What About Lp(a)? To Test or Not to Test and the Current Treatment Landscape

Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC; Matthew J. Budoff, MD


January 05, 2023

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This transcript has been edited for clarity.

Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC: Hi. My name is Seth Baum. I'm a preventive cardiologist, past president of the American Society for Preventive Cardiology, and the chief scientific officer for Flourish Research. I'm very happy to be here today to discuss lipoprotein (a) [Lp(a)] with my friend and colleague, Matt Budoff.

Matthew J. Budoff, MD: I'm Matt Budoff. I'm a cardiologist, a preventive cardiologist at UCLA, and I've also been involved in cardiovascular research and early detection of heart disease research for many years now.

Coronary Artery Calcium (CAC) Scoring and Elevated Lp(a): Connecting the Dots

Baum: That's great. Let's start our conversation. First, Lp(a) is getting a large amount of attention lately. It's in a number of clinical trials, phase 3 and phase 2 clinical trials. Actually, a new phase 3 is about to start.

Matt, you've done so much work in coronary artery calcium (CAC) scoring and connecting the dots of elevated Lp(a). Maybe you can just start the conversation with that.

Budoff: We often identify patients who have increased atherosclerosis. We do a calcium score or a CT angiogram, and it's not obvious why they have a high plaque burden. Maybe they're not 20-year diabetics or heavy smokers, and yet they still have a large amount of atherosclerosis. We check their Lp(a) and it's often quite elevated. That gives you the genetic determination of why they have this risk.

I think the Europeans, interestingly, have already recommended that everybody get an Lp(a) measurement at least once in their lifetime. We're not quite there yet in the US.

Seth, why do you think we're not quite as adamant as the Europeans?

Baum: That's interesting. I think we're behind the Europeans on many things with LDL, Lp(a), and a bunch of other cardiovascular issues. I think it's a great point that you're bringing up at the outset of this conversation. I'm certainly disturbed by it. I think there should be universal screening.

We know that Lp(a) is genetically determined. We know that Lp(a), when elevated, does increase the risk for cardiovascular events. We know that, globally, 20% of people have Lp(a) over 50 mg/dL. It's higher in the African populations and in South Asians.

If it's a stable number and it demonstrates risk, we should check it. I think the reason we haven't is that there's "nothing we can do about it." That's what we say. I don't know what your thoughts are on that.

Budoff: I think having a lack of a targeted treatment to lower Lp(a) is still a little bit of a barrier. It would obviously be nice to finish the loop. We know that Lp(a) is bad. We know that it's prevalent. We know that it can be easily measured, but we don't really have a way to treat it. Hopefully, it won't work out and go by the way of homocysteine, where we did many homocysteine measures, we treated it, and then found out that those treatments were ineffective.

We kind of moved away from it. I don't think that's going to be the case with Lp(a), and there are already several treatments that lower Lp(a) nicely, including the PCSK9s and inclisiran. I think we have some therapies, but we have nothing approved yet by the FDA, which I guess is the problem.

Baum: I still have a hard time with that line of reasoning, only because if we haven't proved that we have something that when we reduce it, reduces risk, we do know that elevated Lp(a) clearly increases risk or at least is associated with increased risk. If we can identify that and it's an easy thing to identify, it would certainly motivate us and our patients to be more aggressive at reducing other cardiovascular risk factors that we have proved will reduce cardiovascular event rates. Why not just do that?

Clinical Trial Outcomes

Budoff: There are some interesting data that came out of the ASPREE trial not too long ago. It was a genetic test. They didn't measure Lp(a) directly, but they talked about the genotypes that are associated with Lp(a), and they showed that, among those patients who had genotypical associated risk, the highest quintile had a much better response to aspirin therapy as primary prevention. Tying in Lp(a) with treatment with aspirin may be a very effective therapy.

They showed lower bleeding risk and better event reduction if patients had these Lp(a) genomic risk scores. They're still not measuring Lp(a) directly in that ASPREE trial, but again, it talks to what you were saying. We have some now potentially good therapies and there are things you can do.

If I find a patient with Lp(a), besides maybe now considering aspirin based on this JACC article, I'm also very aggressive with LDL reduction. At least get the LDL low and hopefully avoid many of the long-term consequences of elevated Lp(a).

Baum: Right. I do the same. The aspirin results are interesting. I don't know about you, but I've been using aspirin on my elevated Lp(a) patients for quite some time. That was reassuring, especially with the — I don't want to say anti-aspirin literature — push away from aspirin, for primary prevention anyway. It was reassuring and encouraging that we're doing the right thing.

It brings up the pathophysiology of Lp(a), that it has that sort of triumvirate of prothrombotic, proinflammatory, and atherogenic elements. I think we need to look at Lp(a) that way. As clinicians or clinician scientists, we need to be thinking about physiology and pathophysiology and doing things perhaps that haven't been quite proved yet but make sense when we're in high-risk situations like this.

Budoff: I totally agree. One of the issues that I have, and I think is confusing for many people, is that this measurement of Lp(a) is not standardized. For whatever reason, some labs report nanomoles per liter, others report milligram per deciliter, and the values and cut points are much different. I think it causes a large amount of confusion.

Whatever assay you're using for your Lp(a) locally, make sure you know your own normal reference values. I've seen confusion even in the scientific literature, where they wrote the wrong cut point based upon the wrong measurement tool. The lack of standardization is one thing that's a little bit challenging for some people who aren't using Lp(a) a little every day in their practice.

Baum: I think you're right. That's a very good point. There also are a couple of conversion equations that don't work that people have used and they're not good. We need to avoid those as well.

There's also confusion about Lp(a) in that it is this small LDL-type particle with an apo(a) attached to it. The inverse relationship with the length of the apo(a) to Lp(a) levels and risk is confusing. I don't know your thoughts about that, but I think it confuses many people.

Budoff: I totally agree. At this level especially, with a measure that we don't use as frequently as some of our other metrics that we're more comfortable with in practice, I just try to keep it pretty simple. I try to use the same lab when I send out studies for Lp(a). I double-check to make sure it's either reported in nanomoles per liter or milligrams per deciliter. I make sure I have the right measurement and then know the local cut points for risk.

We presented some data out of the Baptist Heart study. We did CT angiography in a couple thousand people in the Miami Heart Study, and we showed that elevated Lp(a) was associated with not only more coronary plaque, both by coronary calcium or by CT angiography, but also high-risk plaque.

We're now getting to some of the pathophysiology of seeing more positive remodeling, spotty calcifications, and low attenuation plaques in those patients with elevated Lp(a), tying this blood measurement to now a phenotype that can explain why it causes more risk — and it's not just a small LDL particle, as you said earlier.

Clinical Scenarios and Treatment Considerations

Baum: That's very interesting. For whatever reason, you just reminded me of this. I went back to the stability of Lp(a), and in terms of measuring Lp(a), we should keep that in mind. There are a couple of clinical scenarios where Lp(a) can shift. Things like chronic kidney disease can elevate Lp(a), hypothyroidism, it can be an acute phase reactant so you don't want to measure it in the midst of some bad event, and then menopause. I have seen some very significant increases in Lp(a) of 50% or greater during menopause.

Back to the Europeans and the stability in that single measurement, there can be a dramatic change during some of these events. I'm actually not sure that we should limit ourselves to that single measurement. It's better than nothing, but when somebody goes through one of these events, we need to understand that things can change. Lifestyle doesn't change it, though, and that's a very important thing to highlight.

Budoff: We have to remember that statins have really no impact on Lp(a) level. You don't want to frustrate a patient by measuring Lp(a), putting them on a statin, and then they get a follow-up test that doesn't show any improvement in that one measure. Then they might be frustrated that the statin is not working or something like that.

We have several trials that are ongoing right now that are very promising that will lower Lp(a) by 60%, 70%, or 80% and really have a significant impact on this metric. I think we should be measuring it in our patients at risk. I agree with you. Sometimes we need to think about re-measuring it. If they're on a PCSK9 or inclisiran, we should expect to see a 20%-30% drop. That's something you can look for as well. I do think there's some benefit in retesting.

There was a nice scientific statement — Don Lloyd-Jones, among others, were authors — on Lp(a) recently. It was a scientific statement from the AHA. I think that there is now more recognition of this and more advocacy for this test to help us identify high-risk individuals.

Baum: I think you're right. With multiple drugs in development now and really getting close, frankly, to having some information about risk reduction, potentially, with treatment, that'll be very helpful. You mentioned the statin topic.

We know that sometimes statins can actually worsen Lp(a) slightly, and I've had patients very worried about that. Personally, given what you said before, that we have all the good outcomes data with LDL reduction and we have yet to develop those outcomes data with Lp(a) reduction, I push through that and encourage patients to stay on the drugs that lower LDL, even if it's a sacrifice plan and they increase Lp(a) to some degree. I don't know what your position is on that.

Budoff: I just think the data on statins are so solid. What I learned when I was a resident and fellow is still true today. Right now, the treatment, if you identify somebody with a high Lp(a), is to reduce their LDL to below 70 — and maybe now an even lower target — to obviate the risk associated with some of the Lp(a). If that Lp(a) measure goes up a small amount, so be it. You've lowered their overall risk by being on a statin and getting rid of much of the apoB that's contained in the LDL — why statins are so effective.

Baum: As you pointed out before, the PCSK9 inhibitors can have a very nice reduction in Lp(a). If you have one of those problem patients, you can always add on a PCSK9 inhibitor to see what happens. That's always an option.

Lp(a) Screening: Automatic Triggers Prompting Its Inclusion in the Workup

Budoff: I want to remind people that any one of these three events occurring unexpectedly should automatically trigger Lp(a) as part of the workup. If they have atherosclerosis out of proportion to their traditional risk, if they have a thrombosis — Seth mentioned the prothrombotic nature of Lp(a) — or if they have aortic valve calcification. Those are three common diseases that are associated with Lp(a).

If you're still going to be selective and we're not going to measure it in all yet, at least measure it where it might be causative and might help explain the underlying condition. As we get these treatments approved, which I think will happen in the next few years, we're going to have a nice population of patients who we can apply these treatments to once we have an approved algorithm of treatment for Lp(a) specifically.

Baum: I think that's a great point. I might add two other patient groups: premature atherosclerotic cardiovascular disease and familial hypercholesterolemia (FH). FH specifically, because Lp(a) is more prevalent in that population and it really is devastating when you have both FH and Lp(a). I've seen some of my sickest FH patients with high Lp(a) as well.

Budoff: We can be so much more aggressive now with FH that, again, may be a trigger to go beyond what we are doing currently in that particular patient if they also have a high Lp(a). We can accelerate those other therapies to get them even lower than they were before, from an LDL perspective.

Baum: I also would highlight the clinical research part of this whole thing. Another reason — neither one of us mentioned it before and now it comes to mind — to check Lp(a) is that there are clinical trials ongoing and there will be more. There are opportunities for patients to engage in these clinical studies. This is how we're going to learn whether there is a great benefit. It's also obviously of potential value to the patients. I would always consider that.

Guidance From Clinical Trials: Highly Anticipated Outcomes

Budoff: I think that's a great point. There are apheresis trials going on. A number of different drug therapy trials are going on, focused on novel therapies for Lp(a). Some of them are further along, as you mentioned; some are in phase 3 already. I think that there is a large amount of excitement here. I do believe we'll have some positive trials — maybe not all of them, but I think we'll have a couple mechanisms to treat.

I always encourage my patients, if they're in this phase where we don't yet have an approved treatment, to enroll in one of these clinical trials. The other benefit of clinical trials is that many of the patients will get rolled into the active arm at the end of the study as a long-term observation. They might get a drug for free for 5 years.

We did that with our PCSK9s. I had patients who just finished their 5-year follow-up of the FOURIER trial. They were in a randomized trial for a few years and now they had 5 years of open label on treatment for free to look at long-term safety and efficacy of the drug.

Looking Ahead

Budoff: There are great opportunities for both patients and clinicians to help us learn about Lp(a), when to treat it, how aggressively to treat it, and what the percentage of that reduction will be when we do treat it.

Baum: That's a great point about the open-label extension because we saw with PCSK9 inhibitors, the barriers to access were just terrible. They're much better now. You had all these patients on drug when they wouldn't have been able to get the medication probably. That's great.

Budoff: It's almost an automatic refusal by insurance to cover it. We didn't have to go down that road for 5 years because they were just getting it in the clinical study.

Baum: Great. Very smart. I've enjoyed this conversation. I don't know if you have anything else to add, but I think we've covered many topics. What do you think?

Budoff: As I said at the beginning, this kind of dovetails off of our prior conversation. You can look at that one as well. That conversation gets a little more in-depth information about Lp(a) and its association with atherosclerosis specifically.

This has been great. Seth, thank you for chairing and taking us through some of these interesting data. I look forward to more in the field of Lp(a) and treatment, and the evidence revolving around how we should be using it, when we should be using it, and more important, what treatments we should be using once we identify a person with an elevated level.

Baum: That's great. Thank you very much. Thank you, everyone, for joining us. We wish you a good day.

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