wow, is that a common single-nucleotide polymorphism that we have, or?

Peter: You know, it depends how extreme it is. So it's not uncommon to see people who are above the 90th percentile, but I've only seen like probably three people that have a level that is so high you'd actually be concerned with it, just in and of itself. Meaning like the actual level, because phytosterols are actually more atherogenic than cholesterol.

Rhonda: And that's also like Boston Heart would measure all these phytosterols.

Peter: Yep.

Rhonda: Okay. They're more atherogenic than cholesterol.

Peter: Yeah. They're more prone to oxidation, more inflammatory.

Rhonda: Are they being carried in lipoproteins? They're, so are they oxidized? They're more oxidized?

Peter: They're more oxidizable. And this is, by the way, is a reason that we don't favor the practice of using phytosterols to lower cholesterol. So there are a lot of sort of over-the-counter treatments where people use phytosterols to lower their cholesterol, and it does. So if you ingest a ton of phytosterols, you will out-compete cholesterol at that enterocyte, and your body will regulate, and you'll end up net reabsorbing less total cholesterol. The problem with that is if you have a defective ATP binding cassette, which again, it's not that uncommon that you do, you will end up really absorbing a lot of those phytosterols. And again, they can, so this is sort of an example of that desmosterol point earlier where you can lower cholesterol, but if you're really raising desmosterol too much, it can be more atherogenic than cholesterol in the first place. So desmosterol has shown up twice today. It showed up in a good sense and in a bad sense. So too much of it, if you're using a drug that blocks the enzyme that comes after it, that was the thing that was producing too much atherosclerosis in the 60s. Too little of it could be a marker of too little cholesterol synthesis in the brain, and that can be a whole problem in and of itself. The final drug, so we can just wrap this up because I'm sure the listeners are tired of hearing about this stuff, is a drug called bempedoic acid. It is a pro-drug, so it's a very elegant drug. It's taken as a pill, but it's ineffective until it's metabolized by the liver, and in the liver, it then inhibits cholesterol synthesis. What makes this drug special is unlike statins, this drug only works in the liver. So statins work throughout the body. They do most of their work in the liver, but technically every cell is impacted by a statin. Only hepatocytes are impacted by bempedoic acid. And it lowers ApoB. Same way, lowers cholesterol synthesis, liver says, I need more cholesterol, puts more LDL receptors up, pulls more LDL in, LDL and cholesterol go down, but no side effects. No type two diabetes risk. Nothing, nothing, it's just, it's only acting in the liver. Well, that sounds... Same problem as PCSK9 inhibitor, it's a $500 a month drug.