← The Metabolic Classroom with Dr. Ben Bikman
The Metabolic Classroom with Dr. Ben Bikman
LDL Isn’t the Problem? The Real Drivers of Heart Disease
00:22:48
More Knowledge, Better Health
Loading summary
Transcript25 lines
- [00:00]
Capital One Bank Announcer
With no fees or minimums on checking accounts, it's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends it's pretty much all he talks about in a good way. What's in your wallet? Term supply see capitalone.com bank capital1na member FDIC close your eyes. Listen to Monday.com feel the sensation of an AI work platform so flexible and intuitive it feels like it was built just for you. Now open your eyes, go to Monday.comstart for free and finally breathe.
- [00:47]
Skyrizi Patient Testimonial
My perfect day has sand, salt water and friends, but my moderate to severe plaque psoriasis can take me out of the moment. Now I'm all in with clearer skin thanks to skyrizi risen Kizumab RZA, a prescription only 150 milligram injection for a adults who are candidates for systemic or phototherapy with Skyrizi. Most people saw 90% clearer skin and many were even 100% plaque free at four months. Skyrizi is just four doses a year. After two starter doses.
- [01:15]
Medical Expert / Podcast Host (Ben Bickman)
Don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.
- [01:27]
Skyrizi Patient Testimonial
Thanks to Skyrizi, there's nothing on my skin and that means everything is everything. Ask your doctor about Skyrizi, the number one dermatologist prescribed biologic in psoriasis. Visit skyrizi.com or call 1-866-Skyrizi to learn more.
- [01:54]
Medical Expert / Podcast Host (Ben Bickman)
Welcome to the Metabolic Classroom Podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. Don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical and engaging. Welcome back to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. Today's mini lecture aims to teach you about the clinical markers that seem to best predict heart disease risk and to challenge some assumptions you might have about cholesterol when it comes to heart disease prevention. We've been told a story. It goes something like Cholesterol clogs your arteries like grease in a pipe. So if we just lower LDL cholesterol enough, we can prevent heart attacks. The narrative has driven decades of medical practice and billions of dollars in statin prescriptions, drugs designed to lower LDL cholesterol. But what if I told you that nearly half of people who have heart attacks have normal LDL cholesterol? What if the markers we obsess over, like LDL or apolipoprotein B or lipoprotein A aren't actually the strongest predictors of who will develop heart disease? Today? I want to show you that the evidence actually says that metabolic health may matter more than these lipid markers. And in fact, metabolic health may matter most. Let's start with a striking observation from a massive study of over 136,000 people hospitalized with coronary artery disease. When researchers looked at their LDL cholesterol levels at admission, they found something remarkable. Almost half had LDL levels below 100 milligrams per deciliter. Nearly 18% had LDL below 70 milligrams per deciliter, well within what guidelines would consider optimal these days, even among patients with no prior history of heart disease, diabetes or vascular disease. People having their first cardiac event, in other words, over 40% had LDL below 100 milligrams per deciliter and nearly 72 were below 130 milligrams per deciliter. Very modest, normal numbers. Think about that. These weren't people with sky high cholesterol finally catching up with them. These were people developing heart disease despite having LDL levels that even current guidelines would consider perfectly acceptable, even ideal in some cases. And here's what else they found. Only about 21% of these patients were taking cholesterol lowering medications before their hospitalization. So this wasn't about over treatment driving LDL too low. These were naturally occurring cholesterol levels that clearly weren't protecting against heart disease. Now, I'm not saying LDL doesn't matter at all. It might. It may have some association with cardiovascular risk. It may have some causal role here. But when you look at the strength of the association with LDL and heart disease compared to other markers, particularly those in the metabolic realm, LDL starts to look very weak very quickly. So if LDL isn't the smoking gun we've been told it is, what is? The evidence increasingly points to insulin resistance and its related metabolic disturbances as far more powerful predictors of cardiovascular disease, especially premature heart disease. A comprehensive study following nearly 28,000 participants for over 21 years examined more than 50 different biomarkers for their ability to predict heart disease at different ages. When they looked at individuals who developed heart disease before age 55, what we would call premature coronary disease. They found something fascinating of all the biomarkers measured, the lipoprotein insulin resistance score had the highest predictive value value for individuals under 55. This marker was associated with a greater than six fold increased risk of developing heart disease. After adjusting for any other risk factor. Compare that to LDL cholesterol in the same population, only a 1.4 fold increased risk. Non LDL cholesterol 1.7 fold. Even apolipoprotein B, which many lipidologists consider superior to LDL, anything including LDL showed only a 1.9 fold increased risk. The lipoprotein insulin resistance score wasn't just slightly better, it was in a completely different league. It was multiples better at predicting heart disease risk retrospectively so looking back in time than even the so called best lipid marker, the apolipoprotein bio. And here's the critical part. The association with insulin resistance was strongest for premature heart disease and gradually weakened with age. This pattern suggests that metabolic dysfunction is particularly important in driving cardiovascular disease in relatively younger people. Type 2 diabetes showed a similar pattern. In individuals under 55 having diabetes was associated with more than a 10 fold increased risk of heart disease. Remember, apolipoprotein B, the so called best marker was only 1.9. Diabetes is a tenfold increased risk. This association remained strong across all age groups, but again it was strongest in the younger people, those at middle aged up to about 55. Metabolic syndrome, that cluster of insulin resistance triglycerides are high, low hdl, elevated blood pressure and abdominal obesity was about a six fold increased risk for premature heart disease. So still far exceeding any of the lipid markers like apolipoprotein B or ldl. Now there's a simple marker that you can calculate and I've in fact mentioned it here, it's for those who are paying attention and you can figure this out from any standard lipid panel that you're going to get. So anytime you've gone in and gotten your blood drawn, you're going to have these markers and they almost all the time. This these markers when used together will outperform LDL cholesterol. So it will help you get perhaps the best way you can with the blood markers you have an assessment of your heart disease risk and that is the triglyceride to HDL ratio. In one of the in one particular study, in fact one of the ones I mentioned earlier, the triglyceride to HDL ratio showed more than a twofold increased risk for heart disease in younger individuals. So not only Was that substantially stronger than LDL alone, But it was even stronger than the much obsessed over and much adored apolipoprotein B. So again, the humble triglyceride to HDL ratio still outperforms even the best of the LDL related markers. But let me tell you about another study that really drives this point home. Researchers wanted to find a simple way to identify insulin resistant individuals at increased cardiovascular risk. They measured insulin Resistance directly in 449 apparently healthy people and then looked at which routine lipid measures best predicted who was insulin resistant. In other words, are there some lipid markers that can be used to assess insulin resistance in the event that you aren't able to get your insulin measured? The winner, the triglyceride to HDL cholesterol ratio. It was the best predictor of insulin resistance and of small, dense LDL particles. So within the family of LDL is a wide or broad spectrum of how big and fluffy or small and dense they are. And the small, dense LDL particles. Particles are thought to be or are often more implicated in driving heart disease risk. In fact, the triglyceride to HDL ratio identified insulin resistant patients with a sensitivity and specificity comparable to the criteria for diagnosing metabolic syndrome. A ratio of 3.5 or higher was a good cutoff in this study for identifying those at high risk. So when you started to get around three red flag. Now, why does the ratio matter so much? It's essentially a crude but effective marker of insulin resistance. A poor man's method, if you will. When you're insulin resistant, your liver over produces triglyceride rich particles like those in VLDL and ldl, but not the LDL number. Here it's the amount of triglycerides they're carrying. And your HDL cholesterol tends to be low. The insulin resistance that is, on one hand, overproducing triglycerides is actually accelerating the uptake of HDL back into the liver, thereby reducing the amount of HDL in circulation. So this ratio can capture that metabolic dysfunction in a way that LDL alone simply cannot. The beauty of the marker is its simplicity. You don't need specialized testing. Just take your triglyceride level and divide it by your HDL cholesterol level. A ratio above 2, if you're using. If these units coming in the triglycerides and the HDL cholesterol are in milligrams per deciliter. If it's above 2, that starts to be a warning sign. You want it to be less than 2. In other words, when it gets to 3, as I noted earlier, that is red alert. But perhaps the most compelling demonstration of the triglyceride to HDL ratio's predictive power comes from the Copenhagen male study. In a cohort of nearly 3,000 men followed for eight years, researchers tested a specific hypothesis. Would men with conventional risk factors still have low heart disease risk if they had a favorable triglyceride to HDL pattern? And conversely, would men without those conventional risk factors, namely LDL cholesterol, still be at high risk if their triglyceride to HDL pattern or ratio was unfavorable? To answer this, they divided participants into three groups based on their metabolic profile. Those with low triglyceride and high hdl, the favorable pattern, those with high triglycerides and low hdl, the unfavorable pattern, and an intermediate group. So, in other words, they're splitting them up based on their triglyceride to HDL ratio. Then they examined heart disease incidence across different LDL levels. So can you see or understand the different things here? So they're looking at who's having heart attacks and who's not. Then they're looking at their triglyceride to HDL ratio, and they're comparing that to their LDL cholesterol levels. The results are remarkable. And in fact, those of you who are insiders, I encourage you to look up this study. It is open access, and you can get access to the citations to read it there. The figure is very, very telling. Among men with LDL levels, LDL cholesterol levels at or below 170 milligrams per deciliter. What most clinicians would consider kind of an acceptable cutoff. The incidence of ischemic heart disease varied dramatically based on their triglyceride to HDL ratio. Men with the unfavorable ratio. So high triglyceride, low HDL, had about 14% incidence of heart disease over those eight years. But men with the same LDL levels who had the low triglyceride HDL ratio, they only had about a 4% incidence. So it's a fraction. It's about less than 30% of the same risk. In the men who had high triglyceride HDL ratio. Remember, even though their LDL levels were the same. So that's more than a threefold difference in heart disease risk among people with identical LDL cholesterol levels. The only thing different, their triglyceride to HDL ratio. But this wasn't just about low LDL being protective even among men with high LDL cholesterol to those above 170 milligrams per deciliter. Those with favorable triglyceride to HDL ratios so low only had 5% heart disease incidence. Meanwhile, men with similarly elevated LDL but unfavorable triglyceride to HDL ratio about 12%. So it's actually lower than those who had low LDL, but a bad triglyceride to HDL ratio, ironically. Now think about the clinical implications here. You could have two patients both with LDL cholesterol of 165 milligrams per deciliter, a perfectly acceptable level by conventional standards. But if one has high triglycerides and low HDL while the other has low triglycerides and high hdl, their actual risk of developing heart disease differs by more than threefold. The LDL number tells you almost nothing about which patient is actually at risk. This finding underscores a critical reality. Metabolic health reflected in triglyceride HDL ratio in this case is a far more powerful predictor than LDL cholesterol is alone. It's the underlying metabolic dysfunction, not just the cholesterol number, that drives the cardiovascular disease risk. Multiple studies across different populations have confirmed the predictive power of this ratio in patients with stable angina, for example. So ongoing chest pain, the highest quartile of triglyceride to HDL ratio, was associated with a nearly three fold increased risk of death or heart attack, independent of any other risk factors. Notably, there were no differences in total cholesterol or LDL cholesterol across the triglyceride to HDL ratio quartiles in that study. Even still, the cardiovascular risk was dramatically different. And again, that risk coincided with changes in the triglyceride to HDL ratio, not the other LDL related markers.
- [16:13]
Capital One Bank Announcer
With no fees or minimums on checking accounts, it's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends it's pretty much all he talks about in a good way. What's in your wallet? Terms apply. See capitalone.com Bank Capital One NA Member FDIC.
- [16:43]
Hannah Berner
Hi, this is Hannah Berner, co host of Giggly Squad. Let's be honest, we've all done things in our lives that may have just followed the crowd, like drinking matcha even if you think it tastes like grass or pretending skinny jeans were actually comfortable. Have we been doing the same thing with Zero Sugar Cola? Last year, people across America took the Pepsi Challenge. No labels, no bias. Judged on taste alone, 66% of participants agreed Pepsi Zero Sugar tastes better than Coke Zero Sugar and Pepsi Zero Sugar won in every single market. Go out and try Pepsi Zero Sugar today. You deserve taste. You deserve Pepsi.
- [17:21]
Medical Expert / Podcast Host (Ben Bickman)
Now you might be wondering, do these findings apply equally to men and women? In fact, of the studies I cited, the first several I studied were based in women. The next ones I cited were based in men. So there is some nuance, but I think there's also some similarity. While some studies have focused on specific populations, the fundamental connections between insulin resistance and cardiovascular disease appears robust across both sexes, though it may manifest somewhat differently. Interestingly, some research suggests that insulin resistance may actually predict cardiovascular disease more strongly in men than in women in certain populations. One study in African Americans, for example, found that the association between insulin resistance and coronary heart disease was present in men, but not in women. However, when it comes to diabetes, the most severe form of insulin resistance, we see a fascinating paradox. Diabetes confers a greater relative cardiovascular risk in women compared to men. In fact, meta analyses show that diabetes is associated with about 25 to 50% greater excess risk of cardiovascular disease in women compared to men. This means that while men generally have higher absolute rates of heart disease, the jump in risk from non diabetic to diabetic is steeper for women. The triglyceride to HDL ratio appears to work well in both sexes, though optimal cut points may differ slightly. Some studies suggest a ratio of 3.5 works well for identifying high risk men, while a more rigorous ratio of 2.5 is better in women, so the ratio is a little more strict in women. The bottom line? Metabolic dysfunction, whether measured by insulin resistance scores, diabetes status, or the easily obtained triglyceride to HDL ratio, appears to be a powerful cardiovascular risk factor regardless of sex, even if the precise manifestations differ slightly between them. Now, if lipid markers like LDL aren't the strongest predictors of heart disease, what does that tell us about therapies designed primarily to lower ldl? When we look at statin trials for primary prevention, that is, Giving statins to people who haven't yet had a heart attack or stroke that's almost always based on their LDL cholesterol levels, the benefits are far more modest than most people realize. Large meta analyses of primary prevention trials show that you need to treat somewhere between 60 to over 100 people with a statin for five years to prevent even one single cardiovascular event. That means for every person who benefits, there are dozens of people who have no benefit from the medication. And in fact, they may have some harm. Consider that in the study of the hospitalized heart disease patients that I cited earlier, even among those taking lipid lowering medications before admission, 64% still had LDL below 100 milligrams per deciliter and nearly 25 were below 70 milligrams per deciliter. They were hitting their LDL targets and yet they still had heart attacks. The issue isn't necessarily that these medications aren't lowering ldl. They're very effective at lowering ldl. But the issue is that LDL reduction doesn't really appear to do much. At most, the most generous perspective could be that it has that it's a modest contributor, while it leaves the other more relevant, more powerful drivers like insulin resistance completely untouched. And in fact, to make the whole matter worse, it can often exacerbate that problem in women that take statins and use statins for primary prevention. Like I just described a moment ago, you find that there is about a 50% increased risk of developing type 2 diabetes. And remember, the study I noted earlier was in women where it found that diabetes elicited or carried with it a 10 times greater predictive power than. Well, it was a tenfold increased risk. And so that was multiples. That was about five times higher predictive power than even the best of the LDL related markers like apolipoprotein B.
- [21:46]
Capital One Bank Announcer
With no fees or minimums on checking accounts. It's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs.
- [22:02]
Medical Expert / Podcast Host (Ben Bickman)
Needs?
- [22:02]
Capital One Bank Announcer
Yep. Even on weekends it's pretty much all he talks about. In a good way. What's in your wallet? Terms apply. See capitalone.com bank capital1na member FDIC.
- [22:16]
Hannah Berner
Hi, this is Hannah Berner, co host of Giggly Squad. Let's be honest, we've all done things in our lives that may have just followed the crowd. Like drinking matcha, even if you think it tastes like grass. Or pretending skinny jeans were actually comfortable. Have we been doing the same thing with Zero Sugar Cola? Last year, people across America took the Pepsi Challenge. No labels, no bias. Judged on taste alone, 66% of participants agreed Pepsi Zero Sugar tastes better than Coke Zero Sugar and Pepsi Zero Sugar won in every single market. Go out and try Pepsi Zero sugar today. You deserve taste. You deserve Pepsi.
- [22:54]
Medical Expert / Podcast Host (Ben Bickman)
So what does this all mean for how we should think about cardiovascular prevention? There are a few points. First, we need to shift our focus from being LDL centric to being metabolism centric. If someone has evidence of insulin resistance, like elevated fasting insulin, high triglycerides, low hdl, or the high triglyceride to HDL ratio, or they just have outright type 2 diabetes, that should be ringing alarm bells far louder than any marker of LDL cholesterol. Second, we need to recognize that the most powerful interventions for improving metabolic health aren't pharmaceuticals, dietary changes that reduce refined carbohydrates and improve insulin sensitivity. They help with things like improved physical activity, controlling carbohydrate consumption, adequate sleep. These address the root causes of metabolic dysfunction in ways that any drug, certainly statins, simply cannot now. Third, this doesn't mean we should ignore lipid markers entirely, but we should view them in context. An elevated LDL in someone who is metabolically healthy so good insulin sensitivity good to low triglyceride to HDL ratio likely carries far less risk than the same LDL level in someone with significant metabolic dysfunction. I am not saying LDL doesn't matter at all, but the evidence certainly suggests that it matters significantly less than maybe certainly than the average clinician would expect. The study data support this. When researchers looked at ideal lipid levels defined as LDL below 70 and HDL above 60, only 1.4% of people hospitalized with heart disease met these criteria. Meanwhile, over half had HDL below 40, a marker much more closely tied to metabolic health. The triglyceride to HDL ratio gives us a simple, accessible way to identify individuals with metabolic dysfunction who are at high cardiovascular risk of even if their LDL cholesterol looks perfectly fine. On paper, the narrative we've been told about cholesterol and heart disease is not necessarily wrong, but it is not right, and it is very incomplete. LDL cholesterol may matter, but it's not the primary driver of cardiovascular disease that we've been led to believe. The evidence increasingly shows that metabolic health, insulin sensitivity, glycemic controlled, the absence of metabolic syndrome is far more predictive of who will develop heart disease, particularly premature heart disease, so those that are middle aged and younger. This should fundamentally reshape how we approach cardiovascular prevention, moving us away from an obsession with lipid numbers, especially ldl, and toward a more comprehensive focus on metabolic health, especially when we can leverage some of those lipid markers in order to get an indication of insulin resistance status, namely the triglyceride to HDL ratio. The markers that matter most aren't necessarily the ones we can most easily treat with a pill. That is such a profound idea that I hope resonates with you. I believe one of the reasons we focus on LDL so much has less to do with its ability to predict a heart disease and more to do with the fact that it is a druggable target. We have drugs that can lower LDL very well, and unfortunately some part of modern medicine the way it's practiced is driven by profit. So we need to address the fundamental metabolic dysfunction, and that requires us to look beyond what a prescription can do and address lifestyle. Remember, the food we eat is either the culprit or the cure. Thanks for joining me. Remember, more knowledge, better health.
- [26:57]
Capital One Bank Announcer
With no fees or minimums on checking accounts, it's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends it's pretty much all he talks about in a good way. What's in your wallet? Terms apply. See capitalone.com bank capital1na member FDIC.
- [27:29]
Medical Expert / Podcast Host (Ben Bickman)
My.
- [27:29]
Skyrizi Patient Testimonial
Perfect day has sand, salt water and friends, but my moderate to severe plaque psoriasis can take me out the of the moment. Now I'm all in with clearer skin thanks to Skyrizi Risankizumab RZA a prescription only 150mg injection for adults who are candidates for systemic or phototherapy with Skyrizi. Most people saw 90% clearer skin and many were even 100% plaque free at four months. Skyrizi is just four doses a year after two starter doses.
- [27:56]
Medical Expert / Podcast Host (Ben Bickman)
Don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.
- [28:08]
Skyrizi Patient Testimonial
Thanks to Skyrizi there's nothing on my skin and that means everything.
- [28:13]
Medical Expert / Podcast Host (Ben Bickman)
Nothing is everything.
- [28:16]
Skyrizi Patient Testimonial
Ask your doctor about Skyrizi, the number one dermatologist prescribed biologic in psoriasis. Visit skyrizi.com or call 1-866-Skyrizi to learn more.
- [28:27]
Medical Expert / Podcast Host (Ben Bickman)
Everyone deserves to be connected. That's why T Mobile and US Cellular are joining forces. Switch to T Mobile and save up to 20% versus Verizon by getting built in benefits they leave out. Check the math@t mobile.com switch and now.
- [28:43]
Capital One Bank Announcer
T mobile is in US cellular stores. Savings versus Comparable Verizon plans plus the cost of optional benefits, plan features and.
- [28:51]
Medical Expert / Podcast Host (Ben Bickman)
Taxes and fees vary.
- [28:52]
Capital One Bank Announcer
Savings with three plus lines include third.
- [28:53]
Medical Expert / Podcast Host (Ben Bickman)
Line free via monthly bill credits. Credit stop if you cancel any lines. Qualifying credit required.