152. Nick Norwitz: Cholesterol Myths, Insulin Resistance, and the Real Drivers of Heart Disease

Cholesterol remains one of the most debated biomarkers in cardiovascular medicine, yet many people still misunderstand what it actually tells us about metabolic health and disease risk. As research evolves, the conversation is shifting from simple cholesterol numbers toward deeper drivers of cardiometabolic dysfunction. In this episode of Extend, we sit down with Nick Norwitz, metabolic health researcher and physician scientist, to unpack the science behind cholesterol, insulin resistance, and cardiovascular risk. We break down the difference between LDL and ApoB, why insulin resistance may be a stronger predictor of heart disease, how statins work beyond cholesterol lowering, and what emerging research reveals about metabolic health, biomarkers, and individualized risk. We also explore how curiosity driven experimentation, data tracking, and deeper metabolic literacy can help people move beyond simplistic cholesterol narratives and better understand their own cardiometabolic health. Nick Norwitz is a physician scientist and metabolic health researcher who graduated valedictorian from Dartmouth College before earning a PhD in Human Metabolism from the University of Oxford and an MD from Harvard Medical School. Following a personal battle with inflammatory bowel disease, he became a leading voice in metabolic health education and the author of the widely read newsletter StayCuriousMetabolism.com http://staycuriousmetabolism.com. What We Discuss: (02:14) The biggest misconception about cholesterol, LDL, and cardiovascular risk (06:03) How sleep, inflammation, and plaque formation connect to heart disease (08:18) Why insulin resistance may predict cardiovascular risk more strongly than LDL (10:40) The atorvastatin study that showed suppressed GLP-1 levels (16:54) Statins, pleiotropy, and why lowering LDL is only part of the story (22:16) Coronary calcium scans and how imaging can change treatment decisions (24:48) The Lancet statin meta-analysis and how headlines distorted the findings (33:20) CoQ10, TUDCA, and supportive strategies for people taking statins (35:15) Ezetimibe, how it works, and why it may have neuroprotective potential (46:09) Bempedoic acid and how it compares with statins (51:47) PCSK9 inhibitors, pros and cons, and who may benefit most (54:20) ApoB versus LDL and why particle count matters (56:15) The Oreo experiment, lean mass hyper-responders, and individualized cholesterol responses (59:19) What to do after a high LDL result instead of automatically defaulting to a statin (1:02:00) Berberine, nattokinase, and other non-prescription options for cardiovascular support (1:06:03) The challenge of communicating nuance in health content online (1:10:18) Why personalized experimentation matters more than one-size-fits-all medicine (1:12:36) Lp(a), waist-to-hip ratio, and why cardiometabolic context changes risk Thank You to Our Sponsors: IM8: Try IM8 today with a 30-day money back guarantee. You can get 10% off your first order with code DRSHAH at https://im8health.com/discount/DRSHAH. Learn more about Dr. Shah: Website:drshah.com https://www.drshah.com/ Clinic:next-health.com https://www.next-health.com/ Instagram: darshanshahmd https://www.instagram.com/darshanshahmd Learn more about Nick Norwitz: Newsletter: staycuriousmetabolism.com http://staycuriousmetabolism.com YouTube: nicknorwitzMDPhD https://www.youtube.com/@nicknorwitzMDPhD Instagram: nicknorwitz https://www.instagram.com/nicknorwitz/ Twitter: Nick Norwitz MD PhD https://x.com/nicknorwitz

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:03Dr. Darshan Shah?

  Welcome to Extend with me, Dr. Darshan Shah, a podcast dedicated to cutting-edge science, research, tools, and protocols designed to help you extend your health span. Having become one of the youngest doctors in the country at the age of 21, and trained and board-certified at the Mayo Clinic, I've accumulated three decades of practice as a board-certified surgeon and longevity expert. Over that time, I've discovered that a mere 20% of health knowledge yields 80% of the results when it comes to your health span. We're living in a new era where we are creating a new healthcare system, no longer focused on disease management, but achieving optimal health and vitality. Join me as I interview world-renowned experts, offering you a step-by-step guide to proactively avoid disease, and most importantly, extend your health span.

• 0:49Dr. Darshan Shah?

  Cholesterol remains one of the most debated biomarkers in cardiovascular medicine, yet many people still misunderstand what it actually reveals about metabolic health and disease risk. As research evolves, the conversation is shifting beyond simple cholesterol numbers towards deeper drivers of cardiometabolic dysfunction. In this episode of Extend, we sit down with Nick Norwitz, metabolic health researcher and physician scientist, to unpack the science behind cholesterol, insulin resistance, and cardiovascular risk. We break down LDL versus ApoB, why insulin resistance may be a stronger predictor of heart disease, how statins work beyond cholesterol lowering, and what emerging research reveals about metabolic health and individualized risk.

• 1:32Dr. Darshan Shah?

  We also explore how curiosity-driven experimentation, data-tracking, and deeper metabolic literacy can help people move beyond simplistic cholesterol narratives and better understand their own health. Nick Norwitz is a physician scientist, a metabolic health researcher, who graduated valedictorian from Dartmouth College before earning a PhD in human metabolism from the University of Oxford and an MD from Harvard Medical School. Following a personal battle with inflammatory bowel disease, he became a leading voice in metabolic health education and the author of the widely read newsletter Stay Curious Metabolism. I want to make it very clear that this episode with Dr. Nick Norwitz presents a different side to the story, but every patient is different.

• 2:16Dr. Darshan Shah?

  And there's going to be a lot of argument and disagreement about talking about statins. I think that everyone should have both sides of the story. However, to be clear, as a doctor, I do try to steer people towards better metabolic health as they're on statins. I do think there's a lot of patients that benefit from statins. And I also think that there's a lot of patients that should look at other potential therapeutics before they get on statins. It's always good to have both sides of the story, and this is one side of the story. Nick, so great to have you back in person this time.

• 2:52Speaker 01

  In person is always better. Very excited to be here.

• 2:54Dr. Darshan Shah?

  I know, I came all the way out to Cambridge to come and find you, get you back on, because there was so many important things to talk about.

• 2:59Speaker 01

  You found me. I'm excited for on too.

• 3:01Dr. Darshan Shah?

  Yeah. So, you know, what I really wanted to focus today's conversation on, because I've been seeing you post a lot of YouTube videos, and by the way, your YouTube videos are incredible. I get so much education from them. And what I love about them is every claim you make is like based on a paper, that you've actually read the whole paper, not just the headline. And you talk about cholesterol a lot. And I think this is a topic that I wanted to have you back on the podcast for, because it is very confusing for people. People are struggling, and for some reason, there's a ton of controversy around cholesterol levels, right? And we're going to talk about that for sure. So, let's get the topic started. Like, what's the biggest misconception people have about cholesterol and LDL?

• 3:44Speaker 01

  That is a really good question. I'm going to give an intellectual answer, so people hopefully not scared off, but I'm going to break it down. And I think it's the confusion between the ideas of causality and importance. So, one area of, I would say, debate is whether or not LDL cholesterol is quote unquote, heavy quotes, causal in cardiovascular disease. And I just see like, you know, bickering on social media, people saying it is causal, isn't causal, without really understanding what that word means. The word... By definition means it's part of a causal cascade. So you, it's involved in the chain, but that doesn't mean it alone is sufficient to cause disease.

• 4:28Speaker 01

  And really importantly, it doesn't mean that you need to treat high cholesterol in all cases. So there's a difference between causality and importance, and I think that often gets missed. And an analogy that, actually, this derives from Peter Attia, but I thought was apt from a 2018 podcast, is talking about the relationship between oxygen and fire, where he says, you know, oxygen is necessary and also causal for fire, but it's not sufficient. So just because we're breathing oxygen right now doesn't mean our lungs are going to burst into flames. By extension, just because we have LDL circulating doesn't mean you're going to get cardiovascular disease. And that analogy of Peter's actually quite like because it draws out the issue with

• 5:11Speaker 01

  the idea of, hey, just because something is causal, we should target it and lower it. Because what happens if you lower oxygen more and more? Your chance of a fire goes down, sure, but you might suffocate and die. Obviously, it's an extreme analogy, but it does draw out this point that, yes, something can be causal and also not the most important thing in the discussion of, in this case, cardiovascular disease.

• 5:33Dr. Darshan Shah?

  Yeah, it's such an incredibly valid point because when I sit down with a patient and they have a high LDL, for example, the first thing I have to do is like talk them off a ledge because the first thing they're like, oh, now you're going to give me a statin, right? I'm like, absolutely not. It doesn't mean you need to be on this because cardiovascular disease, and let's focus in on blockages in the cardiac blood vessels, is due to a chain of events of which high LDL is one part of that chain of events, not the whole event, right? So you have to have damage to your blood vessel wall. You have to have some level of inflammation and then the LDL will come in.

• 6:14Dr. Darshan Shah?

  To then deposit in the blood vessel wall, causing eventual blockages, depending on how much it ends up depositing, right? And so I think it's an important point to make that just because you have high LDL doesn't mean that you will get cardiovascular disease.

• 6:29Speaker 01

  Yeah. I'd also, I just want to like draw out how much we still don't understand because you think this will be worked out. And there are models, there are prevailing models about LDL getting into the blood vessel wall and then getting trapped there. It's called the response to retention model and that causes inflammation. But in truth, the degree to which we actually have a sense of what is the, I wouldn't even call it a causal cascade because it's not linear, it's a web. What are the web of factors and how do they truly interact in an individual is much more complicated. If you don't, if you'll forgive me a tangent, just to give an example of like how cool this becomes, and then we'll talk about protocols later. I was reading a paper this morning, it was a reference in another paper, I think this was a 2019 paper. And as I mentioned before we started, like anything I say, I'm happy to send you all

• 7:14Speaker 01

  the PubMed IDs, DIYs afterwards, so people can check the show notes. I always have a paper in mind for a claim I make. But it was looking at the relationship between sleep and cardiovascular disease. Now, I know you know, and your audience probably even knows, there's an association between poor sleep and cardiovascular disease. This is a very cool paper. It was an animal model because you need animal models for the mechanistic cascades. But what it was showing is that poor sleep causes suppression of a hormone. It's an arousal hormone called hypocretin. Don't get scared away with the terminology, always bring it back. But basically what this leads to is it causes the bone marrows to like spit out more inflammatory immune cells, which then go to the blood vessels and drive plaque formation. Now, the reason I bring this up is just one example, is because then you, even that, you

• 7:57Speaker 01

  sort of puzzle the pieces together like, oh, well, maybe my, you know, sleep quality is affecting how atherogenic my LDL is because it's changing the inflammatory environment in my blood vessels. So there's just one microcosm about like how different threads on this web intersect and how complicated it can be.

• 8:16Dr. Darshan Shah?

  Yeah, it can be super complicated. So some of the biggest levers in this web, I think of are inflammation, hypertension, for example, metabolic health abnormalities, hyperinsulinemia, and all going all the way to diabetes, right? And then also. LP little a will talk about, will also talk about other lifestyle factors, specifically diet, right?

• 8:40Speaker 01

  Yeah.

• 8:40Dr. Darshan Shah?

  I want to talk about your Oreo story.

• 8:42Speaker 01

  Yeah, and more on LP delay. I'm surprised how hot that is right now in the general public.

• 8:46Dr. Darshan Shah?

  Right.

• 8:47Speaker 01

  I remember the first thing I wrote on it, I'm like, this is esoteric. Nobody's gonna like it and it blew up. So people definitely aware of it. And I do have protocols for that as well, that I think you and your audience will find interesting. So we'll table that.

• 8:57Dr. Darshan Shah?

  Yeah, I would love to focus in on LP little a for a little while.

• 9:00Speaker 01

  Sure.

• 9:01Dr. Darshan Shah?

  As well. Are there any other major topics that I didn't mention though? Besides, besides the ones I talked about, anything else that kind of feeds into this web? The things that can lead to cardiovascular disease that I didn't cover in that list?

• 9:17Speaker 01

  I mean, you mentioned most of the things. I think the one thing I would highlight, which is not a new variable, but in terms of what gets the spotlight. So let's take insulin resistance.

• 9:27Dr. Darshan Shah?

  Yep.

• 9:28Speaker 01

  If you look at like large cohort studies and you're going to get different numbers from different studies. But, you know, one study, for example, shows that the cardiovascular risk associated with insulin resistance, the high lipoprotein insulin resistance score is 14 times more powerful predictor of cardiovascular disease than say LDL cholesterol.

• 9:47Dr. Darshan Shah?

  14 times more.

• 9:48Speaker 01

  14 times more. The, the numbers are like a hazards ratio, which is risk of an event occurring versus not. Was like 6.4 for high LPIR versus like 1.38. So one's being neutral. Do the math out and ends up being like 14 times. So anyway, the exact numbers not important, but then the question arises. Why aren't we focusing this? Why is the spotlight on LDL? And this is where I want to draw out like the idea of the incentive structures that drive discussions. And I want to be really careful here because there's a tendency to go follow the money. And then immediately jump to the idea that, oh, if it's pharma funded, these data don't count. That is not what I'm saying. What I am saying is that when it comes to science in clinical medicine,

• 10:33Speaker 01

  we need to understand that the questions that get asked and the studies that get done and the data we collect are driven by financial incentive structures. So if you can develop a drug to target a biomarker, then you're going to fund that study because the business model works. And that's not saying anybody's evil. That is just like basic economics. And it does color the data we end up collecting and the data we don't. So I want to, I know we have an example about, we're going to talk about that with respect to the GLP-1 study, but it's a difficult thing to talk about, but it is an important thing to talk about because it just highlights like why medicine tends to talk about the things it talks about. Why does LDL get the spotlight and not insulin resistance? Because there's a business model. Not saying anyone's evil, but that's the truth.

• 11:17Dr. Darshan Shah?

  Yeah, that's, it's true. I mean, I mean, the, the whole cholesterol lowering industry, pharmaceutical industry is a multi-billion dollar industry. So, and unfortunately, you know, the same amount of attention, to your point, doesn't go into lowering insulin levels until just recently with the GLP-1s because we didn't have anything to target.

• 11:35Speaker 01

  Yeah.

• 11:36Dr. Darshan Shah?

  Yeah, so let's talk about that a little bit. Before we move on to drugs, let's talk about the GLP-1 study and kind of the little debate that you had going online there for a little while.

• 11:47Speaker 01

  Yeah, so this is a study published in Cell Metabolism in 2024. I found it, I think it was February 2024. I found it in 2025. At this time, I was a, as a medical student and I read it and I was shocked. Basically, what it was, is it was a controlled human trial, published in a top science journal. Cell Metabolism is a pretty prestigious journal.

• 12:10Dr. Darshan Shah?

  Very.

• 12:10Speaker 01

  And it, it showed that atorvastatin, which is the single most profitable drug in history. Brand name's Lipitor. I think it's grossed well over 150 billion. That single statin alone. Crushed levels of GLP-1 in a human-controlled trial. Now, if you look at the graph, maybe we can display it. But like, an eight-year-old could tell you what's going on in this graph. There's a blue line, which is the control group, which is like, you know, a flat line. The x-axis is time, 16 weeks, which is how long the trial was. The y-axis is GLP-1 levels. And there's this big red line that is dropping down at a 45-degree angle, straight down. And it is the statin group. Yeah. And the takeaway from this is, in a human-controlled trial, atorvastatin, the most profitable drug in history, is crushing levels of GLP-1,

• 12:55Speaker 01

  which is a hormone at the center of now the trendiest drug class in history, GLP-1s. Right. That is an astonishing finding that you would think should be breaking headlines. And yet, not only was it not breaking headlines, nobody had heard about it. I even went around like Harvard hospitals, asking doctors, including cardiologists, "Have you heard of these data? And what would you predict?" Even before I like reveal the data with respect to how statins interact with GLP-1s. Interestingly, and we can sidebar this, but none had heard about it. I polled 12 people. Those who were willing to guess could guess correctly. Because actually, the physiology starts to make sense when you unpack it. Now, what am I saying, what am I not saying? Hmm. I'll be clear. I'm not saying this alone has proven clinical relevance. Mm-hmm. I think it's kind of hard to believe that it wouldn't have any clinical relevance.

• 13:40Speaker 01

  I mean, you're crushing levels of this hormone by like 50%. Fasting levels, we can get into that. Peter Attia got a little confused. But that aside, what concerned me is that it didn't even make it into this discussion. And this is where this idea of incentive structures comes up. I'm like, well, why isn't this being talked about? And importantly, why isn't it being chased? Right. The number-one pushback I get when I talk about this study is like, "Aren't you making a mountain out of a molehill because it was only a 40-person study?" To which my response is, first of all, an end value doesn't, the number of people in a study doesn't determine the quality of the study. That's just not how things work. But second of all, the fact? That this clearly has potentially huge biological relevance and doesn't get followed

• 14:21Speaker 01

  up on in a larger trial to, one, generalize findings and then, two, subfractionate people to see who's being most impacted.

• 14:28Dr. Darshan Shah?

  Right.

• 14:29Speaker 01

  That is a travesty because it shows, or it's an example of how the compass of medicine is not dictated about what's best for patients or where the most learning can occur, but where there's a business model.

• 14:39Dr. Darshan Shah?

  Yeah.

• 14:39Speaker 01

  And one other thing I'll add to it, and I'll get off my soapbox for a minute, was another interesting element of this study was they did dissect a mechanism, which had to do with how statins impact the microbiome and change levels of bile acids, which led to a hypothesis.

• 14:52Dr. Darshan Shah?

  Hmm.

• 14:52Speaker 01

  Could we just supplement back the bile acid and fix the problem? Actually, the bile acid in question, U D C A, is already a drug given for liver disease.

• 14:59Dr. Darshan Shah?

  Oh, oh, oh.

• 15:00Speaker 01

  So they just took patients, in this case, five, only five, but still, and then they gave them this bile acid supplement. What happened? Blood sugar dropped, insulin resistance improved, GLP-1 levels resurged, which reveals, actually, there might be real clinical benefit in understanding what's going on here. So why is this not getting talked about and why is it not getting chased when tens of millions of people are taking this drug?

• 15:26Dr. Darshan Shah?

  Yeah. Well, I mean, if you find a solution to the problem that's as cheap and easily available as a bile acid.

• 15:34Speaker 01

  Yeah.

• 15:35Dr. Darshan Shah?

  It could decimate the GLP-1 market.

• 15:37Speaker 01

  Well, the crazy thing is, and now I'm not making medical claims, bile acid's U D C A. People might have heard of T U D C A, some people call it Taduka. What is T U D C A? It's U D C A with a taurine on it.

• 15:48Dr. Darshan Shah?

  Mm-hmm.

• 15:49Speaker 01

  You can buy that off Amazon and your body will just chop the taurine off, so it'll increase U D C A levels. So in theory, speculating, this hasn't been proven, but if you have a crushed GLP-1 level from statins, you could just go on Amazon and buy T U D C A. It might fix the problem. I'm not saying it does because the studies haven't been done, but why haven't the studies been done?

• 16:09Dr. Darshan Shah?

  Right, right. That being said. Does UDCA increase GLP levels without being on atorvastatin?

• 16:18Speaker 01

  We don't know. I would speculate probably not. And I also just want to clarify, we're talking about fasting GLP-1 levels. This is a point that I'll just respond. There was a back and forth. It wasn't, he didn't name me, Peter Attia had basically a rebuttal letter to my commentary. Go through the timeline, it was very conspicuously targeted at me. And one of the things he was talking about was relative levels of GLP-1. So he said, like, you know, after you have a meal, GLP-1 surges much more than the actual absolute change in GLP-1 in this study, which is true. And then here's where things get a little bit complicated because there is a huge difference between fasting levels of a hormone, postprandial, after eating levels, if it's a food responsive hormone. And then also, in this particular case,

• 17:03Speaker 01

  superphysiologic levels when you're drugging people. So the GLP-1 receptor agonists aren't physiologic replacement of GLP-1. They're super doses.

• 17:13Dr. Darshan Shah?

  Yeah.

• 17:14Speaker 01

  Which is why they're effective for weight loss. So we can talk about this a little bit more because there are some data suggesting that statins might cause weight gain. But it's not a matter of because atorvastatin does this to you, you're just going to pack on the pounds. It doesn't work like that. None of that is what I'm saying. It's just more about like, why isn't this part of the discussion and what the clinical relevance could be, rather than making a strong claim of clinical relevance, if that makes sense.

• 17:35Dr. Darshan Shah?

  Yeah, that makes total sense. Okay, so going back to statins, just in general. You know, there's one of the most controversial drugs right now. I mean, everyone is either completely against statins or for statins. And I think there's so much nuance is being missed there. And I like to dive into all of those nuances. So first of all, let's talk about LDL levels and statins. What's the relationship between the two from your vantage point?

• 18:02Speaker 01

  Yeah. Well, statins are known to lower LDL. The way they do so is inhibiting cholesterol synthesis, this enzyme, HMG-CoA reductase. And this enzyme is throughout tissues in the body. We'll get back to that a little bit later, but there's relevance here because statins do pervade the whole body. Right. Including like muscles and brain. Not all drugs that act kind of like statins do. So there are other options that we can talk about. But statins do lower LDL by inhibiting this enzyme in them. Basically, what happens is the liver tries to compensate for an internal, let's say, cholesterol starvation state. It's not like dangerous starvation in the liver, but the liver gets low. And so then it compensates by putting LDL receptors on the liver. So then it's pulling particles out of the bloodstream.

• 18:44Speaker 01

  Basically, all LDL lowering medications operate in some way, shape or form through increasing LDL receptors on the liver. So we can get back to that. Right. But that's how statins work. Now, the interesting thing about statins, and really all lipid lowering drugs as we can get into, is they're not one-trick ponies. They do a lot of things. Yeah. You know, we're funny as humans. We like categories, so you call something a cholesterol lowering drug and then you put it in that toolbox. An analogy I had in a newsletter I released this morning is it's like, imagine if, you know, I labeled a spoon a pea shooter. Uh huh. And then you just thought, this is what a spoon is for. The purpose of a spoon is to shoot peas, like a catapult, a pea catapult. And then you realize, oh, wow, you can drink soup with it. This is a revelation.

• 19:28Speaker 01

  It's the same way with medications. Sometimes we like, oh, this is this purpose, but it's doing a bunch of other things. Statins are no different. So they have a lot of different effects, some positive, some negative. They can impair mitochondrial function. I call that a negative. We talked about GLP-1. They can cause insulin resistance. They can alter calcium signaling in muscles and other tissues. Very interesting paper we can talk about in a minute. But they can also do other good things that are totally cholesterol independent. So increased nitric oxide and endothelial function, reduce inflammation. And the reason I highlight all these things is because what you can start to see coming together is a list of pros and a list of cons. Yeah. And how these pros and cons weigh out in an individual context is very complicated. It's not a matter of

• 20:12Speaker 01

  Oh, LDL is causal, let's lower it with this drug.

• 20:15Dr. Darshan Shah?

  Right.

• 20:16Speaker 01

  And in fact, if you look at some of the, you know, the, let's say the data are mixed, but some of the studies, including some of the meta-analysis, when you look at statin efficacy, how well they work for reducing cardiovascular risk versus how much they reduce LDL, the correlation's like crap. Like, it's really terrible. Like, yeah, like the, there's something called an R-square value, which can go from zero to one, one being great predictive value, zero being like nil. It's like zero to 0.1. Like, the predictive value can be very bad. And what that kind of tells us is that where statins provide benefit, it's not just a cholesterol story. There might be other things going on. So if you're very inflamed and you have poor endothelial function, they might be providing benefit there, then more than offsets negative effects on, say, GLP-1 levels or insulin resistance as one example.

• 21:01Dr. Darshan Shah?

  So, when people are taking statins then, so what you're talking about then is, let's talk a little about pleiotropy. And I sent you that article.

• 21:07Speaker 01

  Yeah.

• 21:07Dr. Darshan Shah?

  As well.

• 21:08Speaker 01

  Yeah.

• 21:08Dr. Darshan Shah?

  Can you talk about that a little bit, just real quickly?

• 21:10Speaker 01

  Yeah. Pleiotropy is just a name for what we just described, where a single drug, or honestly, a single gene or anything, has multiple effects. So it's not one-to-one, it's one too many. That is just the concept. And so it then becomes a difficult game of, in the human context, attribution. Because if you get this medication and it changes one variable, but it's changing many others, how do you know for sure that the benefit's coming from manipulating the, in this case, LDL? And the fact of the matter is, you don't really go down, like, have a three-hour conversation about mendelian randomizations that people watch interpretations of and stuff, but we'll leave it at that for now.

• 21:45Dr. Darshan Shah?

  So, okay, and the reason I want to highlight that is that you brought up an important fact, is that statins do lower LDL, which is one aspect of what they do. That lowering of the LDL doesn't really correlate very well with lowering of actual cardiovascular risk, is what you're saying, right?

• 22:04Speaker 01

  In this- There are, the data are mixed, but in general, I would say, yes.

• 22:09Dr. Darshan Shah?

  Okay. But there are other effects of statins such as increased nitric oxide, lowering inflammation that could also determine the efficacy of statins in lowering cardiovascular risk.

• 22:21Speaker 01

  Right?

• 22:22Dr. Darshan Shah?

  Yeah. So that's why we prescribe statins to people is because the idea is we want them to not just lower LDL levels, but also lower cardiovascular risk. But because there's so many different effects, we just don't know for you as an individual, an N of one.

• 22:37Speaker 01

  Yeah.

• 22:38Dr. Darshan Shah?

  How well the statin will lower your particular cardiovascular risk.

• 22:42Speaker 01

  Yeah.

• 22:43Dr. Darshan Shah?

  Right?

• 22:43Speaker 01

  I would say the most practical thing, because now, I know the audience is probably thinking, well, how do I figure it out for myself?

• 22:49Dr. Darshan Shah?

  Yeah.

• 22:50Speaker 01

  Probably is cardiac imaging.

• 22:51Dr. Darshan Shah?

  Right.

• 22:51Speaker 01

  It's becoming now so cheap and available. So basically, if you're above 40, and you get, say, like a coronary artery calcium scan, and your score is zero. Now, there are more advanced scans, but even just looking at calcified plaque, the data tend to show pretty minimal benefit for LDL lowering. So I would say that provides some degree of warranty, not a complete lifetime warranty, but some degree of warranty and does help, as you said, triage people to like, you, let's say, have less buffer room and want more aggressive therapy versus you're someone who, you know, honestly, probably shouldn't be that concerned. I'll give you an example from my own family. My mother, who's an M.D. Ph.D., she's had a lifelong

• 23:32Speaker 01

  high LDL, like, you know, as high as 400. Her lifetime burden is massive, and she's 60. She recently had a, not just a coronary artery calcium scan, but a coronary CT and geography. No plaque.

• 23:45Dr. Darshan Shah?

  No.

• 23:45Speaker 01

  So by standard guidelines, like her LDL is 400, she should be treated, but she's had this whole lifetime exposure and had no plaque accumulation. Should you treat her? And the answer is, there's really no evidence to suggest you should. And so in that scenario, I would say the cost benefit analysis leans towards not medicating with statins. She's going to start something else that I've actually encouraged her to start, I have, and we can talk about what that is and why.

• 24:08Dr. Darshan Shah?

  Yeah, yeah, I would like to. But I do want to highlight another fact that you mentioned earlier, too, is that, you know, insulin resistance is a major factor in cardiovascular disease as well. So if you're going to treat someone with a statin, you should always also have the conversation of what is your fasting insulin level? Right? And those two things. Don't normally get talked about together in your typical primary care offices.

• 24:34Speaker 01

  Well, your fasting insulin doesn't even get measured usually.

• 24:36Dr. Darshan Shah?

  Yeah, that's the problem.

• 24:37Speaker 01

  Which, I mean, if you're getting a fasted lipopanель and you should get your lipopanель fasted, I know that's like a trend towards not doing that, which ticks me off. You should get, you should ask your doctor for a fasting insulin because it's a canary in the coal mine for poor metabolic health. If your fasting insulin is elevated, I would say above like seven or eight. The reference ranges are too broad. That's a suggestion that you're becoming insulin resistant and that's probably something to be addressed.

• 24:59Dr. Darshan Shah?

  Okay, yeah, exactly. And before we move on to other medications, because I really want to talk about that, let's talk about the Lancet study that came out on statins.

• 25:07Speaker 01

  Yeah. So for context, there are a few journals that are just like huge in academia. The New England Journal of Medicine, the Lancet, these are the journals that like, doctors and academicians like, oh, what, like, you know, you're having your coffee and tea. Like, did you see the Lancet this morning? Like, talk about sports. And so this is, you know, when something drops in the Lancet like this, this is big news. And basically, the headlines were running, like, you know, Oxford Group shows in major meta-analysis of double-blinded, large randomized controlled trials, you know, all the bells and whistles.

• 25:38Dr. Darshan Shah?

  Yep.

• 25:38Speaker 01

  Statins are much safer than, you know, we previously thought. And most side effects of statins aren't actually attributable to statins, and millions more people should be taking this life-saving drug. Those were the headlines that everyone's running with. The study did not show that. And it frustrated me so much because it was a misrepresentation of what the data actually showed. So what they showed, what they did was they took 66 quote-unquote "additional" potential side effects of statins. I say "additional" because muscle pain and increased diabetes risk were just kind of taken as a granted and kind of like not even discussed. They're in the graphs.

• 26:16Dr. Darshan Shah?

  No.

• 26:17Speaker 01

  But like, oh yeah, statins do these things. We're not even going to like discuss that. So we're taking additional things on the package inserts and saying, in the top most quote "rigorous" trials, so the double-blinded randomized controlled trials with at least, I forget the threshold, but they need to be large, do statins cause X, Y, and Z outcome?

• 26:35Dr. Darshan Shah?

  Right.

• 26:36Speaker 01

  And the punchline was there were not statistically significant effects of statins on...

• 26:42Speaker 01

  I think it was 62 of the 66 outcomes. They found a few, including new signals like edema that were apparently caused by statins. But then where everybody jumped was this proves statins are safe and don't cause these outcomes, which is a manipulation of what the data say. So when we do a test, a statistical test, in science, we want to have a very high bar of certainty before we say X causes Y. So let's take weight gain as an example, because this came up in the study. We can talk about absolute levels, but this kind of ties back to G P one, et cetera, et cetera. But let's say I want to examine, do statins cause weight gain?

• 27:21Speaker 01

  What I don't want to do is publish a false positive, meaning I say they do when they don't. So we have a very, very high bar for certainty to actually make the certain claim of causality. Usually the threshold is 95% quote unquote certainty, which is where the P value of 0.5 comes from. It's a very arbitrary threshold, but it's saying we have a 5% tolerance of like saying false positive. What this means, to simplify it, is if you're 94% certain X causes Y, that is not significant. It is no commentary on the clinical relevance. It is no commentary on the effect size. It's just saying, hey, we have a very high bar for like calling this out.

• 28:05Speaker 01

  So we're going to assume the null hypothesis unless we can really prove it. It is not proving the opposite. So if we say we are not, there's not statistically significant effect of statins on weight gain. It is not saying statins definitely don't cause weight gain. Right. Those are two separate things. And what was interesting was if you look at the data, there were a lot of trends, like very strong trends towards statins causing negative effects, including, there are two figures and they're very convolutedly presented. I don't know why they are. Actually, let me sidebar on this for a second. It was, so if people look at the figures, they're gonna be confused. It's like this weird radial circle plots. I have no idea why they're presented like this because they usually are presented as forest plots. So to describe it, it's like, you've seen a forest plot.

• 28:50Speaker 01

  It's a straight line down. Right. And that line represents neutral risk. Right. If you're to the right of the line, increased risk. The left of the line, decreased risk. Right. I've never, ever seen somebody twist it in a convoluted circle for Yeah, why would they do that? I have no idea why they present. It didn't save space. It just made it look confusing. Yeah. In addition to some weird statistics, false discovery rates, we won't go into that. But it was just like, that was a, I won't speculate on why it's presented like that, but it's weird. Bottom line, though, is in figure one, there was a trend towards statins, all statins versus placebo causing weight gain. It didn't reach, quote, "statistical significance." What happens is there's a, is an error bar, a line that goes through a circle. And if it crosses the neutral line, you say, quote, "not statistically significant."

• 29:35Speaker 01

  It just made that line. It just made that line. And so, you know, if you had like a higher powered study, for example, in theory, you might see, quote, "statistical significance." It's really just this idea of it being arbitrary. Then in figure two, which looks similar, what they did is high dose versus low dose statins. And again, you see the same thing emerge. So you just put two and two together. You could have a hypothesis, could high dose statins cause, like they did a high dose statin versus placebo analysis, would that, like, statins cause weight gain in these double-blind randomized placebo-controlled trials? Point being is there were a lot of signal to harm. It didn't reach a threshold of significance, but that doesn't mean they don't exist. Right. It just mean they weren't proven beyond a shadow of a doubt. Sure.

• 30:20Speaker 01

  And that message was manipulated. Hmm. And I think there's a lot of curiosity here because when we start to put two and two together and see this mechanistic picture, it's like, well, there's a strong trend towards weight gain. There's even maybe a dose response effect. There's some tests you could do to suss this out. Now, we don't have access to the data because they're kind of hoarded. They're not publicly accessible. But then this dovetails with things like, well, statins lower GLP-1. They also lower leptin levels in some studies as much as 67%. And leptin is a rep, yeah, appetite regulatory hormone. Right. If you like Google, like, you know, congenital leptin deficiency, you'll get pictures of like kids who are like massively obese. And again, I'm not even making a claim of like extreme clinical relevance. It's just like these things fit together and what questions are actually getting asked

• 31:03Speaker 01

  and pursued has nothing to do with what's best for patients. And the narrative, I think, around statins is overly biased towards emphasizing potential benefits and inappropriately downplaying risks, as proven by this Lancet study as an example. I'm not just saying statins are good or bad. I'm not putting a value judgment on them. It's just like a matter of this conversation is so biased in one direction, it just requires a little bit of rebalancing.

• 31:29Dr. Darshan Shah?

  Sure, sure. Did the study say anything about the neurocognitive effects of statins?

• 31:33Speaker 01

  I think dementia was in there and, I mean, it didn't reach statistical significance. And I, this is somewhere, again, where that is at the extreme end of speculation. I would say on balance, statins probably don't harm or increase risk of dementia for your average person because endothelial function inflammation are so important. But if you take someone who is generally metabolically healthy, could statins increase risk of Alzheimer's disease? It's very plausible. In fact, they're known, atorvastatin, to decrease activity of what's called complex four in the electron transport chain. It's the end of mitochondrial energy production by as much as 50% at nanomolar concentrations,

• 32:14Speaker 01

  tiny concentrations, what is also a disease characterized by low activity in that exact complex, Alzheimer's. So there are circumstances that you could speculate, but has anybody ever done a long-term randomized controlled trial of statins in very healthy people? No, and probably will never get done.

• 32:28Dr. Darshan Shah?

  Never.

• 32:29Speaker 01

  Which is why these things are so hard to talk about, because we haven't proven absence of harm for so many things, but then the default becomes innocent until proven guilty.

• 32:42Dr. Darshan Shah?

  Yeah.

• 32:43Speaker 01

  And that works for a justice system. It does not work for pharmacotherapy.

• 32:45Dr. Darshan Shah?

  Exactly.

• 32:45Speaker 01

  And we see that again and again with history. In fact, some of the earlier statins, after being approved, like a Cervus statin were recalled. Because they were found to like, I mean, 52 people died of rhabdomyolysis.

• 32:57Dr. Darshan Shah?

  Right.

• 32:58Speaker 01

  That was never proven in a double-blind randomized controlled trial. The drug was still recalled, people still died.

• 33:03Dr. Darshan Shah?

  Right, right, absolutely. So what about, you know, there's a lot of talk around statins and taking CoQ10 with statins, for example. Are you a believer of that? Do you think it's a benefit if you're on a statin to take a CoQ10?

• 33:16Speaker 01

  Oh, absolutely. I think, so one of the things statins do is they decrease levels of CoQ10 because the enzyme they inhibit also leads to the generation of this CoQ10. CoQ10 is an antioxidant and it's very important in mitochondrial energy metabolism. It's called an electron carrier. So it shuttles electrons from complex one to three and complex two to three. So if you're impairing that, that's one area of mitochondrial function that you might be impairing. And yes, you can supplement back with CoQ10. As an added tip, if you can find one called phytosome phospholipid complex CoQ10, the absorption is much higher.

• 33:49Dr. Darshan Shah?

  Interesting.

• 33:50Speaker 01

  I would say if somebody's on a statin, particularly Lipitor, a torbostatin, CoQ10, and then TUDCA, which we talked about, are probably two supplements that are far more likely to help than harm. In fact, the TUDCA, Taduka, has also been shown to reduce inflammation in arteries. Some of the animal model work is really cool. You can like do dissections of the arteries and see just this massive reduction in arterial plaque, completely cholesterol independent. So that might have an added benefit independent of cholesterol levels. So with statins, a CoQ10 supplement and probably TUDCA will be good additions.

• 34:22Dr. Darshan Shah?

  Great.

• 34:23Speaker 01

  Continue on it.

• 34:23Dr. Darshan Shah?

  That's a great tip. And I always put my patient on statins on CoQ10. I will be doing TUDCA now because of the GLP effect. Why not?

• 34:32Speaker 01

  Yeah, it's not going to hurt. I mean, like if you can afford an Amazon supplement.

• 34:36Dr. Darshan Shah?

  Yeah, yeah. So let's go, you know, there's. Other meds besides just statins, right? And we know this. And obviously, like, people should consider their full range of options, right? And so some of these medications have potential other benefits. And they can actually even be more effective for certain people than even a statin could be, right? And so let's talk about Zetia, azetamide.

• 34:59Speaker 01

  Yeah. Azetamide, a brand named Zetia, is known for lowering cholesterol by impacting the gut. So basically, it inhibits absorption of cholesterol. And that's, to be clear, not just dietary cholesterol. But a lot of cholesterol is secreted into your gastrointestinal system when you're digesting foods and fats. So there's a recirculation. But in inhibiting this reuptake, again, like statins, it causes a compensation in the liver. LDL receptors go up and it pulls LDL particles out of the bloodstream. Now, generally, it's considered a more benign medication because it's thought to be rather gut-specific. Turns out it's not, but in a good way.

• 35:32Dr. Darshan Shah?

  The pleiotropic effect here?

• 35:34Speaker 01

  Yeah, more pleotropy, but this time in the brain. So this is a paper I read recently that got me really, really excited. And I want people to just remember what I said earlier about us putting things in buckets. So calling it a cholesterol lowering drug when it might be doing something totally different.

• 35:50Dr. Darshan Shah?

  Sure.

• 35:50Speaker 01

  So this is a study where researchers were looking at an interaction between two proteins that have relevance in Alzheimer's disease and other neurodegenerative diseases. They have, one has a very boring name. It's called 1433. Is that ring a bell for you?

• 36:05Dr. Darshan Shah?

  No.

• 36:06Speaker 01

  I think in medical school, sometimes during, like, step exams, it comes up in Crohn's Feldt-Jacob disease.

• 36:10Dr. Darshan Shah?

  Oh, my gosh.

• 36:11Speaker 01

  Right? You remember that? It's a diagnostic for this terrible prion disease where you get dementia and die in a year. So like, anyway. It's known in the neurodegenerative space, but basically it's a scaffolding protein. And then another protein, hexokinase, which is just involved in metabolism. And what happens in the brain and Alzheimer's disease? One of the things is the hexokinase, which usually sits on mitochondria, pops off and it binds to this 1433.

• 36:34Dr. Darshan Shah?

  Okay.

• 36:34Speaker 01

  And this sets in motion a cascade of events that can lead to protein aggregation, which is like characteristic of most neurodegenerative diseases, Alzheimer's, Parkinson's, et cetera, amyloid generation tau. So the researchers thought, hmm, what if we can interact and interrupt the interaction between? 1433 and hexokinase. If we can prevent these things from clumping, would that be good for the brain? Long story short, it is. But then they thought, OK, are there tools already available to us that just might happen to hit this? So they do what's called a hypothesis naive screen of available drugs. So they just go to like all the FDA drugs and say, hey, is there anything here that we would predict would interrupt this interaction? Is that amib popped out? It was the only cholesterol lowering drug to pop out and across the blood by barrier, which is really interesting. So then they did a series of studies in human cell models

• 37:20Speaker 01

  and showed that azetimib does indeed interrupt the interaction between these hexokinase and 1433 and that the downstream effects are a massive decrease in amyloid, decrease in phosphatow, also relevant in Alzheimer's disease, and a 40% increase in autophagy, cellular recycling. So potentially, several mechanisms by which it could improve Alzheimer's disease risk, completely independent of cholesterol. This is a cholesterol coincidence, you could call it. Again, just not putting azetimib in just like one bucket. And then they also did an analysis of like patient cases. This wasn't a controlled trial or anything, but found, and I couldn't believe it when I read it, an eightfold risk reduction of Alzheimer's disease in those taking azetimib. So that's on an RCT.

• 38:05Speaker 01

  You know, that is not saying azetimib is proven to lower Alzheimer's risk. But when you have a very coherent biological story and an effect size of that size, like that magnitude, it's like, wow. And so the medication I mentioned that my mom will be starting after reading this, like, we're concerned about Alzheimer's in my family. I was on azetimib. The reason I stopped taking was some diarrhea, which is not uncommon side effects, not dangerous, just unpleasant.

• 38:30Dr. Darshan Shah?

  Right.

• 38:30Speaker 01

  But I was like, wow, like this is potentially a neuroprotective drug. And then that calculus of like individual risk benefit analysis comes to the picture. And we never have all the data. Medicine is an art of making hard decisions with imperfect or incomplete data. But I would say, given potential neuroprotective effects and given that it's pretty safe, even independent of cholesterol, it's something that I would take. And I'm going to retry it at a lower dose.

• 38:55Dr. Darshan Shah?

  Yeah.

• 38:56Speaker 01

  I started at 10mg and I just, I have a very sensitive stomach. In my GI history, I have a history of inflammatory bowel disease and I think some visceral hypersensitivity from that. But for that reason alone, like completely cholesterol independent, it's a very interesting drug.

• 39:08Dr. Darshan Shah?

  You know, I think about The traditional kind of decision-making tree about which drug to prescribe when someone has high cholesterol, first thing you should do, obviously, is also address metabolic disease, get a coronary calcium score, see if it's actually causing plaque accumulation. But say you don't do that, right?

• 39:27Speaker 01

  Yeah.

• 39:28Dr. Darshan Shah?

  But the traditional medical establishment goes straight towards statins like a freight train.

• 39:32Speaker 01

  Yeah.

• 39:33Dr. Darshan Shah?

  And Zetia is only prescribed after doing like some sterol testing, right? A lot of times.

• 39:39Speaker 01

  Or as an adjunct in dual therapy. So like, oh, we want to get your LDL even lower, we'll just give you this additional drug.

• 39:44Dr. Darshan Shah?

  Right, right. So why isn't it the opposite? Why not go to Zetia first? See how much lowering you get?

• 39:51Speaker 01

  Yeah.

• 39:51Dr. Darshan Shah?

  Because there are less side effects, for sure, with Zetia.

• 39:54Speaker 01

  I would say the answer you're typically gonna get, well, the two answers. The one boring answer is statins for your average person, lower LDL more. As we said, that's not the full picture. The other answer you get, which is probably a stronger answer in one aspect and a weaker answer in another, is, well, the preponderance of evidence, you'll hear this term a lot in academia, like, the balance of evidence overwhelmingly supports statins for risk reduction. So there are trials showing decreases in like actual hard outcomes, cardiovascular events. But this brings us back to the topic we discussed earlier of like incentive structure and the way we do research. The fact of the matter is, that is a historical argument, it is not a biological one.

• 40:37Speaker 01

  The studies have been done, so the data are there. And honestly, now it's hard to do randomized control trials, especially, you know, for like monotherapy of these medications, because typically it's considered not ethical to not give people statins because of the historical data. I'm not for that rationale, but it actually is more of like a, well, we've already like shown the spotlight really heavily here, so we have the data, so we're gonna give you the thing that's quote-unquote proven, rather than taking a beat and thinking, okay, let's not take like quote-unquote the preponderance of evidence and just think rationally, from a biological perspective and risk-benefit analysis in this person, what's gonna have the most net effect?

• 41:19Speaker 01

  And you know, when you're seeing a specialist that almost never gets done, like take, I mean, cardiology, your cardiologist is going to care about your heart.

• 41:25Dr. Darshan Shah?

  Yeah.

• 41:26Speaker 01

  And that is always where the discussion is focused rather than the broader picture. Actually, forgive me another sidebar, but we're going to talk about PCSK9.

• 41:33Dr. Darshan Shah?

  Yes.

• 41:33Speaker 01

  I was looking at some of the data on mortality, so all cause mortality. So we have death from cardiovascular disease. Okay, you don't want to die of cardiovascular disease, but really, you don't want to die.

• 41:44Dr. Darshan Shah?

  Die.

• 41:44Speaker 01

  It kind of matters more. So the question arises, well, if you have someone who has a mutation in their genetics to massively lower their LDL and cardiovascular disease is a leading killer, put two and two together, wouldn't you think populations with those mutations would live longer?

• 42:00Dr. Darshan Shah?

  Yeah.

• 42:01Speaker 01

  You would think so, they don't. And then the party line answer you're going to get is, well, the studies aren't powered enough. But if that were the case, you would at least expect a trend in one direction. So where does the trend actually look? If you look at people with very low activity in PCSK9, leading to very low LDL levels, cardiovascular mortality is much better. Is overall mortality? No. Where's the trend? If anything, towards increased mortality. There's one study with an odds ratio of 1.08 with one being neutral. I can send you the forest plot that is not wrapped into a circle.

• 42:32Dr. Darshan Shah?

  Yeah.

• 42:32Speaker 01

  But it just raises this question about trade offs in medications in general.

• 42:38Dr. Darshan Shah?

  Yeah.

• 42:38Speaker 01

  There might be something with cancer there, but it's not even about the specifics. It's just about like, we are so keyhole focused on a biomarker or one system that often you miss the bigger picture.

• 42:50Dr. Darshan Shah?

  Yeah, I mean, it's concerning, right? Because you know, here we are trying to lower LDL as much as possible. And I do want to talk to you about like this whole concept of the lower the LDL number, the better, right? I mean, is that, is that true? Or how do you use it? Like, why don't we just lower everyone's LDL to zero?

• 43:08Speaker 01

  I know. I sometimes feel like we're playing cholesterol Uno. There was a study that came out and there was like, people with low, quote unquote, optimal LDL still had heart disease. And a lot of people were like, well, it's not low enough. The mean was 57. I'm like, that's your excuse? So what do you want at 40, 30? We're literally playing cholesterol Uno, trying to just like slap it down the cards. And that, that tagline, that Mantra, lower LDL is better is such nonsense propaganda. Because what it's really saying is lower LDL in Apple B is better for cardiovascular risk. All else being equal, if we could snap our fingers and lower this one biomarker without thinking about any other organ systems or the side effects of the interventions that lower the LDL. So to go back to the analogy from earlier, lower oxygen is better for fire risk.

• 43:52Speaker 01

  You don't want to be in an environment with oxygen at zero.

• 43:55Dr. Darshan Shah?

  Right.

• 43:57Speaker 01

  So, no, I think lower LDL, like it is medical propaganda masquerading as evidence-based medicine.

• 44:04Dr. Darshan Shah?

  Sure, sure. You know, and I, I look at kind of like some of the newer drugs coming out.

• 44:08Speaker 01

  Yeah.

• 44:08Dr. Darshan Shah?

  Like the mRNA drugs that will just completely knock out genes and create a situation.

• 44:13Speaker 01

  Well, the mRNA drug won't knock out a gene, but like if you like CRISPR somebody.

• 44:16Dr. Darshan Shah?

  Sorry, sorry. I'm talking about, yeah, but the mRNA drugs that they're developing now for LP little A, which is like one dose.

• 44:22Speaker 01

  Yeah. And, and crushes levels like 99%.

• 44:24Dr. Darshan Shah?

  Right.

• 44:25Speaker 01

  And some of the trial, like 97 to 99%. I mean, I'm not anti-pharma. Like, I love innovation. Like, go for it. Just bear in mind, there might be other effects. These tools might have utility for sure. And I think LP little A, we can talk about it. I think it's concerning. So like, I am very for these being innovated. Just bear in mind, there's a lot of data we need.

• 44:44Dr. Darshan Shah?

  One of the other effects, right? And does it actually lead to?

• 44:47Speaker 01

  Improvement in outcome.

• 44:48Dr. Darshan Shah?

  Right, exactly. Improvement in outcome, lower all-cause mortality. Because just like BCSK9 inhibitors, if your mortality rate is the same or higher.

• 44:56Speaker 01

  Yeah.

• 44:56Dr. Darshan Shah?

  Does it really matter?

• 44:57Speaker 01

  Yeah. Yeah, that's true. So we talked about azetimibe, Zetia. We talked about statins. Should we hit on what? Bempedoic acid?

• 45:03Dr. Darshan Shah?

  Let's talk about Bempedoic acid next, yes.

• 45:05Speaker 01

  Yeah, this is a new one. Also has some really cool new data. It's kind of like a statin in that it inhibits the cholesterol synthesis.

• 45:10Dr. Darshan Shah?

  What's the trade name of it?

• 45:12Speaker 01

  Uh, Nexetol, right? And the advantage, though, is thought to be it's liver-specific. So where statins go throughout the body. This is gonna be a plot twist in the story, but generally, the way bempedoic acid inhibits cholesterol synthesis is it gets activated in the liver first by an enzyme that's in the liver. So you're not, say, affecting muscle physiology. At least that's the thought. So it has your off-target effects. I've tried it. Bempedoic acid may lower my LDL by 28%. I had no notable side effects. I have on statins, including like increases in muscle damage markers, physical performance. I actually did an RCT on myself. We can talk about that later. It was harder to do than you think. It's harder to blind myself than I thought.

• 45:52Speaker 01

  But that aside, this is another case where medicine gets humbled because we put something in a box and it doesn't work like that. So a paper that's actually going to print, it hasn't yet, may, also in cell metabolism, showed that the pro-drug form, so the quote-unquote inactive form, everybody's like, oh, this is an inactive drug, has biological activity. It's what called a PPAR alpha activator. In this case, probably something good. PPAR alpha is a transcription factor that controls lots of elements of metabolism, generally activating it will have more positive effects, including, let's relate to Alzheimer's again, skewing the processing of amyloid, particularly amyloid precursor protein, to a neuroprotective pathway, the non-amylogenic pathway.

• 46:34Speaker 01

  So it's a little bit of a catch-22 here, because on the one hand, I'm saying, hey, medicine was like, this is liver-specific. You don't have to worry about other organs. Now we're like, wait, no, it's affecting other organs. However, the only mechanism I'm aware of by which it would affect other organs is more likely to have benefit than harm, including potentially for Alzheimer's risk. So that becomes a complicated calculus, because you have to be humble about what we don't yet know. At the same time, based on what we do know, I'll just, I'll make this self-focus. If I had to choose between statin and bempedoic acid, I go bempedoic acid all the way.

• 47:07Dr. Darshan Shah?

  Bempedoic acid, Zetia versus a statin.

• 47:10Speaker 01

  I would, yeah, so I'm teasing upcoming content, but I may try to recommence azetimibe and bempedoic acid, completely independent of cholesterol. Just because I'm like, from what I know, there might be a gamble for better brain health. And I happen to know I'm aptly for homozygote, which means I'm very high risk of Alzheimer's. So I have a whole Alzheimer's prevention, like, protocol and cocktail that I put together and I'm not, you know.

• 47:36Dr. Darshan Shah?

  Is this coming up in an upcoming video?

• 47:38Speaker 01

  I'll, I'll, I'll put it out in the letter.

• 47:40Dr. Darshan Shah?

  Okay, great.

• 47:41Speaker 01

  But yeah.

• 47:41Dr. Darshan Shah?

  Sounds like another third episode for us.

• 47:43Speaker 01

  For sure. I mean, I can tell you what the things are.

• 47:45Dr. Darshan Shah?

  I would love to, yeah.

• 47:46Speaker 01

  I'll, I'll blaze through them. I'll have content on it, but microdose lithium orate, five milligrams, lyso-phosphatidylcholine DHA. It's a form of omega-3 that has particular access to the brain and enriches brain DHA levels much more, boosts B and A and F. Potent, so I'm not supplementing yet with nicotinamide riboside or nicotinamide mononucleotide, but one of those at one gram after I'm 40. Basically, what has been recently shown is that in Alzheimer's disease, what predicts quote unquote cognitive resilience is levels of this molecule, NAD.

• 48:18Dr. Darshan Shah?

  Sure.

• 48:18Speaker 01

  Even people with high amyloid, if their NAD is high, that they tend to have good cognition. So that's an important thing to kind of keep elevated as we age, which you can do through exercise, aerobic and resistance, like VO2 max, muscle mass, correlate with NAD levels in the body, but also you can supplement. So in like placebo, in, in, in human controlled trials, one gram of either NMN or NR, you can take either will about double NAD levels in about two weeks. So.

• 48:45Dr. Darshan Shah?

  I think it's important to take those too, because NAD supplements themselves don't, are not well absorbed into the cell, into the cell, into the mitochondria. So nicotinamide riboside, which is tru niagen or NMN, which, is that still on FDA restriction?

• 49:00Speaker 01

  Or is. Oh, I'm not sure. I know tru niagen was used in the, there was a new study that came out that was a controlled trial showing this doubling effect and tru niagen was the one supplement they used.

• 49:08Dr. Darshan Shah?

  Right.

• 49:08Speaker 01

  I'll put all the brands out when I drop this letter, but, um, so lithium orate, five milligrams. I use pure encapsulations, no affiliations, just reputable. Lyso-phosphatidylcholine DHA, I use something called like Centrate Omega Max. I do have an affiliation with that company.

• 49:22Dr. Darshan Shah?

  What is that one?

• 49:23Speaker 01

  It is the lyso-phosphatidylcholine DHA. It's actually, it's expensive, but it's very hard to synthesize and concentrate. You can also get that molecule naturally through like critical oil, although that just is expensive, or Fisro, which is people like, oh, the supplement's expensive. Like Fisro is expensive.

• 49:36Dr. Darshan Shah?

  Yeah.

• 49:37Speaker 01

  Anyway, that, that's an expensive supplement, but for somebody at high risk for Alzheimer's, it's something to consider, NAD boosting supplements, and then yeah, Bempedoic acid and azetimibe.

• 49:45Dr. Darshan Shah?

  Oh.

• 49:45Speaker 01

  Those five together, I mean, there's some pretty interesting data and I'll, I already have letters on each of those things, but I can kind of do a synthesis and then draw out all the pathways, doing the sketches, but. That's currently what my protocol would be. Obviously, as new data emerge, it'll evolve. Like the memedoc acid study, it's now February 2026. It's going to print in May 2026. The Zetamib data are new, so like, these things should evolve in real time.

• 50:09Dr. Darshan Shah?

  Sure.

• 50:09Speaker 01

  But that's at high level where I am now. Of course, with the fundamentals like sleep and exercise, you can't beat that.

• 50:14Dr. Darshan Shah?

  Of course, of course. Let's talk about PCSK9 inhibitors a little bit more.

• 50:19Speaker 01

  Yeah.

• 50:19Dr. Darshan Shah?

  These are definitely much more expensive. They're injectable medications, so.

• 50:23Speaker 01

  Mostly. There's now a cyclopeptide that's coming out. I don't think it's hitting the market, but they're doing it oral.

• 50:28Dr. Darshan Shah?

  Okay, great.

• 50:29Speaker 01

  It's about out.

• 50:29Dr. Darshan Shah?

  And would that also be like a weekly or a?

• 50:32Speaker 01

  I think it will be a daily. Don't quote me on that. I think it's just gone completed phase three trials, if I'm correct. But there will be an oral form, but it is not out on market yet.

• 50:41Dr. Darshan Shah?

  Okay. So, you know, when you look at PCSK9 inhibitors, who are they best suited for? What are the pros and cons of them?

• 50:47Speaker 01

  I would say the main cons are, is your insurance going to cover it slash expense? And the fact that currently, right now, they're injectables. But let's compare it to a statin. Statins can cross into the brain, might have, at least for like healthy people. I will be concerned about some of the effects on mitochondrial function. PCSK9 inhibitors, the injectables are monoclonal antibodies. They're huge. They're massive. Molecular speaking, they're not getting into the brain. So you don't have to worry about that. At least I don't think. There also, there's like no PCSK9 expression or very minimal in muscle. So they're not going to affect your muscle, not going to negatively impact insulin resistance. Speaking of LP delay, statins increase LP delay on average. PCSK9 lowers them. So if you're a part of the, you know, quarter of people who has elevated LP delay.

• 51:28Speaker 01

  Another advantage of a PCSK9 is going to be LP delay lowering relative to statins, which tend to increase them, as I said, being redundant now. So yeah, I think those will be the main things. And then actually, it's more potent at lowering LDL and APOB. It's basically the strongest drug for doing that at present.

• 51:45Dr. Darshan Shah?

  And the side effect profile of a PCSK9 inhibitor versus a statin?

• 51:49Speaker 01

  I would say lower on the PCSK9 inhibitor.

• 51:50Dr. Darshan Shah?

  Definitely, definitely.

• 51:56Dr. Darshan Shah?

  Hi, Dr. Shaw here. I want to take a minute to talk to you about cellular health. So in my clinics, I've actually seen 30-year-old people with cells that look like they're pushing retirement. And I've also seen 60-year-olds with cells that look like they're 40 years old. So what's the difference? It's really about how fast their telomeres are breaking down. Your cells, you see, are like phones, and they have limited cellphone battery. Poor sleep, stress, processed foods, all of these things can drain that battery way faster than it should. So this is the reason why I partnered with IM8. IM8 powers that cellular battery. It's not just another multivitamin. It's a comprehensive 92-ingredient formula designed specifically for cellular health and longevity.

• 52:41Dr. Darshan Shah?

  I'm talking 900 milligrams of vitamin C. That's like 20 oranges worth of DNA protection. The clinical dose of CoQ10 that you need to power your cellular engine. You also get zinc, selenium, vitamin E, alpha lipoic acid. All of these work synergistically for cellular repair and protecting your telomeres. So instead of taking a handful of pills every day and all these supplements, IM8 actually gives you everything that you need in one scientifically formulated system. And this isn't just a theory anymore. IM8 had partnered with Oxford University, the International Space Station, San Francisco Research Institute, and they've done studies, and they've gotten this NSF certified to truly power your health.

• 53:23Dr. Darshan Shah?

  Most people are aging twice as fast as they should, unfortunately. You don't have to be one of them. Try IM8. I actually have a discount secured for you if you go to drshah.com/Im8 or go to im8health.com/discount/DrShah and you can get 20% off with my discount code, DrShah. You can also find the link below.

• 53:46Dr. Darshan Shah?

  And then let's talk about another one that I don't think I've heard you talk about this before is low dose cholesterine.

• 53:51Speaker 01

  I will defer conversation on that. It is on my to read list. My to read list is very long, but I would like to form a more informed opinion before I speak on that.

• 54:02Dr. Darshan Shah?

  Right.

• 54:02Speaker 01

  So for round three.

• 54:04Dr. Darshan Shah?

  I respect you saying that because I do think that there might be a role for it also in your anti Alzheimer's protocol.

• 54:10Speaker 01

  Oh, really?

• 54:11Dr. Darshan Shah?

  Yeah, because it's an inflammation lowering agent and inflammation is also a key contributor to Alzheimer's. So I'm interested.

• 54:17Speaker 01

  I will definitely, I promise to dig into it for sure.

• 54:21Dr. Darshan Shah?

  Fantastic. Okay. So moving on to just big picture now, you know, we have this beautiful picture you've painted of all the options out there for lowering LDL cholesterol. Okay. I also want to like bring this to something I talk about a lot in my podcast, which is ApoB levels, right? So I'm convincing my audience, follow ApoB. Don't just be hyper focused on LDL, especially when you're bringing therapeutics into the equation. Right? So what is your feeling on looking at ApoB versus LDL, especially vis a vis, you know, treatments?

• 54:57Speaker 01

  I mean, a simple analogy would be like looking at your weight or BMI versus body comp.

• 55:02Dr. Darshan Shah?

  Right.

• 55:02Speaker 01

  So the reason I use this analogy is for most people, they're going to track more or less. But if you had to choose one, body comp is going to be better. So ApoB is going to be a better marker. Just to describe what it is briefly, it's like LDL is a lipoprotein particle that circulates around. Every LDL has one, what's called ApoB, apple lipoprotein on it. So it's a one to one ratio of LDL particles to ApoB. ApoB is also one of the things like LPD, the LDL. So it gives you a better picture of circulating particle count, which is more relevant in disease than the cholesterol fraction of your LDL. So yes, ApoB better than LDL cholesterol. I don't even think that's controversial right now.

• 55:44Speaker 01

  It's just a matter of like, like BMI. Most people know their weight and BMI and everybody knows their body comp. So it's what data is available to you. But for most people, they're going to track pretty similar. Like my LDL is pretty astronomical at present. It's peaked at 574.

• 56:01Dr. Darshan Shah?

  Oh, do you have familial hypocholesterolemia?

• 56:03Speaker 01

  No.

• 56:04Dr. Darshan Shah?

  No?

• 56:04Speaker 01

  My baseline LDL when I'm not carbohydrate restricted is around 90. So it's not that. It has to do with energy trafficking in my body. So I can manipulate it like in days and weeks.

• 56:17Dr. Darshan Shah?

  Yeah.

• 56:17Speaker 01

  Lifestyle change.

• 56:18Dr. Darshan Shah?

  You did with Oreos, right?

• 56:19Speaker 01

  I did with Oreos.

• 56:20Dr. Darshan Shah?

  Yeah, tell us about that.

• 56:21Speaker 01

  Yeah, yeah. So let me frame this by saying, we learn the most by studying the outlier. This is not something that works for everyone, but it is relevant to everyone in terms of learning.

• 56:32Dr. Darshan Shah?

  Right.

• 56:32Speaker 01

  So I am an outlier in many respects. One of the ways I'm an outlier is just how high my cholesterol is and also the reason why it's high. The reason why it's high is because, and I won't go into the full lipid energy model, but basically, if you're very lean, insulin sensitive, and you go very low carb, this is independent of saturated fat and fiber. But your body is going to change its energy trafficking and fuel utilization system to really boost fat fuel trafficking, which does involve cholesterol containing particles, which is why my cholesterol goes through the roof when I'm low carb. Let's be clear, I've done this like vegan keto. So like this isn't, you know, your standard genetics. This isn't your standard saturated fat fiber. It's independent of all of that.

• 57:17Speaker 01

  But if this is the mechanism, one would predict, well, if you add carbs back into the system, it reduces the driving force that's increasing the cholesterol in the first place. So it leads to provocative hypothesis, if I add carbs in any form, including a pure addition of Oreos, I'm not swapping it out for something fatty in my diet. If I add Oreos onto my diet, what happens to my cholesterol? I did do a controlled crossover experiment. I published it. If people go to PubMed, type in Oreo versus statin, it will come up. And the Oreos in 16 days lowered my LDL by 71%.

• 57:48Dr. Darshan Shah?

  Yeah, yeah. But just to be clear, that's because of your specific scenario because of, what is this condition? Not condition.

• 57:55Speaker 01

  Lean mass hyper responders.

• 57:57Dr. Darshan Shah?

  Lean mass hyper response.

• 57:58Speaker 01

  Yeah, my friend Dave Feldman identified this category of people back in 2017. And it's just kind of taken off because there are, you know, thousands, if not tens of thousands of people like me.

• 58:07Dr. Darshan Shah?

  Yeah.

• 58:08Speaker 01

  Yes, to be clear, your average person will not be able to lower their cholesterol with Oreo cookies. Nor does this experiment actually place any judgment on Oreos, statins, or LDL. It is just a provocative observation explicitly for that purpose because while your average person can't lower LDL with cholesterol, we are all in some way, shape or form biologically unique.

• 58:30Speaker 01

  And what I mean to demonstrate by doing things like that is highlight, hey, if you understand your unique physiology or understand it with your doctor, your doctor understands it, you can have remarkable effects by doing things nobody would have otherwise thought of.

• 58:45Dr. Darshan Shah?

  Right.

• 58:45Speaker 01

  Or even like, let's talk about like ezetimibe versus statins. Like, there are some people, if you understand what's going on with their physiology, ezetimibe might be way more potent at lowering LDL and ApoB. And so it's just about understanding individual context and not applying like population averages to an individual.

• 59:01Dr. Darshan Shah?

  Yeah.

• 59:01Speaker 01

  And, you know, things like that, the OREO versus statin study, they're a great stimulus for like, starting a conversation, and then, you know, bring people to have the nuanced discussion if they're still hanging on here, they'll know what we're talking about.

• 59:12Dr. Darshan Shah?

  Yeah, yeah. So let's bring it back to the individual now. Let's say the listener of this podcast just went to his primary care doctor, LDL is 200, really high, and the doctor wrote a prescription for a statin, and no other discussion was brought up, no other medications were brought up, no other testing was brought up. How should that person rethink what should be the next steps?

• 59:36Speaker 01

  Well, I think, obviously, there should be a general, a risk assessment beyond the LDL. So questions to ask are, do you have a family history? Probably even better than getting like genetic testing. Like, if you have like, you know, grandparents that all died of cardiovascular disease at 50, that's relevant. So, you know, family history is one element. What are your other risk factors? Have you gotten, say, a fasting insulin? Do you have diabetes or prediabetes? Do you have obesity? High blood pressure? These are all variables that can interact.

• 1:00:04Dr. Darshan Shah?

  Right.

• 1:00:05Speaker 01

  With your LDL. And then, probably best of all, is some cardiac imaging.

• 1:00:10Dr. Darshan Shah?

  Exactly.

• 1:00:10Speaker 01

  A basic coronary artery calcium scan will give you a lot of information. So, let's imagine this patient is at least 40. If your coronary artery calcium scan is zero, it's probably an indication that it's, it should be reassuring.

• 1:00:23Dr. Darshan Shah?

  Right.

• 1:00:23Speaker 01

  It doesn't, it shouldn't be like, oh, now I don't have to worry about anything. But it should be reassuring, and maybe triage you down a less aggressive path. At that point, the question becomes, okay, do I want to act? Do I want to monitor and follow up? So say you have no other risk factors, your calcium score is zero. I think it's a reasonable thing to say, hey, let's check this in five years, see if it's progression. Obviously, this is not medical advice, but I think it's just a reasonable thing to do.

• 1:00:47Dr. Darshan Shah?

  Right.

• 1:00:48Speaker 01

  And then if you decide you want to act on this, the question becomes, what are my options? Obviously, diet and lifestyle. Let's assume we're going past that and you're going to go with pharmacotherapy. We've talked about a bunch of options and the pros and cons. So, you know, do you have high LP to delay? If so, maybe you want to go with a PCAS kinase inhibitor because you're going to get additional benefit there. Now, we are having a biological conversation here. I realize like insurance and everything comes into the picture, so it's a whole other kettle of fish. But let's just say you could get any of these medications. Or azetimibe, generally benign. You know, we could see, like you said, what is going to be the impact and effect size? And maybe you're getting a little bit of neuroprotection there, possibly. Lower side effects. And then Bempedoic acid, that's typically a harder one to get. You're probably going to have to quote unquote fail a statin first.

• 1:01:33Speaker 01

  But, you know, just to point out, there are other options in this category of pharmacotherapy for lowering LDL. And nutraceuticals, things like berberine. And, you know, one trial, I think it was, if I recall correctly, Nature Medicine 2004, where they were showing that berberine, which it's like you can get over at a counter, it's a supplement, can lower LDL as much as 25%. The mechanism is actually really fascinating. Basically, the, we talked about LDL receptors, like this is a convergent mechanism. What it does is the instructions to make the LDL receptor in the liver, let's call them the blueprint, the mRNA blueprint. Generally, the cell just like chops them up after an hour or so, and it triples the lifespan of the LDL receptor blueprint. It stabilizes the blueprint.

• 1:02:15Speaker 01

  So it's like, if you had a construction line, you imagine, I had this blueprint for an hour, I'm going to make as many LDL receptors as I can based on this blueprint for an hour. Let's just say you had the blueprint for three more hours, you can just make more receptor.

• 1:02:25Dr. Darshan Shah?

  And berberine does that.

• 1:02:26Speaker 01

  Berberine does that. I can send you there. It's fascinating.

• 1:02:29Dr. Darshan Shah?

  That's fascinating.

• 1:02:30Speaker 01

  It's very cool. And the effect size is going to be quite, like 25% reduction is not like, oh, you got a little blip. So, again, it's like, is that the be all, end all? No, but it also can have other benefits in terms of like glycemic control. So it's like, this is something you can try.

• 1:02:45Dr. Darshan Shah?

  Yeah.

• 1:02:46Speaker 01

  And then you can also piece these things together. Like maybe azetimibe and berberine together have a larger effect than a statin, wouldn't you? So these are all pretty close.

• 1:02:54Dr. Darshan Shah?

  What about nattokinase, speaking of nutraceuticals?

• 1:02:55Speaker 01

  It's very... Cool supplement.

• 1:02:58Dr. Darshan Shah?

  Yeah.

• 1:02:59Speaker 01

  You know, the data are mixed, but I would say high dose nattokinase has been shown in at least some studies to cause regression of atherosclerosis. So one study found, I'm trying to remember the age.

• 1:03:09Dr. Darshan Shah?

  10,800, I think.

• 1:03:10Speaker 01

  It was 10,800 fibrinic units and I think the reduction was something like 21.7%.

• 1:03:16Dr. Darshan Shah?

  In plaque?

• 1:03:17Speaker 01

  In carotid intima media thickness. So they did an ultrasound of the carotids and they looked at the thickness and also the plaque area and there were regressions in both. How it works, nattokinase, it does several things. It's anti-inflammatory and it also lowers blood pressure. It actually is like, you know, whether it's pharmacotherapy or natural supplements, there's often convergent mechanisms. It acts what's like called an ACE inhibitor, which is a very common like class of drugs. So there's a bunch of different mechanisms by which nattokinase would work and it's been shown at least in for blood pressure in like placebo-controlled trials to lower blood pressure by a reasonable degree. So biological mechanism, some studies showing regression of plaque. And again, like I can't think of any downside.

• 1:03:58Dr. Darshan Shah?

  No.

• 1:03:58Speaker 01

  I will say that some of the studies found negative results. I think a lot of the studies underdose. They use it like 2,000 fibrinic units. So I say if you're going to do it, yeah, something like 8,000, 10,000. And there's like no toxicity. I mean, toxicity doses in RAS or something at like the human equivalent of like 14 million or something for brinolytic units.

• 1:04:16Dr. Darshan Shah?

  It's such an interesting option that just, to me, just got brought to light like in the last couple of years.

• 1:04:21Speaker 01

  Yeah, no, I think it has huge potential. And of course, you can just eat natto if you want that. Vitamin K2 as well. But this is the kind of thing that's been around in like, I think, Japanese culture for thousands of years.

• 1:04:31Dr. Darshan Shah?

  Thousands of years.

• 1:04:32Speaker 01

  So you just kind of like rediscover the potential biological utility. But bottom line is like the universe of options for compounds, we've gone over to like just a few, TUDCA, nattokinase, you know, berberine, that could improve cardiovascular health that are totally not prescription, is massive. You just need to kind of like learn about them and figure out what's best for you and then experiment on yourself.

• 1:04:53Dr. Darshan Shah?

  Yeah.

• 1:04:54Speaker 01

  In a safe way, of course.

• 1:04:55Dr. Darshan Shah?

  It's fantastic. It's, I think people, after listening to this podcast, will have so many more options, a new way of thinking of high cholesterol, high LDL. And, you know, I really appreciate you bringing. Such a high degree of scrutiny of the science to the conversation because you're right, there's a lot of, you know, not just misinterpretation, but also misrepresentation of what these studies are showing.

• 1:05:18Speaker 01

  Yeah.

• 1:05:18Dr. Darshan Shah?

  And it's really great to have your perspective kind of shift the way we look at what's being put out there by the media and also by the people talking about it into what's really being said.

• 1:05:29Speaker 01

  Yeah. Would you mind if I reflect and vent to you a little bit?

• 1:05:33Dr. Darshan Shah?

  I would love to, yeah.

• 1:05:34Speaker 01

  Yeah, so I'm new to being like out here talking. I mean, I graduated medical school in May. Like, this is my rookie year of what's called a content creation. And it's been fascinating, let's call it game to observe. And one of the things I struggle with is keeping things digestible and understandable while still serving people the nuance that like respects their intelligence. And there's an added layer to this that I really struggle with, which is, or let's say I'm trying to be very cognizant of as I evolve my positions, which is whenever you put something out, first of all, like, there is an element of you need some degree of like engagement cloaking to bring people into a deeper conversation.

• 1:06:16Speaker 01

  And then you go into, as Peter will call it, a long, arid dissertation, which is what we've done here, hoping people follow along. But what inevitably happens, because social media is so in-group, out-group, is people make caricatures of your position, either because they can't understand it, or more often, I think, because they haven't really tried, or they're willfully not hearing what you're saying. And so something like me saying, "Not all high LDL requires treatment," gets cast as you're an LDL denier. Me saying, "Hey, statins have these side effects that you're gonna, we should talk about," goes into like your anti-evidence-based medicine. Those things are not compatible. And then, and this is where I like, I really try to audit myself, because I think it's

• 1:07:00Speaker 01

  a very slippery slope, is when someone then creates that caricature and it propagates, two things happen. One, you can start to develop like an extreme group of followers who like you.

• 1:07:10Dr. Darshan Shah?

  Yeah.

• 1:07:11Speaker 01

  And then, but also have an extreme point of view. And then you want to pander to that group. So that is a slippery slope in and of itself. And then there's another element of it where there is this impulse, and I'm sure you felt it, where somebody's created a caricature of you and you feel like you need to defend that caricature for some weird reason. So somebody is like, you know, you're anti statin. I'm like, now I have to defend that position, but I should like, to actually just step back and say, look, that's a caricature you made. That is on you. I'm going to keep on talking about the data as I see it is something that I just don't think enough people who are like in the space either think about or talk about it. And something I want to do in my journey, since I'm just starting with it is like,

• 1:07:56Speaker 01

  be transparent as possible, but the struggles I have as a communicator, because there are things out of my control. Like if I say, here's a, you know, a content on why statins can be harmful. And here's another content on why I said I'm going to be great. I have no control over which one really propagates and then like feeds a caricature. And so to like, step back, audit one's behavior and then be like, am I really representing the data the best that I sincerely believe it, I think is more of a struggle than I would have thought. And I know I'm, I'm hoping going to be doing this for years and decades to come. So it's something that I don't want to lose perspective on, which is why I want like, I'm going out of my way to articulate it more for myself than anything else. No, at this like early stage.

• 1:08:39Dr. Darshan Shah?

  No, that's point well taken. You know, I think it's, it's tough out there because people's attention spans are now 30 seconds or less. And, you know, everything is in sound bites and Instagram clips. And then you get whatever that clip is that propagates, that's you, right?

• 1:08:56Speaker 01

  You're right.

• 1:08:57Dr. Darshan Shah?

  It's, it's crazy. Yeah.

• 1:08:58Speaker 01

  Ever in your Instagram comments, people are like, why didn't you go into this nuance? I'm like, it's a 60 second clip.

• 1:09:03Dr. Darshan Shah?

  Yeah.

• 1:09:04Speaker 01

  That is linking out to long form content.

• 1:09:05Dr. Darshan Shah?

  Yeah.

• 1:09:06Speaker 01

  Like, what do you want? And then you give them the nuanced content. Like, I don't want to read that. That was too long. I just can't win.

• 1:09:11Dr. Darshan Shah?

  I struggle with that all the time.

• 1:09:13Speaker 01

  It's a necessary evil. And I know there is no perfection in the communication. And the best you can do is just like.

• 1:09:20Dr. Darshan Shah?

  Well, I also think the biggest nuance here too, is that I think people should. Know what all their options are and also understand that they're an individual and of one biology.

• 1:09:30Speaker 01

  Yeah.

• 1:09:31Dr. Darshan Shah?

  And just because we have large studies that show you know, on a big randomized controlled trial that for most people, this is what worked and these are the statistics around it. There's still outliers on that bell shaped curve for every, for every study, right? And so you really have to be empowered to know not just what the interventions are, but what are the ways for you to track the results in your own biology? And then you need to start doing it on yourself, right? And so I think, just like you did with the Oreo experiment, you know, like these are end of one experiments that you can do on yourself. Once you're empowered with the information and everyone needs to have the ability to do that.

• 1:10:08Speaker 01

  I also want to emphasize to people that I hope it's not an intimidating process. Cause you have two people here now with like a medical background saying, oh, just like test on yourself and follow these biometrics. It's not like that. It's, you can track whatever is meaningful to you. Whatever outcomes are meaningful to you. It's more about the process of applying the scientific method to your own life. Rather than saying, hey, doctor is going to pass down his omniscient knowledge to fix my problems. Be like, hey, I'm, I'm conducting this ship and it's not a chore, but an absolute pleasure and a privilege that I can lead a life where I'm like, I'm going to tweak these variables progressively and learn on my own body. Like that can be so fun. And then when you embrace that mindset.

• 1:10:49Dr. Darshan Shah?

  Right.

• 1:10:49Speaker 01

  That is the thing that unlocks forever to like an uptrend in health.

• 1:10:52Dr. Darshan Shah?

  Exactly.

• 1:10:53Speaker 01

  Doesn't mean things are going to like solve overnight, but like that it's, it's really a mindset more than anything.

• 1:10:58Dr. Darshan Shah?

  Right.

• 1:10:58Speaker 01

  And that's accessible to everybody.

• 1:11:00Dr. Darshan Shah?

  Yeah. And you might discover things that you never even knew because of the pleiotopic effects of everything, right? And so you might discover that, you know what? This intervention that you thought was going to affect this particular marker actually positively affected you in many other ways.

• 1:11:13Speaker 01

  Yeah, no, no, for sure.

• 1:11:14Dr. Darshan Shah?

  Or negatively, right? It's just.

• 1:11:16Speaker 01

  You learn.

• 1:11:16Dr. Darshan Shah?

  Yeah. And life is long. You have time to learn, hopefully.

• 1:11:20Speaker 01

  Yeah, for sure.

• 1:11:21Dr. Darshan Shah?

  Awesome, man. Well, I think this was such a great conversation. Really appreciate you coming and doing this with me again. And it looks like we're all teed up for episode three.

• 1:11:28Speaker 01

  Oh, and four. I think we didn't even hit on LP delay yet.

• 1:11:31Dr. Darshan Shah?

  Oh, yes. That's a whole other hour, right there.

• 1:11:33Speaker 01

  Well, let me feature one high-yield bit, or a few high-yield bits. It'll take me 20 seconds on LP delay because it's super hot. Waist hip ratio. So this is again, a matter of, are you a population average? So in the general population, this LP delay is a genetically determined, about 90% genetically determined risk factor that tracks with cardiovascular risk. I have a bunch of content that I can send you to send to the audience. But one paper that I found particularly interesting is, what happens when you broke people up by a marker of abdominal fat, which is, in this case, waist hip ratio? This is something you can do right now at home. Like, literally get a piece of string, put it on your waist, put it on your hip, and then ratio those distances. And what they found is that in people with low waist hip ratio,

• 1:12:18Speaker 01

  there was no increased risk.

• 1:12:20Dr. Darshan Shah?

  Of LP delay?

• 1:12:21Speaker 01

  No increased risk.

• 1:12:22Dr. Darshan Shah?

  Wow.

• 1:12:22Speaker 01

  Now, obviously, that needs to be replicated. But yeah, the risk in people with, if you had low waist hip ratio, the rates tracked exactly the same, independent of high versus low LP delay. It's people with a higher waist hip ratio, where there was a divergence, where high LP delay caused additional risk. Again, not the definitive study. But when you put it in the context of this idea of population-based medicine, it actually makes sense because, well, of course, all the studies have been done on people who are generally, have excess abdominal adiposity, because that's just most people.

• 1:12:55Dr. Darshan Shah?

  Most people, right.

• 1:12:55Speaker 01

  And so you start to parse these things, you're like, huh, that's interesting. So, you know, I would just say that there's more to the picture here, and more actionability than people come to believe. So we'll have to table actionability statements for later.

• 1:13:08Dr. Darshan Shah?

  No, that's an interesting piece of data. I think, you know... LP little a, yeah, we just have to do a whole episode on it.

• 1:13:16Speaker 01

  A whole thing.

• 1:13:16Dr. Darshan Shah?

  It's so nuanced. And I've seen, I would say probably a couple hundred people now have come through our clinics with LP little a.

• 1:13:22Speaker 01

  Yeah.

• 1:13:23Dr. Darshan Shah?

  And I've seen people with absolutely zero effect of it. And then I've seen people with massive just aortic calcifications.

• 1:13:30Speaker 01

  Yeah.

• 1:13:30Dr. Darshan Shah?

  You know, like valvular issues and so.

• 1:13:32Speaker 01

  But how it works is so interesting. I mean, like, it's so beyond just like, oh, it's going to stick and seed a plaque. Like, I mean, we, a lot of multi-syllable words, tetrahydrabiopteran and blah, blah, blah, blah, blah. But it gets into arteries and does some freaky things. But when you understand what those freaky things are, you learn, oh, here are things that could potentially diffuse the bomb beyond just waist-to-brace ratio. So we'll have to tease that for another time. You've been more than generous with yours.

• 1:13:54Dr. Darshan Shah?

  Yeah. And what's even more incredible in LP little a is just the therapeutics that are coming out.

• 1:13:59Speaker 01

  Yeah, you mentioned that some of them are pretty potent for lowering. We'll see if it translates into improved outcomes.

• 1:14:03Dr. Darshan Shah?

  Yeah, yeah. But also just as a category, you know, that, that being able to affect mRNA synthesis and create molecules into cellular.

• 1:14:13Speaker 01

  Yeah. Well.

• 1:14:14Dr. Darshan Shah?

  Factory.

• 1:14:15Speaker 01

  That, so that, I mean, that circles back to something we were talking about earlier is where does the spotlight of medicine get placed? Like, when I put my first article out on this topic, you know, it was among my top 10 most popular of like over 200 letters. I'm like, why is the general public really interested in LP the delay? And I think it's getting more spotlight because there are now drugs in top journals that are targeting it.

• 1:14:37Dr. Darshan Shah?

  Oh.

• 1:14:37Speaker 01

  And that, again, is not pointing fingers at anybody. It's just like, this is kind of how the spotlight of medicine works. So now we have drugs for it. Now there's a business model. Now it's getting attention.

• 1:14:45Dr. Darshan Shah?

  Yeah, now let's start talking about it.

• 1:14:47Speaker 01

  Yeah.

• 1:14:47Dr. Darshan Shah?

  Although it's been around since the beginning of humanity.

• 1:14:52Dr. Darshan Shah?

  Well, thank you once again, Nick. This was fantastic. And I really look forward to the next two or three or four episodes.

• 1:14:58Speaker 01

  Absolutely.

• 1:14:59Dr. Darshan Shah?

  Awesome. Thanks.

• 1:15:04Dr. Darshan Shah?

  Top five takeaways from my episode with Dr. Nick Norwitz. Number one, LDL alone doesn't tell the full story. Cholesterol isn't a yes or no risk marker. And it's just that, a risk marker. LDL is part of an overall picture that you need to paint about your cardio metabolic health. And without the metabolic. Context, a high or a low number can be misleading. Number two, ApoB is actually a much more accurate signal of risk. It's not just about how much cholesterol you have. It's about how many of those cholesterol particles are actually a risk to getting plaque. More dangerous particles equals a higher likelihood of arterial damage.

• 1:15:47Dr. Darshan Shah?

  Number three, insulin resistance is also a major hidden driver of cardiac disease. Long before cholesterol looks abnormal, insulin resistance can quietly increase your risk and cause metabolic dysfunction, which is almost always step one or part of the initial steps of getting vascular disease. Number four, you can't assess risk from just blood work alone. Tools like coronary calcium scans and clearly scans and also CT angios can actually measure plaque, giving you a much better picture of real disease, not just potential risk factors. Number five, heart disease prevention is definitely not one size fits all.

• 1:16:29Dr. Darshan Shah?

  As I said at the beginning of this podcast, statins and newer therapies, as well as lifestyle changes, might be the right approaches for some and not for others. Your unique biology, your biomarkers, the status of your metabolic health, your status of inflammation, your blood pressure, all come together to form your particular risk of cardiovascular disease, and we have to look at you as an N of one patient. Thank you so much for listening to the podcast today. Please remember to subscribe if you liked this episode and give us a good review and share a link with your friends. It really helps to support all of our efforts. I also want to remind you that the information shared on this podcast is for educational

• 1:17:10Dr. Darshan Shah?

  purposes only and is not intended to replace professional medical advice, diagnosis, or treatment. Please consult with your healthcare provider or physician before making any decisions or taking any action based on what you hear today, especially if you have any underlying health conditions or on any medications. Your doctor knows your personal health situation the best, and it's always important to seek their guidance.