Statins, GLP-1 & the Metabolism Mystery – What Doctors Aren’t Talking About | Dr. Nick Norwitz

It was a major trial that came out about a year and a half ago, and the punchline is this was a human-controlled trial where they showed very clearly that statins not only increase blood sugar, not only promote insulin resistance and increase insulin, but smash GLP-1 levels down. Now, GLP-1, as you mentioned, it's related to, you know, this big wave of— in this era of weight loss drugs, Ozempic, Wegovy. At the metabolic level, it's kind of ironic that the most profitable drug class in history lowers levels of a hormone that the new probably next most profitable drug class in history is trying to mimic. So I'll let people draw their own conclusions about that one. Now, of course, you kind of super physiologically dose Ozempic, yada yada, but not pointing fingers to say anybody's evil. It's just the incentive structure is very clear. So this is a key example where a very commonly prescribed money-making medication— not saying it's a bad medication, just saying money-making medication— has a negative consequence.

We were talking before we started recording. You just finished med school at Harvard. And you've been talking about some of the challenges that you see within the current kind of medical paradigm, medical model, and a degree of cognitive dissonance. And so I thought it might be interesting to kind of start the conversation today around some of the, some things that you were noticing as you were finishing up your education that I'm sure would probably align with some of the things I was seeing as I was exiting the traditional model about 9 years ago. Yeah, because I think the average person probably doesn't realize what's going on beneath the surface in terms of our current medical system.

Yeah, that is a great topic to probe, a great question, and one that I really want to deal with delicately. And the way I want to frame it up is I'm going to go on a little monologue now. We're going to have a discussion, but by the end of this, my goal is to get people to understand this, that evidence-based care, big quotes there, does not equal the best care. Now, going kind of back to the beginning, I grew up in a medical household. I'm an MD-PhD. My mom's an MD-PhD. My dad's an MD-PhD. Both my siblings are in medicine. Like, I grew up in Western medicine, quote unquote, you know, evidence-based care. And I have the highest respect for the profession, for people who practice medicine. It really is a noble profession. But the way the system is set up, the incentive structures built around it direct the spotlight of focus in particular directions. I came to notice this when I went through my own struggles. So I struggled with inflammatory bowel disease and quote unquote evidence-based medicine. The standard of care that was available because of what randomized controlled trials have been done was insufficient to help me. So I, like many other people, did something that was out of the mainstream. And in my case, a ketogenic diet did save my life. And so that was something that happened as I was finishing up my PhD and starting medical school. And it left me scratching my chin and really framed how I went through medical school because I had to reconcile my personal journey where an intervention that wasn't, quote, evidence-based— I have no RCTs to point you to to say that a ketogenic diet is best for ulcerative colitis— was the only thing that helped me. And so I think what I came to realize, and I think you will definitely appreciate this given your background in medicine, is that the system is set up to provide standard of care based on studies that have been done that have met certain checkboxes. And whether or not those studies get executed is not driven by what's best for patients, but by an economic incentive. And I want to be really clear That is not me pointing the finger and blaming any individual, not blaming physicians or nurses, any healthcare workers, or even for that matter, Big Pharma. Like, it's just doing what we built it to do. It is an institution. It's not evil. It's just built with certain economic incentive structures. And that really governs, um, what research is done, what standard of care, but also what we talk about. And of all the things that we can explore and unpack, I think what we choose to talk about is the most in our control, especially now. And this is why I'm so excited to, you know, be coming out of the closet, so to speak, as a public figure, because we live in an unprecedented time with access to information, with social media, this tool that allows for a bridge between academia and the general public. So while I can't, you know, determine what Pfizer is going to study, I can determine what my audience, and you can determine what your audience is aware of. And in that way, we can start to change the tide of things. And I want to get a little bit more specific. But all that's to say, rather than generating, you know, conspiracy theories about evil Big Pharma or like doctors doing bad things, I think the most productive way to look at it is what are the incentive structures that have gotten us to where we are? And recognizing you know, what are the limitations of what we call evidence-based care? Because it sounds great, but part of it just might be a virtue signal because it doesn't actually mean the best care for your condition. Hopefully some of that landed. I know that was a lot.

No, no. I mean, I think it's important because I too, as a licensed medical provider, I always say, listen, the system is in many ways set up to fail us if we are— if we are looking at it as kind of this narrow-minded perspective of unless there's been a randomized controlled trial, the, the power of your experiment with yourself with diet healing your, your, uh, you know, your IBS is significant, inflammatory bowel disease is significant. And yet I think one of the things that, that pulled me out of that kind of traditional allopathic environment was that I saw in so many instances that when my patients changed their diet, when they managed their stress better, when they, you know, changed a lot of their lifestyle measures, it impacted outcomes so significantly that we were able to get them off of medications. And yet we weren't incentivized to do that. And I appreciate and I value how conscientious you are being about the language you are choosing to utilize. And where we're not pointing fingers and saying it's, you know, it's pharma, it's the medical providers. It is a system that is not per se designed to be a well care system. In many instances, it's designed to keep people on medications and kind of on this straight and narrow path.

Yeah, I mean, it's no secret to you and probably no secret to your audience. Like, when you delve into the metabolic health space, there's a lot of medicine bashing that blends with doctor bashing. And what I want to point out to people, not that I'm saying this is per se engineered by evil Big Pharma, but if you wanted to help out those interests, keep doing that. Because the fact of the matter is, at least from my experience, doctors are just as frustrated with the system as anybody else. You know, I have family, my girlfriend's in medicine, like, she comes home every day talking about, like, how she spent 6 hours on the phone when she also needed to be in the OR. She's a surgeon, just trying to, like, deal with, like, you know, bureaucracy and administration, trying to advocate for patients in a system that is shackling her. And so doctors— the doctors I have, the doctors I know, they're working so hard and they're as irritated with the system as anybody else. But if we fight amongst each other, the general public and physicians— and I know there is a gap of trust— that's only going to perpetuate this, I think, sick care system. So I'm all for outing incentive structures. I'm all for interrogating what's wrong with the system and trying to fix it. But I think the best way to do that is through a unity of, you know, the insiders and the outsiders. So a little bit of a sore point for me, but hopefully that makes sense to people.

No, and I think it's important. I mean, ultimately we have to work together to actually change the system. It is not going to be on the backs of just one group or one individual. Really, it has to be shared decision-making, clinicians and lay public coming together and formulating some changes that will allow us, you know, ultimately to be able to focus more— well, I don't want to say, you know, I feel like in many ways, you know, we have allopathic medicine, which is necessary. There's a lot of emergencies. You mentioned your girlfriend's a surgeon. Emergencies, urgencies, we do a better job than just about anywhere else in the world. It's kind of the preventative and chronic disease management where I see that there are some gaps in care. Gaps in access to care, which is another significant piece in there as well.

Yeah, 100%.

Well, most recently you have been talking about a cell metabolism paper and one that, given our current climate, talking about GLP-1 drugs, which I think are certainly during my lifetime, I can't think of another drug that's probably had a larger imprint or footprint on not only the way that clinicians are treating patients, but also the way that patients are receiving care. And so I thought we could talk maybe about statins first, just from a big picture perspective. It is a big business. Then talk about this paper and then kind of loop in some of the work that's been done in the past. I'm thinking about AKA the Jupiter trial from 2016, which is still when I was still in clinical cardiology, where we're dancing around this topic of medications and their net impact on insulin sensitivity, which is a topic that I know is near and dear to both of our hearts.

Yeah, I definitely want to unpack this. And again, I want to frame it as— or let me put it this way— I want to challenge people to really listen to what I'm saying, because as soon as you say anything negative about statins, generally there's a visceral reaction towards either, yes, this is my confirmation bias, or this person is out of the mainstream, let's attack them. And I can give examples of how that happened recently. But the study in question was published in Cell Metabolism, which is a pretty pretty prestigious scientific journal. And, you know, it's hitting the, you know, news now. Actually, there's a couple legacy media outlets that are going to hit it, but not because it's new news per se. It's because I'm talking about it now. And the reason I'm talking about it with a degree of frustration, it was a major trial that came out about a year and a half ago. So February of 2024. And the punchline is this was a human-controlled trial where they showed very clearly that statins not only increase blood sugar, not only promote insulin resistance and increase insulin, but smash GLP-1 levels down. Now, GLP-1, as you mentioned, it's related to, you know, this big wave of— in this era of weight loss drugs, Ozempic, Wegovy, and this combination agonist like tirzepatide. But, you know, it's all GLP-1-centric, another, you know, multibillion-dollar drug industry. And so at the metabolic level, it's kind of ironic that the most profitable drug class in history lowers levels of a hormone that the new, probably next most profitable drug class in history is trying to mimic. So I'll let people draw their own conclusions about that one. Now, of course, you kind of super physiologically dose Ozempic, yada yada. But point being, To me, it was very strange that at the time this came out, I was in my third year at Harvard Medical School, like spending my days in hospitals, including on like cardiology floors. Not only did this not make national headlines, which quite honestly, I have this little thought experiment in the video. If you replace the headline, statins cut GLP-1 levels in half in humans with the word steak, I bet you that headline would have run if you replace statins with steak. So Thought puzzle. You can agree or disagree, but I thought it was interesting. This didn't hit headlines when it should have, but it also wasn't discussed in Academic Medicine. So when I read this paper, I then went and polled 12 doctors. None of them heard about this. And remember, this is not some dinky nothing. This is a human-controlled trial in a major scientific journal. So how is it that doctors don't know about it? And if doctors don't know about it, they're not telling their patients, which means patients can't have proper informed consent. For starting this medication. And I'm not saying they can't take it. I'm not saying don't take statins. I'm not saying don't take GLP-1s. I'm saying this is the basics of informed consent. And the really alarming thing to me is actually in this trial, they figured out the mechanism. We can delve into that. But then they figured out a very easy solution, which I'm not going to make medical recommendations, but in theory, you could reverse this effect via something you can buy off Amazon pretty cheap. So, so then the question becomes, like, this is a key example of where quote-unquote evidence-based care, because the large-scale RCT hasn't been done, isn't necessarily the best care. And the question I got from a reporter when we were talking about it is like, well, it was a small trial. And I'm like, that's the point. These are robust findings. First of all, a study is not determined as rigorous or not rigorous based on its n-value, the number of participants. It's how it's conducted and what the research question was. This is a rigorous randomized controlled trial with very clear outcomes that were consistent with other literature and provided a mechanism and a solution. So the question becomes, okay, if this holds a lot of promise for patient care, why is there no follow-up? Why? Because nobody wants to pay multimillion dollars to not make money. Not pointing fingers to say anybody's evil. It's just the incentive structure is very clear. So this is a key example where a very commonly prescribed moneymaking medication not saying it's a bad medication, just saying money-making medication has a negative consequence. That negative consequence is very clear and actually can be addressed. But there's no follow-up, no discussion about it in doctors' offices, at least not to my awareness. So this is a scenario where patients just aren't getting the information they need, I think, to make a fully informed decision, not because their doctors are hiding it, but because they don't know. So what's up with that?

From your perspective, when you were asking— I'm assuming you were on a cardiology service. Were people surprised? Were they curious? Or was it more like that, more dismissive, like a degree of cognitive dissonance?

This is the interesting thing. So when I put this out on social media behind my, you know, character avatar— I mean, people don't like really interact with you as a person— there's kickback. And we can talk about that kickback, but it's very visceral and reflective, like people wanting to defend the mainstream. But when you're not in that ecosystem, When you're just an academic standing with another academic, there's no defensiveness. The walls come down. So the answers I got when I polled physicians were— there were 12 people I asked. 7 of them just said they don't know. The other 5 said they didn't know, but they volunteered guesses just because they were curious. They're like, oh, I'll guess. And 4 of those 5 guessed correctly. They guessed, you know, now to think about it, We know statins can promote insulin resistance. So it would actually make sense if that mechanism had something to do with the drop in GLP-1 levels. I'll guess GLP-1 levels go down. And it's like, oh yeah, there's actually human trials later showing that. So the weird thing is when you stop and think about it, it already makes sense based on the other data. It's like not like a one-off, that's a unicorn that's contradicting everything else. It makes sense mechanistically to the point that if you just ask a physician to guess, sounds like 80% of them when they guess, will guess correctly, which itself is interesting. And it wasn't like a, like a guess correctly, oh, now I want to hide this information. It's just one of those things where it's like, you have a busy day, your mind goes different places. The mind just hasn't gone to this question before. And then when it's presented with this question, you open up a new discussion. So behind closed doors, when you're walking around the hospital or like talking to a resident or attending, I don't typically find they're defensive. I find they're curious. Which is how things should be. Social media, though, is very different.

Yeah.

I want to pause and then I want to at some point get to why I think it's different and why that's problematic.

So to give listeners context who may not be aware of, of statin drug therapy, as an example, I pulled some information that I thought might be helpful. Um, here in the United States, and this is as of 2019, I was trying to find more current data, it was saying 35% of Americans were taking some kind of a statin to treat their cholesterol. That was a huge increase from 20— 2009 when only 12% of Americans were taking a statin. And more concerning than that, it was saying across ethnicity, statin use varies wildly even when people are at high risk for heart disease. For example, one 2023 study from JAMA showed that more than 37% of high-risk white participants took statins compared to less than 24% of high-risk Black and Hispanic participants. And across the, across the world, there are 200 million adults worldwide using statins. So this is a significant piece of research that came out that no one was talking about. And as you astutely stated, this is like 18 months ago that this came out.

Yeah. Yeah. And, and so to kind of round out the discussion around this and why it's so difficult to talk about, I then want to talk about like how the media responds. So I put this out, you know, I describe what the controlled trial was, you know, what the data showed, show all the graphs. Now, obviously, my audience likes me, so 99% of positive. But of course, once things get traction, you start to get the quote tweets and the rebuttals. So there are physicians and laypeople chiming in that are more in line with convention trying to shut me down. Now, that's fine. I don't mind that. The interesting thing about literally every rebuttal statement, none of them have addressed the data. They've made general comments. They've thrown shade, been like, well, if someone talks about statins and they don't talk about all these outcome benefits, then, you know, 9 out of 10 of them don't know what they're talking about. I'm like, all right, you drop this after I drop a tweet with several hundred thousand views. This is obviously throwing shade at me. You know, I won't even try to argue that I know what I'm talking about. I think I do. But isn't it a little bit conspicuous that you don't refute the argument I made? And the reason I bring this up is because it's so easy to speak past each other. To see the first part of a tweet or to see how other people are replying and assume, you know, the message that is being communicated. Because at no point did I say people shouldn't take statins. I don't make directives about individual care over social media. That's not appropriate. I didn't say they were bad and say they didn't have benefits. But if you want to have a balanced discussion, which we do not have, it's skewed against brushing these side effects under the rug, then you have to highlight these. And so it's totally fair to say, and here's a trial showing a negative effect. And here's the problem, I think broadly, is that on social media we still have a tendency— or I think the physicians, I'd say the older generation of physicians mostly who choose to be active on social media, are still caught in a kind of paternalistic frame where they think they know better and maybe they do. But what that ends up leading to is very one-sided dogmatic statements. So the one we hear again and again, I'm sure you've heard it, um, is lower is better when people talk about LDL and ApoB. And what people are really saying when they say lower cholesterol, lower LDL, lower ApoB is better, is all things being equal, which they never are in an individual case, if you lower this one marker then cardiovascular outcomes are more likely to be better than not. It doesn't say anything about, well, but what are the effects of the intervention? Because you're not just snapping your fingers and changing one marker. And what are the broader impacts on the health of the individual? And the reason this is a problem, in my opinion, is because while the average person might not know all the RCTs or how to, you know, interpret, you know, histology, they can tell when they're being patronized too. So when people try to vaguely shut things down, like even, you know, quote tweeting my thread about an RCT that shows negative effects of statins very clearly, and they make some vague statement in line with the mainstream, that only galvanizes the general public and excites their mistrust and makes them angrier at the establishment. So the irony is the people pushing publicly for the conventional point of view, or let's say the very conservative point of view, by giving the, you know, non-nuanced hot takes like lower is better. They're the ones that are inspiring most. This is my opinion. They're the ones that are inspiring and perpetuating the counterculture when honestly, and I can tell, I'm not even telling you this as a, I'm not saying I'm an expert clinician. I'm saying I've been in the patient chair a lot. And when a doctor says, hey, this is what we know, this is what we don't know, here are the side effects, you know, and here are the benefits, let's do an individualized, you know, risk-benefit analysis considering all the data we have and your preferences. I trust them so much more. And yeah, I might start a medication that has side effects because the net benefits outweigh the side effects. That is informed care. And I don't know why that's so hard, but I can tell you from experience just trying to communicate about, hey, there's a human randomized controlled trial showing a negative effect of a statin. What the public kickback is. And I think that is interesting to dissect from a, like, psychosocial perspective in addition to just the data.

Well, I also think that on social media, people have— they're easily triggered. That's number one, you know. And I oftentimes will see in your very— generally you have a very kind, thoughtful response to a point. And then, you know, you, like anyone else, can get frustrated and upset with people. But I think so many people, their knee-jerk reaction is they don't read. They read like a sentence and come to a conclusion and fire off a response. And you'll actually encourage people. You'll say, did you read the article? Did you watch the video? Did you actually take the time to read my entire synopsis of this study? And more often than not, it's lack of attention. They get triggered. What I find clinically that's interesting is, you know, 25 years ago when I started in medicine versus now, people are— there's a visceral knee-jerk reaction to have, uh, to draw conjectures immediately. And, you know, whatever, wherever someone's cognitive bias is, that's— they, they stay very rooted in that perspective. And oftentimes, or as you say, stay curious. A lot of people are unwilling to entertain the possibility that what they originally learned might be incorrect. That's the point I'm trying to make.

No, um, a quick tangent because people don't believe it. My only tattoo is a Stay Curious tattoo, so I, I went full send on that one. Um, but put that aside. I wrote like a— I call them on my Substack Nuance Nibbles, where they're just like kind of short thoughts, like 300 words or so. And I wrote one on the data don't challenge your n 1, and it was in response to, um, an audience member's comment saying They're always surprised by my perspective that my, like, my opinions are like Russian nesting dolls. Like, of course there's the thumbnail and the title, and then there's like another level and another level and another level. And often if you dig down into it, my opinions don't match the caricature made of me, which is not just me, that is just general. But what I find so interesting, which maybe isn't general, is people let other people's stories and just studies challenge their personal experience. So I'll give an example, or I'll make it a personal example. A ketogenic diet saved my life from inflammatory bowel disease. I was wasting away with ulcerative colitis. I had no social life. My mind was shot. I went from being very physically fit to incredibly frail, uh, and it saved me. No doubt in my mind. But if someone adopts the opposite diet, so let's say I'm eating very high fat, low carb, mostly animal-based, if somebody thrives on like a low-fat plant-based vegan diet, should I be threatened by that? No. Like, why would I be? Like, my narrative is my narrative. What happened to me is what happened to me. I'm an individual. So if somebody else thrives doing something else, or a study comes out that says, hey, this new fiber is really good for you, or really interesting, and like, you know, I don't love fiber for my stomach. I don't feel threatened by it. It's still interesting. And I think it's bizarre, although very commonplace when you step back to say it's really funny that people feel so threatened by other people's stories and by data that doesn't conform to their experience. And my thing is like, that's totally fine. In fact, that's kind of beautiful when you think about it. So I try to be driven by curiosity. Of course, I'm going to be driven by curiosity with respect to what happened to me. But sometimes interesting data come out and I'll talk about them in a positive light, even if they don't align with what I practice and do. And that's not hypocritical. That is just being, like, interested in the complexity and, you know, beauty of human metabolism and physiology.

Well, I mean, the whole concept of bio-individuality— what works for you may not work for me, may work for 5 other people. And the whole concept of You know, I was trained even as a clinician, and I trained at another big research hospital. I trained at Hopkins, and we were taught that what we believe now would be very different than what we believe 2, 3, 5, 10, 15 years from then. And I think some people just— they become more rigid. They're— whether it's rigid dogmatism or it's their just personal philosophy, a lot of people just really struggle with the fact that we can all respond very differently to the same strategies or metrics. And I think that's really what I hear you speaking to.

Yeah. And what I would say on an optimistic note, not to be doom and gloom, is with the advances we have in technology, I think personalized medicine is going to be the future. Um, I'll get more specific. So right now we were talking about like, what is the hierarchy of evidence? What is quote, gold standard of care? And we talk about randomized controlled trials. Well, fun fact, what of the top 10 grossing drugs, they on average help between 1 in 4 and 1 in 25 people who take them. I can send you the Nature letter where that statistic was published. It was out in, I think, 2015. But the point is, you can run a large-scale, quote unquote, rigorous randomized controlled trial, get statistically significant results, and sell the medication at a huge profit while it actually helps a minority of people. But you can still have that p-value that you need. To publish the paper and get the drug approved. That creates a problem because you could be throwing out, you know, the baby with the bathwater and, you know, the majority might be the baby. But what I see happening in, you know, clinical translational medicine coming towards clinical opportunities is really remarkable. So just because it's on my mind, 2 days ago, I don't know if you know the work of Michael Snyder. He's a researcher at Stanford. It's like the Thanos of PubMed. His H-index is 220. He's publishing in Cell Science, Nature, left and right. My understanding is he was just on Huberman Labs. So that podcast is probably going to drop in a moment. In fact, he's the only person I've ever recommended to Andrew. I'm like, you have to have him on. But what his lab is top class in the world in is something called multi-omics. So multiple ohms, genome, proteome, transcriptome, fecal microbiome, all of this. And what they're doing, and other labs like them are doing, is they're doing deep profiling of the individual. So not just like a CGM curve, but your whole genome, your proteome, your transcriptome, and then using machine learning to figure out really what's going on with you and your body. So the analogy I use in our podcast, and I'll share it here because I think it kind of hammers home the point, is like when you go to the doctor's office, you get a lab test, that's like an 8-year-old doing a doodle on a Post-it note of what looks like you. Now imagine you get tens of thousands of biomarkers, right? That's like a, a 4K or 8K image. But then imagine you do it longitudinally over time, multiple measures. That is the difference between a doodle on a Post-it note and like watching, you know, Avatar in 8K on an IMAX screen. And that's where we're going. And the reason that's so powerful is because that provides insights for personalized care. So I'll give you an example from Professor Snyder himself. If you look at him, he's a lean guy. I would guess his BMI is 22. He has type 2 diabetes.

Wow.

Very unusual. Now, one of the research projects his lab did was to uncover subphenotypes of type 2 diabetes. So actually there are 4 types, about 4 types of type 2 diabetes. So the insulin resistance, obesity-associated, typically diabetes. Specifically, there are kind of like underlying pathology. So there's muscle insulin resistance. Your muscles are resistant to insulin. And I'm gonna It's gonna come somewhere, I promise. Not just a biochemistry lesson. There's liver glucose dysfunction, there's incretin dysfunction, so that's the GLPs, and then there's beta cell dysfunction. So your pancreas is misfiring. And depending on what underlying dominant pathology you have, you're gonna respond to different interventions. So Professor Snyder found out that he has beta cell dysfunction. What that means is his muscles are fine. So whereas most people would say, oh, to improve your glucose tolerance, build up muscle, 'cause that's a good glucose sink, doesn't matter for him. He could weightlift all day, doesn't make a difference. And he's a metformin non-responder, which he knows. But unconventional, not first-line treatments work very well for him. So this is a case where if he just went with first-line, he would not be treated well. But then, and this is where things get exciting, to uncover your subphenotypes, say you have type 2 diabetes or prediabetes, typically need to go through a bunch of advanced testing in a lab that you cannot get in your clinic. So people are going to be like, all right, bummer, like I'll never know this is important. But what they did in this study, and I can share with you, the study was in Nature Biomedical Engineering, I'll do a newsletter on this too, was that they could take a CGM, pop it on people, and then use machine learning to decode from the different curves things that no human eye, no physician eye could decode. But they could see the signature. The machine learning could find the signature in the CGM curve to tell the person based on an at-home CGM read what is their underlying pathology, which is crazy. It's like, you know, in The Matrix when they're looking at like all the, like, you know, zeros and ones and they see like what was the woman in the red dress. It's like that. But you could do this with at-home biomonitoring. And I bring this up because I truly believe 3 to 5 years, this will be clinically accessible. You can have an app on your phone that doesn't just say your blood sugar is high, says your blood sugar is high because specifically it's your beta cells in your pancreas, not your muscles. And that means you should eat this or do this. In fact, he hasn't shared with me the protocol. I mentioned on the podcast he's going to send me the protocol. But based on these different phenotypes, there's going to be different responses to food. So you can actually do an at-home test with your CGM based on your relative responses to potatoes or grapes. To figure out your underlying pathology, which to me is cuckoo bananas. It's just so cool.

Yeah, no, that's fascinating. I mean, think about it, having like a very personalized approach to your specific diabetes diagnosis.

Yeah, it's unreal.

It's fascinating. I'm so glad you shared that. I do want to touch back on that cell metabolism research just because I find it really interesting, because my next book is talking about the gut microbiome and what's changing in perimenopause and menopause. So I think this is particularly impactful We know that statins impact the gut microbiome.

Yeah.

And they then impact bile acids. And so this is kind of the pathophysiology of the process of how you get from taking a statin to losing insulin sensitivity.

Yeah. Yeah. So a lot— it makes a lot of sense when you think about it. The microbiome is the interface between the outside world and our bodies. And so when you throw something that is a potent enzyme inhibitor in there, of course things are going to get shaken up. And bile acids, you mentioned that term. People think of them as just helping to digest fat. They are so much cooler than that. So, you know, your body makes bile acids, puts them into the intestine, then your microbiome, the bugs there metabolize them into what are called secondary bile acids. You can think of these as basically your microbiome's hormones or types of hormones because they do then go into the blood and they circulate around. They affect your endothelium, your cardiovascular risk, they cross the blood-brain barrier and bind receptors there. They can even affect depression. Like, there are papers on this, animal model papers, but still, like, this is pretty conserved physiology. So in this case, what they found was that the statin changed levels of certain bacteria and changed levels of a secondary bile acid called UDCA. And what they did in mice and then in humans was they're like, all right, if it's the depletion of UDCA by the statin that's causing the GLP-1 to drop and insulin resistance, What if we just gave back the secondary bile acid? Shouldn't that recover the problem? It did. And by the way, this UDCA is an available medication. It's used for liver disease. So I bring this up again because it's like, okay, I, I never said don't take a statin, but if you're gonna prescribe a statin, it's like giving coenzyme Q with the statin. It's like, okay, there's gonna be these side effects, but we want you to get the benefits in your particular case. Let's maybe supplement you with something else that might be negatively affected. It's not even really polypharmacy. I know people might know that term where you give lots of drugs and they complicate each other. This is more like, no, no, no, we know this is having this effect on this endogenous normally produced compound. So if it's going down, let's just give it back. You know what I mean? It's, it's kind of like if you have hypothyroidism, just give back thyroid hormone. It's not even that complicated. And so what's cool about this study is it actually doesn't just say, it's not scaremongering about statins. It says, oh, here's the mechanism, here's the solution. And that's why this is shocking to me, because it's like— and this wasn't talked about— you could see how this could actually translate into just better patient care. Pro or anti-statin, doesn't matter. This translates into better patient care. Didn't get talked about. Why not? Economic incentives, or let's just say incentives. Not to point fingers, it's just like an observation of clearly what's going on here. So then it becomes interesting. There's this layer of when now you reveal this to the masses don't actually say anything negative per se, other than to just claim, hey, there's Human RCT saying negative side effects, people get automatically defensive. And I'm just going to observe that.

Well, and I think, you know, you bring up a good point. This is not judgment. This is just talking about this is what the data shows and here's a way to address it. And just like when I was prescribing statins, like daily, almost everyone, we talked about CoQ10 because we know statins can deplete that. And in many instances, it either alleviated or improved some of the side effects that we saw, which for most of my patients were things like myalgias or muscle achiness, which is problematic and bothersome.

Yeah, yeah. I have myalgias. I was on 20 mg Crestor for an experiment for 6 weeks, and they were uncomfortable. They weren't like debilitating, but you go to the gym, you're like, this isn't a good way to live life. So, I know. And then there's data on like even in people that are asymptomatic causing mitochondrial dysfunction. I think particularly in complex IV. And now I know what the conventionalists will say. Well, they'll say something to the effect of, well, is that really clinically relevant? And you have to consider the benefits. My bigger thing is like there are the known side effects and there are all the unknown side effects because you don't do a 50-year follow-up phase IV trial or whatever before you approve a drug. And so it really is individual dependent. Let's talk about dementia, for example. I would say the trials on balance say that at a population level, statins don't promote dementia. Maybe they can even protect against it, maybe in particular like vascular dementia. But that is in a broad population with metabolic dysfunction. It doesn't mean that if someone has Alzheimer's vulnerability and is metabolically healthy, the net effect in them might not be a negative consequence. So we can't discard just our basic under— understanding of the physiology and say because there's no proven without a shadow of a doubt negative consequences in this domain, that we don't want to consider the unknown negative consequences. It's just not, I don't think, responsible. And this becomes incredibly difficult. I mean, I'm in this position. I have astronomically high LDL. I'm actually going to do a letter specifically on my case, and I agonize over the decision. I truly do, because I just don't have good information to inform my choice. And there are all the platitudes that people throw out there like, well, the preponderance of evidence shows this, that, and the other. I'm like,, but the preponderance of evidence was collected in people that are not like me. Like the entire body of evidence is collected in people who are not like me. So don't throw these platitudes at me because they're not actually that relevant. Let's think about what's going on physiologically here, what data we have, what data we don't, how they contradict, and then make a decision. And the art of medicine is making, uh, like hard decisions with incomplete or imperfect information. So I'm not being prescriptive and I'm not saying do as I do. I'm trying to bring some like authenticity here to the complexity of these decisions.

Well, and I think one of the reasons why I appreciate and value your work so much is that you are constantly encouraging people to think. I mean, ultimately, it's like, let's talk about a paper, let's look at the information, you know, will this cause us to look at this disease process differently or this medication differently, or should we be anticipatory? And as you astutely stated earlier, you know, having true informed consent with our patients before we're utilizing or selecting an intervention.

Yeah, 100%.

All right. There's another really interesting paper that you talked about recently, both on Substack and social media, in Nature Aging, the biomolecular aging of two key spikes, which I thought was really interesting. And how, you know, there are things that we might be able to do to— I don't know if I want to use the word lessen, lessen the, the impact or just proactively.

Yeah.

Proactively look at these spikes in the aging process, which ironically enough, when I think about females, I'm going to be slanted, gender slanted here, 40 and 60, you're talking about perimenopause and, you know, so many years into menopause.

Yeah.

I can give you a little insight on this paper because actually this was— I mentioned Michael Snyder earlier, the subphenotypes of diabetes, also his lab. Not only that, but this was the most viral paper ever published in Nature Aging. Its Altmetric score, which is a media attention score, is 5,571, which is like grotesquely high. It's absurd. But it really, it really hit the media huge last year. And basically what they showed was they did what we described earlier, this deep multi-omic profiling of people over time and found, you know, whereas you might think aging is kind of linear, like I age as much between 20 and 25 as I do between 40 and 45. That's not the case. There are spikes in aging. So one around 44 and one around 60, where you age faster during those windows, which is fascinating. Like you look at the graph, it's very stunning. So basically what they did is they took like, you know, multi-omic profiles and just saw like how things changed. Did they change linearly? I think it was 6.6% of biomolecules tracked and they tracked tens, if not hundreds of thousands, um, across the multi-ome. Were linear. So the other 90+% were not linear patterns, which is fascinating. And then there were particular things that popped out. So for example, I think both at the 44 and 60 peak, like caffeine and alcohol sensitivity changed. What does this mean? Well, maybe at, you know, 65, a cup of coffee hits much harder than it does at 35. I don't know if that lines up with people's experiences. I'm neither 35 or 65. I'm 29. So I have an experience on the life experience of these things. A quick aside, I was just on a— it's funny, I talk about healthspan and longevity. So I was on a pod and people were like, so what are your tips for people over 30 to stop aging? And I gave 2 tips and the 3rd tip was like, and then don't listen to anything a 29-year-old says. So I appreciate the life wisdom of everybody listening. I can talk about the data, but yeah, their life experience, they don't have. That aside, very fascinating work by the Snyder Lab. We can get into some of the most actionable specifics. But one thing I want to highlight, and I put, put Michael Snyder on, on the spot about this, is I said, do you think you can flat out these aging peaks? Like, why do they occur? Are they genetically primed? Are they like lifestyle? And he's like, he doesn't know for sure, but he thinks, you know, the next step now that we've discovered the pattern is to figure out like, well, how do you intervene to flatten out the pattern? And I definitely think we can, you know, maybe you can't flatten it to zero, but if you know what's causing the spike, And also your own aging profile. So other work they did basically shows people have different age-omes. So like you might have a, you know, 20-year-old liver and a 60-year-old heart. Like your organ systems age differently. So as you start to develop a picture, you can develop very precise interventions to like curtail your aging and at least extend your healthspan. So That was the high level of the paper.

Well, it's interesting because as you started to say, you know, you could have this discrepancy between, you know, the age of your liver versus your heart. And then I start thinking about, you know, at least in younger women, the most mitochondria in our body are in our ovaries and for men in their testes. And so it's like, I just start to think about, I'm sure there are life choices that we make that will accelerate the aging of specific organ systems.

Yeah. If we get a chance, some of the most exciting work going on, I talked to him briefly about, um, mitochondrial transplants are something that is actually being explored very seriously. There's some very cool work there. But quickly, also just for actionable takeaways on this, this Nature Aging paper, things that I was reading, I think maybe the most interesting to me— well, two. One was in fatty acid metabolism and the other was in antioxidants. So on fatty acid metabolism, they noted changes. I think it was at the 60 peak in particular. In like omega-6 and omega-3 fatty acid metabolism. The reason I think this is so interesting is it relates to this whole seed oil controversy and omega-6s. Um, my high-level point, and I'll focus on omega-6s because they're the one that gets a bad rap, these are precursors to a ton of different things in your body. And so it's not that they're good or bad, it is what does your body do if you give it omega-6, if you give it in particular linoleic acid, What happens to that? It can be turned into, you know, it can be oxidized. In fact, if you have more body fat, it's more likely to be oxidized. There's an enzyme body fat makes called myeloperoxidase. If you're younger, it turns out that you have a better capacity to turn the omega-6 linoleic acid into something called 12,13-dihome. And what this does is it actually slows heart aging. Oh, so I can go through other examples, but the point is like this is a precursor biomolecule that can go down many different paths depending on your metabolic status and where you are in your life frame. So I can't give a definitive protocol, but I, I can say it's, it's interesting to consider you might have different fatty acid sensitivities. So I could speculate that maybe above age 60, you're more omega-6 sensitive.

Mm-hmm.

Than someone who's younger. Food for thought. And as just a quick aside, there's actually a way irrespective of your age to boost generation of this 12,13-DHA HME, it's cold exposure. So the human trial showing about a 40%, 39%, I think, increase in this molecule, um, when you engage in cold exposure. So if you like cold showers, want to add a benefit. And the other thing was on antioxidant status. So antioxidants decline around age 60, antioxidant defenses. The reason I bring this up is because evolution wasn't optimizing for us to live to 100. So it kind of makes sense if we know as you age, your antioxidant defenses decline, then maybe that's the appropriate timeframe in which you start supplementing. You know, it makes sense. People are like, you know, ancestral principles. Well, you know, our ancestors didn't plan to live to 100. So if you know this is changing in your body at age 60 and you wanna give some, we were talking about Coenzyme Q, vitamin C, whatever, as additional defenses, why not? Probably.

Yeah, it cert— it certainly makes sense. And To kind of round out the conversation, I think you and I both share a high Lp, and so I know that you did an amazing Substack around this. I'd love to kind of round out the conversation because I think you and I both share this desire to address it, but be conservative and kind of navigate, you know, what does this actually represent? We know on paper and in the research it can be a causal risk factor for heart disease, It's more atherogenic. You know, you probably inherited it from your parents like I inherited it from mine.

Thanks, Nick.

How do we navigate conversations around Lp?

Yeah. So first on what it is, you think of LDL particles, it's like an LDL particle, but it has a little tail that makes it a little more sticky, so to speak. The tail is made up of something called kringle repeats. The longer the tail, the less Lp, the shorter the tail, The corgis. More, more the corgis. Yeah. I use an analogy. I like little analogies. And then the video I animate in, you know, it's like if you had dangerous little corgis because they have short tails, there's going to get, you know what, this isn't even landing. This is going to be on audio. Nobody's going to get it. It's not going to be funny. I like to pull in jokes and I like to show corgi butts and among other things. So this was just an excuse to me to show little corgis because now they're just like all my Instagram feed. By the way, you'd think my Instagram feed was nutritional stuff. No, it's girlfriend boyfriend memes. Dog butts and Harry Potter and puns, dad jokes. That's like my entire Instagram feed. So you can use that for, for whatever. I don't even know why I'm bringing this up. Sometimes I just go off. But anyway, so LP, it is thought of as a causal risk factor. I want to caveat that word though. Causal doesn't mean most important. All ApoB lipoproteins are probably causal. LDL particles are probably causal. It doesn't mean it's going to cause, you know, oxygen is causal to have a fire, but just because you have oxygen around you doesn't mean you're going to combust into flames. So just a point on that word causal, um, because I sometimes think people overinterpret it. But yeah, Lp is more resistant than say LDL to changes with lifestyle. Like I can bounce my LDL around. Lp is pretty genetically set. Um, ask for the risk it like the absolute risk set. I do think the data suggests a large influence of your metabolic state. So for example, one thing Lp does is it's kind of the janitor for oxidized and damaged fats, oxidized phospholipids. And so most people have a, you know, a very pro-oxidative environment. They're metabolically unhealthy, they have a lot of inflammation. So they're going to have more oxidized phospholipids that Lp can kind of serve as a reservoir for. But interestingly, some of the data show that if you control for oxidized phospholipids on Lp, the negative effects are reduced. They're not eliminated, but they're reduced quite a bit. So I think, you know, on basic principles and what I understand of the physiology, step one is just the basic, are you metabolically healthy? Do you eat well? Do you sleep well? Do you exercise? Low inflammation. You know, low insulin, low HSCRP, yada yada yada. And if you're in that category, I will be more reassured, all else being equal. In addition to that, I mean, I still do have some concern, but the question is, what is the action item? What can you actually do about it if it's genetically set? One thing I will say is there are drugs in development, which again, we're talking about incentive structures. It's probably why it's the hot kid on the block. It was one of the most popular newsletters I ever put out. Kind of esoteric, right? Lp, you wouldn't think it's that popular, but now everybody's talking about it because there's 5 drugs published in some of the major journals like the New England Journal, including— I think most of them are siRNA therapy, small interfering RNA, to lower Lp. They haven't translated to improved cardiovascular outcomes, but they are incredibly effective at lowering Lp by up to 99%. So like basementing it. And then the only lifestyle hack that I would mention— actually, I'd mention two. One is niacin, but that's kind of controversial. It will lower Lp, but it's not been shown to improve outcomes. The other one, which I just find very scientifically curious, is vitamin C. So the origin of the vitamin C idea for Lp actually derives from a guy named Linus Pauling.

Pauling.

Maybe that name rings a bell for people. He's a smartish dude. He won 2 Nobel Prizes, which, yeah, kind of smart to win 2 Nobel Prizes, him and his colleague Dr. Rath. This was around 1990. And one of the things they observed is, okay, what does Lp do? It clots stuff up. It helps with wound healing. But here's an interesting thing. There's this pattern where organisms that make vitamin C don't have Lp. Mammals in particular. And mammals that don't make vitamin C do make L-pi-dylate. So humans lost the ability to generate our own vitamin C about 40 to 60 million years ago. I think it was the GLO gene they lost, or we lost. And then subsequently we developed the ability to generate L-pi-dylate. And it helps with like wound healing, you know, broadly speaking. Um, but there's a pattern whereby this happened independently in other organisms. So I think the European hedgehog is one also doesn't make vitamin C, also makes Lp. Um, I think some rabbits, but for example, mice don't make Lp naturally. They do make vitamin C. I'm pretty sure they make vitamin C. So in general, there's this interesting pattern where, oh, it suggests Lp might be a surrogate for vitamin C. And so this has led to this idea that maybe if you supplement vitamin C and also potentially combine with an amino acid, L-lysine, has to do with how the, uh, Lp binds with something called lysine binding sites. In theory, it could make one for a less oxidized environment because vitamin C is an antioxidant, and two, it potentially could make your Lp less sticky, so less likely to actually adhere to the endothelium and generate plaque. Um, this has been shown in guinea pigs, um, that have been deprived of vitamin C or given vitamin C, so less Lp accumulates in their plaque and say, like, the aorta. You can't really do this in humans without a postmortem. Uh, some people have anecdotally reported vitamin C lowers their Lp, although I wouldn't say you need to see a drop in the Lp numbers to have any benefit. So this is an area of speculation. Um, sorry if it's a little bit waffly. I would say on Lp, jury's still out. Medications in development of interest haven't shown benefits in clinical outcomes. If you're more metabolically healthy, have a lower, you know, oxidation environment, better antioxidant status, lower inflammation, you're going to be better off. And then if you're interested in reading the newsletter, and I did a whole separate one on vitamin C around the science around that, I don't think vitamin C supplementation is going to be harmful. Although a caveat, if you do very high-dose vitamin C, don't take your ketones or glucose afterwards. 'Cause a little postprandial spike can actually lead to oxidation of a lot of the strips and can give you these crazy numbers that make you look like you're in diabetic ketoacidosis. I played this prank on people for kicks and giggles when I discovered it. I did this experiment. I'm like, why is my blood sugar reading at 400 and my ketones at like 9? I don't think I have type 1. So it turns out you can oxidize the strip. So that's more of an aside. Don't play a prank on your doctor.

Yeah, no, so two things. Number one, one time I was getting high-dose vitamin C and I was wearing a CGM.

Yeah.

And it whacked out the CGM, like the data went nuts, and I didn't feel symptomatic, so I, I figured it was probably some vitamin C. Other thing about vitamin C that's interesting, you high-dose it enough, you will get diarrhea. Like sometimes we'll actually say vitamin C to bowel tolerance because if you take too much, it's an osmotic Yep. It, uh, it'll give you some diarrhea. That's pretty hideous.

Yeah.

Yeah. I know. So that's what, that's some people are like, oh, it works if you dose like 18 grams. I'm like, no. Ah, I know people that have done like 18 grams. I, at about even 1 gram, 1000 milligrams, get like bloating.

Yeah.

Yeah.

I was going to say 1 to 2 grams. Usually that's the metric that people will get.

People have like, yeah, 2 500 milligram doses will probably be fine. Especially like consumed with food, should probably be fine. It's pretty cheap supplement to get. But yeah, yeah, 18 grams oral would, would send me—

you would be in the bathroom all day for sure.

Yeah.

Well, Nick, I always love these conversations. I so value the work that you're doing and the voice that you bring to the space. And as you state astutely, keeping everyone curious, stay curious, why it's so important. Please let listeners know how to connect with you, how to get on your Substack email list, or if they've been, you know, underneath a box and weren't aware of what you're doing, how to connect with you across social media.

Yeah.

Um, nice thing about being named Nick Norwitz, nobody else is named Nick Norwitz to my awareness. A little bit of alliteration. N-O-R-W-I-T-Z is my last name. Um, my biggest socials are YouTube. Um, and I'm on X and Instagram. And then my Substack is where I'm having the most fun. So that can be found if you just type in staycuriousmetabolism.com, all one word, it'll bring you there. I put out newsletters at least 3 times per week, typically on deep dives of what, like, I'm, I'm, I'm literally get up at like, you know, 4 AM with insomnia. I'm like, what's new in nature? Let me read. So that's, that's how I spend my time. And I just absolutely love it. And it, you know, has been the pleasure of my life to have people in the community feedback my enthusiasm and curiosity. This is something I do anyway. The fact that I can make, you know, a career of it and, you know, I'm a very transparent person. Like, you know, my Substack makes money. Like, it gives me incentive to like build this up as a business, provide education, and engage with people. I think it's a powerful thing. And I just want to thank everybody in the community for engaging and helping to make You know, with me and you, Cynthia, metabolic health mainstream, because I truly believe that we have the power in a bottom-up manner to change the medical system based on what we discuss. So everybody has that power. And honestly, the last thing I'll say is there's a lot of statistics that are negative about metabolic health in this country. Nothing preventing you from being the outlier. You don't need to be within the statistics. If you understand the physiology, if you're willing to learn and engage in your own n=1 experience, I guarantee you can be the outlier.

Hey, if you like this video, you guys are going to love this video, and I'll see you there.

If you have either uncontrolled diabetes— and this goes for type 1, type 2, LADA, MODY, any form of diabetes— if you follow the standard, if you follow no advice, you're probably gonna hasten your death even more than 3.5 years for each decade you have it. But if you follow the standard advice, the state-of-the-art advice, the scientific consensus advice, then yeah, you're probably going to be knocking 3.5 years off your life for every decade that you follow the American Diabetes Association recommendations.