PCSK9 Inhibitors: Single Agent or With Ezetimibe?


Steven E. Nissen, MD: We’ve got a lot of therapies that we can bring to bear that are well tolerated and becoming more available. Statins are great, but I want to talk about at least a couple of things. One is what do we do with the statin-intolerant patient? I know you guys see this every day; so do I. Every one of the panel members sees this as just a terribly huge burden. What do we do about people who on the maximum-tolerated statin dose don’t have acceptable LDLs [low-density lipoproteins]? I’m going to start it off by saying that in my view, the PCSK9 inhibitors are being underutilized. They’re very effective. Patients do not mind self-injecting. It’s not a big burden.

We have 2 trials, 1 for alirocumab and 1 for evolocumab, that show statistically significant benefits on morbidity. And now the prices have been reduced to the point that it’s about what branded rosuvastatin cost near the end of its life cycle, and that drug was used very widely. It’s in the same ballpark with what branded atorvastatin cost near the end of its life cycle. The question is how did we get in this mess, where we’re not able to get patients to LDL goals because of the pushback on use of the drugs.

Deepak L. Bhatt, MD, MPH: Absolutely. Before PCSK9 inhibitors, what about ezetimibe? You mentioned ezetimibe in passing there. It’s a safe drug, it’s cheap, it’s generic, and it has modest LDL reduction. But 2 outcome trials that have shown benefit—IMPROVE-IT and now more recently EWTOPIA 75. I know in the past, Steve, you thought it’s a really modest LDL reduction, but now that it’s generic, what are your thoughts about using it?

Steven E. Nissen, MD: I use it all the time, but I also am cognizant of its limitations.

James A. Underberg, MD, MS: I think the mistake a lot of people make is that the reported lowering of LDL with ezetimibe is the mean effect, and that many people often respond.

Steven E. Nissen, MD: Hyper absorbers.

James A. Underberg, MD, MS: To greater extent, especially when they’re on statins or if they have familial hypercholesterolemia. Both become hyper absorbers. The reason it’s in our current guidelines is because it’s worth trying, because you may get a greater-than-expected response. You may not, and some people might feel that the distance they need to go is so much, they want to move right through a PCSK9 inhibitor. But I don’t think it’s unreasonable to consider trying ezetimibe. That’s what the data support.

Michael Miller, MD: Yeah, right, the guidelines say that’s a second-line agent right after statins. We’ve had a good experience with it as well.

Deepak L. Bhatt, MD, MPH: As a practical point, many third-party payers, depending at least on the region of the country, won’t let you go to a PCSK9 inhibitor.

Steven E. Nissen, MD: I also think we have to be reasonable and understanding. IMPROVE-IT, while it was statistically significant, was a 6% reduction after 7 years. It was a pretty small reduction in morbidity in a very long trial. Not a huge effect. But gosh, I’ll take it for a generic drug. So if I get somebody— particularly if they’re close to goal, if they’re close to where I want to get them—if I can get them there with ezetimibe, I will.

Deepak L. Bhatt, MD, MPH: And it was a good adverse-effect profile too, right?

Steven E. Nissen, MD: Yeah, very safe.

Deepak L. Bhatt, MD, MPH: Very well tolerated.

James A. Underberg, MD, MS: It taught us a very important piece of information, which is that when you’re at the low end of the LDL scale—those patients were below 70 mg/dL in IMPROVE-IT—if you’re not going to change LDL a lot, you’ve got to treat them for a long period of time to see a benefit.

Deepak L. Bhatt, MD, MPH: It gets back to the area under the curve concept.

Steven E. Nissen, MD: It does. It’s another great thing for younger patients. And for people who don’t want to take a statin, it gives you some real opportunity to do them some good. The problem I run into is I have somebody who’s on the maximally tolerated statin dose and for whom it may be their secondary prevention and their LDL is 110 mg/dL. The question is, am I satisfied with dropping the LDL from 110 to 95 mg/dL, or am I not?

Michael Miller, MD: Would the insurer pay for it? That is the question.

Steven E. Nissen, MD: We’ve been hammering the third-party payers pretty hard, and we’ve been successful at getting them to approve a lot of our patients for PCSK9 inhibitor.

Deepak L. Bhatt, MD, MPH: Even without ezetimibe.

Steven E. Nissen, MD: No, we usually have ezetimibe on board. But these are people who still have higher LDLs than we believe to be desirable. The wonderful thing about PCSK9 inhibitors, there’s no diminishing returns on top of statins. If you’re at 100 mg/dL—if your LDL is 100 and you had a PCSK9 inhibitor, you’re going to get to 50 mg/dL.

Michael Miller, MD: But will insurers pay for an LDL? They’re on a statin, ezetimibe. What is the lowest level of LDL they’ll pay for? Is it 70 mg/dL, so the patient has to be above 70 and the insurer will pay? Because I think primary care physicians need to know this information.

Steven E. Nissen, MD: It’s highly variable, and it also depends on how well one articulates. We have a whole team of people who deal with this. Unfortunately, we have to spend a lot of resources in order to get through it. Now, I’m not a big fan of pharmacy benefit managers. I have been extremely critical of them because they are not public health organizations. They’re interested in 1 thing; it’s called money. If they could keep you from using the drugs, they make more money. I don’t think that’s even morally acceptable, so I fight them pretty hard.

Deepak L. Bhatt, MD, MPH: I agree with you. What about EWTOPIA 75? What do you guys think about that?

Christie M. Ballantyne, MD: For me, the take-home was the benefit in older adults. That’s a group people have asked if they had benefit or not. They had benefit in JUPITER. They had benefit in EWTOPIA 75. It is a group that has benefit.

Transcript edited for clarity.

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