The Cholesterol Data That Didn’t Fit the Narrative

What if I told you there's a medication that increases LDL "bad" cholesterol, but it actually saves lives, including from cardiovascular disease? Now, this isn't hypothetical. I'm not pulling your leg. This has been demonstrated in rigorous randomized controlled trials. It's been published in some of the most prestigious medical journals in the world. And the results have been replicated time and time again. So if everything I'm telling you is true, Why haven't you heard about this? Well, rather than telling you, let me show you. But first be warned, this video isn't gonna be a cakewalk. I'm gonna make you think, but I promise you, if you're able to stick with me to the end, you're gonna have enough knowledge to give a cardiologist a heart attack. Let's go. I could eat a McDonald's Big Breakfast while still being low carb. It's like crying direwolf or dragon and then getting a cavapoo. It sounds like a conspiracy until you read the studies for yourself and piece the puzzles together. What we're seeing here is a fascinating convergence of dietary therapy and pharmacotherapy. Aha! See? Now we're coming full circle. Alright, you got me? Warm-up over. Now quickly, before we begin, I just want to shout out that if you're looking for all the references, extra details, and early access to information like that we're about to review, you should definitely check out the Stay Curious Metabolism newsletter linked below, which remains a top 3 global bestseller in science thanks to your curiosity and hunger for depth and intellectual rigor. But now let's get to the video. I want to start us off with a quick roadmap. In Chapter 1, we're going to look at a conspicuous pattern, specifically how we talk about cholesterol and heart disease in the media and literature. In Chapter 2, I'm going to tell you about the medication in question. And walk you through a landmark randomized controlled trial that made waves in medicine, but buried a detail you're definitely going to want to see. Then in Chapter 3, which is my favorite, we'll build to it, we're going to dive into the fascinating mechanistic details of how this medication actually works and how you might be able to mimic its effects without popping pills. So let's begin Chapter 1. The pattern: LDL equals bad cholesterol, at least according to the headlines. Whenever LDL cholesterol increases and something bad happens, the narrative is amplified, sometimes dramatically, and often in a twisted fashion. Take, for example, a study published last March in a cardiology journal. It made headlines for claiming that low-carb keto-like diets more than doubled the risk of cardiovascular events. The low-carb high-fat diet group also had significantly higher LDL cholesterol and ApoB levels, which sounds dramatic, right? Scary enough to have you running to your nearest white coat for protection. The perfect fit for the prevailing narrative, or if we're being generous, the scientific consensus. Cut the saturated fat, lower your LDL bad cholesterol, and save your heart. But let's take a closer look. The low-carb group here, in this observational study, wasn't even that low-carb. It was defined as under 25% of calories from carbohydrates, which is nowhere near low-carb high-fat ketogenic like some of the headlines suggested. Just to give you a sense of scale, by that definition, I could eat a McDonald's Big Breakfast with biscuit, hash brown, pancakes, and maple syrup and still have room for a few Dunkin' Munchkins while still being low-carb. Does that sound low-carb to you? Doesn't to me. But that's not even the worst part. The dietary data came from a single, one 24-hour recall questionnaire, a notoriously flawed method that the authors admit themselves, now quoting, is prone to measurement error and recall bias and is a short-term assessment of dietary pattern which may not accurately reflect longer-term food intake. And when another analysis was conducted using just 2 questionnaires instead of 1, the effect was no longer significant. So the headlines shouting "Keto-like diet increases cardiovascular risk" based on that alone, they hold together as well as a snowman in a sauna. But dig deeper and get this, the story unravels even further. The so-called low-carb group had more diabetes and obesity, which are clear confounders, and— the best part of all— that scary LDL cholesterol increase highlighted in the abstract without an actual number, guess how much it was? 3.48 mg/dL. That is tiny. That's clinically irrelevant. It's like crying direwolf or dragon and then getting a cavapoo. That's Lucy, by the way. Anyway, this paper, despite being widely shared and cited, essentially weaponized weak data to reinforce a preconceived narrative. And to see that clearly, you had to go past the headlines. But now with that foundation in place, and we're gonna build on it, let's name and give the nature of the medication in question and the randomized controlled trial evidence. That brings us to Chapter 2: SGLT2 inhibitors, cholesterol, and cardiovascular risk. The medication at the center of our story is called an SGLT2 inhibitor. It works by blocking the sodium-glucose cotransporter 2 protein in the kidneys, so its name makes sense. This protein is responsible for resorbing glucose, sugar, back into the bloodstream, so by inhibiting this transporter, SGLT2 inhibitor drugs cause excess glucose to be excreted in the urine, peed out, lowering blood sugar levels. But their benefit extends far beyond glucose control. At least that's what they teach in medical school, but we're going to discover together in Chapter 3 the story is much more interesting and much more complex than just peeing out sugar. I promise we're going to get back to this in Chapter 3, but first let's review the core randomized controlled trial I need to tell you about. This was a 2015 major trial in the New England Journal of Medicine, the highest impact medical journal in the world. And in this study, patients with diabetes at high cardiovascular risk were randomized to receive an SGLT2 inhibitor or placebo control, and they were followed for a median of 3 years. What were the results? A 38% relative risk reduction in death from cardiovascular causes and reduced all-cause mortality—all death. But here's the twist. You ready? The study also reported increases in LDL cholesterol in the SGLT2 inhibitor group. This wasn't heavily featured though. In fact, in the paper there's only one subtle mention that there was a small increase in LDL and HDL. For that see Figure S3 in Section P of the supplementary appendix. Then, to actually see it, you need to dig back dozens of pages to the end of the supplementary appendix to see the data. Yes, the LDL cholesterol did increase. Though it was modest, it was actually larger than in the observational study that made all those headlines that we just reviewed. This trial though has been cited nearly 15,000 times in the academic literature. That is an enormous impact, yet I haven't seen a single instance where the narrative included LDL went up, but— Now, if the field of cardiovascular medicine were not so singularly focused, obsessed with LDL cholesterol and ApoB, that might be understandable. But it seems to me that every opportunity to vilify LDL is seized, often exaggerated or misused as we went over, But when the data don't fit cleanly with the prevailing narrative, you get, "Please see Figure S3 in Section P of the supplementary appendix." So let's recap. An observational study with weak methodology and a negligible change in LDL cholesterol linked low-carb diets to increases in LDL cholesterol and heart disease. It went viral and reinforced the prevailing narrative that low-carb and keto are bad and LDL is the boogeyman. And then a randomized controlled trial with high-quality evidence shows that a medication reduced cardiovascular mortality despite raising LDL. But that detail was buried. What explains the difference in communication? It's not consistent standards. It's not meritocracy. It's not facts. It's not data. It's simply narrative building. And just to double-click on that point, cuz it's really important. In a large-scale meta-analysis of phase 3 placebo-controlled trials testing SGLT2 inhibitors across a wide range of patients—78,607 diverse patients in total— Researchers found, again, that SGLT2 inhibitors reduced the rate of major adverse cardiovascular events by 9%. That's nothing to sneeze at. Their conclusion? SGLT2 inhibitors reduced the risk of major adverse cardiovascular events across a broad range of patients, but— this is strong evidence, right? Right? Now do the Ctrl+F test. Search the manuscript for LDL. Anywhere in the manuscript. It appears nowhere, except for the title of the 24th reference and in one use of the word "mildly" if we're being technical. That's it. So, say it again with me: narrative building. Again and again, we see a pattern. When there's an opportunity to vilify cholesterol, it's seized, often unfairly. But when high-quality evidence contradicts the narrative that elevated LDL cholesterol is the be-all end-all when it comes to cardiovascular disease, that information gets buried or ignored. Now, to be clear, I am not giving a blanket statement that LDL cholesterol or ApoB don't matter. I didn't say that. They do in context. Did you hear me? In context. But the way the data are framed and published and reported to the public is often skewed to such an extreme degree that what I'm saying now, if I give it in a soundbite, sounds like a conspiracy until you read the studies for yourself and piece the puzzles together, which I'm trying to do here with you. Alright, you got me? Warm-up over. Here is where things get Wild. To truly understand what might be happening here, we need to go beyond the human clinical data. Because while outcome-based data—trials—are essential for guiding medical decisions, they don't reveal the deeper why—the mechanism. And I love that. I hope we love that here on this channel. In fact, if you revisit that landmark New England Journal study, the authors themselves admit the mechanisms behind the observed benefits remain speculative. And that brings us to my favorite chapter, Chapter 3: Mechanisms and Mysteries—how SGLT2 inhibitors work and what we can learn from that. So let's turn the page to an impressive investigation published in Nature Aging in 2024. In this study, researchers treated mice with an SGLT2 inhibitor and observed something striking: the drug helped clear out senescent cells. Senescent cells are zombie-like cells that no longer divide but refuse to die. They linger in tissues and release inflammatory molecules that contribute to aging and disease. And the researchers found that administering an SGLT2 inhibitor to mice on a Western-style diet improved insulin sensitivity and glucose control. But that's expected. That's not the weird part. What truly stood out is that SGLT2 inhibition cleared the senescent cells from tissues, a process believed to improve both healthspan and lifespan. We're gonna get to lifespan in a minute. This was something new. Then digging deeper, the team discovered that SGLT2 inhibitors activate an enzyme called AMPK, heavily involved in energy metabolism and longevity pathways. This activation of AMPK helped modulate the immune system to better target and eliminate senescent cells. So simply put, SGLT2 inhibitors activated AMPK, and promoted immunosurveillance to help clear out senescent zombie cells. And the consequences were profound. SGLT2 inhibition reduced cellular senescence, improved atherosclerosis—you see that here—and strikingly increased both lifespan and healthspan. These are the survival curves. Increased lifespan in both male and female mice. So to summarize, this study reveals an entirely new mechanism by which SGLT2 inhibitors may extend healthspan and lifespan not just by lowering glucose or cholesterol—cuz it doesn't do that—but by activating immune and longevity pathways. And this is consistent with what we see in the human randomized controlled trial data—reductions in all-cause mortality and cardiovascular mortality even when LDL cholesterol goes up. But now let's double-click on AMPK, this key enzyme involved in energy metabolism, the one activated by the SGLT2 inhibitors that helps clear out these zombie-like cells. Well, here's the interesting next twist: lifestyle interventions can activate AMPK too, including fasting and ketogenic diets. Aha! See? Now we're coming full circle. This raises the compelling question: could there be a memetic effect between carbohydrate restriction, like fasting and keto diets, and SGLT2 inhibitor drugs? Or otherwise put, Could SGLT2 inhibitors be chameleon-ing keto? I really wanted to say that. Well, here's a fun fact now. SGLT2 inhibitors do indeed promote ketogenesis, the metabolic pathway that produces ketone bodies. They do so by activating an enzyme called BDH1, which is the key enzyme involved in ketone body production. So in a sense, these SGLT2 inhibitor medications function as a ketogenic diet mimetic of sorts. They lower blood glucose, in part by increasing urinary glucose excretion—you pee out sugar—and they stimulate ketogenesis via an independent mechanism. How cool is that? The researchers studied human subjects with metabolic disease and fatty liver. Patients were randomized to receive either an SGLT2 inhibitor at 10 mg or a placebo for 12 months. And the results? Significant improvements in inflammation and fatty liver scores in the SGLT2 inhibitor treatment group. And immune cells from human patients treated with the drug showed increases in ketone body production. So in short, kind of stepping back, what we're seeing here is a fascinating convergence of dietary therapy, say keto and fasting, and pharmacotherapy, SGLT2 inhibitors. This class of drugs activates the same pathways—AMPK, ketogenesis—and has similar metabolic effects: lowering blood glucose, increasing ketone body levels, immune modulation, and sometimes increasing LDL cholesterol as well. And I think you're smart enough to put two and two together. And as a quick nuance note, ketogenic diets in animals have also been shown to increase lifespan. Go figure. Anyway, I hope you appreciate what's really happening here. This is effectively, what we've done here together, Big Pharma judo. No one can accuse us of being anti-pharmacotherapy. In fact, I almost never am. I'm just pro-nuance, committed to looking at the data in context, understanding the physiology, and thinking hard about how it applies to real human biology beyond blanket statements and lazy platitudes. Now here's where I celebrate you. Sure, some people think the general audience doesn't care about this level of detail, but you are living proof that you do. The fact that I can say everything I just said and that you're here listening is proof that people want to look past the surface. Past the headlines, past the lazy narratives and platitudes, and sometimes even past the scientific consensus. Because the truth, the truth is complex and sometimes controversial, but the truth is also always empowering. You just have to stay curious enough to connect the dots. That's what we do here. I really appreciate you for it. Stay curious.