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Evolving Strategies for Cholesterol Management and Atherosclerotic Cardiovascular Disease Risk Reduction - Episode 13

Managing ASCVD in Patients With Statin Intolerance

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A panel of experts discusses recommendations for managing statin intolerance in patients with hypercholesterolemia.

Erin D. Michos, MD, MHS, FACC, FASPC: We talked about how so many patients are not at goal with statin therapy. One of the reasons is lack of adherence with their statin therapy. If we don’t see the anticipated 50% or more reduction [in low-density lipoprotein] with a high-intensity statin, they may not be adherent. One of the main drivers of adherence is patients stopping because of perceived statin intolerance. I was pleased that the NLA [National Lipids Association] recently this year 2022, updated and had a new statement specifically about statin intolerance. They also refined the definition of statin intolerance a little. It’s been defined differently across various statements. Alison, why don’t you walk us through the new definition of statin intolerance from this recent statement from the NLA?

Alison Bailey, MD, FACC: Pam brought this up earlier in our talk today. There’s this concept of complete or partial statin intolerance, which is important because we’re not sure that any dose of statin is not beneficial. But complete intolerance means a patient doesn’t tolerate any dose of a statin, even a low dose a couple of times a week, because of adverse effects they attribute to the statin, which are frequently mental status changes, cognition is a big one that patients complain of. The most common are muscle complaints, statin-associated muscle adverse effects. Partial intolerance means patients will tolerate a low dose of the statin, but you can’t get to the dose you need to reduce events that we want, that more than 50% reduction, or a goal of less than 55 mg/dL in our high-risk patients. It’s really important, because we can send the message that taking some statin is still beneficial, and that’s OK. But we have lots of other options to work on to try to 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] expert decision statement we’ve mentioned also mentions statin intolerance in that document. As we’re thinking about these nonstatin therapies we’ve been discussing, maybe you can talk a little about what does the ACC say about this? What is your approach to statin intolerance?

Jorge Plutzky, MD: Often, patients who may have had those experiences and are informed by resources we would question—what they’re seeing online, or a friend of a friend, and things that aren’t very well established—haven’t heard that laying out of the evidence and the rationale. I think that’s important. Folded into that is the idea that there are certain LDL levels we need to achieve, and we may be moving on to other therapies. I think that incorporation is what we see emerging in this discussion, an attempt to deal with statin intolerance, but then moving on, which is what we see in the ACC statement.

Because ultimately, you’re going to have some patients who are just not going to tolerate a statin, whether it’s partial or complete. To leave patients untreated without moving into some of these other therapies, I think is what we see incorporated in the ACC consensus update. If a patient’s not getting to the right number, then we do need to move on. If we’ve paid attention to the possibility that maybe they’re just mistaken, and they attributed an issue to the statin that wasn’t related to the statin, and that they haven’t gone through an explanation of the rationale, that we should move on. We have options for moving on, as we’ve talked about, bempedoic acid, ezetimibe, their combination, PCSK9 inhibitors, inclisiran; these are all tools that we can use in patients and help convey to them that this is separate from the statin, and we’re not expecting those same adverse effects.

That’s another thing we see, not infrequently, in the clinic, we’re going through this with statin intolerance. Probably 30% of the patients we see in our lipid clinic are referred for statin intolerance. We’ve gone through that, and they say, “I’ve had a problem with every statin that’s ever been made.” And you say, “Have you been on ezetimibe?” They will sometimes look at you like you’re crazy and say, “I told you, I can’t tolerate any statins.” You say, “Well, ezetimibe’s not a statin.” And they go, “Oh, I didn’t know that.” That becomes important as we move on to other therapies, such as bempedoic acid and PCSK9 inhibitors, that these are completely different, and there’s no reason to expect a similar kind of issue. One of the impressive things with the CLEAR Outcomes study is taking on patients with a statin intolerance, which can often be a challenging patient group, and working through that with another agent. It’s important for us to set the stage for patients to not be anticipating harm, which is this nocebo effect and can be very powerful. Not the placebo effect, where you expect it not to be doing anything, but the nocebo effect, where you’re anticipating harm, and then you experience it.

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

Robert Busch, MD: The one that I found very 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 20 mg of atorvastatin for, I believe, 8 weeks, then switched them to placebo. You can be on statin, placebo, or placebo, statin. There were 4 possibilities: you could get symptoms on both; you could get symptoms on neither; you could symptoms on the statin, not on placebo; or symptoms on placebo, and not on the statin. The difference was 42% had symptoms while they were on the atorvastatin, and 26% had symptoms not on the atorvastatin but had it on the placebo. That difference of 16 percentage points there, that’s the nocebo effect, that you’re anticipating harm from the drug. Some people get statin intolerance when they open the bottle of the statin and put first one in their mouth. As Jorge very nicely said, you could hear from your neighbor or Doctor Oz on TV that statins are going to cause some problem, and the patient’s going to get that. Remember, keep the eye on the prize. You’re lowering heart disease, that’s why I’m giving you this. Whatever you could take, whether it’s an alternate dosing, or a lower dose, or some other dosing, and the other drugs that we were talking about, that would be imperative.

Erin D. Michos, MD, MHS, FACC, FASPC: There have been a couple of others, too. In addition to that, there was the SAMSON trial and the StatinWISE trial. I like that the design of the SAMSON trial took patients who reported statin intolerance and gave them 12 bottles, 1 for each month. One-third of these bottles had the statin, one-third had an identical match placebo, and one-third of the bottles were empty. They would use a different bottle each month. On the empty bottles, they didn’t take anything that month, and they knew they weren’t taking anything that month. Patients did have muscle symptoms when they were taking a statin compared to the months, they were taking nothing. But 90% had the same symptoms when they were taking the placebo, too. So it was thought that it was the act of taking the pill rather than the medication itself.

We know that there’s incredible safety data despite the fact that, in blinded trials, there isn’t much difference in statin-associated muscle symptoms. People have argued that, well, these trials screen. They have this run-in phase, look for tolerance. In real-world practice, up to 30% of patients report statin symptoms. Even though it may be a nocebo effect, it’s very real to them, and that can be really challenging. That’s why I do like to emphasize what Jorge said, with the guidelines, the NLA statement says that although we do want to try at least 2 statins, 1 at the lowest dose, in these very high-risk patients, we don’t need to keep wasting time to try all 6 statins and all kinds of combinations. We just need to move on, so that we can limit the time of exposure to these atherogenic particles and get patients on therapy quickly. But it is challenging, because although we know the nocebo effect is real, the symptoms are real to the patients and shouldn’t be discounted. Because they’re clinically meaningful, and we know that patients who stop their statins are at increased risk for events.

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

Jorge Plutzky, MD: I find it interesting, as you probably all encounter, the segment of my clinic that is physicians, some of them seeking me out because of statin intolerance. That’s an interesting subgroup, because as I approach this and say, “Well, is there a bias in this patient who’s anticipating harm 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 this feeling that there are some people who just have a hard time with it, and that we need to move on, because we do have other alternatives. Sometimes ezetimibe is helpful even as just a test to say, “Well, this patient’s not reacting to ezetimibe.” Now I don’t have to worry so much that this is, as we say, supratentorial. As I say to patients, it would be like…I tell you that 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 can help establish the fact that we’re now moving on to other therapies that shouldn’t cause those same kinds of issues. I do think there’s a subset of those patients, as supported by the physicians, including cardiologists I have, who say, “I really feel like I can’t do this.”

Transcript edited for clarity