In this video, Dr. Peter Attia discusses the development and use of statins as a pharmacologic tool against atherosclerotic cardiovascular disease (ASCVd). He explains that the first statin was developed in 1987 and since then, several other statins have been introduced with various strengths and advantages. While statins are effective at lowering LDL cholesterol, they have side effects such as muscle aches, insulin resistance, and changes in liver function. However, these side effects are reversible. Dr. Attia also discusses the potential impact of statins on mitochondria and the association between statin use and neurodegenerative diseases like Alzheimer’s and Parkinson’s. He suggests that more research needs to be done in these areas. Lastly, he mentions alternative drugs to statins, such as PCSK9 inhibitors, aetam, and bempedoic acid, which have shown positive effects with minimal side effects. However, cost is a major factor limiting their widespread use.
Key Insights:
- The development of statins in the late 1980s was a turning point in the pharmacologic tool against atherosclerotic cardiovascular disease (ASD).
- There are currently seven statins in existence with different strengths and advantages, but they are not without side effects.
- About 7% of statin users may develop muscle aches, but this side effect is reversible by discontinuing the medication.
- A small subset of about 4% of statin users may develop type 2 diabetes as a result of insulin resistance.
- Statins can cause changes in liver enzymes, which indicate inflammation rather than liver function.
- Studies on the relationship between statin use and Alzheimer’s disease or dementia as a primary outcome are lacking.
- There is a neutral to the beneficial relationship between statin use and the incidence of dementia and Alzheimer’s disease based on secondary outcomes in studies.
- Desmosterol (desol) levels can be a proxy for brain cholesterol synthesis, and desol levels below 0.8 mg/dL may increase the risk of dementia.
- Phytosterols, a marker for defective cholesterol transporters, can affect the response to certain statins.
- Other alternative drugs to statins include PCSK9 inhibitors, aetam, and bempedoic acid, but their high cost poses a significant barrier.
Transcript
So it really wasn’t until the mid to late ’80s, 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 um, basically the uh, you know, pharmacologic tool that became valuable against ASCVD. Now, the first, second, and third-generation Statin 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 Statin in existence, and each of them, you know, offers some strengths and advantages over others. And they’re not a benign class of drug, 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 the 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 Statin. 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 subset of people, about 4% of people, put on a Statin might go on to develop type 2 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 Staten 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 2 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 aami can. I interrupt for a second and ask you about statins. Yeah, of course. Um, because I have a lot, I have some questions about them. So um, I, and I, 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 post-docs. And um, you know, they would come over and show me data. And we would talk, uh, because, you know, I had a lot of experience in aging, mitochondrial function, and mitochondrial biology during graduate school. And um, I remember saying this to Ron. I’m like, you know, so statins are affecting the HMG co co pathway that you mentioned, the cholesterol synthesis with which also is important for the synthesis of ubiquinol y right. This is is an important, or coq10 as I should probably call it. Um, this is important for mitochondrial function. I mean, it’s necessary for mitochondrial function for transferring electrons across the electron transport chain, which is essentially coupling the oxygen we breathe with the food that we eat to make energy. Um, 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 ubiquinol or coq10, um, measuring mitochondrial function in terms of B2 Max or something. So, um, it’s a great question, actually, and something I have thought a lot about. Um, so the literature has nothing to offer here, unfortunately. So… 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 2 testing with lactate production. So I know what this is ‚cause 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 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 gly–as opposed to oxidative phosphorylation. So how do we–how could 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–the glycolytic pathway versus the oxidative phosphorylation 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 2m. 2 m is about the threshold beyond which you are now shifting away from the maximum capacity of the mitochondria 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 1 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 2 output. They hit that lactate 2 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. But I don’t think metformin is a great drug for someone like you or someone like me. We don’t see this with Statin, so if it’s happening, it’s dose-dependent. Or, no, just don’t see it. Yeah, just don’t– 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 really small. Now, you mentioned ubiquinol or CoQ10. And there have been a number of clinical trials looking at using or supplementing ubiquinol with patients taking Statins. They have mostly done this to assess the muscle soreness issue. So they’ve mostly done this as a way to ask the question, „Can you reduce the incidence rather of muscle soreness with Statin?“ I haven’t looked at those literature in a couple of years. The last I looked at them, there was still no difference. 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 don’t think there’s any harm in taking it. I really don’t think there is. And if there’s a chance of benefit, then I would say, „Let’s take it.“ But again, 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. So I kind of want to– The other, going back, circling back to the Statins and here’s my question to you: 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, you know, cross the blood-brain barrier, get into the brain, inhibit, you know, HM COA in the brain, particularly at higher doses, but generally speaking, what question 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 diseases that I’m terrified about, uh, one Alzheimer’s disease? I have a genetic, uh, it’s a family history genetic risk factor, and Parkinson’s disease, family history. Um, both of those diseases have been associated with Staten use. They’ve also been– The literature, as you know, is, you know, you can find what you want, right? So do you have any, you know, advice? 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. Let us know or let the viewers know. I did an entire AMA on this topic because it is so, uh, important, and I think it’s, as you said, 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 for less– 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 ‚cause 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 Statin, 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 Alzheimer’s disease. So that includes vascular dementia. I mean, I– That sort of makes more sense. Parkinson’s disease, have you seen– Have you looked at the literature on that? 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 ‚cause 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 hydrophobic and hydrophilic Statins with respect to the to these outcomes, no difference whatsoever. So counterintuitive, 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 imp–“ But it didn’t. It didn’t seem to have. Is there a difference in those two types of Statins with respect to the diabetes increased diabetes risk that you’re talking about or– or that’s a really good question. I– I didn’t look at that. And that wasn’t looked at in this. Yeah. So– Yeah, here’s what– Um, here’s what, um, I would say. And, um, this is something that we spend a awful lot of time looking at in our practice. And, um, actually just last week, Tom Dring, 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 desol levels and dementia risk. So you may recall a moment ago I mentioned desol. So desol 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 desol to cholesterol. So desol 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. Like, are these measure– Could you measure these? You can measure these on a– Like, they’re very difficult to measure in most labs. We use a lab that measures them. So we measure desol and– and lathosterol in every patient, with every blood drop. Unfortunately, this is not standard of care. Most labs can’t measure this. Boston Heart does. That’s why we use Boston. There are enough data suggesting that if desol 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, medicine 3.0 at its finest, which is you have to treat every patient individually. And we are 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 that Tom made because we recorded the internal meeting because it was so valuable. But basically, the cutoff we use is .8. So if desol falls below .8 mg per deciliter, we think the risk of dementia is sufficiently high enough that we would abort the use of the Statin. Very good information. And you think there is a correlation with APOE status on that no one has done that study yet in your clinical– in your clinical practice. We just decided, like, why would we take the risk? But, but yes, no one has done the study to show our desol levels lower in APOE4 individuals. That’s actually a very testable hypothesis, and it makes a lot of sense ‚cause 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 Alals, one Al, or two Al E4 Alals, and then just looked at desol levels. Like, that would be a very easy, mindless study to do. Just a survey, like, just a quick, like, „Is there a correlation? Yes or no.“ So that’s one thing I’d love to know the answer to. Um, but even absent that knowledge, our view is, um, there’s–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 unintended consequences just to control your lipids. Well, I would make the exact same statement here. It makes no sense to get all to…to take unnecessary risks with Statin in a…in a higher-risk individual when we have these other tools we have, as I said or we will talk about aetam, PCSK9 inhibitors, bempedoic acid. These are unbelievable tools that have no bearing on brain cholesterol synthesis. But Peter, aren’t people that have an APOE4 allele more likely to be prescribed Statins based on their sure. None of this. This isn’t personalized. It’s not medicine 3.0, right? So–Yup. No, it’s very frustrating. Um, and it’s also frustrating that, of those three drugs that are an alternative to Statin, two of them are still very expensive. That’s–Okay. So the three drugs– I know the PCSK9 inhibitor, y–um, and highly effective, insanely safe, zero side effects. Um, cheaper than when they came out. So they were approved in 2015. Um, and we have long-term data with the Natur people walking around with a natural mutation, right? Just amazing. Yeah, exactly. We have the natural experiment. We have all of the data from these drugs. Um, 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. Um, but they’re expensive, right? They’re– 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 U.S. when it comes to drug pricing. But in the U.S., you’re talking about 500 bucks a month for that drug if it’s not covered by your insurance company, right? Um, and if you can get a doctor to say, „I’m gonna get– I’m gonna prescribe it,“ I mean, like, I mean, at this point, a doctor who doesn’t, um, who’s not willing to prescribe a PCSK9 inhibitor just is a fool. Um, 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. Or what about myopathy? Like, if you have muscle. Yes, significant myopathy on multiple Statins, but you’d also have to be at high enough risk to justify it. So insurance companies are going to go out of their way to not pay for this. Okay. Then you have aetam. Now, aetam is relatively inexpensive. Um, it’s just not as potent. So aetam 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 got to get more cholesterol,“ puts more LDL receptors on, pulls it out of circulation. Um, 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 cytol, one is called compol. Those are phytosterols. So these are cholesterol we don’t make. It’s phytosterol, not self, pardon me, it’s phytosterol, not self, it’s phytosterol. And so when we measure those levels, we know that it speaks to how much phytosterol–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 aetam. It’s like a blockbuster in those people. Wow, is that a common, you know, single nucleotide polymorphism that they have– or, you know, it depends how– how extreme it is. So, um, 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 ‚cause phytosterols are actually more– more atherogenic than cholesterol. And that’s also, like, Boston Heart would measure– all these ferro– Okay. Um, they’re more atherogenic than cholesterol. Yeah, they’re more prone to oxidation, more inflammatory. Are they being carried in lipoproteins? They’re–uh, so they’re–so, yeah, are they oxidized? They’re more oxidized. 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, um, it does so if you ingest a ton of phytosterols, you will outcompete cholesterol at that, uh, sitosterol– Oh, sure. Stutter, whatever it– Oh, sitosterol, okay. Yeah, like that thing, right? So, basically, you’ll– you’ll outcompete, um, cholesterol at that, oh, sit, at that AOCY. Um, and your body will regulate, and you’ll end up in– net reabsorbing less total cholesterol. The problem with that is, if you have a defective ATP binding cassette, which, you know, 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 an–it’s sort of an example of that DMOL point earlier, where you can lower cholesterol, but if you’re really raising DMOL too much, it can be more atherogenic than cholesterol in the first place. Um, so DMOL 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 we can just wrap this up, ‚cause I’m sure the listeners are tired of hearing about this stuff. Uh, is a drug called bemped– bemped–, bemped– bempedoic acid. Um, that is a prodrug. So it’s a very elegant drug. Uh, it’s taken as a pill, uh, but it’s ineffective until it’s metabolized by the liver. And in the liver, it then inhibits, um, 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 bemped–ic acid. And it lowers ApoB the 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 2 diabetes risk, nothing, nothing. It’s just only acting in the liver. Well, that sounds, uh– Same problem as PCSK9 inhibitor. It’s a $500-a-month drug. Okay. Y– So again, we’d have every– Look, honestly, at this point, like, if money were– Were no issue, you’d probably just be on PCSK9 inhibitors, aetam, and, um, and bemped–ic acid. I mean, eventually, we’ll get there, right? Yeah, yeah. They just have to come down in price.
