The Role of Lipoprotein A in Lipid Lowering

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: We’re going to switch gears [and] go to an LDL [low-density lipoprotein]–like biomarker; it’s a substance that’s a causal agent for atherosclerotic cardiovascular disease, [and] that’s lipoprotein a [Lp(a)]. Now FH is not just familial hypercholesterolemia. The [Family Heart] Foundation also embraces putting more attention on lipoprotein a…. Dr [Mary] McGowan[, MD, FNLA], you want to tell us about Lp(a)?

Mary McGowan, MD, FNLA: Sure. Lipoprotein a…has an LDL-like particle, but it also has an [apolipoprotein] a [apo(a)]. That combination of apo(a) and LDL, in addition to oxidized phospholipids, creates a lipoprotein that is more toxic; much more of an endotoxin than LDL alone. One in 5 [persons] have an elevated lipoprotein a in the United States. Yet, based on research from the Family Heart Foundation, fewer than 1% of [individuals] have had their lipoprotein a measured. Lp(a), because it has an LDL portion, is atherogenic. The apo(a) has homology to plasminogen and it competes with plasminogen for fibrin binding. So, it looks like fibrinolysis is impaired. We see an increased risk of thrombotic issues. Then the oxidized phospholipid is really inflammatory in nature and may increase the action of osteogenic genes, making the aortic valve become more calcific. What we see with [persons] with very elevated Lp(a) is they may get into trouble with very early cardiovascular disease [and] sudden cardiovascular disease.

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: There’s a number you said, and you can continue with Lp(a), but there’s a number you said [that] I don’t want our audience to miss. You said that elevated lipoprotein a may be as [common] as 20% [of the population]. So, if you’re in a classroom of 100 [persons], 20 of them might have elevated lipoprotein a?

Mary McGowan, MD, FNLA: That’s right. Right now, we’re still in a fact-finding mission, but what would be defined as a high lipoprotein a is an Lp(a) greater than 50 mg/dL, or greater than 125 nmol/L, and nmol/L is the preferred way to measure lipoprotein a. But regardless of which way it’s measured, most labs are switching over to nmol/L; what’s high is high and increases the risk. Because so few [individuals] have had it measured, it’s not being factored in. It is recommended that everybody have a lipoprotein a measured in Europe. The European guidelines suggest that, [and] the Canadian guidelines. We have fallen short in the United States of saying everybody should be measured. In our current guideline, it’s a risk-enhancing factor. But we at the Family Heart Foundation believe that [persons] deserve to know what their lipoprotein a is.

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: Dr [Erin D.] Michos[, MD, MHS], any impression on what we should be doing with lipoprotein a? Or you can discuss whether…you think it’s causal for atherosclerotic cardiovascular disease [ASCVD] and aortic stenosis.

Erin D. Michos, MD, MHS: Well, I can touch on both. We have good genetic data that does show that lipoprotein a is causal for both ASCVD and aortic stenosis. Just like LDL, it’s not binary. Certainly the higher the value, the higher the risk. In my practice, I measure everybody at least once in their lifetime, and I hope that we move to that in the United States because elevated lipoprotein a is actionable now. Dr [Christie] Ballantyne [MD, FACC] and I [are] writing a statement about this because it hasn’t been fully adopted in the United States [as] we don’t yet have the dedicated Lp(a)-lowering therapeutics that are currently in phase 3 outcome trials. You’re going to hear more about this in a minute, but those are not FDA approved yet. So, some [individuals] are like, “Well, we don’t have [the] therapy to lower it. Why should we measure it?” Well, we absolutely have things we can do now. It’s actionable. It’s already in the guideline as a risk-enhancing factor. If somebody has elevated Lp(a), for primary prevention, this would put them in a higher-risk category where we would recommend statin therapy. Although statins don’t lower Lp(a), statins clearly lower LDL and they lower vascular risk. [Implementing] a more intensified lifestyle. Although lifestyle changes won’t lower Lp(a), they certainly lower risk. You could consider aspirin. We know [for] some subsets from the Women’s Health Study [and] ASPRE study, these primary prevention aspirin trials—although we’ve gone away [from] using aspirin in primary prevention broadly in those with genetically predicted elevated Lp(a), there did seem to be a benefit. Now in the secondary prevention population, elevated Lp(a), again, is a high-risk marker. If someone needs additional lowering, [consider] PCSK9 inhibitors and inclisiran because they can lower Lp(a) [by] about 25%. They’re not FDA approved for that indication; they’re FDA approved for LDL lowering. But I tell my patients this bonus is going to help both of those lipid biomarkers, so be thinking about that. Don’t forget there’s still a role for apheresis. If you have a very high-risk patient with clinical ASCVD (eg, multiple heart attacks) who has managed to get their LDL very well controlled, well below that 55 mg/dL threshold, but continues to have [cardiac] events and high Lp(a), [remember] it is an FDA-approved indication to do apheresis for elevated Lp(a). So, there are things we can do, and we should find these patients. If we don’t measure it, we won’t know [whether] they fall into that category of high Lp(a).

Keith C. Ferdinand, MD, FACC, FAHA, FNLA: Dr [Payal] Kohli[, MD, FACC], give us some of your insights on what we should be doing about Lp(a).

Payal Kohli, MD, FACC: I see a lot of South Asian patients. Race and ethnicity, and how that plays into Lp(a) measurements, is really very fascinating and an area that I think we need to explore more moving forward. We know that South Asian [patients] tend to have high levels of lipoprotein a. They have early-onset accelerated heart disease. I checked the Lp(a) as a way to sort of catapult checking their family members [and] kids. [I] use that as a way to begin the conversation and say, “Well, now we’ve found a marker that’s largely genetic, that is causally related to ASCVD, and I really think we ought to look at your children and everybody else.” I find it doesn’t just help me with the discussion that I’m having with that patient, but it helps me screen their family members as well. [It] really helps devise a plan not just for the person in front of me, but [for] all the [individuals] related to them.

Transcript Edited for Clarity