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CHRISTOPHER V. DESIMONE: Hello, and 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. And I'm joined by my colleague Stephen Kopecky, preventative cardiologist and professor of medicine at Mayo Clinic. Welcome, Dr. Kopecky.

STEPHEN KOPECKY: Thank you, DeSimone.

CHRISTOPHER V. DESIMONE: Well, first of all, can you tell us about how inclisiran works?

STEPHEN KOPECKY: Yes. Inclisiran is a very interesting drug. It inhibits PCSK9, but not through the way of the standard original drugs we have. This works actually by it's a small inhibitory RNA molecule drug. So it actually inhibits the RNA from making the PCSK9.

CHRISTOPHER V. DESIMONE: Excellent. So a different mechanism of action.

STEPHEN KOPECKY: Right. End result's very similar.

CHRISTOPHER V. DESIMONE: Now, with the difference in mechanism of action, is there any other effects we see, like any effect on lipoprotein A?

STEPHEN KOPECKY: Well, there is. Just like we saw with the original PCSK9 inhibitors, about a 20%, 25% reduction in LPA.

CHRISTOPHER V. DESIMONE: Excellent. So we have an added benefit from this.

STEPHEN KOPECKY: Yes, very good.

CHRISTOPHER V. DESIMONE: Now, patients that are on this, does that mean they have to or get to stop their statins? Or is that something we keep them on still?

STEPHEN KOPECKY: No. We do keep them on. 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 actually say give ezetimibe too with it.

CHRISTOPHER V. DESIMONE: So it's more of an additive effect, because they have different mechanisms of action?

STEPHEN KOPECKY: Exactly.

CHRISTOPHER V. DESIMONE: And because they have an additive effect, our patients have better outcomes from this?

STEPHEN KOPECKY: Sure. If you get different mechanisms working together, you can get better a outcome, because as you get on a statin or the PCSK9 inhibitor drugs, you absorb more cholesterol in your gut. So that's where the ezetimibe works.

CHRISTOPHER V. DESIMONE: Excellent. So it's like hitting it from two different angles.

STEPHEN KOPECKY: Yeah, just like blood pressure. We give a vasodilator, a diuretic, a beta blocker. They all work together. At lower doses, you can get away.

CHRISTOPHER V. DESIMONE: Makes sense. One thing I think for our audience is, how do you take this medicine? Is it a pill? Is it just like a statin medicine? Is it an injectable like insulin?

STEPHEN KOPECKY: Yes. It's very interesting. It's injectable, sub-q injection, but the regimen is different. It's a baseline one month-- or I'm sorry. Baseline three months, and then every six months. You can check lipids at one month, and you'll start to see a reduction, a significant reduction by one month. So then, every six months after that. So the adherence, we hope, will be much higher.

CHRISTOPHER V. DESIMONE: Excellent. So 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 six months sounds much easier than doing something every day.

STEPHEN KOPECKY: Yes, 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. So we'll know exactly when the patient got the drug. Did they get the right dose? Because we're doing it all ourselves. So it'll be very helpful too, I think. It'll help adherence, because we're finding that the PCSK9 inhibitors that are sub-q injected, self injected, every two weeks-- and at the end of the year, only about 60% of patients are really still taking those. So we need to increase our adherence.

CHRISTOPHER V. 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.

STEPHEN KOPECKY: Exactly. So the less shots, the better the adherence.

CHRISTOPHER V. DESIMONE: And when do you check the lipids? So when can patients expect the benefit, I guess?

STEPHEN KOPECKY: Yeah. Well just like the statins, which we'll start to see the optimal benefit in four to six weeks, the same with the inclisiran. And then, we can check it yearly after that.

CHRISTOPHER V. DESIMONE: Yearly after that, that's nice. Now, what do the FDA-- Or our practice guidelines say, yes, this patient, they're on statins. They're tolerating this well. Maybe they have some additional work they can do with their diet. But where does you say, this is the patient that would benefit from this? Maybe not just the patient that's not completely compliant but needs more. Who would be your ideal patient?

STEPHEN KOPECKY: Yeah. Well, the FDA has said, if you have a heterozygous familial hypercholesterolemia or heterozygous FH, those, that's an indication for the drug. Or if you have ASCVD, cerebral vascular coronary or peripheral disease, and you're not at goal--

And remember, we haven't talked about this, but the new goals came out just a few weeks ago. So now, if you have ASCVD, the goal is 55 milligrams per deciliter for the LDL, which is a reduction from the 70 it was for the past four years. So that's the ideal patient to give it to. They can't get to goal on a statin, on ezetimibe, on a good diet, on a good healthy lifestyle. Then, this would be someone to think of adding it in.

CHRISTOPHER V. DESIMONE: Excellent. And one other question, sometimes people have issues with statins, as you well know, and sometimes we try different doses or different types of statins. But side effects from this drug?

STEPHEN KOPECKY: Yeah. Side effects don't seem to be a significant problem. There's always injection site. That's an issue. There is a little bit, just like the PCSK9 inhibitors, every two weeks, they get a little nasal stuffiness, or bronchitis, or rhinitis. We're not really seeing any liver problem, per se, no infection problems, per se. But again, you study a drug in 20,000, 50,000 patients, and you release it to hundreds of thousands. And so we'll just have to monitor that closely.

CHRISTOPHER V. DESIMONE: Sure. But appears relatively safe.

STEPHEN KOPECKY: Yes. No. It is quite safe.

CHRISTOPHER V. DESIMONE: Excellent. Any issues if someone was to take this around pregnancy, things of that nature?

STEPHEN KOPECKY: Well, it's the same guidelines we have for the other lipid-lowering drugs. We don't want to give during pregnancy. And so I tell patients that 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.

CHRISTOPHER V. DESIMONE: Got it. And now, in terms of cost of this drug, how does someone go about-- Obviously, they would see their general practitioner, cardiologist, and they want to be seen at a specialty clinic, lipid clinic. But how do they go about getting this prescribed? And what do patients have to go through? What are their expectations?

STEPHEN KOPECKY: Yeah, 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 center at the office. So it's not where the patient brings it in. It's there for them. And so the payment structure is a little different. And 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. But every drug is a little different, and every payer is a little different too, as you know.

CHRISTOPHER V. DESIMONE: And it seems like that also helps the patient know, well, I'm going to go pick this up rather than them storing it in the refrigerator or storing it in the cabinet, and then helps with that compliance.

STEPHEN KOPECKY: Yeah. They just show up, get the shot. They don't touch the drug. The shot's administered to them, and they leave.

CHRISTOPHER V. DESIMONE: Excellent. Aside from the shot, anything that you tell patients not to take in terms of medicines? Do we know of any drug-drug interactions?

STEPHEN KOPECKY: Yeah. There really don't appear to be any drug-drug interactions. That'll be something that has to be studied more, obviously, but we're not seeing that.

CHRISTOPHER V. DESIMONE: Excellent. And then, for a patient, what do you tell them what they could expect of benefit? So they're not at goal. And thank you so much for bringing that out that 70's not the goal. The new goal is going to be 55, or the goal should be 55. But what does this give the patient? So if we say, take this medicine, what is like the reduction in mortality, cardiovascular events?

STEPHEN KOPECKY: Yeah. Well, the it is interesting. We have great data for the statins and the PCSK9 inhibitors every two weeks but remember the statins it was years before we had evidence that we actually lowered mortality the statins were approved the same now with inclisiran those studies are ongoing. The ORION studies, those will be out in a few years. And we all think they will show benefit, because they're lowering it by very similar mechanism, lowering the LDL. So I think they will show a benefit clearly. We just don't have the evidence just right now.

CHRISTOPHER V. DESIMONE: Sure. So it's like, don't wait for something really good to show up. Be on it. And if there's low side effects, low risk, and potentially really good benefit, that's something I would offer my patients as well.

STEPHEN KOPECKY: Yeah. I think it's going to be the convenience issue and the adherence issue that may really make the difference.

CHRISTOPHER V. DESIMONE: Sure. That sounds much better to me rather than taking a drug every day, well, in addition to taking the drug every day, but shots frequently once every six months.

STEPHEN KOPECKY: Yeah. And there's a model for that. It's called the osteoporosis drug every year or so. We have a lot of patients. The snowbirds fly up. They get their shot. They fly back down on the winter. They're happy with that.

CHRISTOPHER V. DESIMONE: Exactly. Anything else important about the drug or things coming down the pipeline, differences of this drug, or stuff for patients to know, or even our cardiologists, primary care?

STEPHEN KOPECKY: Yeah. For these drugs, we're starting to see that less frequency is starting to be the name of the game with this. We're starting to see drugs come along that will actually lower lipoprotein A. That's a whole different set of drugs. But now, these drugs that we're talking about today will lower it 20%, 25%. The new ones will probably lower to 70 to 75.

CHRISTOPHER V. DESIMONE: Wow.

STEPHEN KOPECKY: So we have something to look forward to in the next few years.

CHRISTOPHER V. DESIMONE: Impressive, impressive. But we're always trying to get what's best for our patients as soon as we can, making sure-- safety, really.

STEPHEN KOPECKY: Oh, exactly, exactly. And the one thing to remind patients, it's not just about the pill, 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.

CHRISTOPHER V. DESIMONE: Agreed, agreed.

STEPHEN KOPECKY: So patients need to eat healthy and do the things that we tell them that really can help their life.

CHRISTOPHER V. DESIMONE: That's its own pill, and its own shot in itself.

STEPHEN KOPECKY: Exactly, exactly.

CHRISTOPHER V. DESIMONE: Exactly. Well, thank you, Steve, for these very important insights. And thank you for joining us on theheart.org Medscape cardiology seminar.

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