The New Skinny on Lp(a)

When it comes to heart health, my dad kind of screwed me. Because he passed down to me high levels of what's called Lp. Maybe this is a marker you've heard of, maybe not. But you should have, because Lp has suddenly become the new hot kid on the cardiology block. Lp. Ever heard of Lp? Lipoprotein little a. Lipoprotein little a. It's a genetically determined risk factor that can raise your risk for heart disease and a heart attack. You can think about it as LDL's more dangerous cousin. It's similar in structure to LDL particles, but with an extra sticky tail called apolipoprotein little a. That tail makes Lp more likely to clot and more likely to build up plaque in your arteries. So in short, Lp is worse, far more dangerous than LDL. And right now, This is the scary part: we don't have any proven way to lower it and reduce heart disease risk, which is kind of depressing if you're in the boat with me of having high Lp. But here's where things get interesting. Brand new 2025 data just dropped, and they gave me heart and hope. Hope that the genetic hand my dad dealt me might not be as bad as it looks because of something else about me, something I'm actually showing you right now, something you might share too. Let's find out. This is a striking and really encouraging finding. Appears to elevate cardiovascular disease risk only in individuals with a high— a clear pattern emerged. Genes aren't fake. Activates a protein that promotes clotting. Improve body composition. Optimize waist-hip ratio. Here's another way to look at the data. Much of the cardiovascular risk disappears. The goal of this new 2025 study was to determine whether a measure of adiposity, waist-to-hip ratio, modifies the relationship between Lp and cardiovascular disease risk. So to explore this, the researchers analyzed data from 4,652 participants in the Multi-Ethnic Study of Atherosclerosis, the MESA cohort. They followed them over a median time frame of 17.4 years. And during this time, 792 of the participants developed cardiovascular disease-related events. The study stratified individuals based on Lp levels, high Lp being defined as greater than 50 mg/dL, and you can see the conversion to other units on the screen. And the researchers investigated how this risk with high Lp was modified by waist-hip ratio as a marker of central adiposity and visceral fat. We're going to get to more details on that later. Anyway, the findings were striking. Among those with high Lp, individuals with a higher waist-to-hip ratio—so more central adiposity, more apple-shaped, less pear-shaped—were 3 times more likely to experience cardiovascular events compared to those with high Lp but lower waist-to-hip ratio. And remarkably, in individuals with lower waist-to-hip ratio, Lp levels were not significantly associated with increased risk of cardiovascular disease-related events. In other words, if your waist-to-hip ratio is lower, even high Lp levels may pose much less of a concern for cardiovascular disease. So to drive the point home, look at this graph. It shows the cumulative incidence of cardiovascular disease-related events over about 20 years. Each line represents a different combination of LP levels and waist-hip ratio. So the blue line is a lower waist-hip ratio and a lower LP. The black line is a high waist-hip ratio but low LP. The red line is high waist-hip ratio and high LP. And the orange line is lower waist-hip ratio and higher LP. And what stands out is how closely the orange line and the blue line representing people with low waist-hip ratios, but high versus low Lp, how closely they couple. This suggests that in leaner individuals with lower waist-hip ratios, even genetically elevated Lp carries minimal to no additional risk for cardiovascular disease. This is a striking and really encouraging finding for those with high Lp, like me, who maintain a leaner, more metabolically healthy profile. Now here's another way to look at the data. Look at these graphs. When the researchers divided participants into tertiles—3 equally sized groups based on waist-hip ratios sampled in the study—a clear pattern emerged. In both the lowest, off to the left, and middle tertiles of waist-hip ratio, high Lp did not confer higher incidence of cardiovascular events compared to lower Lp. The increase in cardiovascular disease events only appeared in the high waist-hip ratio tertile off to the right, i.e., those third of participants with the greatest central adiposity, the greatest waist-hip ratio. In that group, elevated Lp was clearly associated with an increased risk of cardiovascular disease-related events. So the takeaway is simple. According to these data, Lp appears to elevate cardiovascular disease risk only in individuals with a high waist-hip ratio. Now, I'm sure you wanna know what waist-hip ratio values to aim for yourself. Well, in this study, participants were grouped based on percentiles of waist-hip ratio. However, the 90th percentile cut point used doesn't actually reflect modern population distributions. I know that's a little bit confusing. So, that said, the specific values are more useful, and they were as follows: 1.03 for men and 1.00 for women. And if you really want to target excellent waist-to-hip ratios, even beyond those used in the study, a level of less than 0.85 for men and less than 0.75 for females is elite in the waist-to-hip ratio category. You can measure this pretty easily at home. Just measure your waist at its narrowest point. Ideally in the morning, fasted, and maybe after a bowel movement for a consistent measure, and then measure your hips at the widest point. Divide your waist measurement by your hip measurement, and that's your waist-to-hip ratio. If you don't have a tape measure, that's not a problem. You can just use a piece of string or a belt and mark it and then measure it with a ruler or a yardstick. So for example, the math, my own measurements are about 26 to 26.5 inches for waist and about 33.75 inches for hips, giving me a waist-taper ratio of about 0.78. And given my Lp is quite elevated, this result I find reassuring based on the data. I likely face a far lower cardiovascular disease risk associated with high Lp than I might have otherwise believed. So now let's tangent, or move on, and get into the mechanisms. You guys know I love mechanisms. Why would a high waist-to-hip ratio have a strong influence on Lp-related risk? Well, waist-to-hip ratio is a proxy for abdominal adiposity, or visceral fat, the inflammatory fat stored deep in the abdominal cavity. This kind of fat is biologically active and contributes to both inflammation and clot formation, two mechanisms behind atherosclerosis—cardiovascular disease. So, here's a few things that we know and that are relevant to this conversation. Lp activates plasminogen activator inhibitor 1, or PAI-1, a protein that promotes clotting. As a quick aside, PAI-1 is coded by the SERPINE1 gene, and I share this in case you've heard this gene mentioned before, and because honestly I think it's a fun word to say, serpine one, and I love snakes. As a random fact, as a kid I owned a python named Monty. Monty Python, anyone? I'm invincible! Also, visceral fat— sorry, I like to jump off on tangents— visceral fat also increases levels of the same protein, the PAI-1, and this creates potential synergy, a synergistic prothrombotic environment between Lp and visceral fat. Additionally, visceral fat promotes chronic low-grade inflammation, which may further act via Lp to amplify cardiovascular risk. So with respect to inflammation, now speaking practically, a marker you should know is your high sensitivity C-reactive protein level, hs-CRP, a general marker of inflammation. You should target an hs-CRP level less than 2, although less than 1 is really ideal. Now, here's another important layer: oxidative stress, which kind of goes hand in hand with inflammation. Fat, not just visceral fat, but other forms of body fat, produce enzymes like myeloperoxidase. We actually reviewed it earlier on this channel. See this video for more. Anyway, these enzymes made by body fat, they can oxidize fatty acids, especially polyunsaturated fatty acids, PUFA, creating oxidized phospholipids. And these oxidized lipids are actually carried around on Lp particles, these are so-called oxPLs on ApoB, and they're directly involved in the development of atherosclerosis, cardiovascular disease. Lp actually acts as a reservoir for these oxidized phospholipids, these oxPLs, and studies show that when you control for oxPLs, much of the cardiovascular risk attributed to Lp disappears. And this suggests that Lp's danger lies in part in its ability to transport and concentrate oxidized lipids. So to simplify the cascade, body fat generates oxidative enzymes like MPO that oxidize lipids, Lp collects these lipids—oxidized phospholipids—and this can promote atherosclerosis. Isn't that interesting? Now, The protocol I mentioned. Well, based on the data I just reviewed, you can start to piece the puzzle together. But there's a plethora of additional data that I can use to develop a protocol, in fact I did, based on the physiology and metabolism, what we know about LP to turn insights into action. Now, if I were to review all the data that went into this protocol, this would be a 4-hour-long video. But if you want access to the protocol, please check out the newsletter linked in the video notes. Parts of all my letters are entirely free and available. With additional bells and whistles like protocols available to the premium subscribers who really keep this community, the Stay Curious Learning community here, my Substack, my other socials, afloat and vigorously growing. I'm really grateful for them. So for what it's worth, if you do wanna become a premium subscriber to the newsletter, it costs only $0.67 or less per letter for full access. Maybe you can afford that, maybe not, something to consider. Anyway, shameless plug over. Now I want to summarize the key points. 1. Lp primarily increases cardiovascular risk in those with a high waist-hip ratio. 2. A high waist-hip ratio suggests more visceral fat, which amplifies the pro-inflammatory and pro-thrombotic environment and properties of Lp. And 3. If you have high Lp but a low waist-hip ratio, low inflammation like an hs-CRP, and low oxidative stress like an MPO, marker, your actual cardiovascular risk associated with an elevated Lp may be much lower than previously assumed. And if you don't check all of these boxes, that's an opportunity, not a cause for alarm. Focus on the fundamentals: improve body composition, optimize waist-to-hip ratio—I know, easier said than done, but still—prioritize quality sleep, stay physically active. And for the elite, you can check out the protocol I mentioned in the notes. So, in conclusion, my final words: genes aren't fate. Your genetically determined Lp isn't your cardiovascular fate. Metabolic context matters. Knowledge is power. And while binging on donuts won't help your visceral fat, binging on more Stay Curious Metabolism content just might. Thank you, stay curious, I really do appreciate you.