Jeffrey Geske, MD: Greetings. I'm Dr Jeff Geske, an assistant professor of medicine cardiologist at Mayo Clinic. During today's round table review, we'll be discussing PCSK9[1,2,3,4,5,6,7] inhibitors. I'm joined by my colleagues, Dr Scott Wright and Dr Stephen Kopecky. Thank you so much for being with us. They're both professors of medicine and my go-to experts for cholesterol management and all challenges in that regard.
I'm excited to talk to you today as the FDA has approved evolocumab (Repatha, Amgen) for use.
Scott—when do you use these drugs? How do they work, and how do they differ from statins?
How PCSK9 Inhibitors Work
Scott Wright, MD: Those are really good questions. It's always an honor to join my good friend and colleague, Steve Kopecky, who has the most experience of any Mayo physician with both of these compounds. He is our go-to investigator for using the drugs.
In July, the FDA approved alirocumab (Praluent, Sanofi/Regeneron), the first monoclonal antibody to inhibit a new protein that we discovered 10 years ago, called PCSK9. Now this protein regulates the lifespan of the receptor on the liver that clears cholesterol. If you bind the protein, paradoxically, you lower cholesterol, because the protein causes the liver receptor that clears cholesterol to be destroyed and recycled. So if you bind the protein, the receptor stays on the liver longer and clears more cholesterol from the body.
If you're taking a board exam down the road (anyone in the audience who might be watching) if you give these drugs, they don't raise cholesterol, they lower it by binding the protein. Statins work by lowering cholesterol by inhibiting the synthesis of cholesterol and also by causing the liver to upregulate the number of clearance receptors. But compared with the PCSK9 antibodies, statins perform weakly in that regard. These drugs are very, very powerful. When given in combination with statins, we can take bad cholesterol to very low levels, like 40 or 30 mg/dL. If you really wanted to, you could take LDL-C to below 10 mg/dL, although no one recommends that, and we don't even know if it's safe.
[The PCSK9 inhibitors] work differently than statins in the following ways: 1) they promote the modulation of the receptor that clears cholesterol—if you give the drug, you prolong the receptor and clear more cholesterol; you don't block synthesis, you block clearance. 2) They're injectable. So instead of taking a pill every day like a statin, you take an injection of these drugs every 2 to 4 weeks.
And the differences [between the two PCSK9 inhibitors] are: do you dose the drug every 2 weeks vs every 4 weeks? Alirocumab is every 2 weeks at two different doses, and evolocumab can be 2 or 4 weeks, depending on what you hope to do. That's how these drugs work.
That's why they're so exciting, because we can now take cholesterol to much lower levels and, hopefully, further prevent recurrent cardiovascular events and also prevent certain patients, like those with heterozygous familial hypercholesterolemia, from developing heart disease in the first place.
It's quite exciting. It's been a decade or more since we've had a breakthrough.
Which Patients Should Get These Drugs?
Dr Geske: Steve, knowing that these work in a different mechanism, what patients would you target? Should everyone who is on a statin be receiving these drugs? What has the FDA approved it for?
Stephen Kopecky, MD: Well the FDA came out very specifically and said they would approve it for homozygous hypercholesterolemia—at least evolocumab got that indication—and those people have very high cholesterols, LDL-C levels of 500 to 600 mg/dL. The second group was the heterozygous hypercholesterolemia or mixed hyperlipidemia, and they said both drugs could be used for that as an adjunct to diet and statins, if necessary. Then as a supplement to that, if you're intolerant to statins, then you could use it [alone] instead of with a statin.
Dr Wright: The language is very important, because most of us are interpreting the FDA language just as Steve did, but the language doesn't use the term "statin intolerance." It says for those who are taking the maximally tolerated statin dose who need additional risk reduction—and that can mean zero statin tolerance or tolerating 40 mg of atorvastatin or 40 mg of rosuvastatin but you still need your LDL-C lowered. Isn't that fair to say, Steve?
Dr Kopecky: Clearly. If you can't get to the goal you're supposed to be at, you can add these drugs in.
Dr Wright: But I think there's a danger with these new drugs, and the danger that I'm getting at is something Steve just alluded to, and that is—don't forget lifestyle, diet, and exercise.
We tend to believe we can cure everything with pills or injections, but these are predicated on patients being adherent to a very healthy lifestyle and being on an appropriate exercise regimen. Don't you agree, Steve?
Dr Kopecky: Most patients can get their cholesterol under control. The ones who are genetically high, they can't. Most can, but very few of them do.
Dr Geske: Right.
Dr Kopecky: So the thing we have to be careful with is that we don't start giving these drugs, which are very expensive, to patients who just don't have a good lifestyle. You've got to really push them to change their lifestyle and help them change their lifestyle.
Dr Geske: What sort of cost are we seeing for these?
Dr Wright: $13,000 a year, more or less.
Dr Geske: Wow!
Dr Wright: There is about $800 difference, on a yearly basis [Editor's Note: The price difference is about $500 more for alirocumab vs evolocumab]. Now, it will depend on your insurance, your copayments, whether you've met your deductible, and whether you are within the doughnut hole if you're on Medicare. But compared with statins, which you can purchase for probably less than $100 a year generically, this is a substantially higher cost.
Dr Kopecky: I'd like to ask Dr Wright, what do you think of the difference in cost in the countries? In Europe, the cost is about half as much.
Dr Wright: You know it just fits the trend we've seen for many years or decades that the United States subsidizes the rest of the world for the R&D cost of the new compounds as well as the actual delivery costs. We allow the market here to better negotiate prices than a central governing agency like the health authority, and most European countries do just the opposite to get the cost down. For the patients, it's an expensive trade-off, but at the same time, if we went to the European model we would have less money for research. So I don't know the right societal answer.
Dr Kopecky: I do think there's a real plus, and that is I tell my patients, here's this drug—it's $14,000 a year. If you want to go to Europe, spend $7000 and have a great vacation with your spouse, pick up the drug, and come back, you're equal but you've had a great trip.
Dr Geske: And pick up some new diet tips on the way, maybe?
Dr Kopecky: Exactly. Eat Mediterranean while you're there.
Dr Geske: What sort of side effects do we end up seeing with these new agents?
Dr Kopecky: It's very interesting, because even though, as Dr Wright pointed out, [instead of] blocking a pathway, it enhances a pathway, so the receptor can be used over and over again, we're still seeing some side effects. We do see some muscle aches, and they do occur with these patients. And it may be the rapidity with which we drop the LDL cholesterol or the cholesterol overall that can cause that. There is a signal in one of the studies that you have some memory problems—in the placebo group, it was about 0.5%; maybe double that in the participants who got the actual drug. That got everybody pretty excited, and we're following that very closely in our patients. And then third, there is another signal. If you get the LDL-C too low—we've always thought you can't get an LDL-C too low, when you're born, it's about 50 mg/dL, and if you keep it under 50 mg/dL, that's great—but if it falls under 20 mg/dL, you may start to get cataracts. So we have to be careful with that and watch that closely.
Dr Wright: That's why it's very important to continue long-term follow-up with these medicines. In fact, one or both of the approved drugs have a registry where the FDA has said, we want to see potential side effects postmarketing approval. That's why it's important to continue the clinical trials with these drugs so that we know the consequences. Because we're going where we really have never gone before in terms of LDL-C lowering, but we don't know the long-term safety and/or benefit of that.
Effect on Risk of Heart Attack and Stroke
You're probably going to want to know—do these drugs reduce the risk of heart attack and stroke? And the answer is, we don't know. We think so. Both of the compounds have been analyzed in their initial studies. Now, the studies were not designed to see whether the drugs could have an impact on end points like heart attack, death, and stroke. They were simply designed to see if you could lower LDL-C in various populations. They pooled these data and they did a quasi-meta-analysis of on-treatment effects—it's not a randomized trial where we can be fairly confident of a cause and effect. But is there an association between being on the drug with a low LDL-C and having less risk of a heart attack or stroke? The answer is consistently, yes, there is. So it fits the hypothesis that in the lowering of LDL-C, the lower we go, the better, but we don't have definitive proof of efficacy or safety, and that's why the "outcome trials" need to continue and be done.
We think these [drugs] will work, but we don't know. We're very hopeful they will work. They fit all of the science that we know, but we have to continue the science to be sure for the safety and benefit of our patients. And at the cost these drugs are costing, we need to be really sure because we're asking everyone, whether it's an individual payer or an insured group, to sacrifice a lot to use these drugs, and so we need to be sure the return on the money spent is a good health benefit.
Dr Geske: So exciting times but, obviously, a lot of unknowns still that we need to follow up on. Steve, any closing pearls or comments that you want to leave us with?
When Should We Give the Drug?
Dr Kopecky: There are a couple of things that are of interest. One is that we all have different levels of PCSK9—maybe the people with more PCSK9 may have much more benefit than the ones with low. Now that hasn't really been borne out in the studies, but that was just a mass assay of PCSK9. If we do an activity assay, it may be different, and that may help us pick who should get the drug. The second thing is, if you look at some of the antibodies used for the arthritic drugs, there are about 10% of people that develop immunity to them, or they don't react anymore to it, because antibodies can build up, and so the drugs are no longer effective. So we need to follow that too.
Dr Wright: Steve, what do you recommend to the average Mayo physician who calls you and says, 'Should I be using this drug?' For the people watching, and for Jeff and me, who do you recommend that we use these drugs in?
Dr Kopecky: If you have events and you need to get your LDL-C under control and you can't because you don't respond to the statin or you can't tolerate the statin, and you've done all you can do with lifestyle—I think it's very important, as you pointed our earlier, changing your diet, changing your lifestyle—then I would think of giving the drug to them. But you really have to have some good heart-to-heart talks and say, how much are you really working at this? How much can you do? Your lifestyle may be such that you can't change what you eat because of your job or your family or work position, and we need to help patients do that.
Dr Wright: Do you recommend, for the clinician, that they first try to get them on a maximal statin dose before considering these drugs?
Dr Kopecky: Without a doubt, and not just one statin. Try a different statin because there's evidence that different statins have different benefits in different patients.
Dr Wright: Given the cost difference between, a drug like ezetimibe (Zetia, Merck) and the PCSK9s, do you advocate a strategy of adding ezetimibe to the statin before you escalate to the third therapy, which would be a PCSK9?
Dr Kopecky: Sure, without a doubt. Much cheaper.
Dr Wright: You think that's cost-effective?
Dr Kopecky: It could be in some patients. We have to do all we can, spanning from diet and lifestyle to managing medications including statins, before we jump to these medicines. I think that's clear.
Dr Wright: But for maybe someone who's got an LDL-C of 290 or 300 mg/dL who's had a heart attack and has, maybe, a heterozygous or genetic dyslipidemia, it may be very rational to just simply go to a PCSK9 inhibitor plus a statin as opposed to trying a variety of escalations. But for the average patient who doesn't have a genetic dyslipidemia, it's very rational to try a stepwise approach. Would that be a fair approach?
Dr Kopecky: I've seen some good responses to statins in very high LDL-C levels. I wouldn't give up on that first.
Dr Wright: I agree. I'm just trying to decide how I factor ezetimibe into this, and I think there is, sometimes, a situation where using a PCSK9 right after a statin is probably the most medically appropriate thing, especially in someone who's high-risk and has a very high LDL, like heterozygous FH.
Dr Kopecky: That's very reasonable.
Beginning of a New Paradigm
Dr Wright: Jeff, I think I'm quite optimistic. Given the safety profile so far, the low risk of side effects, the dramatic reductions in LDL-C, I think it's very possible that your generation of cardiologists will be able to see a dramatic reduction in coronary artery disease. I'm hopeful that's where we're at. We've been struggling. Steve and I have been working the past 2 decades on that, and I'm hopeful that we'll see it in our lifetimes, and you'll see it in your career, and that our viewers will also see it because it will be a big breakthrough if that's what works.
Dr Geske: Wonderful.
Dr Kopecky: If it's an antibody, they can make a vaccine to it. You can make a vaccine to it and you can get it once a year. So come in, Dr Geske, for your vaccine once a year, then go eat whatever you want.
Dr Wright: There are at least one or two companies who are testing antisense compounds, which will be less frequent injections, and there are rumors that there may be a pill. This is the beginning of what we hope is a new paradigm, because Dr Kopecky and I both refer to ourselves as interventional lipidologists at times.
Dr Geske: It's great to have some new ingredients for the cholesterol cookbook, and it's wonderful to hear the different framework of approaches and hear some of the different ways that this can impact our practice.
Thank you so much, Scott and Steve, for joining us here, and thanks to our viewers for tuning into this round-table discussion. And you can find more at Mayo Clinic and theheart.org on Medscape.
Cite this: Jeffrey B. Geske, R Scott Wright, Stephen L. Kopecky. PCSK9 Inhibitors: How They Work and Who Should Get Them - Medscape - Dec 03, 2015.