**EP328: Discussing Statin Intolerance**
**Dr. Auric Bishop:** Welcome, my name's Dr. Auric Bishop. I'm a cardiologist, an author, and a keynote speaker. I'm CEO of the Healthy Heart Network. I'm all about trying to help people live as well as possible for as long as possible. Heart disease is huge in Australia. Every 20 minutes, someone suffers a heart attack. Most of these could probably have been avoided if only we knew what to do. This podcast is all about helping you understand blood pressure, weight, cholesterol, for better health. If you enjoy this podcast, I would be honored for a five-star review. You can share it with your family and friends. It may well save someone you love.
**Warwick:** Hi, Warwick here, and welcome to my podcast and videocast station. Today, I would like to share with you a little bit around statin intolerance or difficulties that people have taking cholesterol-lowering medications. That seems to happen fairly regularly. For those who are tuning in on audio, then you'll just have to listen to the presentation, and I'll go through it as slowly as possible and make it as clear as possible. But for those who are tuned into video, which should be available on Vimeo or YouTube, you'll have the benefit of looking at a couple of slides I'd like to share with this presentation.
One of the things that comes up pretty regularly is patients reporting that they have problems taking cholesterol-lowering medications. Of course, this happens regularly because I'm in the space of finding people who've had something going on with their arteries, whether they've had a heart attack, need a stent, or need bypass grafting. Lipid-lowering therapy, based on all our research, tells us that if we can get the cholesterol down, that's a really good thing to do for that person to reduce their future risk. I also identify patients through primary preventative strategies, such as imaging the arteries, and can find high-risk patients before they've had an event. In that situation as well, lowering cholesterol makes lots of sense.
The foundational therapy in 2024 remains statins. Now, that means that in those situations I just described, I prescribe statins pretty frequently. Now, quite reasonably, patients ask if the medications have side effects, and that's important because almost anything can have a side effect. I make it pretty clear to patients that you can't possibly expect to have a drug that everyone can take without any problem at all. For example, something as well-known as harmless or innocuous aspirin, if taken by a large population, can lead to problems with an increased risk of bleeding. Almost anything could carry some side effect. I often say to people, "Well, look, there are individuals who report aches and pains if they eat too many tomatoes. There are people who get an allergic response if they eat peanuts."
So when we look at introducing cholesterol therapy, I spend some time explaining to patients that we just have to suck it and see, and really evaluate for that individual: are they tolerating the medication? Is it doing the job? Are we achieving what we're wanting to achieve? All this is made a little bit more complicated by the fact that there's been a lot of attention given to statin and potential statin side effects and intolerances, and even statin and cholesterol-lowering conspiracies within social media. So let me try and unravel a little bit of that today for you.
What I'm going to start with is a paper called "Efficacy and Safety of Elirocumab in Statin Intolerant Patients Over Three Years." This is an open-label treatment intervention of the Odyssey Alternative Trial, and it was run by Sanofi. Elirocumab, for those wondering, is one of these new agents, which works through a completely different pathway to the statins. It works through a pathway called the PCSK9 pathway, which is a receptor. Elirocumab is an antibody against that particular protein, which helps lower cholesterol.
What does all that mean? Sanofi, a large drug company that developed Elirocumab, thought to themselves, "There are a few people out in the community who can't take statins; therefore, let's test if our medication can provide cholesterol lowering in those individuals in a safe and effective way." Great question if you've got an agent that may be able to offer a completely alternate type of therapy for the people who are currently unable to take what would be considered foundational standard therapy.
So what they did was take a number of patients, and these were patients who were said to be statin intolerant. Now, these patients, to get into the trial, not only had to report symptoms, but they had to convince their specialist that they actually had good-going statin intolerance. Generally, as a specialist, we wouldn't accept that unless we had tried maybe a different agent, a different dosing regime, or a withdrawal and re-challenge of the medication. So you can imagine this group of people was fairly rarefied when it comes to being selected as people who couldn't take statins.
So how did they run the trial? Well, for those who have the benefit of looking at this on video, you'll see I'm showing a little summary slide, but I'll read that out for those who are listening. They took these statin intolerant patients, and I'm pretty sure they were in the hundreds, so it was going to be a statistically significant number. Don't quote me on the number; I don't remember it off the top of my head. But they had a four-week run-in, and that four-week run-in was giving people nothing more than a sugar pill for four weeks, just to actually make sure that there was nothing in the body before they started the trial. This makes perfect sense because the cholesterol-lowering agents actually only hang around in the body for a number of days. That's why you have to take them daily.
During that four-week placebo or sugar tablet run-in, 6.4% of patients reported statin intolerant symptoms and therefore withdrew. This is particularly interesting because these people weren't on anything; they were on a sugar pill. File that away because that's pretty important and pretty interesting. That group of people, quite likely, you can already tell, were attributing aches and pains to the pill, which almost certainly weren't related to the pill.
They then put people on atorvastatin, probably the most commonly used statin in our medical armamentarium. At that dose, it's not a super high dose. We often go up to 80 milligrams, but 20 milligrams is a reasonable starting point. They ran those people for 24 weeks. At the end of that, 46%, almost half, reported some sort of statin-associated muscle symptom. We call those SAMs, statin-associated muscle symptoms. Of that 46%, about half of those, 22%, had to discontinue because those symptoms were just too much. From a practical perspective, that's fine. If you are taking medication and it gives you intolerable side effects, you shouldn't take it.
That means, though, that 24% were able to continue because those aches and pains were pretty mild. So after 24 weeks, 46% had some symptoms. That means 54% had no problem at all, which is interesting. File that away. Fifty-four percent, half of these people who thought they were truly statin intolerant and had persuaded their specialists to believe they were statin intolerant, had no symptom whatsoever. Of the 46% who did get some sort of symptom, about half of those, just over, were able to continue. So that extra 24% plus the 54% who didn't have any symptoms leaves us with 78% of patients who were able to take the medication when at entry to the study 100% believed they could not take the medication.
This is incredibly important, and the reason why this is incredibly important is if we can get 78% of people onto these therapies in the situation where they really need these therapies, that is super important. It also means that if we accept that 100% of people who report statin intolerance are truly statin intolerant, then we're doing a disservice to the patient and not allowing them the best possible care they could have in the future.
Well, is the Odyssey Alternative trial the only trial that's shown this sort of information? Well, the Cleveland Clinic, one of the huge and highly regarded centers in America, really did exactly the same sort of study through their clinics, an observational study, and they came to the conclusion that 72% of people who were reported, self-reported as statin intolerant, were actually able to take the medication without any problem at all, if blinded to the therapy.
Well, that does beg the question: why is this the case? I did allude to a lot of information on the internet, really priming people for the possibility that there could be a problem with these agents. Well, this is really quite concerning. Musculoskeletal side effects were reported at a rate of about 16%, 20%, and 22%. These are not majorly discrepant, actually, and give us some sort of idea that people may be anticipating some problems. When we move to open-label Elirocumab, which had a reported musculoskeletal symptom rate of nearly 16%, it had a reported rate down to 2%.
Why is all this important? Well, it raises the possibility that we're seeing what we call a nocebo effect. So I'm going to share with you another paper. This is called the Samson Trial, done by a really clever group in the United Kingdom. Samson is not the biblical character, but Samson stands for self-assessment method versus statin side effects or nocebo. Nocebo is that concept that by telling somebody that this particular medication will cause a problem, they have a problem. It's the opposite of a placebo. A bit like if you give somebody a sugar pill that they don't realize, and you tell them this is the best headache treatment therapy that's available. It's extremely expensive, it's brand new, it's been tested all around the world, and you give them the sugar pill. We've got a very powerful placebo response rate. It's almost 50% or more. That pill is going to have a placebo effect in a positive way. A nocebo effect is that anticipation in a negative way with a negative outcome.
Well, what did they do in this trial? Super clever. They took only 60 patients, which is not many. They ran a trial for 12 months. They had basically three bottles: in one bottle, it was empty; in a second bottle, they put sugar pills; and in a third bottle, they put the active ingredient or statin. Now they rotated the patients, so they had one month on each bottle and then repeated that over the 12-month period. They also provided the subjects within the study with a phone app to go from 0 to 25 to rate their symptoms so that they could report on a daily basis whether they were having statin-related muscle symptoms or statin-associated muscle symptoms or not.
So here's the data for those who are watching this on video. For those who are not watching it on video, imagine this: we've got a graph with two axes. On the bottom axis, we've got no treatment, placebo, and statin; we've got bar graphs. And on the side axis, we've got average symptom score during the time that people were on those different bottles. No treatment, placebo, or statin. Now, this is amazing. On no treatment at all, people reported a score of eight on a daily basis out of 25. On the placebo, that nearly doubled to 15.4. And then on the active ingredient, it went to 16.3. Amazing.
What this is telling us is that a huge component of the reported side effects in this cohort was driven by the anticipated side effects that they might get. The authors of this particular paper called it a nocebo ratio, where the symptom intensity on placebo minus the symptom intensity on no tablets was divided by the symptom intensity on statins minus the symptom intensity on no statins, basically telling us what percentage incremental increase the actual active agent gave us over the nocebo effect. And it was tiny, meaning that it was about 10%, meaning that about 90% of these side effects were attributable to the nocebo effect alone—90%.
Now, why is this so important? Well, in my own practice, I see patients who will come and literally be adamant they can't take these medications. I've got, in my mind, a patient I saw a year or two ago who very clearly articulated that he was convinced that the statins were causing him side effects. What we found was that when I examined this patient, the aches and pains in his legs were associated with weakness and altered reflexes in his legs, which I then went on and ordered a lumbar spine MRI, magnetic resonance imaging scan, to identify that he had severe lumbar disc problems, severe lumbar spine nerve impingement. I sent him off to a neurosurgeon. He came back, the pains in his legs had gone, and remarkably, he was able to restart statins without any problem whatsoever.
The point of this is to recognize that statins are wrongly accused much of the time. It doesn't mean that they're tolerated in everyone. Of course, they can't be. Like I said before, tomatoes give some people arthritis, and peanuts kill some people. But there are a large number of people who attribute their problems to statins when really we have an obligation to be looking deeper and making sure we're not missing something that could be amenable to other therapies, like this patient with his bad lumbar spine.
Well, I'm going to finish off on reducing statin doses in patients. One of the things that we can do is lower our frequency of dosing. It's really important to recognize that if we lower our frequency, so ask patients to take these tablets two times a week, for example, or three times a week, this is not giving up on treatment. It's actually a way to find a solution to the patient's potential side effects. It turns out that if we do dose people twice a week or three times a week, we can have up to 60% of people, even a shade more, achieving the targets we want to achieve. This is really, really important.
It's nice to know because with those statins, we can add in ezetimibe, and that almost turbocharges the statin, making it even more effective than doubling the statin dose that we're on. So we can reduce the statin frequency, we can still get a good number of people to target, but we can also add in an agent that works in a different way altogether, enhances the action of the statin, and will give us a great outcome and a tolerable outcome for that individual in the longer term.
Well, I'm going to wrap up there. I hope you found statins, statin intolerance, the nocebo effect, and intermittent dosing with statins interesting. For now, I'm going to wish you the very best. Of course, if you have any queries or questions, drop us a note as always. But now I'm going to wish you the very best. Hope you live as well as possible for as long as possible. Take care and bye for now.
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