Welcome to Dr. Warrick's podcast channel. Warrick is a practicing cardiologist and author with a passion for improving care by helping patients understand their heart health through education. Warrick believes educated patients get the best health care. Discover and understand the latest approaches and technology in heart care and how this might apply to you or someone you love. Hi, my name is Dr Warrick Bishop and I'd like to welcome you to my podcast and videocast station. Today I'm looking forward to speaking with Dr Karam Kostner, who's a lipid expert and a cardiologist based in Queensland and we're looking to talk about statin intolerance. But first of all, welcome Karam and thank you for joining me. Thank you Warrick, very good to speak to you and thank you for inviting me to be part of this. Look, statin intolerance is something that I come across every day in my practice. I seem to be hearing concerns, things on social media, patients report aches and pains and symptoms. It seems to really be a conundrum. So just to help me and help those listening, how would you define statin intolerance, Karen? Warik, I perfectly agree with you. Statin intolerance is real, and we often talk about it, and many of our patients are concerned about it. We'll get to the incidence in a second. The definition is simple. It's the inability to have tried at least two different statins and to tolerate them due to clinical side effects. That's my definition. People like you and I have been part of many panels where we come up with complicated definitions of statin intolerance. But the simple definition is the inability to be able to take statins due to clinical side effects. So when we think about those side effects, Karim, there's a number of things that immediately spring to mind. And in fact, I had a patient today. who was describing muscle problems. So we'll talk about muscle problems. I've also had patients report problems with memory. And I've also had people concerned about the risk of diabetes. So maybe we could talk on each of those briefly and cover them as appropriate. How does that sound? Very happy. The one side effect that we see in approximately 5% of patients who take statins, especially higher dose statins, such as atovastatin 80 milligrams and rosovastatin 40 milligrams, is muscle pain. Now, the first and important thing to remember is that musculoskeletal pains are very common. We all have them. In most cases, they're due to having worked and exercised all our life. And in most cases, they're actually not due to the statin, but they occur at the same time as we take medication naturally. So a lot of these musculoskeletal side effects that we hear about are actually not due to statins. But as I indicated, in about 5% of patients who take statins, muscle side effects are real. And in those patients, we have to distinguish between dangerous muscle side effects leading to rhabdomyolysis and significant potentially clinically problematic side effects, such as rhabdomyolysis, as I mentioned, which is extremely rare. And myopathy-type side effects, where patients experience muscle pain without significant CK elevation, but still enough to not want them to take the statins. Now, the feared side effect with statins is rhabdomyolysis. And it's a situation where there is significant muscle pain and an elevation of creatinine kinase, CK, often referred to, of at least 5 to 10-fold above normal limits. It's often in older patients, in patients who have decreased renal function, in immune-compromised patients who take other medications that interfere with statins, and in patients who take a combination of statins and fibrates. And that's why GPs and specialists like you and I, in somebody who has significant muscle pain, recommend a CK level. And if that's significantly elevated, that's really a side effect where we have to stop the statin and try something else. So just to jump in there briefly, the CK or creatinine kinase is a blood test that we can do that can give us some idea as to whether there's any irritation or inflammation in the muscle. Myopathies or aches and pains don't seem to see very high CK levels, but the rhabdomyolysis that you mentioned can reach very high CK levels. My understanding is that this rhabdomyolysis is... is almost a perpetuating condition. These people almost get caught in a spiral of worsening clinical condition. It's a very serious condition. And the figures I saw were somewhere about one in 80,000 people. Is that sort of the number that you understand with the severe spectrum of this condition? Overall, it's probably a little bit more common. It's probably one in 10,000, but it depends how old the patient is and how many comorbidities are existing. So you're right. In some people, it's one in 80,000. In some populations, it's one in 10,000, but it's extremely rare. I think we both agree on that. So one of the other intolerances that I come across are concerns about memory. Is there any... information about memory that you're aware of that you share with your patients when they raise that concern or offer that intolerance, offer that side effect? The important thing to realize is that statins and all lipid lowering strategies, including esotrol and PCSK9 inhibitors, significantly reduce vascular dementia, which is the most common dementia in our patients. And they do that by preventing mini strokes and strokes. cholesterol accumulation in brain vessels, which leads to vascular dementia. So more patients are actually prevented from developing dementia on these lipid-lowering therapies than developing dementia. Short-term memory loss has been described in very few patients on high doses of atorvastatin, but that is extremely rare. And in my own practice over the last 15 to 20 years, I have maybe had one or two of these patients. In the majority of patients, effective lipid lowering strategy prevents vascular dementia, as I said. Okay. So in terms of intolerance, we know that statins can, in certain people, increase their risk of development of diabetes in the longer term. But patients often don't report that as a symptom. That's just something that we would track as their doctor, being aware of that. My understanding is that all the data would suggest that that small increase in risk of diabetes is offset by the benefit in cholesterol lowering. Is that your understanding? That is my understanding too. And in fact, statins can slightly increase glucose levels. And if you are a pre-diabetic, if you're in a pre-diabetic range, that can push you into the diabetic range. But once you are a diabetic, statins prevent macrovascular complications, as you mentioned, and are very important. So there's very few patients where we have to be concerned about this. It's also important that ezetrol, for example, or pravastatin have not shown to increase glucose levels and can be very safely used. And a small dose of estatin in combination with ezetrol gets cholesterol to target in many patients without significantly increasing glucose levels. Yeah. Look, I think... One of the things that we find as clinicians frustrating is this inability to have a specific test that tells us that someone has a side effect from the medication. We would love it if the CK... was precise, but I know from my own practice experience, I have many patients who describe problems with aches and pains and muscles and their CK is plumb normal. And I have a number of patients whose CK is elevated and they report no problem at all. So it's very difficult to tease out really who has and who hasn't got the aches and pains. Can you talk about any studies that inform us in terms of people who report statin intolerance, what the studies show us in those individuals when they're looked at in a scientific process. Very happy to do that. But first of all, what comes out of these studies is that statin-associated muscle symptoms, if it is really the statins causing them, affect the big muscles, the quads, the shoulders. It's often symmetrical and it's a significant pain, similar to the pain that you experience if you exercise too much. But what the studies have actually shown is that very few patients really have these muscle pains due to statin therapy, because when the studies looked at patients who were on placebo, the amount of patients that developed muscle pain was almost the same as patients who were on statins. And in fact, when they re-challenged them with a placebo after a statin, almost the same amount of patients reported these side effects as with the real therapy. So that's the first thing. The other thing that these studies showed is that there is a difference between the different statins. So the lowest amount of muscle-related side effects was with fluvastatin and pravastatin, some of the older, less effective statins, and the highest rate of muscle side effects seem to have been with the high-dose, very effective statins, such as atovastatin and rosuvastatin. So that is important to note as well. Is there a mechanism that... proposed for this muscular discomfort, which presumably might tie back with the effectiveness of these agents, a more effective agent for greater effect? Several mechanisms have been proposed, but none of them has been conclusively confirmed. Some of the mechanisms discussed relate to coenzyme Q10 levels and magnesium levels within the muscle themselves. Other mechanisms relate to mitochondrial changes in muscles that are possibly affected by part of the statin metabolism. But the conclusive evidence has not been connected. So those studies that you talked about, my read of that, and I'll just get you to confirm if that's right, is that when a number of these patients, I think it was about 4,000 in a six-month study, were taken and these individuals were sworn intolerant of statins both by themselves and by their clinician enrolled them into this study part of the odyssey trial group these people were randomized to sugar tablet or placebo versus statin and crossed over without any awareness whatsoever of what they were taking My understanding was about 75% were able to take the statin when they weren't told it was a statin after six months without any problems at all, but 25% really did have a problem. Are they about the breakdown that you... Absolutely. They're the numbers that I remember as well. So the important... I think this is... I often share this study with patients all the time, and I think the importance of it is to recognise that if the group of people who really swear... that they can't take this tablet from side effects, that 75% of those people are potentially denying themselves the medication that could be beneficial for them. But the other really important component of that trial is that 25% of people really are getting the side effects that they're reporting. So clinically, Karam, how do you tease these people out? How do you work with them in your clinic? That's a very good question. So there's various strategies that we use, that you use, that I use, to mitigate this problem slightly. First of all, it is really worth trying two or three different statins at various doses, one of them at least, one of them at a low dose, and if possible, one of these lower prone to side effects statins, such as fluvastatin and pravastatin. The other options that we have in clinical practice is to use very small doses of effective statins three times a week, for example, such as rosubastatin 5 to 10 milligrams every second day. And then adesitrol, which does not have any muscle side effects to get cholesterol levels into the desired range. The second thing that we often try is magnesium. So magnesium orotate especially has shown to reduce muscle-related side effects a significant amount of patients, and it is very safe. And it is something that the heart muscle needs also for other purposes. So magnesium is a very safe therapy. And apart from that, we use ezetrol as a substitute for statins, as we've discussed in a different podcast, and some newer lipid lowering agents in patients who have very high cholesterol levels who really do not tolerate statins. But I think the key is to inform our patients very well and to try several different statins and to incorporate some newer approaches, such as the therapies that we have discussed. You mentioned coenzyme Q10 within the muscle previously. Do you ever recommend supplementation with coenzyme Q10? I do. Not in many patients, but in patients who do not respond to magnesium, I sometimes try coenzyme Q10. And again, some of them will respond and others won't. But I have to mention that there is no conclusive evidence from big randomized controlled trials that Q10 really works very well. But we do have some smaller studies that seem to indicate this, and it would fit into one of those mechanisms. And again, it's a very safe therapy that does not have any side effects. What would be your personal experience using it? It is probably the same as magnesium. You know, I find that as many people respond to coenzyme Q10 as respond to magnesium, but magnesium is significantly cheaper. And as I mentioned, is a therapy that's good for the heart anyway, independent of reducing muscle pains. You mentioned magnesium in the orotate form. What's the specific reason for that? There are several different magnesium preparations available. The one that I personally find most useful is magnesium orotate, which is a different salt that magnesium binds to. And I use the dose of 800 to 1200 milligrams a day usually. Okay. So... Is there anything that you'd like to mention about statin intolerance before we wrap up? I think we've covered this complex topic pretty thoroughly. Is there anything you'd like to leave as a passing remark? Yes, I would like to summarize by saying that real statin intolerance is rare. Most of these symptoms are related to musculoskeletal problems and people using their muscles and joints their lifelong and having some symptoms, obviously. Feared complication is rhabdomyolysis, which is significant muscle pain and a significant elevation of creatinine kinase. And the last thing I'd like to mention is that it's important to try different statins at different doses and other lipid-lowering therapies in people who have a real statin intolerance. Karam, not only was that a great summary, but it was a great opportunity to speak with you about statin intolerance. I'm going to wrap it up there. I hope that those listening have learned a bit like I have as well today. If you have any queries or questions, please drop me a note at members at drwarakbishop.online. I do thank you for joining me. If you've enjoyed this podcast, please share it or leave us a message. If you've got any ideas for future podcasts, again, drop us a note and let us know. Until next time. I wish you the very best and please don't die from a heart attack. Goodbye. You have been listening to another podcast from Dr. Warrick. Visit his website at drWarrickbishop.com for the latest news on heart disease. If you love this podcast, feel free to leave us a review.
