Low Cholesterol Won’t Save You. Measure This Instead.

Let me hit you with a stunning fact about your heart: 37%. 37% of people with very low LDL "bad" cholesterol still have atherosclerosis—that's plaque—in their arteries, despite optimal cholesterol. Now, here's another fact: despite decades of medical innovation, laser-focused on slaughtering LDL like we're turning a pig into irony bacon, cardiovascular disease remains a world-leading killer. So if you can get heart disease with pristine, optimal LDL, and if lowering LDL further and further like we're playing cholesterol limbo hasn't erased the cardiovascular disease epidemic, why are we still doubling down? Why do we insist on making one number the whole story? Why do we insist on missing the cardiovascular forest for a stupid little cholesterol shrub? Or, playing devil's advocate, maybe we just haven't gotten LDL low enough. These are some of the questions we're going to tackle in today's video, and what we should be measuring instead. Let's roll. Very low LDL cholesterol levels did not prevent atherosclerosis. 12% relative difference, it's not nothing, but if that is the entire payoff, I think that's kind of pitiful. There is a long list of risk factors that carry far greater consequence than LDL alone. I'm describing a clear systemic problem. Why is this personal? The loved one of a friend suffered a heart attack. LDL doesn't belong in the center of the room. It deserves far less attention than it's currently receiving. Now, real quick before we begin, I just want to highlight you can always find more details, all the references, and early access to data digests at the newsletter at staycuriousmetabolism.com. Thanks to you, our community, we are a top 3 overall bestseller in science on the whole platform globally. That is a win for curiosity, yes, and our Stay Curious Metabolism community. And there you can also find so much more information, like a masterclass on cholesterol-lowering drugs, or a guide to why this is such a divisive topic in the first place. As always, it's about information, not prescriptions. But with that, a quick roadmap on what we're going to cover in this video. Chapter 1: What happens when your LDL cholesterol is optimal? Chapter 2: What the critics say. Chapter 3: What I'm saying and what I'm not saying. Chapter 4: Why This Is Personal for Me, Chapter 5, The Not Low Enough Trap, and Chapter 6, Biomarkers You Should Track. But let's get on to it. What happens when LDL cholesterol is in the optimal range? I want to review a controversial paper published in the journal Atherosclerosis that asks a very straightforward question: What is the prevalence of atherosclerosis in adults with optimal LDL cholesterol, less than 70? In fact, the group mean was 57. That is super low. As the authors themselves note, some have questioned whether atherosclerosis, plaque in arteries, can develop at all alongside very low LDL levels, with less than 70 mg/dL being considered optimal. Now, I already told you the punchline in the intro: 37% of individuals with LDL cholesterol less than 70, a mean of 57, 57, that is super low, still had evidence of atherosclerosis. Specifically, 30% had a positive coronary artery calcium score, and 18% were in the highest quartile for carotid intima-media thickness— thickness of the carotid arteries going to the brain— with some overlap between groups. So this isn't even coronary CT angiography for soft plaque. In fact, 37%— that figure— is probably an underestimate of the actual plaque burden based on the technology that was used. To be fair, 37% is modestly lower than the prevalence of atherosclerosis in the overall populations studied, which was 49%. And 12% relative difference, it's not nothing, but if that is the entire payoff for driving the biomarker that monopolizes all the conversation all the way down to optimal very low levels, I think that's kind of pitiful. And importantly, as mentioned, the landscape of atherosclerosis is changing. New drugs are lowering LDL, total cholesterol, and ApoB lower and lower and lower, while larger risk factors like insulin resistance, obesity and diabetes persist. But let me not just wave my hands and give you vaguities, let me give you concrete numbers in case you want a direct comparison. Take Lipoprotein Insulin Resistance score . It shows a much stronger association with cardiovascular disease. In fact, in a highly cited 28,000 individual study published in JAMA Cardiology, the adjusted hazards ratio for LP-IR was 6.4 compared to just 1.38 for LDL cholesterol. That's a 540% increased risk versus 38% increased risk because 1.38 is risk-neutral. That means the insulin resistance score is a more than 14-fold more powerful predictor of new coronary heart disease than LDL cholesterol. But we know who gets all the attention— the LDL. That's not proportional medicine, that is distorted and it's not serving the best interests of patients. But that brings us to Chapter 2: What the Critics Say. Before we progress further, let's review criticisms of the study because there are no perfect studies. The first criticism raised of this study is that only a small fraction of the overall cohort studied, there were two, had those very low LDL cholesterol levels, less than 70, mean 57. Only about 3%. And the implicit question is whether you can draw conclusions from such a small subgroup, right? 3% sounds small. But in this case, 3% is still 263 individuals, and when more than 1 in 3 people with very low LDL in a 263-person study has atherosclerosis, I think that's a signal worth taking seriously, and that actually brings us to the second criticism, which reveals why we really want to study just those 3%. The second criticism is that only a single time point lipid measurement was taken, and it might not accurately capture lifetime LDL exposure. Maybe their LDL just dropped and then the lipid test was taken, right? But this objection largely falls apart because these individuals were all untreated, not on medication. This was in fact part of the exclusion criteria and a key point and strength of the study. Is selecting individuals with untreated low LDL as opposed to those who are being medicated helps differentiate the effects of naturally low LDL as a single biomarker from the broader pleiotrophic benefits of certain medications, which are often mistakenly attributed to LDL and ApoB lowering alone—see this content for more. The simple point is that this approach, studying the unmedicated people with very low LDL, allows us to fairly put forth that they've likely had low LDL their entire life and to avoid the— all too common mistake of misattributing the benefits of medication specifically to LDL cholesterol and ApoB lowering, when there may be other effects of these medications like reducing inflammation on the background of someone who is metabolically unwell, which is most of the population. So the punchline remains, if I'm losing you: in two very diverse cohorts of untreated patients, having optimal, very low LDL cholesterol levels did not prevent Atherosclerosis, plaque in arteries. These were untreated people with presumably lifelong very low LDL cholesterol and atherosclerosis still showed up. So, that brings us to Chapter 3: What I am and what I am not saying. What I am saying is let's look at the larger puzzle, the bigger picture. There is a long list of risk factors that carry far greater consequence than LDL alone. Take obesity, type 2 diabetes, insulin resistance, we already reviewed data on LPI-R score versus LDL, elevated blood pressure, chronic inflammation, smoking history, I I could go on, but the point is actually really obvious. When LDL cholesterol monopolizes the spotlight, the problem is that the framing is incomplete. Instead, it becomes actively harmful to patients to pull away attention and resources and clinical urgency from factors that matter more than LDL for public health, and redirect that attention, those resources towards what's easiest to monetize and medicalize—LDL cholesterol, a marker that's easy to smash with a drug that makes money. Now, I'm not making an argument about bad intentions. I'm describing a clear systemic problem, one that perpetuates the broader metabolic health epidemic we continue to find ourself in, including cardiovascular disease. Now, I've already said it, but let me reinforce the answer to the question: what actually drives the spotlight of attention in medicine? Because it's not what's best for patients, at least not primarily. It's incentive structures and business models. The market for LDL-lowering therapies is literally a decabillion-dollar annualized industry. Statins alone represent a $20 billion per year industry and uptrending. And that reality dictates what doctors are taught, what medical students are taught, what residents are taught, what research gets funded, and what clinical guidelines recommend. None of these statements—they're facts—are incompatible with the idea that lipid-lowering drugs can be useful in the right patients. That can be true too. But it would be naïve to believe that a 10+ the 10-plus-figure revenue stream flowing into the pharmaceutical industry doesn't shape the biomedical spotlight. And that is how we end up here, where cardiovascular disease remains a leading cause of morbidity and mortality. And I think that's unacceptable. We needed to widen the lens, the aperture of what we're talking about, what we're viewing. That brings me to Chapter 4: Why is this personal? Because I'll be honest with you, you probably already know it, but I've spent countless hours in doctors' offices having the rule book thrown at me, being chastised for my untreated lipid levels, and To date, to be honest, my arteries remain perfectly clean. But that alone wouldn't bother me— I get it— if it weren't for what's happening alongside, which is far more troubling. Friends, family members, loved ones— people who are not doing as well despite having what they're told are optimal LDL cholesterol levels on usually multi-drug management. For example, recently, the loved one of a friend suffered a heart attack with an LDL cholesterol level of 51, slightly below the average in this study. Fortunately, they lived, but they were stunned and confused. They had been led to believe, implicitly or explicitly, that they were in the "safe zone"—that with LDL cholesterol levels that low, they were essentially protected from further cardiac events. Clearly, they weren't. This person had a host of other risk factors known to confer a greater cardiovascular risk than LDL cholesterol, including obesity, prediabetes, and a smoking history, although they're no longer a smoker. Yet those factors never took center stage in the cardiology discussion of their overall risk. The overwhelming focus remained on LDL cholesterol. And the impression that left behind—again, not necessarily stated outright, but clearly communicated to the patient, that's what they walked away with—was that if LDL was low enough, they had a kind of get-out-of-jail-free card. That impression I will tell you is not rare, and it's a huge problem. But that brings us to Chapter 5: The Not Low Enough Trap. Because let's steelman the conventionalists' argument. When faced with data showing that optimal LDL cholesterols fail to prevent atherosclerosis, the final retreat is almost always the same: the LDL just wasn't low enough. Lower is better is the mantra. If a mean LDL of 57 mg/dL isn't sufficient to make atherosclerosis an orphan disease, the solution must be 40, or 30, or 20, or 10. Heck, let's just hit zero like we're playing cholesterol UNO. What this reflexive response reveals, and it's pretty consistent if you have your finger on the pulse, is the profound keyhole thinking that has come to dominate conventional cardiology. Medicine has become so siloed and subspecialized that success is often defined within the narrow boundaries of a single biomarker like LDL or organ system rather than in terms of whole person health. Now in fairness, it's It's possible, at least in theory, that taking a sledgehammer to LDL and ApoB, driving them as close to zero as possible, could prevent cardiovascular events entirely. But that framing dodges the far more important question: "If you can dodge a wrench, you can dodge a ball." "What?" What are we trading to achieve that reduction? Because LDL-lowering therapies are not benign. You're not snapping your fingers and changing a single biomarker. Statins, for example, are well documented to increase diabetes risk, suppress GLP-1 levels massively, worsen insulin resistance, impair mitochondrial function, and potentially contribute to muscle loss. More on that in this video. Anyway, these are clinical scenarios in which patients have to figure out trade-offs. Maybe they're justified in particular patients, particularly in individuals with poor metabolic health or multiple high-risk features. I'm not denying that. But even in those cases, the core issue remains, the forest remains: LDL cholesterol is not carrying the bulk of the risk. That doesn't mean treating it can't be helpful, it just means we need to take a wider view, and that brings me back to the central point of this video. LDL doesn't belong in the center of the room. It should not be the keynote speaker or leading antagonist. It deserves far less attention than it's currently receiving, and if we truly want better outcomes, we need to shift the spotlight away from a single overemphasized biomarker and towards the broader metabolic health landscape that actually drives true cardiovascular risk. Only then can we start practicing medicine that is proportional, rational, and truly patient-centered. Now, that brings us to our final chapter, because critiques without alternatives are just complaining. And as much as complaining can be cathartic, I don't want to leave you with just that. So Chapter 6: Biomarkers to Track. Now, first, to be clear, the targets I'm going to discuss are not cutoffs handed down from on high. Biology doesn't work in binaries and black and white. They're based on judgment grounded in physiology rather than dogma. I chose a starter list of 6, and if you can hit all 6, you're doing a bang-up job to start, but also feel free to suggest biomarkers that you like to track that I didn't mention in this list of 6. Anyway, first, CRP or hs-CRP. Aim for a level less than 1. This high sensitivity C-reactive protein is a marker of systemic inflammation. Levels below 1 are associated with lower cardiovascular risk, better endothelial function, and reduced inflammatory burden overall. 2. HbA1c less than 5.5%. HbA1c reflects the average glucose exposure in your blood over approximately 3 months. There's a little give and take based on the red blood cell lifespan, but about 3 months. Values below 5.5% are associated with lower risk of microvascular and macrovascular complications. And importantly, even high normal A1c levels like 5.6 can conceal glycemic variability and hyperinsulinemia. So I think less than 5.5% is a good target. That brings us to fasting insulin. Aim for a level less than 7. Fasting insulin is a good proxy for insulin sensitivity. Elevated fasting insulin often precedes abnormal glucose by years and reflects a sort of metabolic strain long before diabetes or prediabetes is diagnosed. Lower fasting insulin suggests better insulin sensitivity, up until a point, better metabolic health, and lower cardiometabolic risk. Next on the list, triglycerides. Aim for a number less than 80. The general reference range is less than 150, but I think less than 80 is a better threshold. Triglycerides are a marker of metabolic health and liver insulin resistance. Low triglycerides reflect efficient fat burning and efficient VLDL turnover. If you want to nerd out on that, see this paper. In general, it reflects a favorable metabolism, and elevated triglycerides are linked to cardiovascular risks, even more so than LDL. Triglycerides though can be a noisy marker, so make sure to get your lipid labs 12 to 16 hours water-only fasted. That's an important tip. Next up, and this one requires some heavy caveats, HDL cholesterol. In general, levels above 50 mg/dL for female and greater than 40 for male are good. Higher HDL correlates with improved reverse cholesterol transport, up until a point, and better insulin sensitivity and overall metabolic health, whereas low HDL often travels with metabolic dysfunction. It's more of a litmus test rather than a cause and effect. In fairness, HDL is a very complicated group of molecules with particles representing enormously diverse, functionally complex classes of compounds. So if you want to go the extra mile, you could get HDL subfractionation, although even then the results require very careful interpretation and meaning in specific clinical context. In truth, this topic probably requires its own content, and maybe I'll generate that, but 50/40, stick with that for now. Next, waist-hip ratio. Aim for a level less than 0.85 if you're female and less than 0.9 if you're male. Waist-hip ratio reflects visceral adiposity, This fat around your internal organs is metabolically active and strongly linked to insulin resistance, inflammation, and cardiovascular risk, not to mention Alzheimer's. Lower waist-to-hip ratios indicate healthier fat distribution and reduced metabolic stress on the whole body. In addition, if you have high Lp, lower waist-to-hip ratio is associated with a massively reduced risk. See this video for more. Now, finally, before we wrap up, I want to re-emphasize that I'm not I'm not anti-lipid management per se, I'm just pro-seeing the bigger picture and want people to make informed decisions with open eyes. And I know, despite emphasizing this point time and time again, and providing clear supportive educational resources like this masterclass on cholesterol-lowering drugs, the cons and the pros, some will choose to paint me as a cartoon villain. Because nuance is challenging and otherization is a good ego defense. Especially from insecure doctors. But if there is a single takeaway from all of this, it's not that LDL or ApoB don't matter. It's that the meaning has been misallocated at large. We have mistaken prominence for importance, and familiarity for biological truth. And in doing so, we've allowed one biomarker—LDL cholesterol—easy to measure, easy to target, and easy to monetize—to crowd out far richer and more consequential understanding of cardiovascular risk. And the result is a system that optimizes for what it can easily track and target with drugs rather than what actually keeps people healthy. Let me know if I'm being reasonable. Stay curious, and thanks for your input.