The Lowdown on Lipoprotein(a) – Medscape

This transcript has been edited for clarity.

Thomas Allison, PhD: Greetings! I'm Tom Allison, cardiovascular specialist at Mayo Clinic. During today's roundtable, we'll be discussing lipoprotein(a). I'm joined by my colleague, Dr Steve Kopecky, who specializes in this area. Steve, what is lipoprotein(a) and why do we have it? What role does it play?

Stephen L. Kopecky, MD: Lipoprotein(a) is a combination of a couple of standard molecules that we all know about. One is an LDL cholesterol-type molecule or low-density lipoprotein. The second is an apolipoprotein(a) which is bound to the LDL-like molecule at the ApoB receptor with a disulfide bond. Now, what does that mean? Lp(a) is a cholesterol-type molecule, basically.

Allison: I understand that there are different sizes of these Lp(a)s.

Kopecky: Yes, there are different sizes because the apolipoprotein portion can have different kringles. Some are very big, some are very small. The smaller ones seem to be more atherogenic or cause more problems.

Allison: Like the small dense LDL.

Kopecky: Like the small dense LDL. One question that comes up is, why do we even have this molecule? It seems to promote clotting, which may not be a good thing, although years ago if you had trauma, it may have helped with wound healing or clotting. It may have helped prevent excessive bleeding in childbirth, so there may be a reason why we have it in our bloodstream.

Allison: What evidence do we have that this causes heart disease or contributes to our risk for heart disease? And I presume that we're talking about coronary artery disease, right?

Kopecky: Ischemic stroke also could be involved.

First, what is it about this molecule that may be causing problems? The LDL particle can actually promote atherosclerosis. We also know that the apolipoprotein particle is similar to plasminogen, so it can promote clotting. It inhibits fibrinolysis. And the third factor is that it is an inflammatory molecule.

So it does three things: causes atherosclerosis, causes the plaque rupture with inflammation, and then causes clotting at the site of plaque rupture. Large observational studies, such as the INTERHEART study, which involved many nations, show that individuals with elevated lipoprotein(a) have an increased risk for myocardial infarction (MI).[1]Mendelian randomization studies in large numbers of patients/subjects suggest that if you have an elevated lipoprotein(a), you also have an increased risk for MI and stroke.[2]

Allison: Am I correct that some recent trials have shown that the on-treatment level of Lp(a) in a clinical trial actually correlates with the event risk?

Kopecky: Yes. If you look at LDL cholesterol trials where they gave statins to control LDL, the best predictor at that point of recurrent events was actually the lipoprotein(a) level, not the LDL level.[3,4]

Allison: What is the cut point? At what level do we see the increased risk? I know there's some controversy about what the cut point is.

Kopecky: Yes, because a lot of it's observational, and [approximately] 80% of individuals globally have normal levels of less than 50 mg/dL. In the US, we have an average of about 20 mg/dL. If you look at certain ethnic groups, Asians and Caucasians are very similar; African Americans and Arabs also have higher levels, maybe two or three times higher. The question is, how much of that goes into risk? And that's not quite clear. Is an African American's risk higher because they have a higher Lp(a)? That has not been worked out.

Allison: So 50 mg/dLis that the number?

Kopecky: In general, the average number is 20 mg/dL. Over 50 mg/dL, we start to call it increased risk; that's what most guidelines have said. If you're using nmol/L, 100 or 125 is elevated risk.

Allison: In the prevention clinic at Mayo, do you measure Lp(a) on everybody, or are there specific groups for whom you think it's more important?

Kopecky: People have said that we should measure it in everybody. I don't think we're quite there, mainly because we don't have a treatment yet. But also because the people who may benefit the most are the ones who come in with early atherosclerosis or they have a family history, and they say, "My older brother just had a heart attack at age 48." That may be a good time to check it.

Patients who have recurrent atherosclerotic events in spite of optimal treatmenta case has been made to check those patients. And then there are patients who have FH, familial hypercholesterolemia. About 1 in 5 people (or 1 in 3) with FH have elevated lipoprotein(a). It increases risk, so we check.

The last group is aortic stenosis; bicuspid aortic valve is probably the prototype of that. There's evidence that individuals with elevated lipoprotein(a) and bicuspid aortic valve have more rapid progression of aortic stenosis.

Allison: That's new, right?

Kopecky: That's fairly new. We're starting to think of that when we look at patients with the bicuspid aortic valve.

Allison: So now you have lipoprotein(a) and it's over 50. What do you do?

Kopecky: First off, you make sure that when we're talking about over 50, we're talking about over 50 mg/dL versus like 125 nmol/L. The reason why that's important to differentiate is because the mg/dL is the mass concentration whereas nmol/L is the particle concentration. And as you implied, the particles are different sizes, so we can't convert one to the other like we can with LDL or HDL. It has to be a completely different measurement. There's a push right now to have a single way of measuringthe nmol/L, which would take into account the particle size.

Allison: And that's 125 nmol/L.

Kopecky: It would be like 125 nmol/L. So if it's high, what do we do? Well, lifestyle is always very important, although 80%-90% of your Lp(a) level is genetically determined. It's a codominant inheritance, meaning you can get a gene from each parent, and both will raise it more.

You can give things like niacin or hormone replacement therapy. We know that can lower it, but it doesn't lower events; in fact, it may increase cardiovascular events, so it's not recommended. Statins don't affect it. The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors lower it by maybe 25%, but they're not indicated for high lipoprotein(a).

Lipoprotein apheresis can be helpful in a very small percentage of patients. So we have some treatments, the PCSK9 inhibitor, but it's not yet indicated for lowering it.

Allison: Am I correct that there is a new drug under development that was presented at the American Heart Association scientific sessions, that has shown a significant (ie, 80%) lowering effect, but it's not available? Is that right?

Kopecky: Right. It's an antisense oligonucleotide that actually lowers Lp(a) significantly. It's undergoing clinical studies and we don't know the outcomes yet. It sounds like it's a good idea, but we would need the outcome studies to show that it benefits patients.

Allison: No dietary therapies?

Kopecky: Lifestyle is important, but it doesn't lower your lipoprotein(a). It lowers your risk, but that's separate from the Lp(a).

Allison: Steve, any other points we should make about this?

Kopecky: It's always good to look at the guidelines. The recent ACC/AHA lipid guidelines say you should consider lipoprotein(a) over 50 mg/dL or 125 nmol/L as a risk enhancer ,so be a little more aggressive in treating those patients.[5]

It may be the risk enhancer you use with some patients in primary or secondary prevention, and it's something worth checking, especially if you have patients who have recurrent events or early events, or a family history of early events, because it helps you be more aggressive in treating the patients.

Allison: Do you ever bring in a patient's family members and check them? If, for example, you're 40 years old and you have an MI, should your brother and your kids get checked?

Kopecky: The cascade screening. Yes, we actually have a letter that we give patients. Once we check them and it's elevated, we say, "Give this letter to your first-degree relatives. You don't have to talk to them; the letter explains everything." It says the patient had this elevated lipoprotein(a), which can be associated with increased risk for heart disease, and the relative should take this letter to their primary care provider to check [lipoprotein(a)].

Allison: Steve, thanks for this update and for your insights. I want to thank everyone for joining us on the heart.org | Medscape Cardiology.

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The Lowdown on Lipoprotein(a) - Medscape