You've probably heard that statins have a ton of side effects. Muscle aches, brain fog, fatigue. It's a major reason why so many people are afraid to take them. But is that the whole story? Or is it possible that these side effects are actually much more rare than social media have you believe? Today, we'll dive in and talk all about the statins and their side effects. Let's get started. Welcome back, team, to the Building Lifelong Athletes podcast. Thanks so much for stopping by. I really appreciate If we haven't had a chance to meet yet, my name is Jordan Renicki. I'm a dual-board certified physician in family and sports medicine. And the goal of this podcast is to keep you active and healthy for life through actionable Evanson Forum Education Today, we're attacking a clinical paradox we all see, right? So, statins are a very, very common medication, can be effective for helping prevent heart disease and heart attacks Yet up to 75% of patients are reported to stop taking them within two years due to side effects. And this isn't a benign outcome, right? If this is a life-saving medication, discontinuing them may have consequences online, things like increased risk of heart attacks Coronary heart disease, strokes, all cause of mortality, all those things. And so, the goal of this podcast here today is to give you a clear evidence-based framework for navigating this challenge, right? Covering everything from The formal definitions of statin intolerance and talking about something called the nocebo effect, which we'll talk more, and then kind of give you a step-by-step management plan and talk about additional therapies as well. So, this is hopefully going to be a deep dive in all this stuff. So, let's dive in right here. So let's start with the fact that we can all agree, right? So, statins are helpful in certain situations, right? I think I'm trying to be light about that. You know, I think in the modern world, a lot of people will say, like, oh, statins are a waste of money. Big pharma just wants you to To prescribe statins. And I think we can all agree, for some people, they're a very good decision to be on. People are high risk for cardiovascular disease, who've had a heart attack, all these things, probably beneficial. They've been a big, big player in cardiovascular disease and treatment of that. And there's lots and lots of evidence on there that they can be helpful for people. And the core principle behind that is lowering the bad cholesterol, quote-unquote bad cholesterol, the atherogenic cholesterol. Specifically, Apo B containing particles, and reducing those can decrease your risk of cardiovascular disease and prevent additional things to happen. So, if you've already had something go on, this can help prevent that as well. Here is the clinical paradox, right? So, statin intolerance, or even just the perception of it, right, is a leading cause of non-adherence, leading to people stop taking medication. With, as I mentioned before, some data suggesting up to 75% of patients stopped therapy within two years because of side effects. And this can have big consequences, right? So it is discontinuation is tied to increased risk of heart attacks, coronary heart disease, and all-cause mortality. And one analysis I looked at found poor adherence was linked to a 45% higher rate of death in these patients. So, this creates a really critical situation for us, right, as clinicians. A potentially life-saving medication is frequently abandoned, leaving high-risk patients. Undertreated and potentially vulnerable. And so, why does that happen? Why is it so controversial? We're going to dive into that here. And first things first, we have to understand definitions, right? To manage any condition, you need to understand the foundation, and that starts with a precise and consistent definition. For years, statin intolerance is kind of this vague concept of like, oh, like you took something and you don't feel good, but now we kind of have a more structured clinical diagnosis The most widely accepted definition comes from the 2022 National Lipid Association Scientific Statement. The NLA is a great source if you are a lipid nerd They're all lipid nerds too. So, I mean, I say that because I am as well, and they are even more so than me. So, they're a very great resource. But they define statin intolerance as one or more adverse effects associated with statin therapy That resolves or improves with dose reduction or discontinuation. So you're on something, you take it, you have some sort of side effect, it gets better when you reduce the dose or stop it. That's what it is. This definition is powerful and helpful because it establishes a clear and simple cause link, right? So, like you take it, you have these symptoms, you stop it, it gets better. This is, yeah, very helpful. These symptoms must be tied to the presence of the drug. And they must get better when the drug is either stopped or the dose is lowered. So that can be very helpful. Nice definition there. And to prevent us from prematurely labeling a patient as intolerant, the NLA also. And other panels establish kind of a crucial diagnostic criteria called the two-statin rule. And so formally here, they say to classify this, you should have a minimum of Two attempts of different statins and still have symptoms. And that's what they call like true statin intolerance, right? So at least one of those statins must be tried at the lowest dose, the lowest daily dose, and ensure that we've made a robust effort before banning the entire class of medications The European Atherosclerosis Society adds a helpful timeline as well. They say for a symptom to be truly statin-related, it should appear within about 12 weeks of starting or increasing the dose. And resolve within two to four weeks of stopping. So the diagnosis is really solidified if the same symptoms reappear when you re-challenge patients with the same drugs. Some people. Don't tolerate one drug, right? And that's just very common. You have side effects to anything, like literally anything you take. I always tell people: if someone says there's no side effects for a medication, then I'll show you a medication that doesn't do anything because right now, In the current pharmacologic environment we live in, like there's always going to be unintended consequences. You know, maybe as we get more genetically focused and CRISPR technology and like really, really laser-focused things, we won't have symptoms and side effects, but right now we do. Anything you take may have symptoms. And so if you just take one pill, have a symptom, it could just be that specific composition or formulation or something like that. So we have to kind of give two to say, hey, actually, this is it. This is not going to do well for us. And another thing happened in the definition there and kind of tease out there is there's kind of a paradigm shift, right? So moving the clinical focus from just presence of symptoms to our ability to achieve therapeutic outcomes, meaning How can we make sure we're still doing the best for the patient, like and dividing it up a little more? So we can have complete and partial intolerance, is what we're looking at. So, complete intolerance is defined as the inability. To tolerate any dose of any stat. So it's like, hey, I can't take this. I get symptoms no matter what I do, no matter the dosing, no matter the frequency, anything like that. I can't get that. And it's pretty rare that this actually happens. The studies seem to show about less than 55%. I'm sorry, 5% of patients who report statin-related symptoms with every single thing they've tried. So, like very, very few people are actually completely intolerant and can't tolerate it. But That's where partial intolerance comes in, right? So, this is a far more common scenario. This is when a patient can tolerate a statin, perhaps a different agent, or a lower dose, or a different time interval, but at a level that is insufficient to achieve the recommendation of their lowering their APOB. So, obviously, we have recommendations for lowering your LDL or APOB. And if you're on a partially intolerant, I mean, you can't go on a statin high enough to get to that recommendation, right? For example, a patient with established heart disease needs a 50% reduction, but can only tolerate a mild or moderate intensity statin due to myalgias, that would be a partially intolerant person. And the classification is key here because it provides A clear evidence-based rationale for adding non-statin therapy on top of maximally tolerated statin dose to bridge with treatment grabs. So, what we're saying here is Taking a step back, you know, do we have intolerance? Is it partial? Is it complete? From there, it kind of gives us an opportunity to understand why we might add additional things. I think. This is also changing. I think a lot of people are starting to go more dual therapies to begin with, in terms of like a low dose azetamib or low-dostatinine. Azetamime and just kind of getting multiple areas to decrease your chance of having side effects because the higher you go with the dose, the odds are having more side effects. Same thing with our blood pressure medications, all those things. So, things we just need to think about as we're going there, but that's some helpful definitions. Another question I have is: how common is statin intolerance, really? So, the answer is complex because the reported prevalence varies dramatically depending on the setting, right? So, in controlled environments like RCTs, There's often a placebo arm in there. So we have very good control. The prevalence of intolerance is quite low, typically reported between about 4. 9 and 7%. However, that doesn't match up with what we see in the real world. So, real-world observational studies. And what we see in clinics, the reports are anywhere ranging from five all the up to 30 percent. A recent large global meta-analysis estimated the overall prevalence to be about nine percent, so right around nine, ten percent. So that's definitely higher than the RCTs. And this discrepancy is largely explained by lots of different things, right? So we don't know necessarily what it is, but it could be. Something called the nocebo effect in patient selection bias as well, and maybe the broader range of symptoms attributed to statins in everyday practice, meaning Could it be the population we choose in these trials? Could it be something called the nocibo effect, which we'll talk about later, which is you kind of think yourself into having symptoms? Or could it be that They have different definitions of what symptoms are. Regardless of the exact percentage, the clinical consequences potentially are problematic, right? So, statin intolerance leading to discontinuation is associated with a 36% higher rate Of recurrent heart attacks and 43% higher rate of subsequent coronary heart disease events compared to patients who adhere to them. So, once again, I am not here to say you need to be on this for a life. That's a nuanced discussion you're gonna have with your doctor, not me. I'm just some dude on the internet. But Stopping them when they are appropriate and indicated could lead to problems on the line. So that's just all I'm going to say on that. And so now that we have a solid diagnostic framework, let's pivot to the specific adverse effects that patients report, right? So, there's a wide variety of symptoms and that are anecdotally attributed to statins. So, there's a lot of people saying I have symptoms from there, but it's crucial to understand the evidence for a true cause relations Varies significantly from what people are reporting necessarily. So, in this section, we're going to walk through the clinical spectrum of potential adverse effects. For each one, we'll cover its frequency, severity, and most importantly, the strength of evidence supporting this association. So, the first one let's dive into is the statin-associated muscle symptoms or SAMS. This is by far the most common adverse effect reported by pati And the leading cause of statin discontinuation, right? If I had to pick one, this is the one that most people say, hey, they stopped because of this. The clinical presentation is often described as muscle soreness Aches, which we kind of call myalgias, right? So you might have cramps, stiffness, tenderness, or weakness as well. That can all happen. So that's by far and away the most common one is this muscle soreness, aches, myalgias. What really characteristic of Sams is the pattern, right? So symptoms are typically bilateral, so both sides symmetric and tend to affect large proximal muscle groups like the thighs, buttocks, calves, back muscles, potentially shoulders. That's the most common pattern. And patients will often note that symptoms are worsened with physical exertion and typically begin within a few weeks of starting the static medication, right? It could be up to up to 12 weeks. We talked about kind of that definition previously by the A European society, but up to about 12 weeks or after increasing the dose, we might notice that. So, once again, mias is just kind of tenderness, not feeling good, achiness, soreness, bilaterally, both sides, usually big muscle groups. That's what we think about. And to accurately diagnose and manage these symptoms, we need to use precise language, right? So the term SAMS itself is a broad descriptor for any muscle symptom that doesn't necessarily. Imply causality, though. So, the most common presentation is myalges, right? So, this involves muscle aches, soreness, cramps, like we mentioned, without significant weakness, and importantly, no changes in lab values. So, specifically, there's something called creatinine kinase or CK. Which is a marker of muscle damage. You will not see this elevated with just run-in-the-mill Sams. So, this is not going to have that. You will see that though And the next one we're talking about is myopathy or myositis. This is a more significant issue involving unexplained muscle pain and weakness with a CK level. Greater than 10 times the upper limit of normal. And this is uncommon, occurring in less than one in 10,000 patient years. So very rare. And the next step up, though, from that is something called arahabdomyelsis, which is a rare but potentially Really problematic emergency. So it's a severe myopathy where we have muscle breakdown, evidence of acute kidney failure as well, because we have so many byproducts, and really, really elevated CK, usually about 40 times the upper limit of normal And that is an option, very, very rare, also as well. And the most rare one is something called an extreme extreme condition called statin-induced necrotizing autoimmune myopathy It's a severe, progressive weakness that uniquely persists or worsens after a statin medication is started or even persists after stopping and is associated with anti-HMG CoA reductase antibodies. That's how you make the diagnosis. Once again, incredibly rare this happens, but it's just something we have to mention because, for completeness, yeah, things can happen. By far, far, far, far, far and away is just kind of muscle aches and myaster Um, then occasionally kind of work up the momositis, but very rarely, those other things can happen. But I just wanted to mention about it as well. Um, do I think that it's very common? No, it's not, but we want to include that for completeness. And so, what's actually happening though in the body that's causing these symptoms? Well, the honest answer is we don't quite know, right? The exact pathophys is not fully understood, and it's likely caused by a lot of different factors. The most well-known theories involves mitochondrial dysfunction and coenzyme Q10, so CoQ10. Statins work by inhibiting. A specific pathway to block cholesterol production. However, that same pathway is also responsible for producing other essential compounds, including ubiquinone. Also known as CoQ10. And CoQ10 is a vital component for our mitochondria, which is very important with energy and metabolism, and it produces energy with that. But the theory is that depleting CoQ10 statins could impair energy production in muscles. And kind of leading to these myopathy symptoms. So, kind of having these muscle aches and whatnot. It's a compelling idea, but I do have to stress that the clinical trial evidence supporting the use of CoQ10 supplementation to prevent. SAMS is limited and inconsistent and doesn't seem necessarily eliminated that. I've seen studies that look at that. Start of statin, startoQ10, doesn't seem to decrease that. But that's one plausible mechanism for what's going The next major theory for this has meaning looking at genetic predisposition, right? Meaning, people who have this certain gene may be at risk. And we know that certain genetic variations or polymorphisms In a gene called the SLCO1B1 are strongly associated with an increased risk of myopathy. So, this gene provides the instructions for transport in the liver that's responsible for pulling statins out of the bloodstream. So, variants of this gene need to reduce statin clearance. It means there's more statins in the bloodstream at higher concentrations for longer, leading to the exposure in muscle tissue and raising the risk of myopathy. This risk is particularly pronounced with simbostatin, for whatever reason, that seems to be the most risky one with the specific genes. But if you have this gene variant, you may be more sensitive to it. Something worth mentioning. Not a common thing that people check, but it's something we could check to look at to see if we'd be at a high risk for it. And the last major theory for SAMs comes down to the chemical properties of the statins themselves. So specifically their solubility So, the idea is that there's two main classes: lipophilic and hydrophilic. So, lipophilic or fat-loving statins like simostatin and atorvostatin can passively diffuse across cell membranes. In contrast to hydrophilic or water-loving statins like Pravostatin and Rosuvastatin, they require active transport to enter cells. And so the hypothesis is that Lipophilic statins may penetrate muscle tissue more readily, thereby increasing their potential for myotoxic effects. And this provides a direct pharmacologic rationale for a very common management strategy, which is switching the type of statinuron from a lipophilic to hydrophilic. I've talked more about this in terms of do satin causes dementia. It's the same idea in that these lipophilic ones can cross the blood-brain barrier easier. So, mechanistically, another reason for why we may experience that, but it's definitely not a slam dunk like, yeah, this definitely causes that And moving on from muscle symptoms now, let's keep rolling. Let's talk about the link between statins and increased risk of new onset diabetes. This association is well established, but often kind of misinterpreted, and on social media is portrayed a little more aggressively than it probably really is. So, numerous large-scale meta-analyses have consistently shown, though A modest increase in the risk of developing diabetes with statin use. And so that's scary. When you hear that, you're like, what the heck, Jordan? Like, why would I ever start a statin medication? We kind of have to put this into perspective first. The magnitude is small, right, with the number needed to harm of 255, meaning you'd have to treat 255 patients with a statin for four years To cause only one excess case of diabetes, right? So 255 patients, four years, one extra case. That's not a huge number in terms of like, we're not causing tons of people having this, but The risk is also not uniform across all patients. It's highest in individuals who already have risk factors like prediabetes, obesity, and metabolic syndrome In this context, statins may simply unmask or accelerate a diagnosis in these already predisposed patients. And the risk appears also to have a class effect. So it's more pronounced with high-intensity statins like rosuvastatin And a torque reset. And so, you know, people hear that, oh my gosh, what's going on? And why are we causing it? It's not a slam dunk that we're just causing straight up diabetes in people. A lot of times they're borderline, right? It just kind of pushes them over the edge. Why does that happen? Not entirely sure, but that's what we're seeing. But It's still really important, though, to frame this small risk in the context of the other benefits you're getting, right? So let's go back to the numbers. For the same 255 patients treated over four years, It's predicted that statin therapy prevents 5. 4 major cardiovascular events for every one case of diabetes. So we are preventing five cardiovascular events, meaning stroke, chart attacks, what have you. But causing one potential case of diabetes. And so it's kind of that risk balance. The benefit in preventing heart attacks probably outweighs that small risk of diabetes in general in the big overall studies. Once again, it's an individual risk factor and thing you'll talk about with your doctor. But the critical point is here. Patients who develop these nuanced diabetes while on statin still seem to derive the same proportional reduction in cardiovascular risk from the therapy as those who don't. So the people who Start statin medications, like they still get benefit regardless if they develop diabetes or not, which is kind of interesting. But therefore, the development of diabetes is currently not recommended as a reason to withhold or discontinue statin therapy in patients who stand to benefit And once again, this is nuance, right? Like all things in medicine, it's nuance. You'll hear people online say, oh, never take statin. And it's, you know, black and white And those people have probably never taken care of a patient in their life. Because, right, when it comes down to when you actually have to take care of a patient and you're responsible for them and making sure that they don't have a heart attack or don't have a second heart att It changes a lot. The discussion changes a whole lot. And so, this is a nuanced discussion, kind of understanding that. But I think the main takeaway I had from this research is that if you have Kind of insulin resistance already, you're a higher risk of developing into diabetes with statins, whereas it doesn't seem like it's happening too much for people who are just like normal, like insulin response, all that stuff. But there is some, there is definitely some Actual evidence that it can increase your risk of having diabetes. So I do want to mention that, not just sweep better than the rug. Next, let's top it and kind of talk about another topic. Comes up all the time. I did a whole different podcast already on this, so we'll kind of go over it a little quicker. The fear that statins cause cognitive issues like memory loss, Alzheimer's, or brain fog. And so this is very common, and a lot of patients are worried about. Why this happens and can lead to non-adherence. And these fears, as I mentioned before in my previous podcast, started in 2012 when the US FDA kind of put a safety communication that highlighted rare post-marketing reports of reversible cognitive issues. The FDA warning really stuck with the public consciousness. And the key question we had then is: well, shoot, is this real or is this not? And we'll kind of talk about that. And so, while the fear of brain fog is out there, the overwhelming weight of scientific evidence from large-scale trials and meta-analyses does not support a causal link between statins In long-term cognitive decline or dementia. In fact, the evidence leans almost in the opposite direction, where several other analyses have found that statin use may be associated with a reduced risk in developing Alzheimer's or dementia, and to look at that. So, and I put a number on it in 2022, a recent meta-analysis. 36 studies found that statin use was associated with a 20% reduction in the risk of dementia, right? And so that's kind of what they're saying. And furthermore, a large ASPRI trial from about 19,000 people they had there found no association between statin use and incident and dementia, mild cognitive impairment, or declines in cognitive function. And the bottom line is that we can confidently reassure our patients that, based on the highest quality evidence, statins do not cause dementia and may even help protect against it. However, I do want to say that people are reporting these brain fog symptoms, right? And so when they have this and they stop the medications, they get better. That is a very real thing. So, people are feeling this and they're like, oh my goodness, but it's reversible, right? So, if you are on a statin medication and you do detect brain f I wouldn't be like, well, just keep pushing through, man. Like, let's no, I think you can, it's reasonable to pull back on the dose, try a different one, stop it altogether. Lots of different things we can do. I'm not saying that. But when people say statins cause dementia, that doesn't seem to be the case. It causes potentially in some people, you know, maybe they're genetically predisposed to it. Maybe it's the lipophilic versus hydrophilic, lots of ideas we have, but We do see these symptoms of these kinds of brain fog, but they are once again transient, short-lasting, and very, very different from actual dementia. So I do want to mention that. And I do want to talk about another topic here, though, is do statins harm the liver? And it's true that mild asymptomatic elevations in liver enzymes like ALT and ASC can occur in some people who start statin medications, usually within the first three months of therapy. But what's important to know is that these elevations are typically transient. They come and go and often resolve on their own, even if the patient continues to take the statin. So essentially, your body just gets used to it and calms back down Clinically significant statin-induced liver injury is exceedingly rare. And because of this, major guidelines actually no longer recommend routine monitoring of LFTs, these liver function tests. In asymptomatic patients. The guidance is to check these liver values at baseline, just to make sure they're not very elevated, because we know it can attack the liver. Make sure they're not elevated at baseline. And then only again if a patient develops symptom Suggested of liver issues like fatigue, loss of appetite, they're turning yellow, jaundice, or maybe even if someone's having lots of symptoms in terms of weaknesses, I'll probably check them as well. But they're saying overall, yes, it can harm it, very rare, but something to keep an eye on as well. And now, this next session is one of the most important parts of this entire podcast. If you take nothing away, this is what I want you to take away. No talk about statin intolerance is complete without a thorough understanding of something called the nocebo effect. And so, this phenomenon is the inverse of the placebo effect. I think most people are probably aware of the placebo effect, meaning, hey, if you think it's gonna work, it's gonna work. This occurs when a patient's negative expectations of harm from a treatment lead to the experience of real, subjective, adverse symptoms that are not. Caused by the drug's pharmacological action. So, essentially, what we're saying is that you think something bad might happen, you've heard lots of bad things, and you take it, and then sure enough, you feel something bad. So, in the context of statins, this is driven by factors like media reports, internet searches, warnings from clinicians. Things you read on the internet, information contained in package inserts, all those things. And the nocebo effect is now understood to be the primary explanation for the vast difference between. Low rates of side effects in blinded trials and high rates reported in unblinded clinical practice. So, this is the biggest explanation for that, which is really, really fascinating. We'll talk more about this here, but it's a very, very important concept. And this isn't exclusive to statins, right? The nocebo effects can be anywhere. Hey, you've heard this medication may cause this side effect, and that's in the back of your brain, and then you have it. Hey. I just started this SSRI. I heard it can lead to sexual dysfunctions or GI upset. And sure enough, that happens to you. It might be one of those things where, was it the medication? Was it nocebo effect? We're not sure, but something worth looking into And so, how do we know the nocebo effect though is so powerful? Well, it's been really well studied, which is very interesting. An early trial called the Stomp trial showed that while muscle symptoms were more common in patients on high dose of torvastatin, Nearly 5% of patients taking the placebo also develop new onexplained muscle aches. So, this established that at a baseline rate, these symptoms exist in the general population when taking a placebo. But there's also a more sophisticated trial called the GOSS III trial, which really drove home this point. They took patients with a documented history of intolerance to at least two statins, right? So they're intolerant to two statins and had them take a torvostatin and a placebo in a crossover des So, the results were pretty remarkable. Wow, about 43% of patients had symptoms only on the statin, incredible 26. 5%, more than a quarter, reported intolerable muscle symptoms. Only while they were taking the placebo. So that was a huge finding, right? It demonstrated that for a significant portion of patients who believe they are statin intolerant, their symptoms are actually not caused by the statin's pharmacology necessarily. So that's kind of interesting. But there's even more evidence as well. The most definitive evidence on the no subo effect comes from a truly innovative N of 1 trial called the Samson trial. So, N of 1 just means looking at very individual results and how they feel things. In this study, 60 patients who had previously quit statins due to side effects took one-month courses of a torvostatin, an identical placebo pill, or no tablets at all in a randomized order, all while tracking their symptoms, right? The results were absolutely striking. The average symptom intensity score was nearly identical during the months that they took the placebo and the months they took the actual statin. The trial calculated a nocebo ratio of 0. 9. And this means that. 90% of the symptom burden that patients felt while taking a statin was also triggered by the same placebo. So essentially 90% of the symptom burden That patients felt while taking a statin were also triggered while taking the placebo. And that's crazy. 90% of the symptom burden attributed to the nocebo effect, which is pretty insan And the symptoms were real, though, right? But they were overwhelmingly caused by the simple act of taking a pill they were worried about, not necessarily by the drug's chemistry. This was a very, very fascinating trial. Might be one of the most interesting trials I've read. Just because what they did essentially had an app every day and they were marking their symptoms and they took the placebo or they took the statin and they took nothing and they marked their symptoms every single day. And to see the responses was striking, saying, Hey, these peop people who had Issues with this pill and this pill, like all the time. It was, yeah, it was really, really elegant. It was cool. And it just definitely got me thinking about something I don't think about all the time. But the most incredible and therapeutically powerful part. Of the Samson trial is it's a gate which is a game changer for our practice. And after the trial, when participants were shown their own personalized data, demonstrating the powerful nocebo effect. Oh, 50% or about half of the people who were previously intolerant were able to successfully restart and continue taking stats. So that's huge. It transforms the nocebo effect from a medical curiosity into a diagnosable and, more important, a treatable condition, right? So. Our clinical approach should kind of shift from simply switching drugs to engaging the patient to collaborative investigation, right? So the goal is to validate their experience, right? I never want to hear that a patient got dismissed, right? I want to validate your symptoms are very real. But we need to figure out: let's work together. Is this being caused by the drug? It kind of empowers us to understand, you know, what's going on. We can work with the patients so they can understand their own bodies and successfully salvage. Um, all the medications possible. It's the same thing if, like, this were happening to any other drug, high blood pressure, antibiotic, would be like, is it actually causing that? I want to know, and so it's helpful that You know, and I think it's really cool design that hey, they said, Hey, here's the data. Like, you actually had these symptoms with and without the medication. Like, do you want to try? And those people said, Oh, cool. So, once again, there's clearly something going on that the belief is very, very strong. So, really cool study there. But. So, we've definitely established that, right? The nocebo effect is real. I'm not blaming all symptoms on nocebo, but it can be something we have to consider. But let's get into the practical step-by-step management we can use in clinic, right? So, this is kind of an approach. That will work for a lot of people, and true complete intolerance is uncommon, as I mentioned before, but this approach works for people if they're intolerant or just don't want to. Regardless, we have lots of options, right? So, in today's world, in 2025. We don't have to have a reason why we can't lower someone's, you know, Apo B, whether if they want to take a Statinuron take statin. We have lots of different options now. So Most patients who report side effects can tolerate some form of statin if we're patient and methodical about this. And so, step one is the initial evaluation. Before we even think about labeling the patient as statin intolerant, we have to go through a workup first Right, so the goal here is twofold: first, to rule out any other conditions that could be causing their symptoms, and second, to identify any modifiable risk factors that may be mimicking or worsening their muscle symptoms. So, what are we looking for in this initial evaluation? Well, I want to highlight the key modifiable risk factors we should be screening for. So, first is untreated hypothyroidism. This can Present very similar to statin intolerance. It's a classic and reversible cause of myopathy, so ordering a TSH should be done. Similarly, vitamin D deficiency can contribute to general muscle aches So, checking a vitamin D level is also a good idea. And the next one is drug-drug interaction. So, you have to review a patient's full medication list, specifically looking for something called a CYP3A4 inhibitor. So, this is a specific. Enzyme that metabolizes medications in the liver, and it is actively involved in a lot of these statin medications. So, certain antibiotics, antifungals, also may use this pathway in this Specifically, if patients are on a torvostatin, simostatin, and lovostatin, they have a high chance of kind of crossing over and having issues. So, if you have medications that are competing for the CYP3A4, you may have varying levels, you might have more around or less, and people might not tolerate that well. And we also have to ask about exercise and lifestyle factors, right? Like, kind of Dr. Mine, if I'm not asking about lifestyle factors, you can ask about alcohol use as well. Have they started a new vigorous exercise program, which you could call as DOMs And on top of that, we also have to ask, are they drinking lots of grapefruit, which one can be a CYP3A4 inhibitor? But things like alcohol can increase how much symptoms patients feel. And so there's lots of things that could be causing it. And I want to say once again, We never want to just blame something. Obviously, if you just started a medication and you have symptoms, it's probably going to be that. But it's worthwhile investigating these other things just to make sure we're not missing something right. And after we've addressed all these modifiable risk factors, we move to step two, which is D challenge, which is kind of a statin holiday. So, this procedure is pretty simple: discontinuing the statin for a period of two to six weeks And this is important. Ask a patient to keep a symptom diary during this time, see how they're feeling. Right, this has huge diagnostic value. If the muscle symptoms resolve or significantly improve during this period, it strengthens the likelihood that the These truly are statin-related side effects. On the flip side, though, if symptoms don't resolve, it strongly suggests some other underlying cause, and the original statin can potentially cautiously be returned You know, some patients who are super high risk, who had a heart attack already, may not be recommended to completely stop, maybe add on some other lipid-lowering medication during this drug holiday. Once again, don't get your medical advice from the internet. Not from me. Talk to your doctor, but can be something to think about as well. And if the patient's symptoms resolved during the D challenge, we now move to step three, which is the re-challenge phase. And this is truly kind of the cornerstone of managing statin intolerance. And this is where we can really be optimistic with our patients. An overwhelming majority, up to 90% of patients who report intolerance to one statin, will be able to tolerate a rechallenge using a different strategy, right? So there's no single superior strategy, right? The approach should be tailored to the individual patient. We have three main approaches we can use. First, is lower the dose on the same statin, right? So just lower the medication. As I mentioned before, the higher you go on medications, the more side effects you will have. So maybe we can take it down. The second is to switch to a different statin. Specifically, we talk about maybe going from lipophilic to hydrophilic. You know, that's kind of a big thing: a torvostatin, resupostatin, in different categories may be helpful Or use an alternate, less frequent dosing schedule. And we'll break down each three of these that we just talked about here. And so different statin. I just mentioned that specifically. This is highly effective for a lot of people. And probably the mainstay of, you know, if I have someone who's statin talent, I'm gonna try switching it. And it can be helpful because it actually is guided by like different pharmokinetic properties. And as I talked about earlier, Solubility is a big difference. If a patient has an issue on a lipophilic or fat one, like a torvostatin, switching to, as I mentioned, hydrophilic like a pravostatin or suvastatin May be helpful. Another crucial factor is how the statin is metabolized. A torostatin and simostatin are primarily metabolized by the CYP3A4 enzyme Which has a lot of potential drug interactions. So, if you are suspecting a drug interaction or just want to try a different pathway, you can switch to a statin like pravastatin, maybe resuvastatin, which is metabolized differently. And so, once again, switching classes, very, very common. The third strategy we talked about, so we had lowering the medication, switching the pills, and then is finding a kind of alternate dosing schedule. And so, with statins that have long half-lives, sometimes less frequent dosing can also maintain the LDL lowering we need, right? So It still minimizes the peak drug concentration while causing less side effects. So if you can spread it out, you may get less high peaks and have a lower level in the blood for longer. So it still does its job, but you're not having those side effects, which can be kind of cool. And this is an excellent option for patients who have faced, you know, who have failed daily dosing, saying, hey, I just can't tolerate it. And specifically for this, Rosuvastatin and a Torastatin can be dosed every other day or even just two to three times per week. So if you're taking a pill maybe two to three times a week and still getting the benefit from it, That may be what we need to do. And there actually is data on this. Studies have shown that these less frequent regimens have good tolerability and still provide a substantial reduction in LDLC. So we have lots of options that we can always try. And we've covered the technical strategies now, but none of them will work without step four, which is mastering communication as a team, right? Physician and Patient, that's really important. And it's a delicate conversation that requires, you know, a patient-centered approach and building trust. So, the core principle here is validate, then educate. Right? If a patient reports vague muscle aches, don't say it's probably not statin. Instead, say something. I'd say, like, hey, I hear you, man. It definitely can cause us. Let's take it seriously. Let's pause the medication. Let's keep a symptom diary. Let's see what we want. Validating concerns and patients' concerns is very, very important. You know, I hear all the time You know, my doctor never listens to me, and I, once again, I'm good on both sides of these things as a doctor and as a patient, and understanding as a primary care doctor, you have you know, like seven minutes to talk with the patient, it's just our system's so broken But when you don't feel listened to, it's just very challenging, right? So when I introduce this, I would never say, like, hey, it's all in your head, right? Like the nocebo effect. Actually, there's this thing called the nocebo effect, and it's all in your head. Instead, I'd say, hey, the symptoms that you're feeling are absolutely real, right? You definitely feel these symptoms. What's really interesting, though, is that lots of studies show that for many people, the simple act of taking a pill they're worried about Can trigger these symptoms. So let's be detectives, let's work together and see if that's what's happening. And you can kind of go back and we can stop, we can reintroduce, we can do all these things and kind of work together to see if it actually is the medication or kind of thinking about that. And so it validates a patient's experience while empowering them. And yeah, there's lots of things that you can do, which can be helpful. So, once again, just listening to patients, probably a good idea. But hopefully, that's at least a strategy to talk about And so, what do we do though for people who can't take satins, right? They can't tolerate them, or a growing number of people who just aren't willing to try them, you know, based on the internet. It happens a lot where patients come and say, I don't want a satin. And I say, hey, you know what? Like instead of fighting and say, let's work together, let's figure this out. You know, it's hard if you don't have a relationship with them. But if you have a relationship and you know them, let's work together and figure it out. But there's lots of things that we can do. The first is azetamide. This is an oral medication that works by inhibiting cholesterol absorption at the brush border of the small intestine. So we remember statins, they decrease the since Cholesterol synthesis in the liver. This works by decreasing absorption, right? It can be very helpful. It may reduce LDL by 15% to 20%. Its role for satin intolerant patients is very well established. In fact, in the Odyssey alternative trial, it showed it was significantly better tolerated than atorvastatin in patients with a history of intolerance. So we have good data showing that. Yeah, it's into the guidelines as well. 2018 ACC AHA guidelines recommend adding on azetamib to a maximally tolerated statin dose if for very high-risk patients that are still above 70, right? So Once again, it's all about reduction of ApoB and LDL, is what we're thinking about. So, if we can get this certain target and if you can do it without taking a SAD, then that's great. This could be like your first and only line for some people, and that's great. But it is one there, but thinking about 15-ish, 20% lowering. Next up are PCSK9 inhibitors like Ivalocumab and Allarocumab. These are huge leap forward in lipid-lowering therapy. They're crazy. They're injectable monoclonal antibodies, and they work by inactivating a protein called PCSK9. This dramatically reduces LDL particles. What it does is it increases the number of LDL receptors on the liver, which pulls in LDL from the cholesterol out of circulation. And it can reduce LDL grade by 50 to 60 percent, which is crazy And yeah, these drugs specifically do well in patients who are statin intolerant as well. There's been studies about that, and it has a very favorable side effect profile. And they also seem to benefit in terms of proven for high-risk patients. They reduce clinical outcomes as well. And so these are ones getting more common, can be a little expensive right now. So if they're not covered by insurance, it's going to be a decent amount out of pocket. That's something to consider. So, you know, satins, really cheap. Even out of pocket would be cheap, but usually covered by insurance, very cheap. Zettamibe, not crazy expensive, more expensive than satins, but still reasonable. And then these are getting to be pretty expensive. And next medication that we have is something called bempidoic acid. It's an oral medication. Its mechanism is really fascinating and the key to why people use it. It's a prodrug, so a prodrug means it needs to be activated. This is activated by an enzyme found in the liver, but not in skeletal muscle. So, satins will get into muscles and liver. This is pretty much targeted just at the liver And it gives it an excellent muscle safety profile, making it ideal for statin intolerant patients. So it lowers LDL by about 20 to 28 percent, and its place in our toolkit was cemented by the Clear Outcomes trial. It was a big trial looked at 14,000 statin intolerant patients, and it showed that bemfidoic acid significantly reduced the risk of major cardiovascular events by 13%. And this was kind of a game changer because it's the first. Trial to prove a cardiovascular vent reduction with an oral non-statin drug in a population made up of entirely statin-intolerant patients. So, like this, drug was like made for people who can't tolerate a statin It's relatively new, so it's going to be probably pretty expensive, but something to consider and look for. And you'll probably have to get a prior authorization for it, but we have another option out there. And then the last non-statin therapy I want to touch on is enclivrocin. And it is interesting, I don't even know how to pronounce it, I'll be honest with you, but it's a small interfering RNA And it works by targeting and destroying the messenger RNA that tells the liver to make the PCSK9 protein. So instead of just blocking the protein, this drug shuts down its production at the source. It's a powerful And very durable LDL reduction of about 50%, right? Which is similar to what we see with monoclonal antibody inhibitors. So major advantage to this and the headline for this is its dosing schedule. After the starting dose, it's given as a subcutaneous injection just once every six months. So, six months, that's crazy. It's cardiovascular alchemy trial is still ongoing. We anticipate it'll be well, it'll work well just due to the reduction of LDL, but that's why we do the trials and not show. Just, this is more of a picture of what might be coming in the future. You know, twice a year dosing, which is pretty crazy. And once again, this is going to be crazy expensive. So, not like your primary care is going to do this right away. I'm not prescribing these, but it's on the horizon, which is cool to think about. And that was a quick tour of these non-statin medication options, right? So let's put them all together here, head to head, to clarify. So, first, for a modest LDO reduction of 15 to 20%, our goal-to agent is azetamide Perfect for first-line non-statin for intolerant patients. It's very easy, well tolerated, very, very, yeah, that works well. If you need a big hammer in the toolbox, Then PCS canine inhibitors can decrease 50 to 60 percent. That's a big one. Another oral option we talked about, bempidoic acid, gives you 20 to 28 percent. And then finally, we talked about the small interferent RNA, which can be another 50 percent with way bigger dosing. The thing is, these can all be stacked, right? It's not like, hey, oh, I'm on one have to stop the other. A lot of times they're stacked. So, you know, it's very, it's not uncommon to see someone on a statin medication, a Zetamide, and a PCS canine inhibitor for a really high-risk patient. That is possible. You can do that, you can stack them. It's all about figuring out your risk, right? So, where do you feel comfortable? Where do you want your members to be? Work with your physician and kind of go from there. And so, we've covered a lot of ground here. This is a longer one. I apologize, but let's synthesize everything into a Few, a few kinds of clear actionable takeaways for clinical practice, right? So, first, the benefits of statins in preventing cardiovascular disease can be very, very profound in the right patient population, right? So, we have to keep this open. I want to keep all the tools we have in our toolbox available. Because if someone says they're intolerant, we have to kind of remember and look at that, right? So remember that complete intolerance is rare, affecting less than 50% I'm sorry, 5% of the patients' population. So, yeah, definitely less than 50, but less than 5% have true, true intolerance. And the vast majority can tolerate some form of statin therapy With patient education and a systematic approach. But yeah, that's never make this diagnosis after a failure of just one single medication. And then, next, the nocebo effect is a big driver of symptoms. Educating patients about this is powerful In and of itself, it is almost like a therapeutic intervention. So we have to kind of consider that. And then finally, we have to remember for a small subset of patients with true intolerance Or those with partial intolerance who remain above the goal or who don't want to take a statin medication, there are other options we have, right? And so I think a lot of times people say, you know, you're just a big pharma shill pushing statins, like I don't know what to tell you, man. I didn't make no money from Big Pharma, that's for sure. I think a lot of people think there's someone back in the hallways just printing money for me for prescribed medications. Really comes down to patient preference, right? I have plenty of patients who are on these. I have plenty of patients who don't want to take them. And at the end of the day, I'm fine with either. You know, I think as long as you understand the risks and benefits and potential side effects, all those things. I just want to work together, and I'm just one beggar to another beggar telling me where to find food. Like, that's really what it comes down to. I'm just a guide in people's journey, and I'm not telling anyone what they have to do, but If you're very much like, no, no, no, never statin, then we have other options as well. And yeah, so this, I wanted to mention, I thought it was interesting. But that is going to be it today. Thank you so much for stopping by. I really appreciate it. If you did enjoy this podcast, it would mean the world to me if you either. Share this with a friend, left a five-star rating on your podcast platform of choice, or subscribed on YouTube. But that is going to be it for today. Now, get off your phone, get outside, have a good rest of your day. We'll see you next time Disclaimer, this podcast is for entertainment, education, and informational purposes only. The topics discussed should not solely be used to diagnose, treat, or prevent any condition. The information presented here was created with an evidence-based approach, but please keep in mind that science is always changing, and at the time of listening to this, there may be some new data that makes this information incomplete or inaccurate. Always seek the advice of your personal physician or qualified healthcare provider for questions regarding any medical condition.
