This transcript has been edited for clarity
Christopher V. DeSimone, MD, PhD: Hello. Welcome back to the Mayo Clinic Medscape video series. I'm Christopher DeSimone, electrophysiologist here at Mayo Clinic. Today, we'll be discussing lipid management and inclisiran, specifically.
I'm joined by my colleague Stephen Kopecky, preventive cardiologist and professor of medicine at Mayo Clinic. Welcome, Dr Kopecky.
Stephen Kopecky, MD: Thank you, Dr DeSimone.
A New Kind of PSCK9 Inhibitor
DeSimone: First, can you tell us how inclisiran works?
Kopecky: Yes. Inclisiran is a very interesting drug. It inhibits PCSK9, but not through the way of the original drugs we have. It's a small interfering RNA (siRNA) molecule that actually inhibits the RNA from making the PCSK9.
DeSimone: It's a different mechanism of action.
Kopecky: Right. The end result is very similar.
DeSimone: Now, with the difference in mechanism of action, is there any other effects we see, like any effect on lipoprotein(a) [Lp(a)]?
Kopecky: Just like we saw with the original PCSK9 inhibitors, there is about a 20% or 25% reduction in Lp(a).
DeSimone: We have an added benefit from this.
Kopecky: Yes, very good.
DeSimone: Now, patients that are on this, does that mean they get to stop their statins? Or is that something we keep them on still?
Kopecky: No. We do keep them on statins. In fact, the FDA recommended it in addition to healthy diet — the Mediterranean diet, like we recommend here — and optimal statin therapy or maximum tolerated statin therapy. Some of the guidelines say to give ezetimibe too.
DeSimone: It's more of an additive effect because they have different mechanisms of action?
DeSimone: Because they have an additive effect, do our patients have better outcomes from this?
Kopecky: Sure. If you get different mechanisms working together, you can get a better outcome. As you start on a statin or the PCSK9 inhibitor drugs, you absorb more cholesterol in your gut. That's where the ezetimibe works.
DeSimone: It's like hitting it from two different angles.
Kopecky: Yeah, just like blood pressure. We give a vasodilator, a diuretic, and a beta-blocker. They all work together at lower doses.
DeSimone: Makes sense. For our audience, how do you take this medicine? Is it a pill? Is it just like a statin medicine? Is it an injectable like insulin?
Kopecky: Yes. It's very interesting. It's injectable — a subcutaneous injection — but the regimen is different. It's at baseline, 3 months, and then every 6 months. You can check lipids at 1 month and you'll start to see a significant reduction by 1 month. Then, every 6 months after that; so the adherence, we hope, will be much higher.
DeSimone: Basically, when they do the injection, they don't have to inject it all the time? It's going to be, once you get on that regimen, every 6 months. That sounds much easier than doing something every day.
Kopecky: Yes, it's much easier, and it will be done in the office or in the infusion center. There are infusion centers around the country. We have an infusion center here, as you know, at Mayo Clinic. We'll know exactly when the patient got the drug and if they got the right dose because we're doing it all ourselves.
It'll be very helpful too, I think. It'll help adherence, because we're finding that, for the PCSK9 inhibitors that are self-injected subcutaneously every 2 weeks, at the end of the year, only about 60% of patients are still taking those. We need to increase our adherence.
DeSimone: You want to increase the adherence because you get so much of a benefit from these drugs, but patients aren't taking them or no one wants to take shots so frequently. Then, you won't have good adherence and you won't have good enough outcomes.
Kopecky: Exactly. The less shots, the better the adherence.
DeSimone: When do you check the lipids? When can patients expect the benefit?
Kopecky: Just like the statins, where we start to see the optimal benefit in 4-6 weeks, it's the same with the inclisiran. Then, we can check it yearly after that.
DeSimone: Yearly after that, that's nice. Do our practice guidelines say to use this in, say, a patient on statins? They're tolerating them, but maybe they have some additional work they can do with their diet. Where does it say that this is the patient that would benefit from this drug? Who would be your ideal patient?
Kopecky: The FDA has said, if you have heterozygous familial hypercholesterolemia (FH), that's an indication for the drug. If you have atherosclerotic cardiovascular disease (ASCVD): cerebral, vascular, coronary, or peripheral disease, and you're not at goal —remember, we haven't talked about this, but the new goals came out.
If you have ASCVD, the goal is 55 mg/dL for the low-density lipoprotein cholesterol (LDL-C), which is a reduction from the 70 mg/dL it was for the past 4 years. That's the ideal patient to give it to. If they can't get to goal on a statin and ezetimibe, on a good diet, and on a good healthy lifestyle, then this would be someone to think of adding it in.
DeSimone: Sometimes, people have issues with statins, as you well know, and sometimes we try different doses or different types of statins. Are there side effects from this drug?
Kopecky: Side effects don't seem to be a significant problem. There may be injection site reactions, so that's an issue. Just like with the PCSK9 inhibitors, every 2 weeks, they get a little nasal stuffiness, bronchitis, or rhinitis. We're not really seeing any liver problems or infection problems, per se. Again, you study a drug in 20,000-50,000 patients and you release it to hundreds of thousands. We'll just have to monitor that closely.
DeSimone: Sure. It appears relatively safe.
Kopecky: It is quite safe.
DeSimone: Any issues if someone were to take this around pregnancy, things of that nature?
Kopecky: Well, it's the same guidelines we have for the other lipid-lowering drugs. We don't want to give it during pregnancy. I tell patients who are potentially pregnant, "Let's stop the drugs when you're thinking of getting pregnant, and we can restart them the day after you stop breastfeeding."
DeSimone: Got it. Obviously, patients would see their general practitioner, cardiologist, and they want to be seen at a specialty lipid clinic. How do they go about getting this prescribed? What do patients have to go through? What are their expectations?
Kopecky: Good question. This is a little different in that it's not a drug they go and pick up, get at their pharmacy, take it home, put it in the refrigerator. This is one where it's given at the office. It's not where the patient brings it in. It's there for them.
The payment structure is a little different. There's still prior authorization. As we're giving more and more with these drugs, we have to go through that. That's more on our end of things. They do have centers that help us. We have prior authorization centers that help us. Every drug is a little different, and every payer is a little different too, as you know.
DeSimone: It seems like that also helps the patient know, Well, I'm going to [get this at my doctor's office, rather than them storing it in the refrigerator or storing it in the cabinet, and that helps with compliance.
Kopecky: They just show up, get the shot. They don't touch the drug. The shot's administered to them, and they leave.
DeSimone: Aside from the shot, is there anything that you tell patients not to take in terms of medicines? Do we know of any drug-drug interactions?
Kopecky: There really don't appear to be any drug-drug interactions. That's something that has to be studied more, obviously, but we're not seeing that.
DeSimone: For a patient, what do you tell them they could expect as benefit? They're not at goal. Thank you so much for bringing that out that 70 mg/dL is not the goal. The new goal should be 55 mg/dL. What does this give the patient? If we say, take this medicine, what is the reduction in mortality or cardiovascular events?
Kopecky: We have great data for the statins and the PCSK9 inhibitors that you take every 2 weeks. Remember, with the statins, it was years before we had evidence that we actually lowered mortality after the statins were approved.
The same is happening now with inclisiran. Those studies are ongoing. The ORION studies will be out in a few years and we all think they will show benefit because they're lowering LDL-C by a very similar mechanism. I think they will show a benefit clearly. We just don't have the evidence right now.
DeSimone: Don't wait for something really good to show up. Be on it. If there's low side effects, low risk, and potentially really good benefit, that's something I would offer my patients as well.
Kopecky: I think it's going to be the convenience issue and the adherence issue that may really make the difference.
DeSimone: Sure. That sounds much better to me. In addition to taking the drug every day, not having to take shots frequently, but once every 6 months.
Kopecky: There's a model for that. It's the osteoporosis drug that's taken every year or so. We have many patients. The snowbirds fly up. They get their shot. They fly back down in the winter. They're happy with that.
DeSimone: Exactly. Is there anything else important about the drug or things coming down the pipeline, differences of this drug, or things to know for patients, cardiologists, or primary care clinicians?
No Replacement for Healthy Lifestyle
Kopecky: For these drugs, we're starting to see that lower frequency is starting to be the name of the game with this. We're starting to see drugs come along that will actually lower Lp(a). That's a whole different set of drugs. These drugs that we're talking about today will lower it by 20%-25%. The new ones will probably lower it by 70%-75%.
Kopecky: We have something to look forward to in the next few years.
DeSimone: Impressive. We're always trying to get what's best for our patients as soon as we can, making sure it's a good safety profile.
Kopecky: Exactly. We need to remind patients that it's not just about the pill and not just about the shot. It's also about the lifestyle. We can't say, "OK, this shot will replace a healthy lifestyle." That doesn't happen, Chris. We haven't developed that yet.
Kopecky: Patients need to eat healthy and do the things that we tell them that really can help their life.
DeSimone: That's its own pill, and its own shot in and of itself.
DeSimone: Thank you, Steve, for these very important insights. Thank you for joining us on theheart.org | Medscape Cardiology seminar.
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Cite this: Christopher DeSimone, Stephen L. Kopecky. Lipid Management: The Ins and Outs of Inclisiran - Medscape - Dec 05, 2022.