Paradigm Shift in Lipid Management - Episode 10

PCSK9 Inhibitors to Help Lower LDL-C

October 9, 2020


Alan Brown, MD: Keith, let’s start with the whole class of PCSK9 inhibitors. In which types of patients should we use them? How do they work? What has your experience been?

Keith C. Ferdinand, MD: I use PCSK9 inhibitors quite extensively. They’ve been a major breakthrough. As you know, they’re monoclonal antibodies against PCSK9, which shepherds the LDL [low-density lipoprotein] receptor into the liver. That causes it to be broken down, so you don’t have LDL receptors that are available. Their ability to lower the LDL is very potent. They achieve anywhere from 45% to 60% LDL reduction. They now have clear cardiovascular outcome events, although there’s some debate about the ability to show a decrease in cardiovascular death. That is probably because they’re superimposed on the platform of maximally-tolerated statins.

Most patients don’t find them difficult to take. The every-2-week injectables are well tolerated, perhaps even better than once-a-month injectables. The biggest barrier was access with the cost. That has been ameliorated to a large extent. The prior authorization process has now been streamlined. Over 90% of benefit managers will accept electronic authorization without charts being faxed, as we did early on. There’s a website, CoverMyMeds, which allows you to electronically enter data and get the PCSK9 inhibitor approved without going to the specialty pharmacy. You can use the regular community pharmacy at this particular point.

They are easier access and not difficult to use. Although it’s an injectable, it’s well-tolerated and very effective for robustly lowering the LDL without causing intolerable adverse effects. Those benefits make it a win-win, in terms of patient and cardiovascular outcomes.

I have 1 comment related to the use of ezetimibe. Seth had mentioned earlier, because we were all agreeing, that he was going to go against the guidelines a bit. I’m going to join in that. They suggested that very high-risk patients use the ezetimibe first, as a step prior to the PCSK9 inhibitor. That was probably related to some cost-benefit analyses. But if you look at the outcome trials for either evolocumab and alirocumab, only about 5% to 6% of the patients were on ezetimibe. You can make a strong case that the evidence is for the use of the PCSK9 inhibitor on top of maximally tolerated statins without ezetimibe in order to get the benefits.

Alan Brown, MD: Yes. As for the cost piece, just to toot my own horn a bit, we published a cost-effectiveness analysis after the price lowering of PCSK9 inhibitors. We showed that if the LDL was over 100mg/dL, it actually was more cost-effective to add a PCSK9 inhibitor than step to ezetimibe. That was because the number needed to treat was so much higher.

Keith C. Ferdinand, MD: One more point, and then I’ll shut it down on my comments.

Alan Brown, MD: Let me finish mine, and then I’ll give it back to you.

Keith C. Ferdinand, MD: Alright.

Alan Brown, MD: The second part was that it had reasonable value with LDL above 70mg/dL, but it was a high-value therapy to give a PSCK9 inhibitor if the LDL was above 100mg/dL. I want to give some support to the guideline authors. As Pam pointed out earlier, the reason they said to step to ezetimibe was not because it was cheap and safe. It was also because of this remarkable variability with some patients getting up to a 40% LDL reduction when adding to ezetimibe. They said, you might as well try it. But I agree with you. It’s going to be a judgement call. That has been a bit controversial. But there were smart folks on both sides of the argument trying to do what was best for patients.

I’m sorry. Go ahead. You were going to finish.

Keith C. Ferdinand, MD: I have 1 last comment on the PCSK9 inhibitors. We know statins have very little effect on LP(a) [lipoprotein (a)], which is another compound that is toxic to the vasculature. PCSK9 inhibitors will lower LP(a) by as much as 15% to 20%. There has been at least 1 analysis suggesting that adds to the benefit, on top of the LDL lowering benefit of the PDSK9 inhibitors. We did an analysis of evolocumab and looked at the cohort that self-identified as black. Unfortunately, that was not a large proportion of the population which was studied, but it did appear to have a benefit. That’s probably because it added a 20% reduction in LP(a) onto the DLD reduction.

I’m an advocate for PCSK9 inhibitors. The cost was a barrier, as you explained. Ezetimibe also has clear benefit, and it’s not unreasonable to use it as a first step. But based on the outcome trials, it’s also not unreasonable to go from high-intensity, maximally tolerated statins to PCSK9 inhibitors in very high-risk patients.

Alan Brown, MD: That was very well said. Pam, you have the floor to talk about your thoughts on PCSK9 inhibitors.

Pamela Bowe Morris, MD: I agree with everything Keith just said. I agree that there are many patients in whom it makes more sense to go straight to PCSK9 inhibitors, rather than stepping through ezetimibe. It depends somewhat on how far above the threshold of 70mg/dL the patient is. Obviously, above 100mg/dL, it makes more sense to go with a PCSK9 inhibitor. But as for the order in which I would use them, each patient is an assessed individually.

The thing that’s most remarkable about PCSK9 inhibitors is how incredibly well tolerated they are. They’ve been such a gift for patients with statin-related muscle symptoms, and they’re very easy for patients to self-administer. The prescribing process has gotten easier. They’re a great addition to our armamentarium.

Seth J. Baum, MD: I want to add something about PCSK9 inhibitors. I, too, think they are a great advance, and the biggest advance in lipid-lowering therapy in 30 years. They’re a huge advance. We struggled through the whole prior authorization and access issue, and we’re now at a point at which access certainly has improved. The problem is, if you look at how many people in these very high-risk cohorts have actually gotten PCSK9 inhibitors, it’s 2 in 1000. We have this gigantic group of people who should have been prescribed a PCSK9 inhibitor. Seventy percent of these people have an LDL over 70mg/dL and have not been prescribed a PCSK9 inhibitor.

The dotted line in the guidelines was specifically included because of cost. Yes, they were released. Unfortunately, 2 weeks later, 1 of the prices had been lowered 60%. You can’t go back. You can’t change that. But it gives us an opportunity, as Keith is saying, to prescribe the PCSK9 inhibitors, understanding that the cost-benefit analysis is probably quite different now.

Transcript Edited for Clarity