Plain English with Derek Thompson - Are GLP-1 Drugs "the Greatest Medical Breakthrough of the 21st Century"?

Episode Date: January 31, 2025

In the past few years, we've learned that GLP-1 drugs don’t just help with diabetes or increase people’s feelings of fullness to help them lose weight. They have broad effects on substance abuse and behavior. They even seem to help with otherwise incurable illnesses, like Alzheimer's and schizophrenia. This month, a team of scientists studying 2 million patients in the Veterans Affairs medical system found that GLP-1s were associated with “a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer’s disease and dementia), coagulation disorders (clotting), cardiometabolic disorders (like strokes and heart attacks), infectious illnesses and several respiratory conditions.” Today’s guest is a coauthor on the paper, Ziyad Al-Aly. He is a physician-scientist at Washington University in St. Louis. We talk about his new paper, the steps he took to make sure his findings were trustworthy, why GLP-1 drugs might work so well, what they’re teaching us about the brain and body, how they’re scrambling our sense of where volition begins and where free will ends, and what scientists should do next with the revelation that these drugs have effects that go far beyond obesity and diabetes. If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek Thompson Guest: Ziyad Al-Aly Producer: Devon Baroldi Links: Al-Aly et al. on the effectiveness and risks of GLP-1 drugs [link] Learn more about your ad choices. Visit podcastchoices.com/adchoices

What's up, everybody. Chris Vernon here and welcome to a new season of the NBA and the mismatch. And huge welcome as well to my new co-host, Dave Jacoby. I can't wait to link with you twice a week every Tuesday and Friday right here on the mismatch to break down everything that's happening in the league. Who's playing well, who we loved, who we loathed, trade rumors, team dysfunction. We've got you covered right here. So follow us, subscribe, and hit us with those five-star ratings on Spotify or wherever you get you. your podcast. And also don't forget to follow us on social media. That's at Ringer NBA and check out the full mismatch episodes with the two handsomest podcasters in the history of podcasting

read on the Ringer NBA YouTube channel. Today, the latest research in the revolution of GLP1 drugs like OZembek and why some scientists are calling it the greatest medical breakthrough of the 21st century. So one of the best stories, most famous stories, of great fortune in science history happened in the fall of 1928. When the Scottish scientist Alexander Fleming was coming back from a long vacation, Fleming walks into his lab in London. He's been working with steflikakis, a common bacterium that causes common infection. This bacterium derived its name from two Greek words,

staphile, meaning a bunch of grapes and cocos meaning berry, because when you looked at staphlicoccus, under a microscope, it resembled a cluster of white grapes. But when Fleming, returning from his vacation, takes off his coat, walks over to the petri dish, he does not see a cluster of white grapes under the microscope. Instead, while he was away, some thing, some substance of unknown origin,

seemed to have flown in through the window and landed on the dish and liquidated the bacterial colony. Just zapped it right off the dish, totally destroying the bacteria where it sat. These little white grapes he expected to see they were gone. Fleming later identified the mysterious material that seemed to have flown in through this window

as a mold belonging to the genus Penicillium. And as for the bacteria-killing substance it produced, he called it penicillin. Many people know the story, if they're familiar with science history in the history of aha moments in science and tech, the famous mold that blew in through the window and became penicillin,

maybe the most famous medical breakthrough of the 20th century. What most people don't know, however, is how hard it was to make penicillin work. For years, Fleming, along with Howard Florey and Ernst Chain, worked tirelessly to show that penicillin could knock out a range of bacteria in mice, and it could. It turned out that penicillin was marvelously effective at fighting bacteria in small animals. But in 1942, in the midst of World War II, they hit a wall. They couldn't grow enough penicillin.

They couldn't grow enough of the mold, fast enough, to test it in humans. Now here's a fun fact to impress science heads out there. 13 years after penicillin's famous discovery, only five human patients had ever been treated with penicillin, and two of them had died. The reason I know a weirdly specific number of details about the story of penicillin is that its development and the story of its development plays a leading role in my new book, Abundance, co-written with Ezra Klein, about where liberalism went wrong in the last 50 years and how it can go right in the next generation.

I also know that the penicillin project was brought to America, where American scientists oversaw its development in the Office of Science and Research Development. Americans turned penicillin from a scientific breakthrough into an actual medicine for broad use, a medicine that by any calculation has saved millions and probably tens of millions of lives in the last 80 years. So here's the story of the little mold as I see it.

The most important drug of the 20th century was discovered by mistake, but its development hit a wall, and we had to overcome that wall if we wanted to change the world. I wonder if one day we'll say the exact same about GLP1 drugs like OZempic, just swapping in the 21st century for the 20th. Like penicillin, GLP1 drugs were discovered as it. essentially by mistake. In 1990, or in the early 1990s, a small team of scientists were studying the Gila Monster, which is this thick, stocky lizard, which famously can survive on less than one meal a month, sometimes no more than four or six meals a year. They want to understand what's

in this guy's saliva that allows it to suppress its appetite. And when the scientists studied the Gila Monster's saliva, they found it contained a hormone. that in experiments lowered blood sugar and regulated appetite. A decade later, a synthetic version of that lizard spit became the first medicine of its kind approved to treat type 2 diabetes. The medicine was called a gluggan-like peptide-1 receptor agonist. That's impossible to say over and over again, so most people call it a GLP-1RA, or more simply, gluggan-like peptide 1.

Over time, we realized that patients on GLP1 drugs also tended to lose a large amount of weight, and this kick-started the current GLP-1 craze with companies like, you've heard their names, Novo Nordisk, Eli Lilly, spending unthinkable sums of money to come up with the next best obesity drug. But if you've been following this space, you probably also know something else. That GLP-1 drugs don't just regulate insulin, and they don't just increase people's feelings of fullness to help them lose weight. In the last few years, several studies have come out suggesting that these drugs seem to help with an array of maladies.

Substance use disorders, liver disease, Alzheimer's, schizophrenia, things that have nothing to do with one another, and certainly don't seem to have anything to do with lizard spit. This month, a team of scientists studying two million patients in the veteran affairs medical system, found that GLP1 drugs were associated with, quote, a reduced risk of substance use and psychotic disorders, seizures, Alzheimer's disease, coagulation disorders, that means like clotting, cardiometabolic disorders, like stroke, heart attacks, infectious illnesses, and several respiratory conditions. End quote. Of course, correlation isn't causation, but the size of the study and the number of studies corroborating these findings suggest that GLP1 drugs might be very, very special.

The Yale researcher F. Perry Wilson offered this summary of the recent VA paper. As more data comes in, I become more convinced that we may look back on these drugs as the greatest medical breakthrough of the 21st century. Now here's the rub. A drug is only as effective as it's used. And right now, some studies indicate that 40% or more of the people prescribed with GLP-1s are discontinuing use. Maybe it's a side effect profile. Maybe they miss alcohol, which GLP-1s famously make people a little bit queasy to ingest. Maybe this is fundamentally a cost issue, right?

They like the drugs, but they can't afford indefinite use of a Zempec. But if these drugs really are a kind of across-the-board, anti-consumption, anti-inflammation, anti-obesity, anti-infection, Swiss Army knife, I think we should be devoting even more money and talent to understanding how to extend their benefits to more people. We should be seeking to overcome the problem of GLP1 discontinuation. Just as 80 years ago, American World War II scientists overcame the problem of penicillin production. Today's guest is a co-author on the paper that I mentioned above. Ziyadh Al-Ali.

He is a physician scientist at Washington University in St. Louis. And today we talk about his new paper, the steps he took to make sure his findings were trustworthy. Why GLP1 drugs might work so well, how they're teaching us about the brain and the body, how they're scrambling our sense of where volition begins and where free will ends, and what scientists should do next with research like this. I'm Derek Thompson. This is plain English. Ziyadh-A-Lal-L-Lay, welcome to the show.

Well, thank you. Thank you for having me. I'm so excited to talk to you about this paper. It's absolutely fascinating. Before we discuss what you found, set the stage for us because it feels like every week there's another study, animal study, observational study, showing that, oh, we just learned that GLP1 drugs do this new thing. It reduces substance use disorders. It reduces Parkinson's. It reduces Alzheimer's. Why did you think we needed this paper? What is your paper adding that the existing literature lacks? Sure. We saw in the U.S. and actually across the globe that utilization

for GLP1 drugs have actually increased dramatically over the past several years. And we saw that they're really actually remarkably effective in treating obesity, but we also saw, as you indicated, you know, a paper here and a paper there showing that, you know, oh, they may be beneficial in this one thing or they may be beneficial in these other thing, and realized that nobody had comprehensively looked at all possible health outcomes, really analyzing things from A to Z, leaving no stone unturned. So we thought about GLP1 drugs. that's kind of like the new territory.

You're landing on a new new land or, you know, you're discovering America for the first place. And then what you wanted to do, you wanted to map it. You literally want to map it. You want to map the landscape to figure out what these drugs do and don't do, you know, comprehensively, leaving no stone unturned. So we decided to do this paper. And what we essentially did here is that, you know, we compared people who started on GLP1 drugs versus several controls looking comprehensively at all possible 175. health outcomes. I actually want to read from the methodology section just briefly because I want people listening to understand how you did what you did so that we can understand how you found

what you found. We've done a lot of episodes in the last few weeks and months over how science can go wrong, how observational studies, for example, can lead us astray. So I want people to understand what the methodology was here so we can understand why we should trust it. It seems to me like you went to Veterans Affairs and you compared veterans on GLP1 drugs to several different controls, to folks on other type 2 diabetes drugs like DPP4 inhibitors and to a control group of just over a million people in what you call usual care. So they weren't on any kind of newfangled medication. And this way you're comparing veterans over several years. These individuals were followed. I read over a median of about four years. You're comparing outcomes from these distinct groups and seeing,

okay, who had higher or lower rates of Alzheimer's, higher or lower rates of inflammation and so forth. Before we go on, what's important for folks to understand about your methodology that I didn't mention? And what's the value of working with a data set like Veterans Affairs? So first of all, this is really a large study.

The value here is that you really have massive amount of data, more than 2 million people followed for nearly four years on this GLP-1 drugs. And we designed it in a way that we look at several controls, We weren't really satisfied by looking at only GLP1 versus, you know, for example, SGLT2 inhibitors or a drug, another diabetes drug called DPB4 inhibitors. We wanted to literally, you know, have a rigorous study examining, you know, the effectiveness and risks of GLP1 drugs versus several controls,

including so really the control that most resembles or actually recapitulate what people do in their real life. This is really usual care, more than 1.2 million people who were all. unusual care. So we compared to these massive numbers of people who were on GLP1 versus these several control groups and followed them for about four years. And then also importantly, that we looked at all possible health outcomes. We didn't look at only addiction disorders or really, you know, at only Alzheimer's disease or only, you know, depressive or psychotic disorders or infections. We looked at heart disease or kidney disease. We looked at all, all of it, everything, to try to help us understand what these drugs do and don't do in people's bodies.

And I don't want listeners to feel like I'm hiding the ball here, but just one more question on the methodology. Tell us what's so useful about using a Veterans Affairs data set. It seems to me like that's a nice way of controlling the health insurance that people are getting, the way that they're being able to pay for these drugs. I want to make sure we just stop very briefly on the benefits of doing the study within the VA. Well, this is very important. Thank you for asking this. So the Veterans Affairs system is really the largest integrated health care system in the United States. And it is and provide equitable care to all people who are enrolled in the system, including drug benefits. So a lot of your listeners now will say, oh, well, like, you know, these drugs are expensive and not everybody is on them and then maybe only rich people are able to access them or people who are really handsomely insured are able to access them. And then it's not really sort of a sort of a surprise. that these people have better health outcomes, right? Well, at the VA, everybody equitably, all enrolled veterans have actually equal access to these medications regardless of their, you know,

their income or other characteristics. And that really provides equity and parity and then enables us to actually compare people without having to worry that maybe people who are, you know, privileged or or handsomely insured have access and people who do not have these characteristics don't, don't have access. And the other really major characteristics is really the volume is really the large number of individuals. So again, this system is really sort of the, you know, the U.S. should celebrate it because it's really the integrated system that delivers equitable care across the board to all enrollees without regardless of their income or socioeconomic status. So let's talk about what you found. We're going to get to the risks in just a second. But let's

start with the positive side. What is the most important? most surprising positive side effects that you found among people using GLP1 drugs, like we now call them OZempec, Munjara? Sure. So what's surprising to me is like several things. First, really the consistent signal and reducing risk of substance use disorders. We thought, you know, people have a reduced risk of alcohol problems, cannabis use disorders, stimulant use disorders, opiote use disorders.

Across the board, whenever we look at substance use disorders, we look at substance use disorders, use disorders, we saw a decrease risk in people who started GLP1. And it would be maybe remarkable if we only found one or two things, even more so when it was consistently across all substance users. That's really a consistent signal. And we also saw it reduced risk of schizophrenia and other psychotic disorders. Very, very importantly, which I think also can teach us about the biology of Alzheimer's disease, reduced risk of neurocognitive disorders, including Alzheimer's disease and dementia.

And although sort of the effect size here or the reduction in risk is about 11%, that could be classified as weak or modest. But when you understand that in the context of now, whether there's really actually no good treatment for Alzheimer's disease. Well, I'll take 11% reduction any day when the alternative is zero reduction. So that's also really a significant, you know, we think it's a significant finding. We saw also reduced risk of clotting disorders, like something called deep vein thrombosis, clotting in veins in the leg or pulmonary embolism, reduced risk of infections. And that's also strange because why an obesity or diabetes drug reduces the risk of infections and reduced risk of chronic obstructive pulmonary disease, liver failure, and liver cancer?

They're really remarkable beneficial profile across multiple organ systems. To me, the widespread nature. of these beneficial effects is absolutely astonishing. And before we get to the specifics, I actually want to keep it a relatively high level of abstraction here. This is such a wildly impressive effectiveness profile that it almost seems miraculous. It certainly seems quite special.

Do you believe that GLP1 drugs or special? Or do you think that our understanding of GLP1 drugs is the thing that's special, Which is to say, is it possible these really are singularly miraculous drugs, or maybe there are other drugs that are doing all of these things for us that we haven't studied in quite the same way as GLP1's? I think the latter, I'm excited about GLP1, but it's unlikely that they're like, you know, that they're really, really unique, you know. It's unlikely that all drugs are like this are like JLP1, but it's unlikely that GLP1 drugs like this is sort of a very unique. class of medication that has, you know, this sort of a broad beneficial effect. But I do think that two things are important here about GLP1 and may explain, potentially may

explain why they have a broad beneficial effect. A, is that they actually treat obesity. And obesity is actually a bad thing. Obesity is a bad thing. It's a bad thing for your heart. It's a bad thing for your kidney. It's a bad thing for mental health. Obesity is a bad thing for a lot of diseases or a lot of problems.

And you can sort of conceptualize obesity as the mother of all ills. And when addressing it, you know, or treating obesity really well effectively with these GLP1 drugs can have downstream beneficial effects. And two, I mean, as our understanding of the biology of GLP1 is evolving. And again, this is sort of a far from complete. The picture here is far from complete. You know, we're still trying to put the pieces of the puzzle together or the pieces of how these drugs really work.

But as our understanding is evolving. and becoming clearer by the day, it is also possible that these medications act on various biologic systems that are responsible for multiple diseases like Alzheimer's disease or addiction disorders. So two things that could be a play that may explain why these drugs are maybe different than just the average drug out there. But they're unlikely to be just unique, like completely unique, that this is the only drug class in the world that has a that has this sort of broad effect, you know, that are in the history

of medicine, there are, for example, statins, you know, that people, you know, listeners may be familiar to. This is a class of drug that people take for cholesterol. But you know what? It also reduces the risk of several other problems. So it also has a broad beneficial effect, although weak, so it's not sort of like, you know, that's not sort of a totally resembled the story of GLP1. But the history of medicine is actually, there are other medications that, that do share some of the characteristics in terms of breadth of effect across multiple organ systems. Certainly what I found most impressive about the findings in your paper is that you have a page where you list all these different health systems within the body,

blood systems, circulation, digestion, endocrine and metabolic systems, infection, mental and cognitive function, musculoskeletal systems, liver, nervous system, respiratory system. There's not a single system that I just named that didn't see some kind of improvement with GLP1 drug use. And the breadth of that side effect profile is really astonishing to me. So I want to keep going deeper into this, in a very specific sequence, I want to talk about obesity a little bit, I want to talk about the mental and cognitive effects, and then maybe we can close on some of the broader mechanisms that might be at play.

on obesity, how do you think the success of GOP-1s overturns our understanding of obesity or overturns our understanding of how to think about or treat obesity clinically? So thank you for this. This is a really actually exciting question. So thank you for asking it. So, you know, previously there was this idea

that obesity is really, you know, lack of willpower, that if you exercise more and eat less, then you'll treat obesity. And people have done this and have been doing this for the past several decades and been going to Weight Watchers and doing various other things and all of this has failed. And I think what these drugs are teaching us

is that literally obesity is actually a disease, is a chronic disease that can be effectively treated with GLP1 drugs. And I think that's really an important concept for people to understand. It's not really lack of willpower. It's really the, it's a chronic disease. Like you treat high blood pressure

or you treat heart disease or kidney disease, you treat it with a drug effectively to really manage the condition. And I think, too, sort of tells us that, you know, there is a theory out there that has been actually postulated close to a decade ago that obesity is a form of addiction to food. It's really that when humans are actually consuming food in excess of what they really need. Like, why would the human body sort of like really tightly regulated with really all these sort of fine feedback mechanisms, you know, go on these like splurges where people are binging and eating a lot of food in excess of what their actually bodies really need. And the people

postulated that actually this is sort of represented, actually this regulation in the brain that, that, you know, leads to addiction to food. And postulated even at that time that actually to effectively treat obesity, people need to come up with the treatment for addiction disorders. And here we are in 2025, you know, have a drug that actually really works really well against obesity. And it turns out, you know, almost like a serendipity that it also works against addiction disorders or may work against addiction disorders. So, I think the pieces of the puzzle are coming together suggesting very, very strongly that obesity is actually disease. It's not lack of willpower. And it's actually at the root of it, we conceptual it as a metabolic disease, but it's actually probably even a neurologic entity or a neurologic disease.

all in the brain, is sort of leading people to sort of like, you know, have that urge to really eat more, actually in excess of what their bodies need and subsequently, you know, gaining weight. And I think that's sort of a radical transformation

in the way we think we can sexualize obesity and we think about it. You created this little thought bubble in my head that is not in my questions, my written questions at all, but I'm just going to try to articulate it. And maybe there's something in here that totally makes no sense

and is totally anti-scientific, but I'll trust you to correct me if I get it wrong. it's interesting that you just compared obesity, which is something where we assume, or have historically assume there's a ton of willpower at play, and something like blood pressure or, say, liver function, where we typically would never assume that there's willpower at play. And it occurs to me, perhaps obviously, that the former involves an external behavior that other people can see, an external mechanism that other people can see. That is, I can watch you pick up a goldfish and put it, you know, a snack, and put it in your

mouth. So I say, ah, you know, Ziyadh clearly can control his ability to eat goldfish, whereas I can't see your red blood functioning. I can't see your hemoglobin health. And so I would never assume that you in this moment are, you know, directing all of your cells to do this or that, either you can control some disease that's internal. And it seems interesting to me that this drug seems to have a very strong mechanical effect on our external behavior. And that that's somewhat complicating our historical, maybe even very American belief, that if I can see the behavior, then clearly there's an enormous ability for the body or for willpower to control it. But maybe pre-will is a lot less free than we think, and that the same kind of automatic

invisible functions happening inside the body also are governing a lot of external functions that we think are a matter of pure willpower, but actually are just as rules. by an invisible set of genetic and environmental factors as something like blood pressure. Is that fair to say, as a matter of summary? This is a beautiful way of characterizing it. This is actually absolutely a beautiful way of characterizing it. And this is, I think, you're definitely on point. So people sort of mischaracterized behavior as like, oh, you know, I can control all my behavior.

And to some degree, people can control, like, some aspects of their behavior. But actually, a good part of it, as you put it, is really driven by genetics and biology. and, you know, prime example of this is addiction behavior. So that's really, you know, previously, like, oh, it's your fault because you're an addict, but it's actually a disease. It is fundamentally a disease. And in a way, the more we understand these things, the more we understand addiction behaviors and addiction disorders and obesity, we're becoming now to like this really radical realization.

These are actually diseases of disordered hormones and disorder signaling in the brain and disordered, you know, sort of a communication mechanism, how the brain communicates with the gut. And all of these are actually diseased in people who have obesity. It's not their lack of willpower. It's not their fault. And these people, you know, to sort of put it, you know, your listeners will sympathize with this.

You know, people who have obesity, did whatever, everything, you know, all the stuff that Oprah told them to do. She told them to go to Weight Watchers, they did that. You remember the Atkins diet fade? They did that. They did everything under the sun and everything has failed. And now with a drug, miraculously, people are losing literally hundreds of pounds. So it's very, very clear to me, sort of putting all the pieces of biology together, human behavior,

and our sort of a collective struggle with obesity over the past several decades. You put all of this together. It's very, very clear that obesity was never like somebody's fault. They eat too much and they don't exercise because they're lazy or something. That's really sort of an oversimplification of the reality. Yeah, I do want people listening to think that I'm some nihilist when it comes to external volition. Like, for example, if you say, Derek, come up with a word that rhymes with goat, I can say boat. But if you say, hey, Derek, increase your metabolic function by 15% in the next five minutes.

I can't do that, right? There are some things that are truly beyond our ability to executively function on, but that doesn't mean that underneath our external behaviors, there's actually this enormous iceberg of genetic and environmental factors that's governing or limiting or providing parameters for our behaviors, and we're in the process of discovering what those factors are. And to me, like GLP1 drugs are a fascinating way to probe what these underlying factors are, how in things that we thought we could control, like caloric intake, it might be the case that we can't, we don't have the kind of entirely free will that we thought we did. I want to move this conversation to the space of mental and cognitive functioning because one of the first things that I, one of the first real aha moments for me with GLP1 drugs was the realization that many people were talking about this as a gut drug, but really it's also a brain drug. This drug is doing something to people's minds. And I'm sorry to keep talking, but I'm just going to read a quote from page five of your paper and then ask you to dilate on it. and please go as long as you want. GLP1 use was associated with reduced risk of alcohol use disorders, cannabis use disorders,

stimulant use disorders, and opioid use disorders. Use was associated with a reduced risk of suicidal ideation, attempt or intentional self-harm, bulimia, and schizophrenia, and other psychotic disorders. GLP1 use was associated with a reduced risk of seizures and neurocognitive disorders, the latter being driven by a decreased risk, risk of dementia and Alzheimer's disease, end quote. This is just an astonishingly broad

number of disorders and cognitive issues that have at least some signal of diminishment with GLP1 use. Do we understand how this is possible? And if we don't, do you have a wild theory of what's going on here? So the short answer that we don't fully, fully understand why GLP-1s are doing this. And this is almost like a penicillin moment in sort of the, that there was all serendipity. Like we, the GLP-1 drugs were not invented to do this, were not really conceived to do this. Initially, they were actually developed as anti-diabetes drugs. And then, you know, by serendipity, we're like, oh, you know, people who have been taking, who have been taking them, they're actually losing massive amount of wage. So the companies went back to the FDA and it said, oh, we needed,

we needed to approve it for an obesity indication for obesity to treat obesity. That was almost like a almost a serendipity. And now with the studies that we and other are doing, we're sort of discovering this really the broad beneficial profile. So going to the core of your question, so what's sort of the mechanism that underlies all of this? We don't completely understand. But as our, you know, both animal studies are being done and human studies are being done, we're beginning to realize that actually people have GLP1 receptors in their brain. So that has been characterized in experiments. Now, in areas of the brain that are also responsible for affect, for mood, for impulse control, and for reward signaling. So how do these GLP1 receptor agonist sort of enter the brain in sufficient amount or sufficient quantity to really act on these receptors and what do they do downstream?

It still hasn't been fully characterized. So I don't want to sort of leave the listeners with the idea that we fully, fully understand what's going on. We're still trying to sort of piece the, you know, put the pieces of the puzzle together. But what it is really clear at this point is that they do have a neurologic effect. And it's not a single thing. It's not only seizure. It's not only psychotic disorder. It's not only Alzheimer's disease.

It's various other, you know, issues that are, you know, that are present or that are encoded in the brain or various other diseases that are, you know, originate with, you know, from neuronal cells from brain cells. There are some animal studies out there suggesting that, in those animal studies, so there's not human studies, that GLP1 receptor agonists, you know, when they enter the brain, it will reduce neuroinflammation or reduce inflammation in the brain. So that actually could also have beneficial properties, that they also reduce something called oxidative stress, sort of the level of oxidative activity in the brain, which is also harmful and reduction of it is actually really good. Reduce amyloid beta deposition.

So those are the amyloid proteins that have been implicated in the biology of Alzheimer's disease and reduce tau-protein hyperphosphorylation. That also has been implicated in the biology of Alzheimer's disease. Again, these are our experiments. I don't want to leave listeners with the idea that these are definitive answers that we completely understand what's going on. But they're giving us clues. These are the breadcrumbs, so to speak.

I think he has clues as to, yeah, you know, these drugs are likely acting on the brain, and these are the clues. And I think our job is to really leverage this understanding to sort of enhance and enhance our ability to treat this disorders. The Yale researcher F. Perry Wilson wrote a long thread on Twitter about your study, very approvingly, really a threat of astonishment. And he made an observation that's sort of a stylized story of what these drugs might be doing to our brain that I want to, I want to read you as observation and then get your reaction. He said, quote, these drugs seem to be anti-consumption agents, not just for food, for drugs, for cigarettes, for risky behaviors. They are essentially

the antidote to the central issue of our time over consumption. And quote, how do you feel about that interpretation? This is a beautiful idea. So thank you to have. And he's, he's really, he's a brilliant writer. So this is really beautifully written. So I do think that, that again, sort of GLP1 drugs are likely, you know, act on the brain and they act to sort of a, not only curb appetite, not only suppress appetite, but also suppress other sort of impulsive behavior, so to speak. And then, you know, they suppress the, you know, that craving for nicotine, that craving for a cigarette, that craving for alcohol, that craving for drug A or or drug B or drug C that is addictive. And, and, and it's unlikely that this is really only limited

to drugs or nicotine or alcohol, it's likely sort of broader and people sort of report that they have now all of a sudden less impasse to go gambling. And there are actually people, scientists at NIH who are studying GLP-1s in the treatment of gambling addiction and other addiction disorders. So definitely I agree with the characterization that there may be something here. These drugs, again, we think about them as metabolic drugs, but they're likely probably more brain drugs or more neurologic drugs than metabolic drugs. And the way in which they work seem to sort of kind of stop that craving for consumption and other addictive disorders.

So it's possible. But again, it's very clear to me that we're in really the early phase of understanding what these drugs do and don't do. And I think we definitely need to keep sort of pursuing that. bread crumbs to try to piece the larger story together. We're about to get to risks, but I just want to close on something I thought when I read the fact that these drugs reduce rates of schizophrenia. I am not a neuroscientist.

I'm not anything close to a schizophrenia expert. But that's stunned me because I've always thought of schizophrenia as being fundamentally a genetic disease. Surely it has some environmental activation factors, but rates of schizophrenia, seem relatively similar in many different countries, suggesting it's fundamentally polygenic arising from an interplay between a bunch of different genes. And it made me think, wait, could this really happen? Could a diabetes two drug really reduce rates of schizophrenia? Did you do any quality tests on this research? To see if, for example, these drugs were

seeming to have effects that made no sense. Like if, for example, these drugs were, you know, reducing the rate of car accidents among drivers, you'd think, wait, what's signal are we really picking up here? It's very unlikely that any anti-obesity drug is having some kind of effect on car accidents. Did you do quality tests on that like that to make sure that you were getting a clear signal here?

Yes, definitely. So we did what we call something. positive and negative control. So let's start with a positive control first. So we know that these drugs actually reduce the risk of heart disease and reduced risk of actually result in weight loss. So what we did is that we first tested their ability in our cohort, in our studies, to actually do that. And those panned out, you know, to be correct. And so that also told us that the design and adjusting for all of different things and cleaning the data, like, this is massive amount of data on more than 2 million people, it really was yielded the results that

are consistent with prior expectations. And we also did what we call a negative control analysis. So basically, these are sort of negative controls that are chosen or picked because we didn't believe or we sort of felt that there would be no really causal. There should not be a causal relationship between. GLP1 and car accidents or accidental injuries. And when we tested that, and there was no relationship or no causal association that we saw. So those are sort of quality controls or indicators that we do use in our studies to try to help us, you know, calibrate, you know,

and help us understand whether our approach, whether our methodology is actually producing results that are consistent with a priori or prior expectations, expectation before we actually do these analyses. And that generally elevate our confidence that that that the results are are likely correct. It improves my confidence too. You know, I read these results and I think some of this is incredible. And some of it is almost incredible, which is just to say, you know, beyond credulity. Like I can't actually believe that one drug could have all these positive side effects. So I'm very glad to hear that you ran those control tests, those quality tests.

Let's talk about the risks. What are the most serious and most common risks that you found? And maybe could you tell me, did you uncover risks that previous work hadn't illuminated in this paper, the same way that you uncovered benefits that previous work hadn't illuminated? So let's start with the known risk. So listeners or people who are now familiar with a GLP1 story and may feel like, you know, we uncovered risk because of the G.I side effect. So that's actually known, you know, like that's actually very frequent too.

And that include people reporting nausea, vomiting, some people constipation, some people are the opposite diarrhea, guess it was a physioreflex disease, some people refer to it as heartburn, gastroporosis that paralysis of the stomach rare but serious problem. We also saw, which has not been reported previously, increased risk of hypotension or low blood pressure. And in some individuals, low enough to lead them to synchapy, to lead to the to them to faint. We also saw sleep problems and headaches and people on GLP1, whereas also has not reported before increased risk of kidney stones. And that's likely because

when people sort of are not eating enough, and they also may not be hydrating enough, and that's sort of a, you know, people remain, you know, on this medication for a year or two that actually increased their risk of developing kidney stones. We also saw increased risk of intersticial lefritis inflammation of the kidney and also, and also, also has not been reported before increased risk of pancreatitis, inflammation of the pancreas. The latter pancreatitis actually is rare but serious because it could put people in the hospital or even worse, it could be fatal. So, well, broadly sort of, you know, feel that there is a, you know, significant beneficial

profile to GLP1. They're not without risks. They're absolutely not without risk. And some of the risks may be manageable, but some risks are actually serious and people need to recognize them and providers who are. considering prescribing these drugs, we need to also take these into account and also monitor them,

monitor for these adverse events in people who are using these drugs. You followed this group for 3.5 years, four years. Is it possible that other side effects, negative side effects, might become apparent as we keep studying these drugs? Oh, this is really brilliant. So thank you for this.

And the answer is definitely possible. So again, sort of the puzzle we're putting, you know, the sort of the pieces of the puzzle together, and we feel this paper is one giant piece of the big puzzle, but it's not the whole puzzle. And then, you know, we don't really completely understand that. If somebody is on G.L.P. You know, for five years or ten years, what will they do to their bodies? What will that do to their bone density, for example? What would that do? They lose weight, but they lose, like, a lot of muscle mass to the point where they, you know, they'd be at risk of falling or breaking a bone and other thing. Will it lead in the long run, you know, As you pointed out, you know, four years is long, but not really long enough. And sort of a, you know, for people who want to be on it maybe for a decade or more. So will that lead to increased risk of cancer? And actually, even for a beneficial profile, is it durable? Is it sustainable over a long period of time?

Or is it just like an initial phase, you know, that people, you know, have these reduced risk, but then sort of a, you know, but then that sort of a phase away with time. And I think, I think, again, sort of the, you know, the people need to do. including us, we're really interested in further following up on these studies to do longer-term analysis about five years than 10 years to help us more deeply understand really the long-term benefits and risks of these drugs. And I also want to mention, you know, something that is also important is really discontinuation of these drugs. So, you know, that story is really important because, you know, although at the VA, that's not really very high because, you know, that is

people get it here at the VA at no cost to them, a lot of people are actually are finding that they're not able to afford it and there's a really high rate of discontinuation, either because of adverse events or because of the inability to sustain those very high co-pay or very high out-of-pocket cost. And understanding what also happens after discontinuation is going to be also very, very important in the story of GLP1. I was just about to ask about discontinuation. So let's just do a little bit more on that. At a high level of abstraction, if I knew that there was a miracle drug that had a discontinuation rate of 30, 40%, so between a third and almost half of people who were initially prescribed the drug fell off or stopped using it after six months a year, I'd say, that's a really, really big problem.

I really want to understand why people aren't adhering to this drug. And there's a really big difference between people are discontinuing GOP1 use because the side effect profile is too gnarly for them, too painful or too plain unhealthy. Or the side effect profile is fine, but the drug's too expensive, right? Those are two incredibly different problems. Problem number one, build a better drug. problem number two, build a better insurance system or co-pay system or financing system to allow people to use the drug that they want to use. Do we have any idea how that discontinuation population

breaks down in terms of people who are discontinuing because side effects are too bad or discontinuing because drugs too expensive? So that picture is emerging. So the different studies have yielded slightly different answers, but it is clear that the lion share of, I'm speaking now outside the VA, sort of the larger U.S. population or larger U.S. landscape, most people are discontinuing because they're not able to continue to afford it. You know, side effect, you know, there is, there is about maybe, maybe among all the people who discontinue that are about 30% of people who discontinue because of side effect, but the lion's share of people discontinue because they're not able to afford it or other or other or other factors and I think both are both drivers are

really important both are very very important and and because and also understanding the consequences or what happens after discontinuation because this idea out there that you know if you want drug street addiction but they're also in by themselves addictive you know now the early result that we're seeing after people discontinue that really that that craving comes back so almost like with a vengeance you know and they and I lose and I guess and I'm and again, massive amount of weight afterwards. And then we worry about that, but we worry about that surge,

and, you know, like, the really massive amount of weight within a short period of time. So that craving kicks in, you know, back with a vengeance. And so we worry what that really does also to cardiac health, to renal, to give me health, to, you know, and then whether that's sort of a reversal in the beneficial profile, you know, completely totally offset and even more the benefits of the,

God. And I think more needs to be done here. And I think there are some people sort of, you know, see what addiction with another and people are not becoming addicted to GLP1 and they get off of them. They can not actually live without them. They gain this massive amount of way. They almost like now need them to become dependent, sort of a quote unquote dependent on GLP1 drugs. So that all need to be fleshed out and to help us better understand what these drugs are doing. The second component I would mention that it also studies out there showing that the human body, because GLP1 are actually proteins, the human body actually develops antibodies to neutralize the GLP 1. And in some individuals, they may keep needing higher and higher doses with time, which lead to higher side effect to achieve the same goal because their body is neutralizing 50 or 60 or 70% of what they take. it generates auto-antibodies, antibodies to really attack that GLP1 protein and neutralize it.

And then you say let's say you take 100 unit, but really in effect, there's only 30 units that are active in the system. So that also needs to be further clarified and flesh out. And long-term ramifications of that immune response should also be investigated. What do you hope people do with this research? I think it's sort of a, from my perspective, sort of the big picture here, it sort of tells us that obesity is a disease can be treated effectively with a drug. And I think really sort of challenges really fundamentally the idea that obesity is lack of willpower that if you exercise more or, you know, or eat less or a combination of this or join weight watchers or something else that somehow, you know, you're going to have the, you know, you're going to be able to cure or address obesity. And I think number of, two is really that, you know, treating obesity and metabolic syndrome likely will have, you know, broad beneficial profile because obesity itself is actually bad for so many things. So, so it's, obesity is bad for cardiovascular health, for kidney health, for brain health,

and treating obesity is really, we think is beneficial and may lead to, may lead to a lot of downstream benefits. And three, and I think really important, really the realization that this drug has really a lot of off-target effects. You know, again, initially was conceived or developed as a diabetes drug and then subsequently as an obesity drug. And now people are using it to treat, you know, sleep apnea, to treat kidney disease, to treat heart disease. And, you know, and the list of expanding indication and uses that will be approved by the FDA will actually expand dramatically over the next several years. So this drug has a really broad, you know, off-targetless or effect, off-target effects across multiple body system is teaching us by serendipity. This is not the smartest of doctors or scientists like me.

This is a drug teaching us about the biology of Alzheimer's disease, about the bio, really pathways, pathways that are now implicated in these disorder or these diseases that we have not thought about previously. Those were not on the radar screen previously, but now literally by the sheer serendipity of this drug, effectiveness in these disorders, thinking, oh, could GLP1 really be implicated in this disease pathway? And could we leverage this new understanding to actually create more potent drugs for Alzheimer's disease or for infection or for other things? So I think it's teaching us a lot about the biology of other diseases that we haven't really, you know, that we haven't really in which we have not really previously considered GLP1 as a significant. pathway. And it also possibly opened, you know, the methodology of this paper and sort of the way we did it, you know, as we discussed, it's unlikely that GLP1 are really unique, that the only drug

in the world that does this, that likely other drugs that also have broad preotropic or broad off-target effects and sort of leveraging advanced causal inference methodologies like we did in this study sort of advanced statistics and big data to give us insights into what these do and don't do, will also really enhance our understanding of not only how to approach these diseases, but also the underlying biology and pave the way for new therapeutics. You mentioned that there might be other drugs that have this kind of, I think the word you're going to use was pliotropy, which is a word that I learned from your paper and looked up and found very interesting. So like a single drug or a single gene that has this enormous span of effects that have

nothing to do with each other, right? Like schizophrenia has nothing to do theoretically with, you know, obesity, and yet this drug seems to have some kind of effect on both. If you were going to do, if someone, the NIH comes to you tomorrow and they say, yeah, this is absolutely fascinating work, we would love to understand the pyotropic effects of other drugs that you think might have this kind of broad effect that's not yet fully understood, what would be your first nominees for drugs to study like this? Is it statins? Is it something else? Well, statins definitely come to mind because they're definitely, you know, they do at least from what we've known about them so far, but nobody has applied the same methodology studying statin, but from bits and pieces from

studies like that have been done on statins, there is very, very possibly, I should say, you know, a broad pleiotropic profile of statin. The other one is really is SGLT2 and which is actually one of the drug that we use as controls here, but we didn't sort of study it on its own as LGL2 inhibitors. And can you slow down there? Because I know what statins are for blood pressure. I don't know what you just said. So just what did you just say and what is that with that drug?

So SGLT2 inhibitors is a kind of drug that is used for diabetes. And one common example of commercially available drug is Jardians. And there are other medications also that under the class of SGLT2 inhibitors. So there are some studies in mice and also early studies. in humans, not similar to ours, but sort of a suggestive, you know, sort of only targeting, you know, a few health conditions suggesting that SGLT2 inhibitors might have a broad pleiotropic profile or broad beneficial profile across multiple organ systems. So I think here the big aha moment for us is really, you know, leveraging these advanced technologies or advanced sort of

causal inference in biostatistics and data science can actually help us understand. what new drugs and actually even all drugs like statins do and don't do and help inform the biology of many diseases because, you know, these studies sort of, you know, help us, help us, you know, sometimes help orient us like, oh, in Alzheimer's disease, you need to think about the LP1 pathway, which has not been previously considered in the biology of GLPA of Alzheimer's disease. The idea that a whole host of diabetes drugs could serve these benefits is really interesting. to me for the following reason. This might be a bit of a just-so story, but tell me if you think it, you know, flows too far into make-believe land. You know, our bodies are made to need and seek

survival in environments of scarcity. And so we should, we are designed to want calories. We're designed to want fat. We're designed to want more of that which is now super abundantly available to us. And we do live in an era where it's easier to get our dopamine from phones or from our environment. It's easier to seek out and over-consume food or drugs or porn. And it's interesting to think that these drugs seem to serve as a kind of corrective for the evolutionary instinct to over-consume in an environment of scarcity. They're drugs that essentially take the human body and put us in line with an age of caloric and stimulative abundance. It's a very interesting idea to me that might go a little bit, at least stylistically, toward explaining why these drugs seem to be so beneficial for us in so many different ways. Because this is beautifully put.

So if you think about it, it's almost like putting the break on overconsumption and putting the break on overeating and putting the break on addictive disorders. And it's almost like a, you know, sort of helping you sort of put back the body and the whole metabolic machinery back in line with what it actually really needs. And arguably, you know, maybe with greater evolution, we're like if we, you know, if we track the human species for maybe an. another a million years. Maybe we'll actually have a, in the presence of a lot of abundant food and a lot of abundant resources, maybe actually our bodies will engineer themselves to actually

have a, you know, a more elaborate system to produce GLP1 and now you won't need GLP1 receptor agonist. But again, that's really speculative on my part. So I do hope that people take from this that obesity is actually a disease that could be managed with medications. And it's not lack of willpower, that these drugs are actually teaching us a lot, not only about the biology of obesity and the biology of diabetes, but also the biology of other diseases. And in demonstrating they have broad, pleiotropic or beneficial profile and risk profile across multiple organ systems, that are opening avenues for us to really treat these conditions, effectively treat, Alzheimer's disease, infections, clotting disorders, addiction disorders. And also giving us sort of a,

a blueprint or where to look for, you know, for side effects to hopefully be able to mitigate those adverse events. And one last note, the story of GLPOM is still being written. This is not far from complete. You know, this is really one piece of the larger puzzle. This is really a larger puzzle that we are sort of putting together. And this story or this paper here is really just one piece out of the very large puzzle that we need to continue to put these pieces together to have a better understanding of what these do. And hopefully that understanding would be leveraged to address the obesity crisis in the United States

and hopefully many other conditions. Ziyadh-A-L-A-L-L-A-L-L-I, thank you so much for writing this paper, and thanks for appearing on the show. Well, thank you for having me. Many thanks to Ziyadh-A-L-L-L-I. My one thing to remember from this episode is actually a kind of door number one, door number two framework. Door number one is what if GOP-1s are truly special?

What if this is akin to the penicillin of the 21st century? If that's true, we should be throwing everything at this. Research to reduce the side effect profile, public policy around reducing cost. Even public policy may be around ideas like advanced purchase commitments of paying some of these companies up front to buy out patents of the drug to make it cheaper to distribute to the general public, which is essentially what we did with the COVID vaccines. Probably some combination of both some advanced market commitments and higher insurance coverage, but it would just be fantastic if indeed people are discontinuing use of GLP1 drugs because of the cost to find ways to make this more

affordable to more people. But here's door number two. Door number two says, What if GLP1 drugs aren't special, as Al-Ali suggested was possible? What if other diabetes medication is similarly miraculous? What if drugs like statins have the same, I love this term now, pliotropy, the same ability of one drug to cause a bunch of different effects that have nothing to do with one another? What if the same way so many of us just sat around for years, while GLP1 drugs were in broad use among diabetes-2 patients,

not recognizing what we had, what if in that same way there are other miraculously pliotropic drugs that are just sitting around in our pharmacies and our doctor's offices whose full benefits we don't know yet and don't understand? It seems like maybe we want to do more

of precisely this kind of discovery research where we take an enormous number of people in these medical systems where we can somewhat control for costs and say, what is the actual effect of the drugs that we're using on our bodies? I find that a really compelling thought. We'll talk to you next week.