Management of ASCVD in patients with statin intolerance

Erin D. Michos, MD, MHS, FACC, FASPC: We talked about the fact that so many patients are not on schedule with statin therapy. One of the reasons is the lack of adherence to their statin therapy. If we don’t see the expected 50% or more reduction [in low-density lipoprotein] with a high-intensity statin, they may not be clingy. One of the leading causes of adherence is that patients discontinue due to perceived statin intolerance. I was glad that the NLA [National Lipids Association] recently updated this year 2022 and had a new statement specifically about statin intolerance. They also refined the definition of statin intolerance a bit. It is defined differently in different statements. Alison, why don’t you walk us through the new definition of statin intolerance from this recent NLA statement?

Alison Bailey, MD, FACC: Pam brought this up earlier in our conversation today. There’s this concept of complete or partial statin intolerance, which is important because we don’t know for sure if a dose of statin isn’t beneficial. But complete intolerance means that a patient can’t tolerate any dose of a statin, even a low dose a few times a week, because of the adverse effects they attribute to the statin, which are often mental state changes, cognition is a big that patients complain. The most common are muscle complaints, statin-associated muscle side effects. Partial intolerance means that patients will tolerate a low dose of the statin, but you can’t get the dose you need to reduce events that we want, that more than a 50% reduction, or a target of less than 55 mg/day dL in our high-risk patients. It’s really important, because we can send the message that taking statins is still beneficial, and that’s OK. But we have many other options to work on to try and get your LDL [low-density lipoprotein] at a good level.

Erin D. Michos, MD, MHS, FACC, FASPC: What is your approach to statin intolerance? The ACC [American College of Cardiology] The expert statement we mentioned also mentions statin intolerance in that paper. As we think about the non-statin therapies that we’ve been discussing, maybe you could talk a little bit about what the ACC is saying about this? What is your approach to statin intolerance?

Jorge Plutzky, physician: Often patients who have had these experiences and are informed by means we would doubt – what they see online, or a friend of a friend, and things that are not very well established – have not heard that imposing the evidence and reasoning . I think that’s important. Folded into it is the idea that there are certain LDL levels that we need to reach, and that we may turn to other therapies. I think incorporation is what we’re seeing emerging in this discussion, an effort to address statin intolerance, but then moving forward, which is what we’re seeing in the ACC statement.

Because eventually you’re going to have some patients who just won’t tolerate a statin, whether it’s partial or full. To leave patients untreated without moving on to some of these other therapies, I think that’s what we’re seeing included in the ACC consensus update. If a patient doesn’t get the right number, we have to move on. If we’ve addressed the possibility that maybe they’re just mistaken, and they’re attributing a problem to the statin that wasn’t related to the statin, and they haven’t gone through an explanation of the rationale, then we should move on. We have options moving forward, as we’ve discussed, bempedoic acid, ezetimibe, their combination, PCSK9 inhibitors, inclisiran; these are all tools that we can use with patients and help them understand that this is separate from the statin, and we don’t expect the same adverse effects.

That’s another thing that we see in the clinic not infrequently, we go through this with statin intolerance. Probably 30% of the patients we see in our lipid clinic are referred for statin intolerance. We’ve been through that and they say, “I’ve had a problem with every statin ever made.” And you say, “Did you take ezetimibe?” They will sometimes look at you like you’re crazy and say, “I told you I can’t take statins.” You say, “Well, ezetimibe is not a statin.” And they say, “Oh, I didn’t know that.” That becomes important as we move forward with other therapies, such as bempedoic acid and PCSK9 inhibitors, that they are completely different and there is no reason to expect a similar problem. One of the impressive things about the CLEAR Outcomes trial is taking patients with statin intolerance, which can often be a challenging patient group, and going through that with another agent. It’s important for us to make sure that patients don’t anticipate harm, which is this nocebo effect and can be very powerful. Not the placebo effect, where you expect it to do nothing, but the nocebo effect, where you anticipate damage, and then you experience it.

Erin D. Michos, MD, MHS, FACC, FASPC: Bob, why don’t you tell us a bit more about the nocebo effect. There have been some studies that have examined the nocebo effect. What is your approach to that?

Robert Busch, physician: The one that I found really interesting was the GAUSS-3 trail that was done with evolocumab. To get the evolocumab, they took statin-intolerant patients who already had intolerance to several statins. They gave them 20mg of atorvastatin for, I believe, 8 weeks, then they switched to placebo. You can take statin, placebo or placebo, statin. There were 4 possibilities: you could get complaints on both; you can’t get symptoms on either one; you could get symptoms on the statin, not placebo; or symptoms on placebo, not the statin. The difference was that 42% had symptoms while on atorvastatin, and 26% had symptoms that were not on the atorvastatin but were on the placebo. That 16 percentage point difference there, that’s the nocebo effect, which you anticipate harm from the drug. Some people develop statin intolerance when they open the statin bottle and put the first one in their mouth. As Jorge said very nicely, you could hear from your neighbor or Dr. Oz on TV that statins are going to cause a problem, and the patient will. Remember, keep an eye on the price. You lower heart disease, that’s why I give you this. Whatever you could take, whether it’s an alternate dosage, or a lower dose, or a different dosage, and the other medications we talked about, that would be absolutely necessary.

Erin D. Michos, MD, MHS, FACC, FASPC: There have been a few more too. In addition, there was the SAMSON trial and the StatinWISE trial. I like that the SAMSON study design took patients who reported statin intolerance and gave them 12 vials, 1 for each month. A third of these vials had the statin, a third had an identical match placebo, and a third of the vials were empty. They used a different bottle every month. As for the empty bottles, they didn’t take anything that month, and they knew they didn’t take anything that month. Patients did have muscle complaints when they took a statin compared to the months when they did not take anything. But 90% had the same symptoms when they also took the placebo. So it was thought that it was due to taking the pill rather than the medication itself.

We know that there is incredible safety data despite the fact that there is not much difference in statin-associated muscle symptoms in blinded studies. People have argued that, well, these trials are screening. They have this running-in phase, looking for tolerance. In practice, up to 30% of patients report statin symptoms. Even though it might be a nocebo effect, it’s very real to them, and that can be really challenging. So I’d like to emphasize what Jorge said, with the guidelines, the NLA statement says that while we want to try at least 2 statins, 1 at the lowest dose, in these very high-risk patients, we don’t need time to stay waste trying all 6 statins and all sorts of combinations. We just need to keep going so that we can limit the time of exposure to these atherogenic particles and get patients on therapy quickly. But it’s challenging because while we know the nocebo effect is real, the symptoms are real to the patients and shouldn’t be discounted. Because they are clinically meaningful and we know that patients who discontinue their statins are at increased risk of events.

Alison Bailey, MD, FACC: Erin, I think you’ve already mentioned this. But those patients labeled as statin intolerance have an even higher risk of events than our age-related patients with atherosclerotic disease who are on other medications. It’s for that really high-risk cohort that we need to find something else that’s beneficial to lower LDL more.

Jorge Plutzky, physician: I find it interesting, as you all probably come across, the part of my clinic that is made up of doctors, some of whom come to see me because of statin intolerance. That’s an interesting subgroup because when I approach this and say, “Well, is there a bias in this patient who expects danger and doesn’t want to take a statin?” In that group, the vast majority of them are upset that they can’t take one. That gives you the feeling that there are people who are having a hard time with it, and that we have to move on, because we do have other alternatives. Sometimes ezetimibe is useful, even as a test to say, “Well, this patient isn’t responding to ezetimibe.” Now I don’t have to worry so much that this is, as we say, supratentorial. As I tell patients, it would be like… I tell you I have a peanut allergy, and you offer me an orange. I say, “Well, I have a peanut allergy.” You would say, “Well, what’s wrong with him? This is an orange, not a peanut.” That may help establish that we are now moving on to other therapies that shouldn’t cause the same kinds of problems. I think there’s a portion of those patients, as supported by the doctors, including cardiologists that I have, who say, “I really feel like I can’t do this.”

Transcript edited for clarity

Management of ASCVD in patients with statin intolerance

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