Does Lipoprotein(a) Play a Causal Role in ASCVD?

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. I'm Dr Michelle O'Donoghue. I'm a cardiologist at Brigham and Women's Hospital, and I'm reporting for Medscape. Joining me today is Dr Stephen Nicholls. He's a professor of cardiology at Monash University in Australia. Welcome.

Stephen J. Nicholls, MBBS, PhD: Thanks.

O'Donoghue: He's really a world expert on the field, in general, of lipid therapies, but one evolving area that we're learning more and more about is this concept of lipoprotein(a) [Lp(a)] and the role it may play in heart disease.

Let's start there and think about the evidence that we have in terms of Lp(a) and its potential role in heart disease and cardiovascular disease more broadly.

Nicholls: We've known about Lp(a) since the early 60s. If you think about it, when most of us did our training, Lp(a) was one of those quirky risk factors that you'd occasionally measure when somebody had a myocardial infarction (MI) and you couldn't understand why. In recent years, we understand more about the biology and the genetics of Lp(a).

Large population studies have shown us that high Lp(a) is not only associates with a high rate of atherosclerotic cardiovascular disease (ASCVD), MI, and stroke but is actually also associated with a high risk for aortic valve disease. The genetic studies have then layered on top of that, suggesting that Lp(a) plays a causal role, particularly in those disease processes. There has been more interest in Lp(a), which then leads to the question of whether we can develop therapies that will target it.

Should We Measure Lp(a)?

O'Donoghue: I think that's been one of the interesting points that people have debated is when is it appropriate to measure Lp(a) in somebody. Currently, it is believed to be a good marker of risk, and yet the typical therapies that we reach for, such as statin therapies, do not actually lower Lp(a). It's been unclear whether or not that is a reasonable strategy to help mitigate risk.

Nicholls: Traditionally, the guidelines have said, well, perhaps it helps stratify somebody to more intensive lipid lowering. Although statins don't lower Lp(a), and they may in fact raise it a little bit, they're really good at lowering low-density lipoprotein (LDL) cholesterol.

Today, if you've got somebody you think is high-risk, particularly if they've got a high Lp(a), lowering their LDL cholesterol seems like a pretty reasonable thing to do, which is what the guidelines have told us to do.

O'Donoghue: You raise an interesting point. We know that the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors do, in fact, lower Lp(a) concentration, unlike the statins. In your practice, if you have a patient with a high Lp(a) in the absence of some of these newer therapies that are in development to directly lower Lp(a) concentration, do you currently reach for a PCSK9 inhibitor?

Nicholls: In my country, Australia, it's a bit challenging in terms of who can access the PCSK9 inhibitor, but I think those are compelling data. I think that both PCSK9 inhibitor trials show us that Lp(a) lowering does associate with some of the benefit. Now, these are really good LDL cholesterol–lowering drugs, but I think if there's somebody who you think is higher-risk, particularly if they have a high Lp(a), then it's a reasonable strategy to think about.

O'Donoghue: What are your thoughts on apheresis? There've been some countries that are quite enthusiastically embracing apheresis as a potential strategy for managing those with high Lp(a) concentrations. What do you think about the evidence there?

Nicholls: I think that it's been the only real option for a long time, and particularly for patients who have got sky-high Lp(a). These patients are really worried. They read the literature, they know that they're at risk, and they know that there haven't been many options in the past.

For the same kind of reasons that the PCSK9 inhibitors have changed the whole landscape for patients with familial hypercholesterolemia, far less of them need apheresis. I think we're trying to identify better strategies to treat high Lp(a) because apheresis is a highly invasive process and I think that we would prefer our patients not to be having that.

Novel Agents In Development

O'Donoghue: Let's think about the therapies that are in development now that directly lower Lp(a) concentration. I think when it came to the PCSK9 inhibitors, it's always been hard to know how much of the benefit of PCSK9 inhibition is actually through LDL cholesterol reduction cs its effects on lowering Lp(a).

Now, with these novel therapeutics in development, they really just lower Lp(a) concentration primarily alone. Albeit, there are some effects on LDL cholesterol, but some of that appears to be just carried along with the fact that LDL is bound up in Lp(a) as well.

Nicholls: They become the one-trick pony, but actually that's what we've been wanting. Now we have multiple development programs. We've got antisense therapy. We have RNA inhibitory approaches — there are a number of them — and we have data being presented here at the AHA that you're leading with another one of those therapeutics. These therapies look really impressive in terms of their ability not just to lower Lp(a), but to lower it a large amount.

Now, we're moving away from having had therapies that can't lower Lp(a) to PCSK9 inhibitors that can lower 30%, to now having a range of therapeutics that can lower it 80%, 90%, and potentially close to 100% lowering of Lp(a). That's a really exciting time in this field. These agents look like they work really well. They appear to be, in general, well tolerated in the short studies that have been done to date. The next question will be, will they lower risk?

O'Donoghue: Exactly. To that point, I think that one of the areas of controversy remains how large of a reduction in Lp(a) we will need to see in order for that to translate into meaningful clinical risk reduction. Do you have any thoughts there, and whether or not we really should be studying exclusively those with higher Lp(a) concentrations at this stage?

Nicholls: The genetic studies, I think, alarmed us a bit. While they showed us that having high Lp(a) was causal from an atherosclerotic perspective, they almost imply that you would need to lower Lp(a) at least 100 mg/dL to find a comparable degree of risk reduction that you'd see in LDL cholesterol–lowering trials. That then makes this a therapeutic that's really only going to be useful for a very small number of people. It's going to make those trials very difficult.

I think most of us active in this field have hoped that we wouldn't need as much Lp(a) lowering. I think that when you get into high-risk patients, particularly those who have clinically manifest disease, they may have additional risk factors — whether it's hypertension, diabetes, race, or C-reactive protein (CRP), for example — that make the relationship between Lp(a) and subsequent risk seem much tighter.

I think that gives us hope that we can be enrolling patients in these big trials with Lp(a) that may be > 70 mg/dL or something like that. Many more patients can get into those trials. We think that will be a good starting point for what these trials should be looking at, and then would potentially be a useful therapeutic for many people.

Changing Outcomes and Aortic Stenosis

O'Donoghue: I think that, as you make these points, it's akin very much to where statin therapy originally started, where we really looked at those with very high LDL cholesterol concentrations at baseline. As the field has continued to evolve and understanding that the shape of the relationship is largely log linear in the case of Lp(a) in terms of risk and not a clear threshold existing, there's no reason to think that you wouldn't continue to have benefit, even for those who are at a lower starting baseline concentration of Lp(a) in terms of further reducing that risk as you go along.

Nicholls: Exactly. It's the same kind of concept in terms of primary or secondary prevention. If these work, they're likely to work in everybody who's at some degree of risk. You would imagine that people who are at high risk have risk that is probably more modifiable. We have to start these clinical trials somewhere.

The statin example is a really great example. The 4S trial had 4400 patients. If you think about it, we're doing PCSK9 inhibitors trials with 27,000 patients. Starting in high-risk patients is always a useful place to start. They have the greatest "unmet need." If we show that they work here, then you can imagine a series of trials over the course of the next 10-15 years that will look at it in a whole range of different clinical settings.

O'Donoghue: Absolutely. One of those settings, as my last question, might be aortic stenosis. You raised this yourself, that we know based on the Mendelian randomization data that it seems like Lp(a) plays a causal role there, and yet we don't currently have any therapies that help to slow progression of aortic stenosis. Do you think that is a promising space as well?

Nicholls: I think it's a promising space. Most of us are struggling to try and understand what those clinical trials will look like, and again, how early in the disease process. If you take somebody whose calcified valves are too calcified, has the horse bolted out of the barn and are you better trying to target a biology that's a little earlier on?

Wouldn't it be exciting if 10 years from now, we can think about a complete game change to aortic stenosis, that you've got two different stages in the course of the disease where you can bring new technologies to completely change the way that we treat. You can have a biologic that targets Lp(a) early and arrests progression. For those people who are much more advanced, we can now replace their valve on a catheter. You get to a point where we eliminate major cardiac surgery for a disease where that was the only thing that we could do for decades.

O'Donoghue: I think it's a very exciting, promising space. We'll continue to see where things evolve, and certainly, phase 3 studies will give us the definitive answer.

Thank you, again, for joining me today. Signing off for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

Follow Michelle O'Donoghue, MD on Twitter

Follow theheart.org | Medscape Cardiology on Twitter

Follow Medscape on Facebook, Twitter, Instagram, and YouTube

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.