Paradigm Shifts in Lipid Lowering - Episode 7

Outcomes and Practical Implications of Newer Agents

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Cardiologists briefly review the outcomes data and practical implications of novel treatment options for hyperlipidemia.

Keith C. Ferdinand, MD: Linda, Dean, what do you think about inclisiran? We’ve heard wonderful things. Anything bad? Anything they’re missing?

Linda Hemphill, MD: It’s interesting, this whole question of RNA at this point in history, because of course we have the messenger RNA vaccines for COVID-19. I have had the question asked of me by patients and even by some physicians, are you changing the cell machinery? How long is this going to be a problem?

Keith C. Ferdinand, MD: Are you changing the cell machinery? How long is this going to be a problem?

Linda Hemphill, MD: In ORION-1, the first inclisiran study, published in the New England Journal of Medicine in 2017, after a single shot, the LDL [low-density-lipoprotein] was trending back up at 180 days. The cell machinery is not permanently changed. That’s very reassuring, and we would not expect it to be.

This is acting through what’s called a risk complex, which is of course different from the messenger RNA for the vaccines is working through the ribosomes. But basically, RNA is disposable. You are not changing the DNA. This isn’t crisper.

Keith C. Ferdinand, MD: Good. Does not hang around.

Linda Hemphill, MD: Right.

Keith C. Ferdinand, MD: All right, Dean, make it practical for our physicians out there.

Dean Karalis, MD: Yeah, I am pretty optimistic about this. At least from the early data we’ve seen from the ORION trials, inclisiran appears to be not only very effective but very safe. We will have more evidence from the outcome trial.

But we must weigh the risk vs the benefit. The real problem is not will this medicine hang around too long and give us too low LDL. The problem we face in clinical practice is that most of our patients have too high LDL cholesterol for their risk, and cardiovascular [CV] disease still remains the leading cause of death among all the patients we see in our offices, compared with other causes of death.

Keith C. Ferdinand, MD: We can’t forget therapeutic lifestyle interventions. Big words for healthy eating, physical activity, maintenance, weight loss, etc.

Dean Karalis, MD: Absolutely. And if you look at the 2019 AHA [American Heart Association] and ACC [American College of Cardiology] general prevention guidelines, there’s a great figure in there of a large circle of all the things we need to do. Even though we may be talking about pharmacological therapy and lipid lowering, lifestyle plays a key role, especially early on when you see a patient who has a family history of early heart disease. Even if they don’t have genetic factors, you want to get their kids on a heart-healthy lifestyle, exercise, and focus on not only exercise and diet but also diabetic control, hypertension control, smoking cessation, and lipids.

Keith C. Ferdinand, MD: When we were talking earlier, Manesh, you said you were going to bring in the PCSK9 inhibitors. We don’t want to forget that group. What is the outcome study show with that group of agents?

Manesh Patel, MD: Yeah, it is important to think about the fact that we just discussed inclisiran. We are definitely very enthusiastic about it and have, as Norm has highlighted, really great studies to tell us that the LDL has been reduced, and there are ongoing cardiovascular outcomes studies. Those would be what key studies that would help us feel really comfortable, to know that we lowered LDL. We all believe lowering LDL leads to better outcomes, and we’ll prove that. The safety profile has been good.

For the PCSK9 inhibitors, there are 2 of them that are actual antibodies—directed monoclonal antibodies to that protein—given twice a month or maybe once a month at the least frequent. The frequency is important because what we’ve heard is obviously that adherence is hard. Taking a statin every day, taking a shot twice a month or once a month, or taking a shot twice a year. Those are the choices of what we are getting at.

For the monoclonal antibodies, both of those drugs have—in the ODYSSEY Outcomes trial and FOURIER and other trials, we have seen cardiovascular outcomes improve in those patients. We’re encouraged that this pathophysiological mechanism, when we’ve done it in patients who have cardiovascular risk or bad cardiovascular events, we’ve reduced future cardiovascular events. We have reduced future cardiovascular events to include myocardial infarction, CV death, nonfatal stroke, but we have also seen it in some of these other vascular events. As I said, irrespective of whether you had peripheral artery disease, we reduced some of those limb outcomes.

Keith C. Ferdinand, MD: We still have add-on ezetimibe. It is old-school right now, but it gives you maybe 18%, 20% added to statins, even up to 25%, depending on how active the uptake of statin is through your…receptors.

Manesh Patel, MD: Yeah, that is a great point. Obviously, we can talk about the therapies and the cost and different things, but ezetimibe is certainly a therapy that a lot of us are using when you don’t get to go with a statin, and you need to make sure the patient is able to take the statin.

For sure we should focus on usual care and escalation as one might think to get people to reduce their risk.

Keith C. Ferdinand, MD: If you enjoyed watching this HCPLive® Peer Exchange, if you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. Thank you very much for listening to this program.

Transcript Edited for Clarity