Speaker 1
A recent paper just dropped and it's making big waves in the world of cardiology, and the internet is going crazy. It claims you can cut your risk of a heart attack by 25% with an injection, even if you've never had a heart attack before. Now, half the internet is going to hype this to the moon, and the other half is going to say it's worth this because it's related to big pharma. But that's just how it goes. You know, I like to sit in the middle, right? The gray. So. The world is a complex place with lots of grace. So, today we're going to cut through the noise, look at the actual data, and see if this tool is worthwhile to have your toolkit or just expensive hype. So, let's dive into it. So, first and foremost, I'm going to nerd out on the history just a little bit here, right? So, but bear with me because it matters. So, for decades, we've had statins, right? A long time. And I know you're going to say, Jordan, statins, I'm sick of hearing this. And they're poison. I mean, like. I'm just giving you what we got, right? So, we've had this. They've been reliable, and they've been the medications we've had, right? So, they work at lowering LDL, they're cheap, we know them. And yes, they do have potential side effects. We know that, but. They are currently the mainstay treatment in this time. So that's where we're at currently. We're going to talk a little bit about what's going on in the future, right? So Now came PCSK9 inhibitors. So, previously before this. So, these PCSK9 inhibitors, we have to understand, to understand the study we're talking about today, we have to go back a little bit, look at the history. The first is the four-year trial in 2017. This was a massive study showing 27,000 patients. But here's the key: every single one of these patients had some sort of cardiovascular event, right? So, this study was looking at people who've already had an event. Does lowering their LDL lower through this medication, these PCSK9s, does it lead to a reduction in something called MACE or major adverse cardiac events? And they found that, yeah, it reduced it by 15% in this study. And on top of that, then we have something called the Odyssey trial, right? So, similar story, but people who had just had a heart attack. So, once again, people who have known disease have had heart attacks. There were 19,000 people here. They were followed for about 2. 8 years. And the results, pretty much the same thing. There was a 15% relative risk reduction in those adverse cardio events, right? So, like, big things like. Heart attacks, stroke, those big things. But the critics will say that these results weren't that impressive, right? So they say that, hey, it's only 50%. But the scientists say, well, it's such a short interval, like two years is not that much. And so. That's what their big issue was there. And I want you to keep that 15% in the back of your brain, right? So I talk about 15% over two years. Remember that because it's going to come back later. So the question remained, though, after this. Hey, they lower, they seem to reduce risk. How important is that? We don't know. But the real question is: can we use these drugs to help prevent a heart attack? Before it happens, that's the big thing, right? Because these past ones here are people who have already been out and they say, Hey, you're the highest risk people we know. We need to plummet your LDL. That's what they're looking at. So, this was the remaining question: like, well, does it actually prevent? And that's what we're going to talk about today. So, but before we do that, I want to explain and kind of figure out what these medications do, right? So, I'm going to use an analogy here. Up on the screen, you see kind of a very complex thing with LDL particle receptors and antibodies, all these things, it doesn't matter. Essentially, what happens is your liver has, I'm going to say catchers mitts. I was a catcher in baseball, so I love catchers mitts, which are known as the LDL receptors, right? So they grab cholesterol out of your blood. And there's a protein called the PC-SK9 that runs around and essentially degrades or destroys these mitts. And so, the drug that we're going to talk about called avalocomab, or rapatha, is the actual name, like the pharmaceutical name, avalocomab is the generic name. Essentially, what it does is essentially tackles that guy who's trying to destroy the mid. So, hang with me to the analogy. I know it's not great, but essentially, what you're doing is you are preventing that receptor from being broken down. And so the result is that you keep your MITs or receptors around longer, your liver clears more cholesterol, and your LDL drops like a rock. So essentially, That's the new mechanism. Before statins kind of inhibit cholesterol synthesis in the liver, this is leading your receptors around so it can actually take the stuff going around the blood and bring it back in. These inhibitors allow these receptors to stay around longer so that you can lower your cholesterol. That's what's working there. So, I just wanted to talk about it. But before we go any further, I do want to take one more step back and look at how this trial actually was run, right? So, first things first. What was the first number? Well, we had about twelve thousand two hundred fifty seven participants. So not a bad study by any means. That's a small city of people, right? Not bad. And it was done over multiple countries, which is great, right? We're not just having one specific location. Wonderful. The median age was 66. And for sexes, the 43% were women. And honestly, that's a huge win. I'm going to give credit here. Historically, cardiology has essentially been a boys' club. Like, all the studies have just been dudes. And so, getting near 50% is legit a win for bedted data and looking at female representation. So, that's wonderful. And one thing we did have, though, we have to talk about race is we had 93% white in here. And so, that is a big swing and a miss, right? So, we Just can't assume that what's happened and find in this study is going to be suited for everyone in the in you know of every background. So it's kind of a big blind spot, but it's it is what it is, it's what we have And what did these patients look like? Well, they didn't have a prior heart attack, right? But they had high-risk features like plaque we could see on scans or hard-to-manage diabetes. And so These groups, make no mistake, they are still very much high risk, right? So it's not like, oh, it's just an average Joe. What happens if I lower an average Joe's cluster? No, there's still high-risk people who either have known atherosclerosis from a scan or like. Diabetes that requires multiple treatments or insulin or stuff like that, or have microvascular issues like retinopathy or nephropathy, all those things. Long story short, not super healthy people, but that's where we're at. And of these people, 92% were on some sort of lipid-luring therapy. That's good. And 72% were on a high-intensity statin. And despite all those meds, though, they're on a lot of meds. Their median LDL was still 120 milligrams per deciliter. And so that's a big number. For us to remember where it was. And it tells us definitely that, hey, they're not at gold, right? So, depending on the association and the cardiologist you're looking at, goals can range anywhere from under 100 to under 70 to under 55, depending on how aggressive they want to be. Certainly, anything over 100 and 122 is not going to be at any goal for someone who has known atherosclerosis, right, or diabetes. So that's not our goal. But that's where they are starting here, even though they're on medications. All right, so now let's talk about the study itself. So it ran for a median of 4. 6 years, right? So this is really important, right? This is almost double the length of the previous trials that I mentioned, right? So 4. 6 years, that's a long time. And what were the main endpoints looking for? So, when I say main endpoints, we're saying, hey, how do they keep score? What are the things that we're looking for that are most important? And the biggest things they're looking for were something called three-point MACE. And so, MACE stands for Major Adverse Cardiac Events, right? Essentially, Uh, it's a combo of three main things: death from heart disease, heart attacks, or strokes. So, the big three right there: death from heart disease, heart attacks, or strokes. If the drug lowers this combo, that's what they're looking for. That's the main endpoint. They also had secondary endpoints, and the secondary endpoints were four-point mace, and it's the same list as before, but they add on revascularization. So that means needing to get a stent or a bypass surgery because an artery is clogging. And so this is a softer endpoint than death. But still, a big deal if you're a patient, right? So you don't have to go undergo any procedure. We don't want that. That's the goal. And then, on top of that, so we're having these things collected, and there's a really important layer of protection, though. And this is that the people deciding if a patient actually had a heart attack. They were, you know, these independent adjudicators, they were an independent committee. So they essentially were blinded to the study of what's going on. They just decided, yes, this is an event or not. So that way the people. Running the actual data didn't decide and didn't skew it. And then the people running it were something called the Timmy Group T-I-M-I. This is a study group based out of Harvard that looked at the numbers. And so Overall, looking at these big outcomes, that's what we're looking at. And a big, big disclaimer I have to talk about here is that, for full disclosure, Amgen is a pharmaceutical company. They funded this study. Like they pretty much funded it and ran it. And the data was also collected by them. And so I know people right now are going to be like, well, automatically disqualified. Just stick with me. Right. So stick with me. It's what we have, and so we'll use what we got, right? Is it ideal? No, it's not, but hey, we can still be judicious. And so, what happened though is that they did collect it, and then, but the Timmy group at Harvard ran the numbers, right? So, as I mentioned, data collected by Amgen, and then this Timmy group. They're the ones who ran the numbers. So the math is solid, right? They're trying to say, hey, we're trying to get eliminate pharmaceutical from the actual math. But the questions they also asked to design it was. Driven kind of by Amgen. So at the end of the day, no, it's not perfect. But at the end of the day, they collected the data and then gave it to this private group and said, Here you go. And the way the paper said it was like the raw data. So whatever they collected, they just handed over to the Timmy group and they run the data analysis. And that's kind of what they're looking for. You know, there's always gonna be skepticism, right? People would say, oh, like it's funded by them. We can't trust it, but it's what we have, and we can look at it. And at the end of the day, like, we do the best with what we got, right? And so, yeah, that's what I mentioned before. And so now we're going to talk about some of the numbers, right? So, first of all, what do they say at baseline versus we talked about that in the results? So, LDL dropped from 122 at baseline to 45 milligrams per deciliter. That's huge. That's a massive drop. That's. At goal for pretty much every single society out there, even for the most aggressive people. The primary outcome there were reduced cardiovascular events by 25%. And so 25%. That sounds incredible, right? Like four years 15. Like, why is this 25? Well, the question is, it's not necessarily magic. We kind of expected this, right? So, we saw in those short time frames of two and a half years or whatever, a decrease in risk by 15%. Well, this one went. Almost double that. So we would expect to see an increase, right? And so the idea is that heart attacks and heart disease is a lifelong disease. So lifelong exposure builds up over time and then leads to this seminal event where you have a heart attack or stroke or whatnot. So if we can Decrease your LDL for longer, the idea would be that it's going to show improvement. And it seems to be compatible with that. Most likely, a longer reduction of LDL or atherogenic lipoproteins will show more improvement at the end. That's probably what we're going for and what we saw. And here you might mention like, well, Jordan, that was your relative risk. I don't care about relative risk. I want absolute. And that's very valid to ask. So, the absolute risk, this is the real world numbers. The placebo group had an event rate of 8%. So, 8% of those participants had an event. The drug group had an event rate of 6. 2%, which led to a difference of 1. 8%. And so going from 25 to 1. 8 sounds way different, right? You're like, wow. What's the point? 1. 8. Well, we have to remember, we have to extrapolate that into: are you that 1%? Like, is it worthwhile to you? That's academic discussions we can have. But those are the absolute Values that we have to talk about. A lot of times, people only hear relative. We have to be fair and talk about that as well. And going with that, when we talk about an Absolute risk, right? So that's like the actual events that happened. We can calculate something called the number needed to treat. So the number needed to treat here in this specific one was 56. And to translate that, what that means is we have to treat 56 people for almost this 4. 6, 4. 8, five years to prevent one event. So treating 56 people with this medication. Theoretically, the other 55 people took this medication and paid the money, it's not in the clinical trial, but pay the money for no difference in the real world, right? So that's a big thing we have to ask: hey, is it worth treating 56 people to save one person? Well, if you're that one person, you're probably going to be like, yeah, it is. But that's the question we have from a population health perspective and guidelines, all those things. So, never need to treat worthwhile, at least knowing and mentioning. And there are some takeaways though. I do have to talk about this. There's definitely, I have to give credit where credit is due. It did seem to reduce the occurrence of heart attacks as well by 36%. And so that's a big win, right? So. It seems to point out that if you really, really, really lower cholesterol, it seems to potentially stabilize the plaque and decrease your risk on that. So, does it prevent death though from heart disease? And we'll talk more about that. Not significantly in this study. We didn't see a mortality benefit. It seems like it may keep you out of the ER, but we can't claim that it saves lives. And I know some people will say that, hey, mortality is the most important thing. And that's totally valid, right? People dying, pretty important. I think we can all agree on that. But I will say that preventing a heart attack is also very important, right? If you've ever dealt with patients who've had heart attacks, it's a big deal, right? It leads to a long-term morbidity and then eventually mortality, right? You lose your heart muscle because of the heart attack, then your heart doesn't pump as well, so your ejection fraction goes down. And then you maybe get heart failure or develop something else, and then your quality of life goes down and it goes in the tank, and then like bad things happen. So, like, this isn't nothing, right? So, decreasing a heart attack is probably a good thing. Is it financially worth it? That's the question we all are going to have to ask. But I think a lot of people will poo-poo and say, like, it's not mortality. I don't care. Like, I don't know, man. Like, I don't want a heart attack. If I could prevent a heart attack, I'd be a big fan of that, big fan of that. And one thing I also want to mention is the safety profile. And here's a piece of great news: safety. Sometimes when we push biology to the brink, right, things break. So dropping a cholesterol this low, there'll be a lot of people saying, is this dangerous? And they found no significant differences in the placebo group versus the people on Ivilocomab. So that's wonderful. On top of that, they didn't see any diabetes signal as well, meaning With statins, we know that some people will develop nuanced diabetes with a statin medication. They didn't seem to see that with this medication. Also, there were no neurocognitive issues like brain fog or dementia or anything like that that's also mentioned with statins. And so. You know, those worried about needing cholesterol for your brain didn't seem to show that signal in this study. And I know a lot of people will say, like, Jordan, this is too short of a study to do that. I get that, man. I don't have to tell you, like, that's just what the data is showing. But overall, it's really, really encouraging. And also, there were no muscle symptoms on top of that as well. So, you know, big things with statins are risk of diabetes, the potential brain fog, muscle symptoms. All those things, and this didn't show any of those signals. And so we're having this super pronounced lowering in LDL with none of the symptoms. It seems like the holy grail potentially, but overall, that's what they saw, which was helpful. And no study is perfect though, right? So let's talk about the limitations that we have and where the data kind of falls short. The first thing I talked about is mortality, right? So did it save lives? Technically, no. The deaths were lower, but statistically didn't cross the finish line, didn't reach significance, right? So the researchers call it a provocative signal, and I call it like, okay, so what, right? And that's A provocative signal just means like maybe we don't know, but it's not what the study was looking for, right? We're looking at for the MACE outcomes, those are the big things. It wasn't powered to look for that necessarily, and that's totally fine. But ultimately, we do want to prevent deaths. It's very important. We want to show that it prevents deaths because otherwise, people say, Well, what are we actually doing here? So, that's something that I'm sure in future trials they'll look for and try to see. But that's at least worth mentioning one weakness there. On top of that, we also had kind of the strategy with head scratcher to me, right? So, no study, we know how it was issues, right? It's never perfect. And it's easy for me to say, like, well, why didn't we do this? One big thing that I saw in there was it's kind of, I call it the azetamib issue, right? So this study is kind of frustrating me. And only 20% of the patients were on azetamib. And if we take a step back, azetamib is a different oral medication. That lowers cholesterol usually through cholesterol absorption in the stomach. So essentially, that's what we're in the gut. That's what's going on. It is a generic cheat pill that we know lowers cholesterol, right? So effectively. The study design just like skipped this cheap option. It's like, we're just gonna go straight to the expensive one, which was, I thought, was interesting. And they kind of said, Hey, we're gonna jump to the big guns without exhausting all the other stuff. And it was definitely a head scratcher because the American College of Cardiology and the AHA both recommend adding azetamibe as like the first non-statin agent for people who aren't at their LDL goal. So, like, it's not like Go to statin, go to the injectable. It's like, hey, we should be putting statin in there. And so they specifically advise adding azetamide before considering a PCS Can I inhibitor due to cost and oral ease of use, right? So these. Ones that we're looking at in this study are injectables. Azetamib is just an oral pill that you take every day. It's, you know, generic, pretty cheap. Like, so I don't, to me, this is just a head scratcher. Like, are we just not following guidelines? Are we not practicing? Because. And I get it. Maybe it's cardiology. They think it's high-risk patients. We're like, we're going to skip that, get to the big gun. Like, maybe that's what's going on. But for me, it's like, are we actually doing like, how are we getting all these patients? In seeing their doctors. And if this is the goal, we're not getting there. It's just kind of an interesting thing to think about. And the last limitation I want to talk about that I mentioned earlier is diversity, right? So it bears repeating, though. 93% of participants were white. And when we talk about applicability, we have to be honest that we have a massive data gap for Black, Asian, and Hispanic populations. From this paper, right? So we can't simply just copy and paste these results to everybody because we don't know if it applies. So, hopefully, in the future, we get better data on a more diverse population, but that's something we have to mention. And so, finally, I do want to talk about kind of the bottom line and takeaways. And so, I'm not a guru. I'm not a cardiologist. Like, I'm just a dude. I'm just one beggar to another beggar telling me where to find food. I've seen people talk about this study. In different lights. I've seen some say it's the best thing in the world, others just say it's worthless. I'm just here to show you what I know, right? And if you don't like it, that's fine. You can click away. But here are kind of the big things that I say is. The first things first is like, don't skip steps. There's no free lunch, right? So max out your lifestyle, nutrition, exercise. That's always the first thing we talk about. I talk about all the time. That should be the base pillar because that gets you. The vast majority of the way, hopefully preventing cardiovascular disease in the first place, preventing diabetes, all these things to like prevent you to be in the study. That's the main goal. And that should always be the pillar, right? So, then after that, though, the big takeaway point that I have is like: talk with your physician and work with your physician, right? Pick what's best for you. I think a lot of people will see this and say, hey, we need to follow this stepwise approach. And I even mentioned before, you know, guidelines. Guidelines are wonderful, they're great tools. There are a lot of people who get together who have lots of collective knowledge and kind of help you guide, but like, it's still like. Guide, right? It's not a rule book. It's not you saying you have to do this. So if something doesn't work for you, or you say, Hey, actually, I'm not comfortable doing this, like, I don't want to be on a statin medication. I get that quite a bit in clinic. Okay, well, then what about a ZMod? Can we do something to lower that there? Hey, what about these PCSK9 inhibitors now? That's great. Regardless, like, I just want you to. Have this knowledge so you can be informed. That's the big thing, right? So, a lot of people, like, they just need a little bit of low dose of medication. Some people, a newer way in cardiology, is to do Two smaller doses. So you do a low dose statin, low-dose zetamide to get the best of both worlds, where essentially the lower dose has much lower chance of getting side effects. And so we just do a little bit of each. That might be helpful. Some people need the big guns, or this is where it comes in, right? You have a genetic predisposition to having a very, very high LDL. Maybe you need to have some help, and that's okay. And if I'm being honest, though, like This will probably be a big, big player going forward, right? So you think about these agents that we've had have been fine. The statins have been, you know, they are what they are, right? They're controversial for sure, but they definitely do lower people's cholesterol. But this seems like it's gonna be the future, right? So, once it becomes cheap enough, though, right? Because we see these drastic reductions in LDL and these athogenic lipoproteins with a pretty negligible side effect profile. Obviously. I'm going to step back and before I get in trouble. I know people will be on this and will have side effects. Like, I know that, but it just seems like it wasn't any different than the placebo. So there was no huge signal that it's way worse. Your experience, if it was different, like Please let me know. I'm not belittling that or throwing that off or dismissing it, saying, Hey, it didn't happen. I'm just saying overall, if the profile is similar to other agents we have, then that's going to be wonderful. But yeah, if it stays Pretty much symptoms minimized, that'd be wonderful. And you're having this huge reduction, then like it's going to be like the thing, but it's just so expensive right now. But at the end of the day, everything comes down to people's risk topons, right? Their personal choices, what they want to do, what they want to take, what they want to not take. And yeah. Am I overly impressed with this study? Like the same way, not necessarily. There's no groundbreaking news here. Other than it's stopping the first heart attack from a higher-risk group, like that's helpful. But I think overall, you could probably do that with other medications, right? Like if you're on that borderline. And you're like kind of around 100s, and you take azetamide and you get down to like below 100s, and you have a heart attack. Like, did you need to spend thousands of dollars on this medication? I don't know. That's the main question. And so, I don't know. We'll kind of see where it goes. I think. In the future, we'll start to see more and more of this, but we'll kind of see where it goes from here. And the other thing, though, is like the future, right? So the big thing is This study kind of shows that this seems to be an option, right? We've done all the stuff. If you've done all the other medications and your numbers are still really high, this study seems to give us a little more confidence that you can use this safely, right? Just based on the side effect profile and the results here. And on top of that, there was actually a recent article that just came out showing there's a new oral version of these medications. And I think that will probably be very, very helpful, right? Nobody wants to inject something all the time. So, if you can get similar results with an oral, that would be very, very helpful. Um, but yeah, we're gonna see what the future holds. All right, team, that's gonna be it for today. Thank you so much for stopping by. I really appreciate it. If you did find this helpful, mean the world to me, if you just share this with someone, that's the best way to get this out to people, is just share it. And I really appreciate it. Anytime I feel like Uh, someone reaches out and says this was helpful, that really means the world to me. But uh, that's gonna be for today. Thanks for stopping by. Now, get off your phone, get outside, have a great rest of your day. We'll see you next time. This is for entertainment, education, and informational purposes only. The topics discussed should not solely be used to diagnose, treat, or prevent any condition. The information presented here was created with an evidence-based approach, but please keep in mind that science is always changing, and at the time of listening to this, there may be some new data that makes this information incomplete or inaccurate.
Speaker 2
Always seek the advice of your personal physician or qualified healthcare provider for questions regarding any medical condition.
