Dr Michelle O'Donoghue:

Hi, my name is Dr. Michelle O'Donoghue. I'm a cardiologist at Brigham and Women's Hospital and a Senior Investigator with the TIMI Study Group.

Can you summarize the current evidence establishing the causal link between elevated Lp(a) and atherosclerotic cardiovascular disease?

Well, for decades, we've had a large body of evidence that LP(a) is a marker of risk in terms of helping to identify people who are at high risk for developing atherosclerotic cardiovascular disease.

But more recently, we have a growing body of also now genetic evidence to really support the causal nature of that relationship. Namely, genetically predicted LP(a) concentrations are associated with a higher risk of developing atherosclerotic cardiovascular disease. And that's just been a strong part of the story to support that causal role.

How should clinicians approach Lp(a) screening and risk stratification?

First, we know that clinicians, by and large, are not checking LP(a). So I think one important message is that really, all patients should be having their LP(a) checked at least once in their lifetime.

Levels are largely genetically predicted. So whatever value you have, it is, by and large, going to be fairly consistent over your lifetime. We are appreciating there's a little bit more variability than we'd previously recognised. But nonetheless, I think if clinicians were to check it at least once, that would already be a big advance.

But one of the more common questions I'm asked is, well, what am I going to do with that information? And that's important because even though we don't currently have therapies to lower LP(a), those are in development. But we know that traditional risk factor modification is going to be important for individuals with very high levels.

It may help to reclassify people. You might think more about screening somebody's family members, given that genetic component. And also, there are a lot of clinical trials that are now enrolling, and you could even think about identifying patients who may be suitable participants for those clinical trials.

When managing patients with both elevated Lp(a) and established ASCVD, how do you approach risk reduction beyond traditional lipid management?

Well, if you have a patient who has established ASCVD already, of course, you're being aggressive with trying to bring down their LDL cholesterol. But it's a little bit, as the European guidelines for dyslipidemia recently put forward, is that you might have individuals who are at more extreme risk where you're going to be even more aggressive with the type of LDL cholesterol control you might be trying to achieve.

We know that statins don't lower LP(a), if anything, they actually may cause LP(a) to rise a little bit. In contrast, PCSK9 inhibitors on average reduce LP(a) by about 25 to 30%, albeit we don't know if that additional LP(a) lowering effect that the PCSK9 inhibitors exhibit offer any incremental benefit. But nonetheless, I think it's a patient in whom you're probably going to want to be more aggressive about LDL cholesterol control.

What are the current gaps in our therapeutic armamentarium for addressing elevated Lp(a), and how do you counsel patients about emerging treatments?

Right now, the therapies that we have in hand only lead to a fairly modest reduction in LP(a). And that matters because, based on the genetic data, it seems like you may need to reduce LP(a) by a pretty large, substantial amount for that to translate into meaningful clinical benefit.

So that's where these new therapeutics that are being developed are very exciting. A lot of them work through RNA interference by blocking synthesis of Apa(a), which is a key component of that LP(a) particle. And by doing that, some of these therapies can reduce LP(a) by more than 90, 95%.

And that's true even for those individuals who are starting at very high values, where they can get down to virtually undetectable concentrations. So for patients right now who find out that they've got high LP(a), really we just focus on traditional risk factor modification and doing what we can.

Especially, we find out earlier in their life we could try to mitigate some of those changes over a lifetime. But otherwise, these therapeutics are hopefully, fingers crossed, not too far away, and so we'll have access to additional options in the not-too-distant future.

What are your key take-home messages for clinicians encountering patients with elevated Lp(a) in their practice today?

Well, I think the most important thing is ignorance is not bliss when it comes to LP(a). A lot of primary care doctors are not exactly sure what to do with that information and so they're just opting not to check. But I have to say that I would, personally, if I had an elevated LP(a) concentration and I was at higher risk, I would want to have that information in hand.

It would absolutely shape how I think about my own risk factor control. And I think that it would be a strong argument for starting earlier in one's life, for instance, on lipid-lowering therapy or something like that, to try to do what you can to reduce your risk of developing worsening atherosclerotic cardiovascular disease, as well as some other disease states that can be related to high LP(a).

Certainly no need for panic if you find that you have a high value. And as there are a lot of people who are worried at this point in time, but I think therapeutics are hopefully not too far off in the distant future. And until then, we can just focus on the risk factors we know help to reduce risk.