Primary Viewpoints Episode 4: Lp(a): The Next CVD Target?
Patrick Moriarty, MD, from the University of Kansas Medical Center, discusses the role of Lp(a) as a risk factor for cardiovascular disease and the phase 3 trials of a potential treatment.
The following transcript has been edited for clarity and length.
Patient Care: Hi, I'm Grace Halsey, editor of Patient Care Online, a website for primary care physicians. Today I'm speaking with Dr. Patrick Moriarty about cardiovascular risk and risk assessment. More specifically, we're going to talk about the evidence for the role of lipoprotein A, which I will call Lp(a) here on, as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and as a target for therapy. Dr Moriarty is a professor in the Department of Internal Medicine at the University of Kansas Medical Center in Kansas City, where he is also the Director of Clinical Pharmacology and the Atherosclerosis/Lipoprotein-Apheresis Center. He'll be speaking on this topic that we're talking about today, next week at the 2020 virtual Cardiometabolic Health Congress. Welcome Dr. Moriarty.
Dr Moriarty: Thank you Grace for inviting me. Good afternoon to you.
Patient Care: Thank you. So, you're involved in the most current research on the role of Lp(a) in the development of ASCVD and also in some promising research on a potential treatment to reduce levels in patients at high risk. Could you just give us a little bit of background on how Lp(a) became identified as one of the more important markers of residual cardiovascular risk?
Dr Moriarty: Sure. It goes back all the way to 1963. A Dr. Berg from Norway - he was a physician but also a researcher - was trying to investigate if there were new blood types. In his investigation, he immunized rabbits with a human beta lipoprotein from a single donor. The antibodies that he found that developed from this procedure, were found in one-third of the population. And eventually he found out that these patients that had this protein, had an increased risk of cardiovascular disease and he called it lipoprotein A, and that's where it originated from. So, we're going all the way back there, and it's progressing and progressing up until now. If you want, I can give you a quick overview of what this lipoprotein is.
Patient Care: Sure
Dr Moriarty: It contains an LDL-like moiety 100 in size, like a typical LDL. It has this apolipoprotein A bound to it and this apolipoprotein A looks somewhat like plasminogen, except it doesn't have an active protease domain. The protease domain of plasminogen is what causes clots to break up because our blood is constantly clotting or unclotting, daily, if not we would bleed to death or we'd clot to death. So, this plasminogen goes to where a clot is and breaks it up. Well, Lp(a) goes where it is, binds to it, but does not increase the fibrinolytic cascade. The clot sustains a longer duration, which in places like cardiac and brain, could be very detrimental. Third, it’s a major carrier of inflammatory molecules, including, more importantly, oxidized phospholipids. About 80% of our oxidized phospholipids in the blood are carried on this lipoprotein. And oxidized phospholipids are major players in the plaque foam cell deposition and degradation of plaque causing rupture, which is a major etiology of a cardiovascular event is a ruptured plaque. So, it's a triple whammy because it has LDL too. It's LDL, inflammation, and coagulation. About a third—20% to 30%—of the world’s population have this lipoprotein, and you're born with it. It's an autosomal dominant gene that dictates it. So, if you have it, 50% chance your children might have it. And you can't change it by lifestyle, diet, exercise has no effect on it. Actually, statins might raise it a certain percentage. Well, the good thing about that, even though statins do raise it, the statins still give clinical benefit. There was a study called JUPITER where they used rosuvastatin—if you remember that—and it was a primary prevention study and they showed a reduction in cardiovascular events and reduction of LDLs quite dramatically, but then they looked back and said "okay, what about the patients in that trial that had a high Lp(a)?" Well, they showed that they still got benefit with the statin, but it was attenuated. It was weakened by the high Lp(a), so you never stop a statin therapy in a patient based on their Lp(a) level.
Patient Care: This new molecule, I believe it's an antisense oligonucleotide, is what you were looking at in your research that was published in the beginning of the year. What is it? And how does it work?
Dr Moriarty: We published a paper in January of this year in the New England Journal of Medicine. It was a phase 2 trial where we had different levels of this drug dosing in patients, about 85% got some dose and 15% got placebo; and it's an antisense oligonucleotide, as you mentioned. Present day monoclonal antibodies, such as the PCSK9 inhibitors, inhibit the protein as produced in the blood to prevent it from being active, with whatever its mechanism of action is. For antisense, this drug causes a missense reading of the messenger RNA to prevent the protein from being read out and made. It inhibits the protein being made itself and the drug has a special addition to it, which makes it liver specific, so it goes directly to the liver only because it can't go out other tissues. So, this is a new version, we had one that didn't have that. This one is 100-times more potent, so the dose is much lower. And we found that the drug could lower LDL, Lp(a) by about 80%.
Patient Care: The results were quite remarkable, if you just look at raw numbers.
Dr Moriarty: Incredibly powerful. And now we're moving into so-called phase 3 trial, which hard endpoint is looking at reduction of cardiovascular events, and dose is going to be 80 mL once a month, compared to placebo. It'd be 50/50. We're talking about thousands of patients worldwide, it started already late last year, and COVID-19 has slowed down the process of it, as you would expect, but it's moving ahead. We're one of the sites and it looks in 5 years, hopefully, we'll be able to show that this drug not only lowers Lp(a), which we know it does, but lowers cardiovascular events on top of that. We have a paper coming out in JACC (Journal of the American College of Cardiology), giving an overview of the drug—its initiation, its progression—because we were working on this drug for a very long time. So, it gives you kind of an overview of the Lp(a) and of this drug itself. Now there's another drug that just finished its phase 1 trial and this is similar in the sense of inhibiting the messenger, but it's an RNA interference. This one has similar powerful effects, like the other one we just mentioned, but they're just initiating a phase 2 trial, so they're a little bit behind the competition.
Patient Care: Well, at least there's competition, that's always good to know.
Dr Moriarty: It helps, your right. It speeds up the process and lowers hopefully the price.
Patient Care: In general, in the world of preventive cardiology, is the idea of lowering Lp(a) well received? I know that the ACC/AHA and European counterpart both recommend using Lp(a) as a risk enhancer when looking at cardiovascular risk. Thirty percent of the population sounds like a big number, but does that mean we should be looking at Lp(a) in everyone, or just in these very specific patients?
Dr Moriarty: Well, I'm biased. I've been in this field for a long time but let me give you an idea. The American guidelines, as you said, recommends you measuring it as a risk enhancer only in patients who have cardiovascular disease, or very severe family history, because it doesn't change levels throughout your lifetime. The European guidelines came out last year and said, "We recommend universal testing for every adult at least once," which I think is the appropriate thing to do. Because it's not an expensive test, and there is ICD coding for it. So, it's a 1-time test and if it's normal, then for the rest of that person's life, they don't have to worry about it. But if it's elevated, then you have that risk enhancer, as you mentioned, on your medical history that should be identified.
Patient Care: Who should be using this test?
Dr Moriarty: Again, I'm biased and I always say everyone should be and I think as time goes on, everyone will be. I don't know if you remember that TV show called The Biggest Loser. It was about an athletic guy who trained people who were overweight. A few years ago, he had a heart attack at age 50 and his heart attack was directly related to Lp(a). He had a massive MI in the gym. Luckily, there were 2 doctors in the gym that did CPR and he was in a coma for 2 days and woke up and found out his Lp(a) was high.
What's interesting—and I'll tell you this as a personal story—is that for strokes in children, unlike adults where 90% of strokes is related to thrombosis and atherosclerotic plaque, <2% of the strokes, thrombotic strokes in children, you find atherosclerosis at the source. And 40% of people <50 [years] when they have their stroke, thrombotic stroke not hemorrhagic, 40% is idiopathic. We just don't know why. We do know now that high Lp(a) in children increases their risk of a stroke. If they have a stroke with a high Lp(a) in the highest 90 percentile, they have a 10-fold risk of another stroke after their first one. I say that personally because I was sent a child from the children's hospital here in Kansas City, who had a stroke at age 11—thrombotic stroke, hemorrhagic, and obviously neurological deficits. They saw the thrombus and they brought him to KU to do, the invasive radiology team did a thrombectomy at the basilar artery. They removed the thrombus, but he still persisted with the symptoms. So, they consult, they did full bloodwork, hypercoagulable state. Nothing was there. His LDL was 60 milligrams per deciliter, but his Lp(a) was 160 where normal is <30. They consulted me and at that time I said the only thing we have at this point are my machines: the lipid apheresis machine, which is approved for treating Lp(a) now. We treated him and lowered his LDL and Lp(a) by 80%. He has been on this treatment now for 5 years, every 2 weeks, and he hasn't had an event. His neurological symptoms have greatly improved. Now, stroke in young children is very uncommon. The etiology is even more uncommon and that's where Lp(a) could be a major informative measure to do to see what's going on with these patients. And it's just a blood test, nothing complex.