Transcription
Is high LDL actually dangerous? Or is this simply one of the biggest myths in modern medicine?
So, lots of people have been asking this question in the comments of my videos lately. And honestly, this one is personal for me. My dad had a heart attack about 30 years ago, and from what he tells me, he wasn't given the right advice. Advice that might have changed everything. So, this isn't about ideology or picking a side because it's fashionable. For me, this is about cutting through the noise and working out what the evidence actually says when it comes to heart attacks, strokes, and ultimately whether people live or die. The only thing I'm interested in is what is the most likely answer based on the evidence that we actually have available. That's it. I'm only interested in what's true.
Hello, I'm Dr. Alex. I'm an emergency medicine doctor working in the UK for almost a decade. And I've seen what happens when preventable disease isn't prevented. And so the purpose of this video is to give you my honest advice on how to prevent the diseases I see every day. So over the next half an hour to an hour or however long this video takes, I'm going to lay out both sides of this debate as fairly as I can, almost like an academic review if I can. We'll look at the strongest evidence suggesting that high LDL and APOB do increase your risk of cardiovascular events and death. Then we'll turn to the papers and arguments that people site when they say there's no link or even that higher LDL might be protective. I'll explain what's good about those studies, what's weak, and where the gaps are. And I'll genuinely do this as best I can. We'll talk about big farmer as well because that comes up constantly in the comments and whether financial influence has genuinely corrupted this field or whether the evidence holds up regardless of all of that. We'll also look at what LDL levels look like in the world's longevity hotspots and what we can reasonably learn from that. And then at the end, I'll tell you where I stand as a doctor who's been watching people die from heart attacks for almost a decade, but only after we've gone through the evidence properly. If you wait until the end, I'll give you my honest, balanced opinion as if I was talking to a family member or indeed my dad 30 years ago.
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So, let's carry on with what LDL and Apple B actually are. So before we dive into the controversy, we need to make sure everyone's on the same page about what we're actually talking about. So LDL cholesterol is cholesterol that's being carried around in your bloodstream inside particles. And those particles have a protein on them called apo lipoprotein B or Apo B for short. Each Apo B containing particle can have only one B molecule. Which means if you measure APOB, you're essentially counting the number of these particles floating around in your body. That matters because when it comes to forming plaques in your arteries, it's the number of particles that get stuck in the artery wall that drives the biology, not just how much cholesterol each particle happens to be carrying.
Now, this distinction is where a lot of arguments start. LDL cholesterol, which is what most people get measured on a standard blood test, is an estimate of how much cholesterol is inside each of those particles, but it's an imperfect proxy for the actual particle count, especially in certain metabolic states. Someone could have a relatively normal LDL cholesterol number, but still have a high particle count if their particles are smaller and more numerous. That's why many researchers and clinicians now prefer measuring Apo B directly because it gives you the particle number without the guesswork. The confusion around this has led some people to conclude that because LDL cholesterol isn't perfect. The entire idea that these particles cause heart disease must be wrong. But to me, that's a bit like saying because your car's fuel gauge is sometimes inaccurate, fuel doesn't matter for making the engine run. the underlying biology is still there. What we're really asking is whether having more of those Apo B containing particles in your blood over years and decades increases your risk of developing atherosclerotic plaques which then lead to heart attacks and strokes. To me, that's the core question and it's what we'll be unpacking for the rest of the video.
But before we go any further, I want to be completely transparent about where I'm coming from on this. As you're probably aware already, it takes the medical community a while to catch up on new developments. Evidence evolves, our understanding changes, and what we thought was true 10 years ago might not be the whole picture today. I want you to know that I don't have an agenda here. Nobody is sponsoring this video. Nobody is paying me to say certain things. My only priority genuinely is to learn what is the thing that gives me the best chance of living a long healthy life. What is the advice that has the most evidence that I would give to my friends and family? And if I'm wrong, then please tell me in the comments. If there's something I've missed out, then join the discussion below. My mind absolutely can be changed if there's new evidence. That's what makes science so great. It's what's so important in medicine, that our minds should be able to be changed when new evidence comes along. So, I'm going into this with an open mind, looking at the data from both sides. And if you see something that I've overlooked or misrepresented, then I genuinely want to hear about it. That's how we all get better at understanding these really complex topics.
So, what would it take to prove causation? Well, when you're trying to work out whether something causes disease, you can't just rely on one study or one type of evidence. Causation is a higher bar than correlation. And in medicine, we use a framework to help us get there. It's not a perfect checklist, but it gives us a way to think clearly about whether we're looking at something real or just statistical noise. So before we dive into the specific studies, let's just lay out what you'd want to see if LDL and APOB were genuinely causal for cardiovascular disease.
First, does the biology make sense? If you propose that these particles cause plaques, you need a plausible mechanism. Do they get into the artery wall? Do they trigger an inflammatory response? Is there a pathway from the particle exposure to disease that holds up under scrutiny? The second thing is do higher levels track with more disease across populations? Not perfectly because biology is messy and there are other risk factors. But broadly, do people with higher LDL and APOB tend to have more cardiovascular events? Thirdly, if you lower it, do the events fall? This is where randomized trials come in because they let you test whether intervening actually changes outcomes. The fourth one is if your genes lower it lifelong, is risk lower lifelong? Genetic evidence is really powerful because it mimics a lifelong trial that started at conception with no confounding from lifestyle changes or adherence issues. And the fifth thing is does the effect scale with how much you lower it? If lowering LDL a bit reduces your risk a bit and lowering LDL a lot reduces risk a lot, then that strengthens the case for a dose response relationship, which is one of the hallmarks of causation. None of these on their own is definitive, but when multiple lines of evidence point in the same direction, that case becomes much stronger. That's the framework we'll use as we go through the evidence and it's also the framework that helps you see where the skeptical arguments might have gaps.
Okay. So, now we come to the evidence that has convinced most cardiologists, lipidologists and guideline communities around the world that LDL and Apo are causal for atherosclerotic cardiovascular disease. This isn't based on one paper or one drug company's trial. It comes from multiple independent lines of evidence. And I'm going to break it down into three pillars that are quite easy to follow, I hope.
Okay. So, let's start with pillar A, randomized trials where lowering LDL reduces cardiovascular events. The most direct way to test whether lowering LDL reduces cardiovascular events is to do randomized control trials. You take a group of people, randomize half to a treatment that lowers LDL and half to a placebo and then follow them for years and count the number of heart attacks, strokes, and deaths. If lowering LDL genuinely reduces risk, you should see fewer events in the treatment group. And that's exactly what we see consistently across multiple drug classes. The cholesterol treatment trialist collaboration is a metaanalysis of statin trials involving more than 170,000 participants. What they found is that for every one millol per liter reduction in LDL cholesterol, there's about a 22% reduction in major vascular events like heart attacks, stroke or the need for procedures to reopen blocked arteries. The effect is seen across primary prevention where people haven't had a cardio event yet and also secondary prevention where people have already had one. It's seen in men and women in people with diabetes and without and it scales with the degree of LDL lowering.
Then you have the PCSK9 inhibitor trials. Forier was a trial of evolomab added on top of statin therapy in people with established cardiovascular disease. It lowered LDL by about 59% on average. And compared to placebo, it reduced the risk of cardiovascular events significantly over the follow-up period. This is a completely different drug class from statins. It works by a different mechanism, but the result is the same. Lower LDL, fewer events. Odyssey outcomes tested alioumab, another PCSK9 inhibitor in people who'd recently had an acute coronary syndrome. And again, it lowered LDL substantially and reduced cardiovascular events compared to placebo. Now, the fact that two different PCSK9 inhibitors tested on different populations both showed benefit is really important because it removes the possibility that this is a quirk of one molecule or one trial design. Asetami is yet another drug class. It blocks cholesterol absorption in the gut and it's been around for years and years. The improve it trial added aetamide to statin therapy in people after an acute coronary syndrome and it lowered LDL further than statin alone. The result was a modest but significant reduction in cardiovascular events over 7 years of follow-up. Again different mechanism the same direction. When you lower Apo B containing particles cardiovascular risk falls. What ties all of these together is that the benefit tracks with how much you lower your LDL. It doesn't matter whether you use a statin, a PCSK9 inhibitor, or a zetami. The more you reduce LDL, the more you reduce cardiac events. That dose response relationship is one of the strongest pieces of evidence for causation because it's exactly what you'd expect if these particles were driving the disease process.
Moving on to pillar B, which is a mandelian randomization or nature's lifelong trial. So, randomized trials are really powerful, but they only last a few years, and they only start when someone is already middle-aged or older. What if you could test what happens when someone's LDL is lower their entire life from birth? Well, that's what Mandelian randomization lets you do. It's a genetic approach that looks at people who inherit gene varants that naturally lower their LDL and then asks whether those people have lower rates of cardiovascular disease over their lifetime. The key insight is that your genes are randomly assigned at conception just like a randomized trial, but the treatment lasts your whole life. Large genetic analyses involving hundreds of thousands of people have shown that lifelong lower LDL exposure is associated with substantially lower lifetime cardiovascular risk. The effect size per unit of LDL lowering is actually larger than what you see in statin trials which makes sense because the exposure has been lifelong rather than just a few years. This work has been replicated across different populations and different genetic variants and the results are consistent. There's also some great work comparing triglyceride lowering genes versus LDL lowering genes. What researchers found is that the benefit for cardiovascular disease tracks with the change in apo not with triglycerides or LDL cholesterol per se. This supports the particle number model. the idea that it's the count of apo B containing particles that matters the most because those are the ones that can get trapped in the artery wall and start the plaque formation process. Genetic evidence like this is incredibly hard to dismiss because it's not confounded by diet, by lifestyle or whether someone took their medication. It's nature's own randomized trial and it points very clearly towards LDL and Apo B being causal.
The third pillar is meta regression work that looks across different types of interventions, statins, PCSK9 inhibitors, aetami, even older drugs like bile acid sequesterance and it asks whether the degree of cardiovascular risk reduction aligns with the degree of LDL lowering. What you find is a remarkably consistent relationship. Regardless of how you lower LDL, the benefit for cardiovascular events scales with how much you lower it. This is really powerful because it rules out the possibility that the benefit is due to some offtarget effect of a particular drug. If five different drug classes working through five different mechanisms all show the same dose response relationship between LDL lowering and event reduction, then the simplest explanation is that lowering LDL is what drives the benefit.
Taken together, these three pillars which are randomized trials, genetic evidence and meta reagression form a very strong case for causation. They satisfy multiple criteria from the causation framework that we laid out earlier. The biology makes sense. Higher levels track with more disease. Lowering it reduces events. Genetic lifelong lowering reduces risk. And the effect scales with the degree of lowering. That's why most clinicians who specialize in this area are convinced that LDL and Apo B are causal for atherosclerotic cardiovascular disease.
Okay, now we need to do the hard part, which is looking at the other side fairly. If you've been reading some of the comments in my other videos or following certain online communities, you'd have seen people claim that the LDL story is overblown or even completely wrong. They site studies showing no correlation or even an inverse correlation where higher LDL looks protective. Now, some of these arguments come from genuine confusion about what the data shows, but some come from real limitations in observational research that are worth understanding. So, let's go through the strongest versions of these arguments, explain what's good about them, and then talk about where they fall short.
Okay, so claim number one, some cohorts show LDL is not associated with mortality or higher LDL looks protective in older adults. One of the most cited pieces of evidence by LDL skeptics is a systematic review published by Ravenskoff and colleagues in the BMJ in 2016. This review looked at cohort studies in older adults and found that in many of them LDL cholesterol was either not associated with all cause mortality or was inversely associated, meaning higher LDL was linked to lower mortality. If you just read that at face value, it sounds like a bombshell. How could LDL be dangerous if people with higher LDL are living longer?
Well, let's start with what's good about this line of evidence. It does highlight something real, which is that risk markers can behave differently in older age, especially when you're looking at all cause mortality rather than cardiovascular events specifically. As people get older, they're more likely to die from things other than heart disease. Things like cancer, infections, frailty, chronic illness, and those competing causes can muddy the picture. The review also reminds us that observational data has big limitations and that we shouldn't just assume a relationship holds across all ages and all populations without checking.
But here's where it gets tricky. All cause mortality is not the same thing as atheroscllerotic cardiovascular events, which is what we actually care about if we're talking about LDL. If someone dies of pneumonia or liver cancer, their LDL level beforehand isn't particularly relevant to that outcome. More importantly, there's a phenomenon called reverse causation that's hugely important in older adults. Reverse causation means that the illness is causing the low LDL rather than low LDL causing the illness. If you're frail, if you're malnourished or chronically ill, your LDL often drops. So, when you look at observational data and see that people with low LDL have higher mortality, you might be looking at a population who are sicker to begin with and their low LDL is a marker of that illness, not a cause. I hope that makes sense.
Now, a large Danish cohort study looked at this exact issue and found a U-shaped relationship between LDL and all cause mortality. Both very low and very high LDL were associated with higher mortality. But the authors explicitly discuss reverse causation as a likely explanation for the higher mortality in the low end. When you account for people who are chronically ill or who lost weight recently, that inverse association often disappears. The point is that these observational studies cannot settle causation. They're useful for generating hypotheses, but they're confounded by factors that we can't easily control for, especially in older, frailer populations. It's also worth noting that the Ravenskoff review was critiqued in a post-publication response by the Center for Evidence-Based Medicine at Oxford. They pointed out methodological issues with how the review was conducted, including selective inclusion of studies and lack of adjustment for confounders. Now, this doesn't mean every study in the review is useless, but it does mean that you can't take the conclusion at face value without understanding the limitations.
There's also something specific worth mentioning here that comes up in discussion about older adults and LDL, which is the Framingham data. Now, some critics point to the Framingham Heart Study data showing that after age 50, cholesterol levels don't predict mortality as strongly as they do in younger people. This is often cited as evidence that LDL doesn't matter. But this falls into the same trap. It's looking at all cause mortality in an older cohort where reverse causation is a major issue and it doesn't account for the fact that the damage from elevated LDL over decades has already been done by the time somebody actually reaches the age of 15. The genetic evidence and the trial evidence which don't have these confounding issues still show a clear benefit from lowering LDL even in older adults which is why guidelines still recommend treatment in this age group for those at elevated risk.
Okay, moving on to claim number two. Half of heart attacks happen in people with normal LDL. This claim comes up constantly and it's often used to argue that LDL can't be that important if so many heart attacks happen in people with normal levels. On the surface, it sounds compelling. If LDL is the villain, why are all these people with normal LDL still having heart attacks?
The answer is that risk is probabilistic, not deterministic. Smoking doesn't cause every lung cancer, but it massively increases your risk. Not everyone who smokes gets lung cancer, and some people who never smoked still get it. The same logic applies here. LDL is one of several risk factors. Others include high blood pressure, smoking, diabetes, family history, and obviously age as well. So yes, plenty of heart attacks happen in people with LDL in the normal range because they have other risk factors or because plaque has been forming for decades before their last blood test.
There's also the issue of what normal actually means. In many labs, the reference range for LDL is based on population averages, not on what's optimal for preventing atherosclerosis. If half the population has elevated LDL, then the average is going to be higher than optimal and calling it normal doesn't make it safe. Many people who have heart attacks have LDL levels that are average for that population. But average in a population where cardiovascular disease is the leading cause of death is not the same as safe. The other thing to remember is that atherosclerosis is a lifelong process. Plaques don't form overnight. They accumulate over decades and your LDL level at the time of your heart attack is not the whole story. What matters is your cumulative exposure over your lifetime. If someone could have had a moderately elevated LDL for 30 years, then lowered it with a statin just before they had that heart attack. Their LDL level at the time of the heart attack might look normal, but the damage was done years before. This is why genetic evidence is so persuasive because it captures lifelong exposure, not just a snapshot.
Now, I want to take a moment to address something that comes up a lot in these debates, which is the role of oxidation and inflammation in atherosclerosis. Now, critics often say it's not LDL that causes heart attacks, it's oxidized LDL. As if this somehow gets regular LDL off the hook. And they are partially right. It is oxidized LDL that drives a lot of the inflammatory response in the artery wall. When LDL particles get trapped in the artery wall and become oxidized, they trigger an immune response. Macrofasages come in to clean up the oxidized LDL. They turn into foam cells and you get the beginnings of an atheroscllerotic plaque. So yes, oxidation is part of the mechanism. But here's the thing. You can't oxidize LDL particles that aren't there in the first place. The more Apo B containing particles that you have circulating in your bloodstream, the more particles that are available to get stuck in the artery wall and the more opportunity there is for oxidation to occur. Lowering your particle number, your APOB, reduces the substrates available for oxidation. This is why the genetic evidence is so powerful. People with gene variants that give them lifelong lower LDL and APOB have lower cardiovascular risk. And that's not because their particles are magically protected from oxidation. It's because they have fewer particles getting into the artery wall in the first place. So the oxidation argument doesn't weaken the case for lowering LDL and APO. If anything, it strengthens it because it tells you that the particle burden is still the upstream driver. You can also work on reducing oxidative stress through diet, through antioxidants, managing inflammation and so on. But that doesn't mean you can ignore particle number. Both of them matter and lowering apo is one of the most effective levers that we have.
Now, another argument that comes up constantly, especially in keto and low carb circles, and indeed in the comments of my recent keto video, is about LDL particle size. The claim is that the particle size matters more than particle number and that ketogenic diets create large fluffy benign LDL particles that don't cause atherosclerosis whereas small dense LDL particles are the real problem. Now yes this sounds plausible and there is some truth to it. small dense LDL particles do appear to be more atherogenic in certain contexts possibly because they penetrate the artery wall more easily or are more susceptible to oxidation but here's what the evidence actually shows when you control for ao B that is when you account for the total number of particles the additional protective value of particle size becomes much smaller or disappears entirely. Now, what this tells us is that particle number is the most dominant driver of risk, not particle size. Yes, small, dense particles might be slightly worse per particle, but if you have twice as many large, fluffy particles, you're still worse off. Now, the analogy I'd use is this. Imagine you're trying to reduce your risk of getting hit by a car. Small fast cars might be slightly more dangerous per car than large slower cars. But if the road is flooded with large slow cars, you're still at high risk. The total number of cars on the road is what matters the most. And this is why measuring Appo B is so valuable. It tells you the particle count directly, regardless of whether those particles are large or small. If your Apo B is 150 or 180 mg per deciliter, it doesn't matter whether those particles are large and fluffy. You have too many of them and that increases your risk. The focus on particle size in the low carb community is in my honest view largely a distraction from the more important question which is about particle number and and the evidence from trials and genetics consistently shows that lowering particle number lowering APOB reduces cardiovascular events regardless of what happens to particle size.
Now, another common argument I hear, especially from people who are skeptical about treating high LDL, is why not just get a coronary artery calcium score. If your calcium score is zero, your LDL doesn't matter. This is a fair question and calcium scoring is indeed a useful tool. So, let's talk about what it can and can't tell you. A coronary artery calcium score or CA score or CAC score uses a CT scan to measure the amount of calcified plaque in your coronary arteries. A score of zero means there's no detectable calcified plaque which is really reassuring. A high score means there's significant plaque burden which tells you the atherosclerosis is advanced. Calcium scoring is excellent for risk stratification. It helps you understand where you are right now in terms of existing disease. But here's the key limitation. A calcium score is a snapshot of existing calcified plaque. It doesn't tell you about non-calcified plaque, which can still be very dangerous, and it doesn't predict future plaque formation. If you're young, say in your 20s or 30s, and you have high epo, you might have a calcium score of zero right now because plaque hasn't had time to calcify yet. But if you continue with a high apple bee for years, for the next 20 or 30 years, you will accumulate plaque and eventually you'll develop a high calcium score and increased cardiovascular risk. So a calcium score of zero doesn't give you a free pass to ignore high APOB, especially if you're young. It tells you that you haven't accumulated significant calcified plaque yet, but it doesn't tell you that you're not accumulating risk going forward. The other thing to remember is that calcium scoring involves radiation exposure and that's not something you want to repeat frequently. APOB is a simple blood test that you can track over time and it gives you direct information about your aogenic particle burden. My honest view is that calcium scoring and APOB measurements are complimentary. They're not substitutes for one another. If you're middle-aged and trying to decide whether to start a medication, a calcium score can help you refine your risk estimate. But if you're younger with higho, you shouldn't wait until you have a positive calcium score to take action because by then you've probably accumulated years or decades of arterial damage. So measure your appo and if it's high then act on it regardless of what your calcium score shows you today.
Now, there's another alternative hypothesis that some researchers have proposed, which is that LDL is found at sites of arterial damage, but isn't actually causing the damage. The idea is that LDL is there as part of the repair process. It's responding to injury or inflammation in the artery wall rather than initiating it. The analogy often used is that firefighters are found at fires, but that doesn't mean that the firefighters caused the fires. This is a really intellectually interesting hypothesis, and it's worth considering for a moment. Maybe LDL is just a bystander, and the real culprits are things like endothelial dysfunction, inflammation, infection, or mechanical stress on the artery wall. Well, if that were true, then lowering LDL might not help because you'd just be removing the repair crew without addressing the underlying damage.
But here's the problem with this hypothesis. It doesn't fit the evidence. If LDL were just a passenger or a repair molecule, then lowering it genetically from birth shouldn't reduce cardiovascular risk, but it does dramatically. Mandelian randomization studies show that people who inherit gene variants that give them lifelong lower LDL have substantially lower rates of heart attacks and strokes over their whole lifetime. They're not more prone to arterial damage or inflammation. If anything, they're protected from it. This is very hard to explain if LDL is just there to repair the damage. The firefighter analogy breaks down because in a real fire, removing firefighters makes things worse. But in cardiovascular disease, removing LDL particles or more precisely reducing their number makes things better. And then similarly in randomized trials, lowering LDL with drugs reduces cardiovascular events. If LDL were an innocent bystander, you'd expect that lowering it would either do nothing or make things worse. Instead, we see consistent benefits across multiple drug classes and multiple trial populations. So while the LDL as a passenger hypothesis is creative, it's just not supported by the totality of evidence that we have, the genetic data and the trial data both point towards LDL and APOB as drivers of atherosclerosis, not just markers of it.
One of the most sobering things you can learn about cardiovascular disease is how early it starts. People think of heart attacks as something that happens to older people. And while the clinical events do happen later in life generally the underlying process begins much much earlier. Autopsy studies in young people teenagers and people in their 20s have shown that early atherosclerosotic changes are already present in a significant proportion of individuals and those early changes are associated with traditional risk factors including lipid levels. The pathobbiological determinance of atherosclerosis in youth study known as PDAY looked at autopsies of people aged 15 to 34 who died from trauma. What they found was that fatty streaks and early plaques were really common even in teenagers and the extent of these lesions correlated with risk factors like smoking, high blood pressure and elevated cholesterol. The Bogaloosa heart study showed similar findings. This tells us that atherosclerosis is not a disease that suddenly appears in middle age. It's a disease that can be quietly progressing for decades before it causes any symptoms. This is why lifetime exposure matters so much. If you have moderately elevated LDL from your 20s onward, you're accumulating arterial damage for 40 or 50 years before you have a heart attack in your 60s. Yes, lowering LDL in your 50s will help, but you've already missed out on decades of prevention. And this is also why the genetic evidence is so important. People with lifelong lower LDL from gene variants have had decades of reduced exposure. And that's why their risk reduction is so dramatic. It's not just about your LDL level right now. It's about the area under the curve. the total burden of Apo B containing particles your arteries have been exposed to over time. This concept of cumulative exposure also helps explain why some trials show modest benefits while genetic studies show larger effects. If you start a statin trial in people who are already 60 years old with established disease, you're intervening late into the game. you'll still see some benefit because you're slowing down further progression, but you're not erasing the decades of damage that already happened. The earlier you intervene, the bigger the potential benefit because you're preventing the damage from accumulating in the first place.
Okay, so let's bring this back to what triggered a lot of this push back in the first place. Now, I've made a few videos where I've talked about keto and low carb diets, and I've said that in a meaningful minority of people, these diets can raise LDL cholesterol and apo quite substantially. I've also said that if this happens to you, it's something you should take seriously and potentially adjust your approach. That statement has generated a huge amount of push back with people saying I'm fear-mongering or that I don't understand that LDL doesn't matter on keto or that I'm just paring mainstream medical dogma. So, let me be very clear about what I actually said because I think some of the push back comes from misunderstanding. I did not say that keto always raises LDL. I didn't say that keto is dangerous for everyone. What I said is that in a subset of people often called hyper respponders, keto and very low carb diets can lead to significant increases in LDL and apoamine. This is well documented in the literature and in clinical practice. For most people on keto, LDL either stays the same or goes up modestly, but for some people it can go up dramatically, sometimes doubling or tripling. If you are one of those people and your Appleo beat is now sitting at 150 or 180, that's not something you can just wave away by saying that you feel great.
Now, I want to acknowledge that there is some interesting research being done in this space, particularly by Dave Feldman and others looking at the lean mass hyperresponder phenotype and the lipid energy model. This hypothesis is that in lean, insulin sensitive, metabolically healthy people on very low carb diets, elevated LDL might reflect increased lipid trafficking for energy rather than pathological lipid accumulation. And that this might not carry the same cardiovascular risk as elevated LDL in other contexts. This really is worth studying and I'm genuinely interested in seeing the long-term outcome data from this population. But here's the reality. We don't have long-term outcome data yet. We don't have randomized trials or even long-term observational studies showing that people with very high APOB on keto have low cardiovascular risk. What we do have is decades of evidence from trials, genetics, and cohort studies showing that high APOB increases cardiovascular risks across a wide range of populations and contexts. Until we have evidence showing that the hyperresponder phenotype is an exception to that rule, then the prudent approach is to treat high APOB as a red flag, even if you feel metabolically healthy. The practical rule I gave was this. If your Apo rises significantly on keto, you're potentially trading short-term metabolic wins for long-term vascular risk. And you should adjust that. Maybe that means changing the type of fats that you're eating, replacing some saturated fat with monounsaturated or polyunsaturated fats. Maybe it means adding more fiber or adjusting the overall diet pattern. Maybe it means that for you, keto isn't the right long-term approach and you need to find something else that gives you the metabolic benefit without the lipid spike. To me, that's not ideology. That's risk management. The reason I care about this is that I've seen too many people in A&E with heart attacks who thought they were doing everything right. They were exercising. They'd lost weight. They felt amazing and then they had a cardiac event. Feeling good today doesn't mean your arteries are healthy. And Apo B is one of the few biomarkers that we have that gives you a window into what's happening at the vascular level. If it's high, that's information that you should act on, not dismiss because it doesn't fit your dietary identity.
Okay, so let's talk about the elephant in the room, which is big farmer and the concern that financial conflicts of interest have corrupted the evidence base around LDL and statins. This is a legitimate concern in medicine generally. Drug companies do fund trials. They do have influence over guidelines and key opinion leaders. And yes, there have been scandals where industry funding has biased the evidence. So, it's reasonable to ask whether the LDL story is just a marketing campaign to sell statins. It all makes sense, but let's start by acknowledging that conflicts of interest exist. Many of the major statin trials were funded by pharmaceutical companies, and many of the researchers involved have received funding or consulting fees from those companies. That's worth being aware of and it's worth being skeptical about. Industry funded trials can be designed in ways that favor the drug. Choosing the right comparator, the right endpoint, the right patient population and negative results are less likely to get published. All of that is true and it's part of why we need independent replication and why we need to look at the totality of evidence, not just one trial.
But here's the thing. The LDL story does not rely on one drug, on one company, or one set of trials. Statins are made by multiple companies, and most statins are now off patents and available as generics. So, the blockbuster drug profit motive is much more weak than it was in the '9s. More importantly, the benefit of lowering LDL has been shown with multiple drug classes. As I mentioned earlier, PCSK9 inhibitors, aetami, bile acid sequestrants, and those drugs are made by different companies with different commercial interests. If this was just a marketing campaign, you'd expect the evidence to fall apart when you look at non-statin drugs, but it doesn't. The same dose response relationship shows up regardless of which drug class you use. And then there's the genetic evidence again, which is completely independent of any pharmaceutical company. Mandelian randomization studies are done by academic researchers using publicly available genetic data. There's no drug company writing the checks and yet the genetic evidence strongly supports LDL and Apo B as causal. If the entire field was fabricated to sell statins, how do you explain that? You can't dismiss genetics as industry propaganda because the genes were assigned at conception long before anyone knew what a statin was. The meta regression work I mentioned earlier also comes from independent academic groups. The cholesterol treatment trialist collaboration is run by researchers at Oxford who have access to individual patient data from multiple trials including industry funded ones. They're not employed by drug companies and their analyses include trials from different eras, different drug classes, and different patient populations. The fact that the relationship between LDL lowering and event reduction holds up across all of this is very hard to explain if the whole thing is a fabrication. So yes, industry influence is real and skepticism really is healthy, but it doesn't overturn the LDL story and this particular debate. The evidence is simply too broad, too consistent, and too independent. You'd have to believe in a conspiracy that spans multiple continents, multiple drug classes, multiple decades, and even human genetics. And that's just not plausible. If you're going to reject the LDL evidence on the basis of big farmer influence, you need a much better explanation for why the genetic data, the meta reagression data, and the independent trials all point in the exact same direction.
Another argument that comes up is about the blue zones, which are the regions of the world where people routinely live past 90 or even 100. The idea is that if high LDL was truly dangerous, you'd expect to see very low LDL in these populations. But some people claim that that's not the case. So let's talk about what we actually know and what we can reasonably infer from longevity hotspots.
So the first thing is what are the blue zones? Well, these are regions identified by researchers where people have unusually high rates of living to 100 or beyond and unusually low rates of chronic disease. The original blue zones include Okinawa in Japan, Sardinia in Italy, Niccoa in Costa Rica, Ikaria in Greece, and Lominda in California. What these regions have in common is not one single factor, but a constellation of lifestyle patterns, minimally processed diets, high physical activity as part of daily life, strong social connections, low smoking rates, and generally lower stress.
When it comes to lipids, the data is actually quite consistent. In Okinawa, traditional diets are low in saturated fat and high in vegetables, legumes, and soy, and average cholesterol levels in older Okanowans are lower than in Western populations. In Sardinia, the diet is Mediterranean style, which is olive oil, vegetables, legumes, whole grains, some fish, and moderate amount of meat. And again, lipid profiles tend to be favorable. People in low mind, many of whom are vegetarian or vegan, have low average cholesterol and very low rates of heart disease. So the pattern you see is that longevity hotspots generally have dietary patterns that align with lower LDL and Apo B. And that fits with what we'd expect if these particles were contributing to disease. But we have to be careful not to overstate this. Blue zones are not controlled experiments. There are multiple confounders. Genetics, physical activity, social support, health care access, smoking rates, selection bias, and even the accuracy of birth records, which has been questioned in some regions. You cannot isolate LDL as the sole reason for their longevity. And it would be wrong to claim that low LDL is the secret to living to 100. But what you can say is that the dietary patterns in these regions are consistent with the lower atherogenic particle exposure and that fits with the broader framework of cardiovascular disease prevention. It doesn't prove causation on its own, but it's consistent with the totality of evidence. One thing I will say is that you don't see blue zones where people are eating high saturated fat diets and have high LDL but somehow live to 100 without heart disease. If high LDL were truly harmless, you'd expect to find at least one population where that pattern holds. But we don't see it. The populations with the longest lives and the lowest rates of cardiovascular disease tend to have diets that keep LDL and Apo B at relatively low levels, even if that's not the only factor at play.
So before I give you my final conclusion, I want to address one more argument that comes up, which is about residual risk. Some people point out that even when you lower LDL to very low levels with statins or other drugs, there's still cardiovascular risk. People still have heart attacks and strokes. They use this to argue that LDL can't be the main driver of cardiovascular disease because if it were, lowering it dramatically would eliminate risk entirely.
Now, this is a fair observation, but it's based on a misunderstanding of how cardiovascular disease works. LDL and Apo B are not the only risk factors for atherosclerosis. There's also blood pressure. There's diabetes. There's smoking, inflammation, endothelial dysfunction, genetic factors, and probably other mechanisms that we don't fully understand yet. Cardiovascular disease is multiffactorial, which means that even if you completely eliminate one risk factor, you can still have events from others. Lowering LDL reduces your risk substantially, but it doesn't reduce it to zero because there are other pathways to plaque formation and thrombosis. The existence of residual risk doesn't mean LDL isn't important. It just means it's not the only thing that's important. If you lower someone's LDL from 160 to 70, you've dramatically reduced their risk. But if they also have uncontrolled hypertension and diabetes, they're still at elevated risk. The solution isn't to say that LDL doesn't matter. The solution is to address all of the modifiable risk factors. LDL, blood pressure, blood sugar, smoking, and so on. This is why I always emphasize a holistic approach to cardiovascular risk reduction. Appo is a critically important lever, maybe the most important single lever that we have, but it's not the only one. You want to stack as many protective factors in your favor as possible and that means attending to the full spectrum of cardiovascular risk, not just focusing on one biomarker in isolation.
All right, so we've been through the evidence from both sides and now it's time for me to tell you where I stand if you haven't already guessed. Now, as a doctor who spent pretty much a decade in emergency departments watching people come in with heart attacks and strokes, but also as someone who cares deeply about helping people live longer and healthier lives, I really do believe that the weight of evidence supports LDL and especially APOB containing particle burden as causal for atherosclerosotic cardiovascular disease. That conclusion isn't based on ideology or on paritin guidelines. It's based on looking at the totality of evidence. Randomized trials showing that lowering LDL reduces events. Genetic studies showing that lifelong lower LDL reduces lifetime risk. Meta regression showing a dose response relationship across all drug classes. And biological plausibility showing that these particles get into the artery wall and drive the disease process. When multiple independent lines of evidence all point in the same direction and when that direction makes biological sense, surely the simplest explanation is that it's real.
Does that mean everyone with high LDL will have a heart attack? Well, no. Risk is probabilistic, not deterministic. There are people out there with high LDL who will never ever have a heart attack or a stroke. Just like there are people who smoke and who will never get lung cancer. But on the population level, higher LDL and higher Apo clearly increases risk and lowering them clearly reduces risk. That's what the evidence shows and that's what I base my advice on. At the same time, I want to acknowledge the nuance. Again, I repeat, not everyone with high LDL will have a cardiac event, and not everyone who has an event had high LDL at their last blood test. There are other risk factors: blood pressure, smoking, diabetes, family history, inflammation, and they all matter. This is not a binary all or nothing situation. At the end of the day, human biology is very complex. Individuals vary and there are always going to be outliers. But that complexity doesn't mean we throw out the signal in the data. It means we use the data to inform risk reduction while acknowledging that we can't predict with certainty what will happen to any one person. I also need to be clear again that I have no agenda here other than trying to help people make informed choices. I'm not selling statins. I'm not employed by a pharmaceutical company. I don't get paid more if you lower your LDL and I don't get paid less if you don't. What I care about is whether the advice I give is likely to help people live longer, healthier lives, and whether it's grounded in the best available evidence. The evidence on LDL and Apo is about as strong as evidence gets in medicine. And ignoring it because it's inconvenient or because it doesn't fit your dietary identity or because there's one study proving the opposite is in my view a mistake.
So what does this mean for you practically? If you're watching this and wondering what to do with your own lipid levels, then here's what I'd recommend. The first thing is to measure your Apo if you can. It's a more direct measure of atherogenic particle number than LDL cholesterol and it's not much more expensive or harder to get than a standard lipid panel if you go privately. If your Apo B is elevated,
Generally above 90 milligrams per deciliter, though some guidelines use a lower threshold, that's a signal worth paying attention to, especially if you're young and you're wanting to live a long life.
The second thing is focus on overall risk reduction, not just LDL in isolation. Like I've said a lot in this video, blood pressure, smoking, blood sugar control, physical activity, sleep, and stress management, they all matter. You don't have to be perfect in every domain, but you want to stack the deck in your favor as much as possible. If your Apo B is high and you've got other risk factors on top, that's when your cumulative risk is really starting to climb.
The third thing is if a diet or lifestyle change pushes your Apo B up substantially, that's a red flag worth acting on. It doesn't mean that the diet is inherently bad, but it does mean that for you in your biology, it's creating a risk profile that's worth modifying. Maybe that means adjusting the types of fats that you eat, adding more fiber, changing your overall dietary pattern, or in some cases considering medication. The key is not to be dogmatic. Don't get so attached to a particular way of eating that you ignore the biomarkers that are telling you something important.
And the fourth thing is if your Apo B is persistently elevated despite lifestyle changes, then talk to a doctor about whether medication makes sense for you. Always talk to your family doctor. Statins are not perfect. They do have side effects and they don't work for everybody, but for many people, they significantly reduce your cardiovascular risk with minimal downsides. The most common side effect is muscle pain or weakness, which affects a small percentage of people. And there's a slightly increased risk of developing diabetes in people who are already at high risk for it. But for most people, these risks are outweighed by the cardiovascular benefit, especially if you're at elevated risk. PCSK9 inhibitors are another option if statins don't work or aren't tolerated, but these aren't available in every country. Isetami is a more gentle option that can be added on if your doctor thinks it's worthwhile. The point is that there are effective tools available and dismissing them out of hand because you distrust pharmaceuticals isn't a rational approach to risk management. Have an informed conversation with your doctor who you trust and who understands your individual risk profile and make a decision based on your actual data and your actual risk not on ideology.
So let me just end this with a simple message. The debate about LDL and APOB is important and it's good that people are asking questions and demanding the evidence, but at a certain point the debate has to translate into action. If you're genuinely uncertain about whether your LDL or APOB matters, the answer isn't to argue about it on the internet. The answer is to measure it, to track it over time, and make decisions with your doctor based on your actual data and your actual risk profile.
Everyone's biology is a bit different. Some people can eat a high saturated fat diet and maintain low LDL. Some people can't. Some people respond well to statins, but then some people don't. The only way to know is to measure. Get a lipid profile, ideally with Apo B included. If it's high, then take it seriously. If it's low, then great. But don't assume it will stay that way if you don't make major dietary changes if you need to. And if you're doing something like keto or carnivore and you haven't checked your lipids in a while, then please do get them checked. You owe it to yourself to know what's happening inside your arteries, not just how you feel on the outside.
Now, I know this has been a long video and I really appreciate you sticking with me until the very end. This is a topic I care deeply about, not because I want to win an argument, but because I've seen too many preventable heart attacks. And my dad's heart attack 30 years ago was preventable. He didn't die thankfully, but his life changed as a result. Many of the heart attacks I see in A&E today are preventable. The evidence we now have is better than the evidence we had back then, and we have the tools, both lifestyle and pharmacological, that can make a real difference. The big question is whether we are willing to use them.
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