Advances in the Management of Hypercholesterolemia - Episode 9

PCSK9 Inhibitors and LDL-C Reduction

Transcript:

Howard Weintraub, MD: There are people who are legitimately statin intolerant. Whether you quote the numbers and studies of 7% or 8%, or the perceived value, which is double that, of people at risk, you feel badly when you know the impact of inadequately treated LDL [low-density lipoprotein] cholesterol. I can say, for my own sake, that the advent of the PCSK9 monoclonal antibodies has been an amazing opportunity for me. I am able to offer my patients an opportunity to get their LDLs down to levels that were very rarely obtained, even in the most diligent patient with favorable genetics whose LDL falls like a stone in response to high doses of atorvastatin or rosuvastatin.

Alan S. Brown, MD, FACC, FAHA, FNLA: That’s a great segue, Howard. As we’re getting on to the PCSK9 inhibitors now, maybe you can spend a few minutes on the available PCSK9 inhibitors’ mechanism of action and whether you think there are any significant differences between the 2 that are on the market. You already mentioned getting LDLs to very low levels and being very satisfied with that. I am too, but you and I both know that a lot of doctors are fearful of that. Could you finish with a bit of data on whether we need worry about very low LDL levels?

Howard Weintraub, MD: That’s a great point, Alan. Thanks. Evolocumab and alirocumab are humanized monoclonal antibodies, which means that these are nonforeign proteins to the human system, unlike partially humanized antibodies. That was a problem with 1 of the PCSK9 inhibitors that was very effective in lowering LDL. It never saw the light of day because of neutralizing antibodies and gradual inactivity. But the good news is that evolocumab and alirocumab are amazing drugs. They act by regulating the LDL receptors. For the listeners, this is a matter of modulating the number of garbage cans that LDL has managed to find a place in. We all know from our studies that the process is a lock-and-key phenomenon. We know that when LDL finds its way into the receptor on the surface of the liver cell, the LDL is taken into the liver cell. What’s supposed to happen is that the receptor is recycled out to the surface of the cell, so you don’t throw away the garbage with the garbage can, and the lipid itself is metabolized and passed on to the bowel. When PCSK9 is present, and it’s made within the same liver cell, this can bind to the complex of the LDL and receptor. Along with the LDL being broken down, so is the receptor. This becomes a very inefficient way of doing things. Just imagine if every time you ended up throwing garbage away in your home, you threw away the garbage can with it. You’d either have to buy long-term garbage cans or you’d have a lot of garbage on the floor. The latter is what happens in the human circulatory system. They tried using small molecules that would inhibit production, which are unsuccessful for a variety of reasons. But the monoclonal antibodies ended up being a great choice. They’re a great choice because they don’t interact with other medicines. They do not require metabolism by the liver or the kidney. A whole variety of conditions that can limit the utility of so many drugs are not concerns with the use of the PCSK9 monoclonal antibodies. At full dosage, both of these drugs can lower LDL as well as any other single drug, besides some very expensive injectables. We can lower this 50% or 60%. The effect of the medication is sustained when looking at outcome studies that have lasted several months up to several years. We’ll have time to talk about the different findings. One of the most important issues was that in the FOURIER trial, which is the study with evolocumab in almost 28,000 patients, about a quarter of them ended up getting LDLs below 25 mg/dL.

In spite of this number, which may make many physicians uneasy and may make patients concerned, when 1 of my patients reaches a value of 25 mg/dL and asks me what to do, I tell them that we should have a party. If there’s 1 food they’d like to try to eat once or twice a month, this is the time to go for it. The people who got below 25 mg/dL in the FOURIER trial, including those in a substudy called EBBINGHAUS, which looked at neurological and cognitive issues, showed absolutely no deleterious effects. The people who identified LDL cholesterol, Drs Michael Brown and Joseph Goldstein, were interviewed a few years ago and asked, “What do you think would be a good level of LDL in the blood?” Their number was 25 mg/dL. We worry about there not being enough LDL, but it turns out that many organs in the body will make their own. It doesn’t need to be in the blood, and all it does when it’s there is get us into trouble, particularly if there are other abnormalities in mechanics. The stuff gets oxidized. Once it’s oxidized, it becomes particularly toxic. This is what starts the cascade of atherosclerosis.

I’m thrilled when LDLs go down. I told you I like the European guidelines because they’re calling for LDLs of under 55 mg/dL. We can talk about the language of the different guidelines, but doctors are still concrete enough that they like the idea of having a number to shoot for. My experience has been that when you get people below 55 mg/dL, you’re paying no price for it. The only price you pay is a benefit in which cardiovascular events are lowered and there may actually be a cessation or slowing of atherosclerosis. There may also be a transition of plaque from a more risky, vulnerable, lipid-rich variety to a more fibrocalcific variety. I tell patients that we turn a risky plaque into a speed bump in the wall of the artery. It may annoy them, but it’s not going to hurt them.

Transcript Edited for Clarity