hey guys, today we're going to talk about lp(a). We got a ton of requests to talk about this, and I agree it's an important topic, so today we focus on it, and we're going to cover everything you need to know to protect yourself. Now, today we have a very special guest. We're very lucky to be joined by Dr. Tom Dayspring, MD. He's board certified in both internal medicine and clinical lipidology, that's the treatment of disorders of lipids like cholesterol and lipoproteins. Tom's career seeing patients and teaching lipidology spanned almost four decades. He's written numerous manuscripts and textbook chapters on lipids. He served as the editor on lipidology journals and as a chief academic advisor for major laboratories, and he's given thousands of lectures to lipidologists and cardiologists. Now, I have enormous respect for Tom as a professional, as an educator.

I've learned immensely from him, and just so you see what kind of person we're talking about, I was nagging him on Twitter for a while with questions, a thousand questions, and he basically DMed me, he slid into my DMs, and he said, Look, you're asking good questions, you obviously have a genuine interest in this field, here's my cell phone number, call me anytime. I'm not shy, when a window of opportunity opens, I jump through it, so I asked him to come on and talk to us, and his answer was, Let's do it and I have no time limit. So we chatted over Zoom the other night and we geeked out over lipids for almost four hours, so that's a conversation that we will be releasing to you guys over many videos on different topics. Today we're going to hear from Tom on what on earth is LP(a), why it raises

cardiovascular risk, what levels are worrisome, and what we can do about it, solutions and strategies. Now, for those who are new to the topic, I'm going to give you a very brief rundown of the basics. The goal here with these videos is always that anyone with no scientific training should be able to understand all of the information and implement it if you so choose. So, cholesterol and other fats travel in our bloodstream packed in these vehicles called lipoproteins. They're like transporters of fat. Some of these lipoproteins you've heard of, LDL and HDL are two examples. LDL stands for low-density lipoprotein and HDL for high-density lipoprotein, and different types of lipoproteins carry different tags. So, for example, LDL carries a tag called ApoB. It's basically just a protein that wraps around the LDL. So, we can measure the number of ApoB tags, and that tells us

the number of lipoproteins that carry that tag. We can also measure the content of your lipoproteins, so for example on your basic lipid panel you'll see something called LDL-cholesterol, that's a measure of how much cholesterol is carried inside your LDL lipoproteins. So to bring this back around, Lp(a) is a subtype of LDL and it has its own special tag, here's Tom explaining it. Lp(a) is an LDL particle that also is carrying a second apo protein called apoprotein(a). The liver is the only organ in your body that can synthesize apoprotein(a) and if you unfortunately have the wrong mother and father you may have inherited the genes that induce too much synthesis of the apo(a) so ultimately you will have X number of particles in your plasma that are, yes, based on their density they're sort of like LDLs but they're not really LDLs because

a regular LDL will never carry apo(a), so if you are doing an LDL particle measurement using NMR, or if you're doing an LDL-cholesterol measurement, it is actually regular LDL particles plus Lp(a) particles, or regular LDL particle cholesterol content plus Lp(a) cholesterol content. Now, Lp(a) is always a minority LDL particle, even when people have super high levels of Lp(a), it's dwarfed by your regular LDL particle concentration, but nonetheless, you could make the case that particle for particle, because of the apo(a), that LDL is way more atherogenic than an LDL that is not carrying apo(a). So we know, just like LDL apoB, LDL particle count, when that exceeds a certain level, wow, atherosclerosis is linear, the higher it goes, the more risk. Well, we know with Lp(a) particle number, once it exceeds a certain threshold, Lp(a)

is likely a contributor to your atherosclerosis. Not in everybody, but in a lot of people it is. It is the most prevalent genetic lipoprotein abnormality associated with atherosclerosis because with high lp(a) the incidence of atherosclerotic and atherothrombotic events are way higher than just apob elevation per se by itself, so it's a worse particle. So lp(a) is an exception, most of these lipoproteins that carry apoB are thought to be about equally atherogenic. Atherogenic means causing atherosclerosis, plaque. So small LDLs, large LDLs, VLDLs, even though they vary widely in size they're about equally as harmful, we covered all this in detail in previous videos, but lp(a) is an outlier, it's particularly nasty, it's particularly atherogenic. Now, the good news is, most of us have low lp(a) levels, it's determined genetically.

the bad news is that about 20% of us have high lp(a), about one in five, so it's a big deal because this is very common, a lot more common than people think, and yet it's unknown. Most people have never heard of lp(a), so if 10,000 people into the future watch this video, that's potentially 2,000 people that have high lp(a) that probably most of them didn't know about it and can find out. So, it's important to get the word out. What are the lp(a) concentrations I start to worry? Sadly, most labs are measuring it not in nanomoles per liter particle numbers; they're giving you mass metrics, the weight of the lp(a) particles in your body. And although that correlates with lp(a) particle count, there sometimes can be a little bit of discordance. So, whatever once your lp(a) mass, milligrams

per deciliter, crosses 30 milligrams per deciliter. You're entering the world of risk, but really the real bad world the risk is much higher, you know much higher, 80, 100 milligrams per deciliter is usually bad news. If you're looking at particle counts, nanomoles per liter under 50 nanomoles per liter is okay, that's physiologic, as they start to hit 75 or 125 you're in a world of potential big-time trouble from the lp(a) particles. The good news is, like apoB, it's not going to kill you tomorrow, but remember, if you have extra lp(a) particles you've had them from the day you're born, because it's steady. By the time you're four to five years old you have the level you're gonna have the rest of your life right now.

can be a minuscule increase when a woman goes through menopause and loses estrogen, but it never takes you from a normal lp(a) level to a pathological lp(a) level, even though it might go up a couple of milligrams per deciliter or nanomoles per liter. So therefore, your arteries are exposed to high lp(a) likely way more than most people as far as what age did they start to develop consequential apoB elevations, because remember, you can have a very high lp(a) particle count and it's a minority ldl particle, so it's not really contributing to apob that much, so those are the levels we look at and we assume if it's high, you're in bad shape. There are perhaps some other modifiers you can look at that would say, is there any way of telling who are the people that have high lp(a) and don't get a vascular event versus those that do?

they're starting to look at something called oxidized phospholipids on apoB. Part of the things apo(a) does is it binds to and traffics oxidized lipid species. They're cellular toxic lipid molecules, not good, so if you had high lp(a) but it's not carrying oxidized phospholipids, maybe that's a less harmful lp(a) particle. Emerging data is starting to perhaps suggest that; we can't make a declarative statement on that right now anyway. So, as Tom explained there, there's a few different tests of lp(a). You can measure the number of lp(a) lipoproteins, and the result is in nanomole per liter. Nanomole per liter is a measure of concentration, or you can measure the mass of the protein, and that comes in milligram per deciliter. And measuring the number is a bit more accurate, so the nanomole per liter

there's also a third test that measures the cholesterol content of lp(a)s, and that's even more indirect. So it goes, in order of accuracy, lp(a) cholesterol would be the least accurate. After that comes lp(a) measured in milligrams per deciliter, and then the most desirable test is lp(a) measured in nanomoles per liter. And Tom also covered the ranges. For the milligram per deciliter test, under 30 is good, above 50 starts to be a problem, and above 100 it's really concerning. And for the nanomole test, under 50 is good, and higher starts to be a concern, especially above 125. So everybody should get their lp(a) measured once. It's much more stable than apoB or ldl-cholesterol or triglycerides, so there's no need to keep measuring it repeatedly for the most part. We'll look at some exceptions in a

second. Also, because it's determined genetically, if your lp(a) is high you want to check your immediate family members, they might carry the same gene and have the same issue. How much does the test cost? I've seen it for 40 or 50 bucks in the US. Depending on your insurance it might cover it, it's something everybody should measure once so definitely talk to your doctor and ask for it. We already touched on how lp(a) raises atherosclerotic risk, risk of plaque, so that's things like myocardial infarction, heart attacks, strokes, peripheral arterial disease but there are some other issues as well, so here's Tom going over some of those. There are potentials for apo(a) to be a pro-thrombotic, anti-fibrinolytic type of peptide, which wouldn't be good, I have no way of measuring that right now, so we're we're pretty

much left to. You have high lp(a). Let's assume you are at risk. I mean, you can monitor coronary calcium over time. One thing you better look at, and people have had it high all their life, apoprotein(a) is osteogenic protein. It really stimulates calcification. So, we know there's a very high incidence of aortic calcification and stenosis in people with high lp(a). I think right now it's the second leading cause of aortic stenosis leading to valvular replacement. So, if you do happen to have high lp(a), I hope your doctor is not only listening for a systolic murmur but at a certain point, might a periodic echocardiogram keep a much closer eye on your aortic valve? So, those are other things you can look at. So, like any other risk factor, there's individual variability. Over some of that, we have no control.

but over other aspects we do. So let's take a look at some of the approaches for management. So the real thing is what do we tell these people with high lp(a)? Is there anything we can do? Because it can take some people out when they're 30 and 40 years old with myocardial infarction or strokes. So all we know is, no, right now we can't lower it to the degree that it's probably necessary to lower it with any existing drugs, but we do know if you have high lp(a), I'm going to also measure apoB. If it's also high, I can give you an apoB lowering drug that will not do anything to your lp(a) particles, but it'll remove any excess of other LDL particles you have, and that will reduce residual risk in people with lp(a). It doesn't obliterate their atherosclerotic risk, but it certainly lowers it, from post-hoc.

analysis of various trials. People say, Hey, the PCSK9 inhibitor. And we now know, because it also can inhibit synthesis of apoprotein(a), can lower Lp(a) concentrations. It can maybe 20-25%, once in a while a more exaggerated response. I don't have outcome data that lowering Lp(a) apart from what a PCSK9 does to lowering ApoB matters. Some post hoc analysis of a couple of the PCSK9 trials suggested that yes, PCSK9 inhibitors do reduce atherosclerotic risk by what they potentially do to Lp(a) particles. So if I did want to take a drug and I had a high Lp(a), I would hopefully want to get on a PCSK9 inhibitor. Bad news, it has no FDA indication to use in that circumstance, ergo no third-party payer is going to cover a PCSK9 inhibitor because you want to reduce apolipoprotein(a).

so you have those roadblocks to it, so I think if I was a person right now, if, and I can afford it, if I had high lp(a), which I do not, I'm on a pcsk9 for another reason but I would use a pcsk9 inhibitor if somehow I could get my hands on it, on the hopeful belief that it probably is going to work. There are drugs in study that reduce the synthesis of apo(a) through inhibiting various genetic mechanisms and therefore they drastically reduce lp(a) particle concentrations, and they are now undergoing clinical trials, which the FDA needs large and powered trials to show that your drug that inhibits lp(a) and does nothing to apob will reduce heart attacks, because I can't say, ah, it's like a pcsk9 inhibitor, it's lowering apob I need a drug that just lowers apo(a) production, does nothing to ApoB, and those are the drugs being

studied, and if they are successful in reducing events and if they show no downsides to their use. Ultimately, they will come on the market. My guess is several years away, probably another couple of years to finish the darn trials. It takes a good year to adjudicate those trials and then another year to go down and get it published and then another year to go down to the FDA to get indications. So unless you're in a clinical trial, you're probably not going to get them anytime soon. And the first ones that are coming out, they're only studying them in nightmare people with significant atherosclerosis and very high lp(a). If they get an indication, that's probably what the indication is going to be. So that means if you don't have atherosclerosis yet and your apo(a) is not through the stratosphere, the FDA is not going to give that drug an indication to be used in primary prevention. And obviously, no third-party payer is

going to pay it. If you're rich enough, you can get it and go off label if it ever makes it to market. But everybody is hoping, Oh, these drugs will be here next year. No, they won't. And even if by some miracle they're really working good and those trials are stopped short of how long they should be going, it's another year or two to go through all the machinations necessary to come on the market, and it will only be for the nightmares of the world or the wealthy people of the world. Yeah, you talked about apoB. Somebody who has high lp(a). This is what a lot of people ask this question, and I've heard it both ways. Somebody who has high lp(a) but does not have high apoB. Does that still raise risk by itself? But again, if you go to what's a physiologic apoB, 30, 40, you show me the people with high lp(a)

that doesn't have an apoB above 50. You know, if you're looking for an apoB of 90 or 100, okay, there will be some of them, but if you're really looking at physiologic apoB, there's room to work in everybody. All things aside, cost and whatever, if you told me you had a really high lp(a) and your apoB is 60, I'm starting you on a pcsk inhibitor. There's no downside to using that drug, other than cost, and I can lower apoB, I would make you physiologic with apoB, and I at least now get a, if I'm lucky, 30% reduction in lp(a) and then wait for the other stuff. So to summarize, if you have high lp(a), the first line of defense is to manage the other major risk factors: healthy diet, physical activity, healthy body weight, not smoking, blood pressure, diabetes.

and ApoB. In fact, this study found that people with high lp(a) had 70% lower risk when they had those risk factors under control. In terms of pharmacological approaches, statins, for example, don't lower lp(a). In fact, they might even raise a bit, by 10% or so, which is not a reason to avoid statins because this has been directly tested, and statins lower risk specifically in patients with high lp(a) due to their other effects. On the other hand, pcsk9 inhibitors, which are other cholesterol and apob-lowering drugs, do lower lp(a) as well, by 25 to 30 percent, which may or may not be enough to lower risk per se. And there are other newer drugs being studied that lower lp(a) by 80%, and the trials for those are currently ongoing. Nutrition-wise, there isn't that much in the literature, but I'll share the

little that I've seen so you have that information. As always, you can make your own educated decision. Some studies indicate that saturated fat lowers lp(a) by about 10 to 20 percent, which may not be clinically significant, not enough to lower risk, plus raising saturated fat intake raises ApoB so the net effect may actually be a step back. I've also seen a few studies reporting reductions of lp(a) on lower saturated fat diets, for example one with a Mediterranean diet, another with a raw plant-based diet, and some with diets rich in nuts, but the experimental design of these trials isn't the best, I don't find them very compelling, and usually the magnitude of the reduction isn't that big either, so based on this alone I don't think it's justified to make sweeping dietary recommendations. Trans fats, on the other hand, may have a stronger effect, about a 70%

increase in lp(a) with trans fat intake, but most trans fats are banned from the market anyway, at least in the US, so just something to bear in mind. So there's no demonstrated diet that's great for lp(a) management specifically, although diet can certainly help with every other major risk factor, like apoB, blood pressure, and everything else, and Tom also touched on this. The data is big that a good healthy diet is going to help your cardiovascular system no matter what the hell is going on, so I don't want to discourage proper nutrition in people with any lipid or lipoprotein abnormality. So to summarize everything, measure your lp(a) once. If it's low, you're pretty much good for life. If it's high, manage your other risk factors. PCSK9 inhibitors, something to consider, talk to your doctor, and keep an eye on further developments, as soon as those

ongoing trials come out, I'll update everybody. For people who want more detail, I highly recommend a Peter Attia interview with Benoit Arsenault, who's a research scientist focusing on LP(a). It goes over all the genetic and biochemical details, and I'll link that below. If you want some tips on how to lower your ApoB with diet, we made a video covering everything the science has taught us so far, and here's one on how to lower your blood pressure with a simple but effective dietary tweak. Let me know your questions below, take care, see you next time.

Everything you need to know about Lp(a) | ft. Dr. Tom Dayspring

Everything you need to know about Lp(a) | ft. Dr. Tom Dayspring