Paradigm Shifts in Lipid Lowering - Episode 11

Inclisiran in the Current Treatment Landscape for Lipid Lowering

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Key opinion leaders in cardiology share their perspectives on using inclisiran post FDA approval within the current treatment landscape based on guidelines.

Keith C. Ferdinand, MD: We’re going to have another segment where we go back over these agents and detail some of the data for the various agents, but I challenged everyone to put on their hats and tell me where they think inclisiran is going to be in the future. Since I’m speaking directly to you, Manesh, what do you think—you don’t know, because it’s investigational—but where do you think it’s going to fit in the future?

Manesh Patel, MD: Well, we’re going to go into a little bit about how these therapies also get onto the market and we get to use them, but I think if the data are as we’ve described and seen where we have outcomes data coming and the LDL [low-density lipoprotein] is the way it is, it’s going to come down to access and availability for our doctors to get it to their patients.

Keith C. Ferdinand, MD: Dean?

Manesh Patel, MD: That’s where I think it’s going to be.

Dean Karalis, MD: I agree with Manesh. I think the key is going to be affordability and how easy it is to prescribe. If it becomes affordable and easy to prescribe to our patients, I think it could be a game-changer.

Keith C. Ferdinand, MD: Norman, and then we’ll end with Linda.

Norman Lepor, MD, FACC, FAHA, FSCAI: Well, my mask doubles as my hat, so you said put our hats on. I agree with Dean and Manesh, I think a game we have to play as physicians is access. We have great therapies. I basically have to spend a full-time equivalent of an employee to get access to therapy because I really do translate clinical trials into practice. So I kind of penalize myself, although I help my patients because there’s a tremendous amount of work involved in this prior authorization process, and then if you’re denied the prior authorization, going through the process of appeals.

I think this is something important that has to be worked out in our health care system. How do we provide these great new medications to our patients in need and make it reasonably seamless, and at the same time make sure that we’re using these medicines in patients where it’s appropriate? That’s going to be, I think, the big issue with inclisiran as we all look forward to it. We know that 50% of patients when started on a statin, even after an MI [myocardial infarction], after a year they’re not taking it. This does deal with a compliance issue. We can all see our patients twice a year and they get their injection either in our office, perhaps, or in some infusion center, so that takes care of the compliance issue.

But at the end of the day, how difficult is it for our patients to access these drugs? I don’t have the cure for that one.

Keith C. Ferdinand, MD: Linda, you have the last comment. We’re going to get more into the data supporting inclisiran’s use and some of the technical aspects of the agent and how to use it. But in terms of a clinical factor in approaching the high-risk patients, where do you think it’s going to be in the future?

Linda Hemphill, MD: My point is the same as Norm’s last point, which is that this takes care of the whole compliance problem, because they’re coming into your office and getting the injection twice a year. I tell my patients, “Keep your eye on that LDL, and keep your eye on taking your medications.” And this basically guarantees that they’re getting their medication.

Keith C. Ferdinand, MD: Dean, you think that it’s going to be similar to the PCSK9 inhibitors in terms of its efficacy, no significant safety signals at this point. How are you going to decide, again, it’s an investigational agent, so we’re doing some conjecture here. But how are you going to decide which patient will get the PCSK9 inhibitor or inclisiran? 

And I’d like all of us to chip in on this Lp(a) [lipoprotein(a)] story. I think it’s a powerful predictor of risk. You look at South Asians, African Americans especially have high Lp(a) levels that add additional risk, but it can happen to any person who has elevated Lp(a). We know the 20% with the PCSK9 inhibitors is not the main story, but it may be an ancillary component of their protection, and we just heard from Norm that inclisiran also has about a 20% ability to modify or lower Lp(a). That’s not the type of 80%, 90% that we want to see with the ASOs [antisense oligonucleotide agents], but it’s in the ballpark of something that gives at least a benefit.

Dean, again with some conjecture, when are you going to decide to use a PCSK9 inhibitor versus inclisiran? And everyone can chip in on this Lp(a) story, do you think that is a part of the potential benefits of inclisiran, similar to what we’ve seen in PCSK9 inhibitors?

Dean Karalis, MD: To dial it back a little, if inclisiran is approved by the FDA, I think it will probably be approved with a similar approval for patients with FH [familial hypercholesterolemia] and patients who have clinical ASCVD [atherosclerotic cardiovascular disease], similar to what is approved for the PCSK9 inhibitors. We’re really talking about treating patients who are at a very high risk of having an ASCVD event, for patients with FH if it’s the first event, or for patients who’ve had an event and had a secondary event.

The guidelines recommend that these patients should be on a high-intensity statin, and that becomes the foundation. What we do know is that many patients who have failed one statin can be rechallenged with a second, or uptitrated. I think the first step when we’re looking at it from guidelines and what’s the right thing to do in clinical practice, is to make sure the patient is really on a maximally tolerated statin.

The next step then is what is your next step when your LDL cholesterol is still not at your target goal? The guidelines recommend that ezetimibe is the next step, and that’s driven by the fact that it’s generic and it was inexpensive, and the PCSK9 inhibitors were expensive at the time the guidelines were written. But the PCSK9 inhibitors have now been reduced significantly in price. And we know that a PCSK9 inhibitor, whether it’s going to be inclisiran or one of the available PCSK9 inhibitors, will lower LDL cholesterol to a much greater degree than ezetimibe.

I think from a guideline base, ezetimibe is the next step, and then PCSK9 inhibition is the third. That may change as the cost of these agents becomes more affordable.

One of the exciting things about inclisiran again, and I think Linda mentioned it as well as Norm and Manesh, is the fact that given a dose of every 6 months, it takes compliance or nonadherence out of the picture. That could be the real game-changer. If you can get a 50%-plus reduction in LDL cholesterol with an agent that’s given every 6 months, and you’re not dealing with issues of compliance, nonadherence, the patient not taking it, that changes everything.

Keith C. Ferdinand, MD: Anyone else? And Lp(a), I’m still interested in what your take is on that. I know it’s not going to get us to the normal levels; if you’re using mg/dL, that’s less than 30, if you’re using nanomoles, it’s going to be a little higher in terms of the goal. But it does have a 15% to 20% lipoprotein(a) reduction. Does anybody else think that’s significant?

Manesh Patel, MD: I think it is important. I just want to highlight what Dean said, that it’s critical. First knowing the indication for what we’re doing, and almost all agents that come on the market are studied in secondary prevention first, and then they’re studied in primary prevention. The highest risk groups, as I think Norm already taught us, we look at absolute risk. If your risk is the highest, we’re going to study you and try to treat you first and most. 

We know that statin therapy there is the basic therapy that we’ve got to get people on and try different ones, and then we escalate, based on guidelines for ezetimibe and/or PCSK9.

Keith C. Ferdinand, MD: If you enjoyed watching this HCPLive® Peer Exchange, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox.

Thank you very much for listening to this program.

Transcript Edited for Clarity