Lp(a) Trial Failure Explained — Full Breakdown & Transcript

[00:00] This may be the most shocking news in heart disease research of the last two decades. A landmark clinical trial that was eagerly awaited by the scientific community just failed.

[00:12] And that challenges our understanding of the causes of heart disease. We all have tiny little particles that float around in our bloodstream called lipoproteins, and that's completely normal.

[00:24] But when those particles get lodged, get stuck inside the artery wall, They can cause black, and down the line, they can cause heart attacks and strokes. And there are different kinds of these lipoproteins.

[00:38] There are some larger ones called remanents, and there are some smaller ones called LDLs, which you've heard of. And then there's another kind called LpA, or LPA. And the scientific evidence so far pointed to LPA being actually the worst of the bunch.

[00:55] One out of five humans have high LP little a, so it's quite common. I have it. It runs in my family. Just to give you an idea, normal LP little a is under 75 nanomoles per liter.

[01:10] 75 to 125 is considered borderline or intermediate risk. And over 125 is considered high risk of cardiovascular disease.

[01:22] And my level is 180. And LPA has a very strong genetic determinant, so it runs in families, and unlike the other particles, the remnants, or the LDLs, there's relatively little you can do with lifestyle.

[01:35] Someone who has very high LPA, like me, there's no known way to bring that down to the normal range. But there was a huge missing piece in this puzzle, and that was a clinical trial.

[01:47] Up until now, no one had randomly lowered LPA in a group of people and seen the risk of heart disease come down. So for the past few years, several of these randomized clinical trials have been ongoing,

[02:04] and the scientific community has been eagerly awaiting these results at the edge of our seats, you could say. And the main trial that's been talked about that was highly anticipated was called the HORIZON, And it was a trial where they looked at 8,000 participants, a little over 8,000, with high LPA and with a history of cardiovascular disease.

[02:25] And these people were given this drug called Pelacarcin that's been shown to reduce LPA levels by 80%, so a very powerful effect. And half of the participants are given the placebo as a control group.

[02:37] So they just announced that Horizon has essentially failed. their main goal, the main thing they were measuring, there was no significant improvement in the group receiving the pellet cars and compared to the controls.

[02:50] The full details are not out yet. That's going to take a couple of months to be completely released but we know that the main metric they were shooting for that the trial was designed for this is called the primary outcome there was no significant difference for that And their primary outcome was a combination of deaths from cardiovascular cause

[03:12] non-fatal heart attacks, non-fatal strokes, or an urgent revascularization procedure. So that's when you have a clogged artery, and they have to go in with a catheter and blow it up again,

[03:24] and either put in a stent or do a bypass surgery, that type of intervention. So basically combining those four types of events, the combined risk of those was not any lower significantly

[03:36] in the group receiving the drug compared to the controls. Now, this happens all the time in clinical trials. Some drugs work, some drugs don't work. That's normal. That's why we run clinical trials. But this trial in particular has stunned a lot of the scientific community.

[03:51] Most people expected these trials and these drugs to work. In fact, the only thing I can remember that was this shocking in heart disease research was when HDL-raising drugs basically failed going back 20 years ago.

[04:06] We've known for decades that people who have higher HDL cholesterol levels have lower risk of heart disease in general. There's that correlation. So a number of therapies were developed during the 90s and the 2000s

[04:19] to try to raise HDL cholesterol levels. And some of those drugs were quite powerful in raising HPL cholesterol, so the expectation was that they might help us prevent heart disease.

[04:31] The anticipation was huge, the promise of those drugs. But the randomized clinical trials of those drugs, by and large, failed. This led to a huge disappointment and basically a rethink of the field

[04:43] where the current understanding is that HPL cholesterol levels are a marker of heart disease risk, But they don't cause, they don't raise or lower risk of heart disease per se. And with this new trial, these shocking results, a lot of people on social media were concluding similarly that this is saying that LPA is just a marker.

[05:04] It's not a cause of disease. And I suspect that conclusion is wrong. And I'm going to explain why. And by the way, my bias would be to believe that. I mean, I would love nothing more than for LPA to be completely harmless.

[05:17] I mean, I carry the grenade inside of me. My family, my sister, my mom have very high LPA, so it would be incredibly convenient for me to believe that LPA is just a paper tiger. But science doesn't care what we believe.

[05:29] Science doesn't care what we prefer. And looking at the evidence objectively, that's just not believable. Because before this trial, we basically had two lines of evidence pointing to LPA being a concern.

[05:42] The first is just the correlation that people who have higher LPA tend to have a higher risk of heart disease. That's not super strong evidence. In fact, for HDL, we had that correlation, and it ended up flopping.

[05:56] But we have another line of evidence that is much more powerful and that genetics We know from a number of studies that people who carry genetic variants in the LPA gene that cause LPA levels in their blood to be

[06:09] higher have a higher risk of heart disease, and vice versa. Populations that have mutations at lower LPA levels have lower risk of heart disease, and it's broader than just the heart. It's really cardiovascular disease. There are manifestations in other parts of arteries that are not just the

[06:26] heart. And we see this pattern with the genetic mutations and the risk across a number of studies and with multiple different genetic variants in the LPA gene itself. So this is incredibly difficult

[06:40] to explain away. And by the way, the other particles that are problematic that we talked about, the remnants and the LDLs, genetic studies back the causality of those as well, over and over and over again. So it would be truly groundbreaking, truly, truly surprising if LPA turned out to be

[06:58] this exception to the rule, the only member of the family of lycoproteins that is harmless, and where the genetics basically get it all wrong. So I'm making a prediction right here,

[07:11] right now, that LPA is not just a marker, that it's actually a cause, and that this randomized trial is a curveball. And I hope I'm wrong. God, I hope I'm wrong. I hope LPA is harmful for my own

[07:25] sake and everybody else out watching that has high LPA. But I think this is the most likely scenario. And we're going to get answers very soon because there are multiple other randomized trials ongoing. They're in motion as we speak, looking at other therapies that lower LPA. So

[07:44] maybe some of those will show a benefit of those drugs. If that happens, then it becomes a question of a specific therapy. And maybe there's something about pellicarsin specifically,

[07:56] where it has some off-target effect. It's lowering the LPA, great, but it's doing something else elsewhere. And so the net effect is no benefit for cardiovascular disease. That's a formal possibility. Another thing to bear in mind is that with genetic studies, you're looking at

[08:12] lifelong exposure. So when someone has a mutation that raises their LPA, they're exposed to that from birth. If they're middle-aged, if they're 40 or 50, that's 40, 50 years of exposure. With the

[08:26] trials, you're basically seeing a lowering of the LPA for about five years, five, six years. So maybe it's too late. Maybe you need to lower it longer or start earlier. Now, we have plenty of trials for the LDL particles, for example, and that works. Lowering for five years, we see a substantial

[08:43] reduction in cardiovascular risk, even started pretty late in life. But maybe there's something different about LPA. Maybe for LPA specifically, the lowering needs to start earlier, at an earlier

[08:57] stage of the disease And the last thing to bear in mind is these participants in this trial they have a lot of risk factors that are already handled So they on lipid treatments that reduces the number of LDL particles

[09:10] and even the number of remnants to some extent. They're being treated for blood pressure as well. So they have a lot of things that are already dialed in. Their outstanding problem is the LPA that's very high.

[09:22] The question in this trial is very specific. if we lower LPA in individuals who have all these other things handled already. Do we see any additional benefit? And that brings us to what I think is the most important question for us right now,

[09:36] which is how do we protect ourselves while scientists are figuring all this out? So here's what I personally do. I can't bring down my LPA to normal, not yet. So I do three things to protect myself.

[09:50] I keep my blood pressure really dialed in. The latest science we have says that keeping the systolic blood pressure, that's the higher value when you measure the blood pressure. There's a higher number and a lower number.

[10:02] The higher number is the systolic blood pressure. We know that if that blood pressure is under 120, the risk of cardiovascular disease is lower. So I try to be a little stricter still. I try to keep mine under 110, if I can, around the 105, 100 range.

[10:22] There's nothing magical about that number. I'm just trying to be a little stricter because I have this extra risk factor, right? This extra weight on my shoulders. And we have a lot of videos going over foods and natural supplements and workouts to lower blood pressure.

[10:38] The second thing I do is I try to keep all these other particles we talked about really low. And there's actually a metric that encompasses all of them, encompasses the remnants of the LDLs and the LPAs all together, and that's ApoB.

[10:53] I try to keep my ApoB very, very controlled. In the 50s or 60s, we're talking milligrams per deciliter. Now, not everybody needs to do that. Again, I'm just trying to do some extra homework because I have this added risk.

[11:09] And finally, body composition. I try to keep my body composition dialed in and avoid any excess of body fat by basically eating a healthy diet and exercising.

[11:21] And that pretty much takes care of blood sugar levels and insulin resistance. By staying lean and active, I pretty much handle all that. I can't bring down my LPA to the normal range, not yet anyway.

[11:33] But if it turns out to be a cause of heart disease, by turning all these other dials down, I'm basically trying to compensate so that the overall risk is kept as low as possible. That's the idea.

[11:45] What if you already have plaque diagnosed in your arteries? Is there a way to turn the clock back, to reverse some of that plaque? Actually, scientists have figured out multiple ways to do that with diet, with exercise,

[11:58] and we covered all of that in this previous video. So check it out, and I'll see you in there. Thank you.