Efficacy and Safety of PCSK9 Inhibitors

Peter Salgo, MD: All of this is very good unless you have familial hypercholesterolemia (FH). In other words, if you’re going to start with diet and exercise in someone with FH, you’re going to fail. What are the current options right now for FH?

Seth J. Baum, MD: Well, the current options for FH are the same options that exist for clinical ASCVD (atherosclerotic cardiovascular disease). So, you’d use statins—high-intensity statin therapy—and then you’d add a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, if necessary. Or you could add ezetimibe if you can get to goal on ezetimibe. For the homozygotes, there are other agents, but it’s only in very rare conditions, about 1 in 300,000, let’s say. So, I don’t think we need to go into those drugs.

Peter Salgo, MD: You did mention the PCSK9 inhibitors, which is where I needed to go in the first place, because these are the brand new drugs. These are the new kids on the block, and they have gotten a lot of press, actually. It was just in the New York Times. What are they and how do they work?

Howard Weintraub, MD: Via epidemiologic studies that were performed in France and in Texas, they were able to identify certain genetic differences in people whose cholesterols were either very high or very low. And they found that the presence or absence of a certain gene, for a protein called PCSK9, would not identify people with high or low cholesterol. So, this is a protein made within the cell that manages to interfere with the way that the LDL receptor is processed. Think of the LDL receptor as a garbage can in which LDL is the positive. It is, then, internalized, and then what normally happens is the receptor regenerates back to the surface and the LDL is degraded. When PCSK9 is present, you destroy the garbage can as well. So, ultimately, if you keep destroying the garbage can, where does the garbage go? It goes everywhere it wants to in the blood vessel. So, these people have very, very high levels of cholesterol versus those who have none of this gene and don’t make this protein. They have a huge number of receptors and their LDL is very low.

Seth J. Baum, MD: And they don’t get coronary disease.

Howard Weintraub, MD: Exactly. These are people with LDLs in the teens.

Peter Salgo, MD: Why don’t you discuss the safety and efficacy in these drugs?

Howard Weintraub, MD: These are monoclonal antibodies. So, what’s great about both of these is they aren’t handled by the liver or the kidney, which immediately removes a lot of the worries that we have. They’re not drugs, so there’s no drug—drug interaction. So, immediately it’s a win. These are injected subcutaneously, and very rapidly, they inhibit PCSK9 in the blood and then LDL levels fall like a stone over the next several days. The LDL stays down for about 7 to 10 days, and then starts to inch back up at 2 weeks. So, the medicines are given every 2 weeks (or there’s a larger-reservoir form given every month). Evolocumab, which is the one that had been studied in the FOURIER study, is given in 1 dose. Alirocumab is given in 2 doses. I’m not sure I know why we need the lighter dose, but it’s there anyway. And these drugs can lower LDL in the range of 50% to 70%.

Peter Salgo, MD: Again, we’re talking percent. We’re talking numbers, now, that were simply unimaginable a generation ago.

Howard Weintraub, MD: Exactly.

Peter Salgo, MD: Which is where the 30-mg/dL goal came in.

Seth J. Baum, MD: And this is on top of maximal statin therapy.

Peter Salgo, MD: Can you use them instead of maximal therapy?

Howard Weintraub, MD: Yes. There are patients who are legitimately statin intolerant, who are miserably debilitated because of muscle inflammation. They can barely walk and do other things. These are people who are statin intolerant, and without statins, these people have plaque in their coronaries and plaque in their carotids. These are accidents waiting to happen. You can prevent this. This is one of the most contentious areas in getting the drugs approved. Many times, managed care companies have asked (and this is no lie), for receipts from drugs bought 5, 6, 7 years before. Who keeps receipts for these drugs that were bought?

Peter Salgo, MD: Without getting into that, let’s focus on these drugs, for just a minute. We could return to beating up the insurance companies later. They’re nice people. They’re sitting here with us. But that being said, these are nice drugs.

Howard Weintraub, MD: Right.

Peter Salgo, MD: So as far as we can tell, in the data that was just released recently…

Howard Weintraub, MD: The side effect profile is spectacular.

Peter Salgo, MD: Side effect profile is what?

Howard Weintraub, MD: Zero, essentially. Just injection site.

Peter Salgo, MD: You mentioned these are injectables. You don’t go home and pop a pill every night?

Howard Weintraub, MD: No. Because it doesn’t interact with other drugs and is not metabolized by the liver or the kidney, a lot of things that would make other drugs dangerous are not there.

Peter Salgo, MD: Now, you mentioned the FOURIER study, and there is the GLAGOV study. What are those 2 studies, and what do they show?

Seth J. Baum, MD: FOURIER was the one that was just released. It was 27,500 high-risk patients, patients with vascular disease and other risk factors (so pretty high risk), and it showed that it met both primary and secondary endpoints—meaning that it significantly lowers the risk of heart attack and stroke. There was a lag period of about 6 months before you started seeing a tremendous efficacy, and that’s because, obviously, people enter the trial having had a history, if you will, of developing vascular disease. It took a while to get them to have the lower LDL take effect. So, although we get the LDL low, very rapidly, it takes a while to see that kick in from an outcomes standpoint.

Peter Salgo, MD: This brings up a question which was at the dawn of the statin era, and I guess it’s being asked again: can you actually reduce, from a baseline, when you start using these drugs, a person’s cardiovascular risk to below where they started? Or do you just hold them at the risk they were when you started giving the drug?

Howard Weintraub, MD: Good point. You do lower it below where it was when they started. You can put trajectories on the development of an event based upon where their LDL is, based upon high, little, medium, and very high risk. You can, then, look at their LDLs and know that if you don’t do something in 6, 12, 18 months, this person is going to have an event. You lower their LDL, and the likelihood of them having an event is much less. Jennifer Robinson, MD, did a publication in Journal of the American College of Cardiology last year that showed these curves very, very nicely. So, this is an important thing to see, and you have guidance on that.

Peter Salgo, MD: Before we leave this topic, if I hear you correctly, these are injectable drugs. They block a receptor, if you will, or a chemical, right?

Howard Weintraub, MD: Right.

Peter Salgo, MD: And they dump your LDL cholesterol way down to levels previously unobtainable, like 20 mg/dL or 30 mg/dL?

Howard Weintraub, MD: Correct.

Peter Salgo, MD: And the side effect profile, so far (and we’re not 10 or 15 years out, but so far), is very good?

Howard Weintraub, MD: Right.

Peter Salgo, MD: What is the implication of this for the country at large, in your view?

Jennifer Strohecker, PharmD, BCPS: Well, my view, as a pharmacist, is that it’s fantastic. It gives an opportunity for patients who have been unable to achieve their goals—they’re high-risk patients. These patients will predictably have an event in the future, and it’s a fantastic alternative to reduce that risk.

Peter Salgo, MD: Are you going to pay for it?

Gary L. Johnson, MD, MBA: I’ll use one of those garbage basket terms, like “medical necessity.” In the appropriate patients, yes, we will pay for it.