Managing ASCVD and Hypercholesterolemia: Statins, Ezetimibe, and PCSK9 Inhibitors


Matthew J. Budoff, MD; Erin D. Michos, MD, MHS; and Paul S. Jellinger, MD, MACE, discuss the role of statins, ezetimibe, and PSCK9 inhibitors for patients with ASCVD and hypercholesterolemia.

Yehuda Handelsman, MD: Let’s discuss medications. There is a whole list of available medications. Who wants to take the lead and say something about statins?

Matthew J. Budoff, MD: I can tackle that one. We have several statins with different potencies, but we have these high potency statins that are widely available, are all generic, easy to take. And we get up to a 60% LDL [low-density lipoprotein] reduction with statin monotherapy, and for many people that might be enough. We talked about the need for going beyond statins, but it’s a great starting point. To Christie’s point, adverse effects, either real or perceived, limit our ability to use them in their full capacity, so we must go beyond statins for many patients, and I think there is now a host of additional medications available.

Yehuda Handelsman, MD: I’d like to see that we move away from the confusing factor of low potency or medium potency; who gets medium and who gets intensive? A couple of studies, for atorvastatin or rosuvastatin, are very good. If you can give the maximum dose, fine, but if not, it’s…tolerated. Let’s get the confusion out, if you have diabetes and you are 47 years old, you can do moderate potency, but if you are 51 years old, you must do intense. It’s getting crazy and complicated. Ezetimibe.

Erin D. Michos, MD, MHS: Ezetimibe blocks intestinal absorption of cholesterol, so it’s a good nonstatin oral option for patients; it’s also generic and generally well tolerated. It reduces LDL about 18% or so, relatively modest. But the big landmark trial course was the IMPROVE-IT trial of high-risk patients with acute coronary syndrome, it was combined with a moderate intensity statin in that trial. While there was only a 6% relative risk reduction in major adverse cardiovascular events, because the event rate is so high in this population, you would only need to treat 50 individuals with ezetimibe to prevent 1 event. Because ezetimibe is cheap, oral, generic, and easy, I prioritize that being the first nonstatin to add to a statin. But in many patients it’s not enough, and then we must move on to other therapies we are going to talk about.

Yehuda Handelsman, MD: I agree. Sometimes it is sad that guidelines are supposed to be based on grade A evidence, and all of sudden a drug is chosen just because it is cheaper, not necessarily because it takes you to your goal. We should look to see, as we said in our recommendation, the goal and how far we are, not just take 1 drug. We know that ezetimibe shows a reduction in LDL somewhere between 16%, 18%, maybe 20% on occasion or slightly higher than that, but if the patient is much further away than that, maybe we should choose something else.

Paul S. Jellinger, MD, MACE: I have been impressed with how low we can get LDL on a high-dose statin, ezetimibe, or bempedoic acid in combination. Rather than jumping from 20 or 40 mg of atorvastatin to a PCSK9, go to 80 mg of atorvastatin, or 40 mg of rosuvastatin, and add either ezetimibe or bempedoic acid, and LDL will often get into the 40s mg/dL.

Yehuda Handelsman, MD: Can you also address the PCSK9 inhibitors?

Paul S. Jellinger, MD, MACE: The PCSK9 inhibitors are remarkable drugs that can get our LDL well into the 20s, 30s, and 40s mg/dL on occasion, especially in combination with statins. I have a lot of patients on PCSK9s. Some of them can’t tolerate statins, and I am impressed with how blunted that PCSK9 response is when they are not on a statin. I said blunted, but diminished, compared to when even a small dose of statin is working with the PCSK9, or ezetimibe or bempedoic acid with the PCSK9. They have been shown to have positive outcomes. They reduced cardiovascular events in 2 very powerful studies. LDL went down to 10 or 20 mg/dL, and it did not show to affect mentation at all, in several studies. They are marvelous drugs to get LDL down into 20, 30, 40 mg/dL when necessary. Sometimes you can get into the 40s mg/dL with a high-dose statin and other agents. But the go-to drug for those kind of LDL levels, which we are all achieving more often, would be the PCSK9 with a statin, and/or ezetimibe or bempedoic acid. They are extremely useful. There is a very little adverse effect profile with a PCSK9, an injection every 2 weeks.

Yehuda Handelsman, MD: Matt, how long would you go if their problem is being very low?

Matthew J. Budoff, MD: The question that comes up repeatedly is how low should we go? We are born with LDL in the 30 and 40 mg/dL range, that’s probably where we need to go. We are not as metabolically active as when we are born, so we probably can go even lower. To Paul’s point, in the PCSK9 trials, the average LDL achieved was 26 mg/dL, and that was very safe. Getting people below 40 mg/dL, especially the very high-risk patients, it’s part of our DCRM [Diabetes Cardiorenal & Metabolism Institute] guidelines. It’s part of the ESC [European Society of Cardiology] guidelines. We need to think that lower is going to be better for our patients, and there is probably no bottom to that. Although, practically I don’t know if you want to get into single digits because people freak out, the primary care doctor will send them off to McDonald’s to load up on something to get their LDL up. So we don’t want to go too low.

Christie Ballantyne, MD: Or they stop their statin.

Erin D. Michos, MD, MHS: I wanted to add that PCSK9 inhibitors can lower lipoprotein(a) by about 26%, which statins cannot. So at least we have 1 agent, and glycerin can also lower lipoprotein(a). I think about it earlier in high-risk patients who have elevated lipoprotein(a), until some of the newer agents are available on the market.

Yehuda Handelsman, MD: We could have continued using niacin, which can also reduce lipoprotein(a) if you really wanted to do that.

Transcript Edited for Clarity

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