Add-On Therapy With Statins and PCSK9 Inhibitors in CVD



Deepak Bhatt, MD, MPH: Let’s move on now to talk a little about other classes of drugs in terms of cardiovascular risk reduction. Jamie, tell us a little about your experience using ezetimibe as add-on to standard therapy.

James A. Underberg, MD: Sure, I’ve been using ezetimibe for a long time now. It’s a drug people love to hate, and then they love to love. It’s getting lost in the myriad of other options that we have out there. What’s great about ezetimibe is currently it’s inexpensive and it’s very well tolerated. One of the reasons that often gets overlooked is because it’s not that robust when it comes to LDL [low-density lipoprotein] lowering. When the pedal hits the road, so to speak, and you look at its impact on cardiovascular risk reduction, you have to treat a lot of patients for a long period of time to make a difference because the change in LDL in general is relatively small. As a lipidologist, I see a lot of patients with inherited LDL disorders, familial hypercholesterolemia. Some of those patients are hyperabsorbers. Ezetimibe works by blocking absorption of cholesterol in the proximal jejunum. Some people do respond to a greater extent than you would think when you give them ezetimibe.

In fact, our current guidelines suggest adding ezetimibe to statins before moving on to other LDL-lowering agents, such as PCSK9 inhibitors, for exactly that reason because it’s inexpensive, it’s well tolerated, and people may get more of a response than you think. If that happens, it’s great. But the experience is that in most cases it doesn’t get people to where they need to go.

If you look at patients who are taking both statins and ezetimibe, there’s still a significant number of high-risk ASCVD [atherosclerotic cardiovascular disease] patients who do not get to where their LDL cholesterol goal needs to be. While it’s a tool we can use, it leaves us wanting in some regard. It’s great that we’ve got a lot of other options for LDL lowering. But in concert with that, we also have options like EPA [eicosapentaenoic acid] for ASCVD risk reduction. This is really what we’re trying to do when we manage lipids in patients.

Deepak Bhatt, MD, MPH: That’s really a nice summary. I’m not sure who those haters are of ezetimibe. I don’t know why someone would hate such a drug.

James A. Underberg, MD: When it was first made available, it was branded. Those who did not prefer it were the payers because it was expensive. No one wanted us to use it in the beginning because it was a branded agent. Once it became unbranded, suddenly it was the step through that you had to use before you got to any other drug. This was a 180-degree change in a medication that never changed with regard to how it worked.

Deepak Bhatt, MD, MPH: I do remember all that controversy about ezetimibe. Is it causing cancer? I never really was concerned about any of that. The data ultimately disproved all that. But there was a lot of noise around ezetimibe for a while; you’re right. I know there were haters. I just never understood why.

James A. Underberg, MD: Neither did I.

Deepak Bhatt, MD, MPH: Brett, perhaps you can speak about PCSK9 inhibitors. There are definitely some haters there. Do you actually use these agents in your practice? How do you use them? Do you use them as single agents, with statins, with ezetimibe thrown in the mix, or all the above? What do you actually do?

Brett Nowlan, MD, FACC, RPVI: I am a very enthusiastic user of all those agents. Statins of course—I, like James, am a big user of ezetimibe. I use PCSK9 inhibitors in hundreds of my patients, literally. Certainly, I do all combinations of those and the largest factor driving that is patient tolerance and acceptance. I’m a pragmatist. I am where the rubber hits the road in terms of treating patients every day.

If a patient doesn’t accept and take a therapy, they’re not going to get any benefit from it. I really do use all those agents in various mixes. I am enthusiastic about ezetimibe, as James was alluding to, because if you use it as monotherapy you get about a 15% to 18% reduction. If you add that onto a statin, it will be like a 22% to 25% reduction. If you’re above the threshold that you’re treating someone but you’re close, then ezetimibe is a good option and generally very well tolerated as well as generic and inexpensive.

Something else I’d like to add is, James was alluding to the IMPROVE-IT trial, where over 6 years the absolute risk reduction of adding ezetimibe onto statins was 2%. But if you were diabetic in the IMPROVE-IT trial, that absolute risk reduction was more like 5.5% over 6 years. That’s nothing to ignore there. We also have IVUS [intravascular ultrasound] data from the precise IVUS trial showing that you can improve plaque regression if you add ezetimibe onto atorvastatin compared with atorvastatin alone. For those reasons, I do use ezetimibe a lot.

The circumstance in which I may reach for a PCSK9 inhibitor instead of ezetimibe would be in my patients with lipoprotein(a) [Lp(a)] elevation. We know that on average, 20% of the population probably carries elevated lipoprotein(a). I measured it in all my patients. We know that PCSK9 inhibitors are the only therapeutic out there that we can lower Lp(a) levels, on average about 20% to 30%. If you look at the ODYSSEY OUTCOMES trial, they did an analysis of those patients who carried Lp(a), and they realized that those patients were getting relatively more benefit from the PCSK9 inhibitor than they were from the statin in terms of MACE [major adverse cardiovascular event] reduction because of the lowering of Lp(a).

Of course, we have intriguing recent data from both the FOURIER trial and ODYSSEY OUTCOMES that show that there is a reduction in venous thromboembolism and a reduction in aortic stenosis events. Certainly 1 of the postulations there is from the reduction in Lp(a). To summarize, I’m an enthusiastic user of ezetimibe in my practice. The circumstances in which I would reach over ezetimibe for PCSK9 inhibitor would be for patients with significantly elevated lipoprotein(a), if someone is significantly above their threshold or their goal or target that we’re aiming for, and of course for that small number of patients who don’t tolerate ezetimibe. But the final statement is that choice is very often made for us by the insurance payers. That it is what it is.

Deepak Bhatt, MD, MPH: Those are really great points, Brett. What you mentioned about Lp(a), in particular, is really interesting. As you know, the European Atherosclerosis Society guidelines had said measure Lp(a) on everybody at least once in their lifetime.

Worldwide that’s going to be something we see more of. Companies are developing drugs to target Lp(a), so I’m glad you mentioned that.

Transcript Edited for Clarity

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