Plain English with Derek Thompson - Plain English BEST OF: If GLP-1 Drugs Are Good for Everything, Should We All Be on Them?

Episode Date: January 6, 2026

Throughout December and January, we’re going to be re-airing some of our favorite episodes of the past year and beyond. This list includes interviews that really stuck with me and some others that you guys had tons of feedback and thoughts on … including this one! “If GLP-1 Drugs Are Good for Everything, Should We All Be on Them?” originally aired September 16, 2025.If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek ThompsonGuests: David D’Alessio and Randy SeeleyProducer: Devon Baroldi Learn more about your ad choices. Visit podcastchoices.com/adchoices

If you're a fan of the inner workings of Hollywood, then check out my podcast, The Town, on the Ringer Podcast Network. My name's Matt Bellany. I'm founding partner at Puck and the writer of the What I'm Hearing newsletter. And with my show, The Town, I bring you the inside conversation about money and power in Hollywood. Every week, we've got three short episodes featuring real Hollywood insiders to tell you what people in town are actually talking about. We'll cover everything from why your favorite show was canceled overnight. Which streamer is on the brink of collapse? And which executive is on the hot seat? Disney, Netflix, who's up, down, and who'll never eat lunch in this town again?

Follow the town on Spotify or wherever you get your podcast. Hi, everybody, Derek here. In December, my wife and I welcomed our second baby girl into the world. I'm going to be taking some time off, but we wanted to keep the pod going through the holidays. So we're going to be re-airing some of our favorite episodes from the last 12 months, a kind of best of compendium. And this list includes interviews that really stuck with me and others that really stuck with you. and you had lots of feedback and thoughts on, including this one.

I'll be back in the new year with fresh content, but until then, happy holidays and happy new year. Today, would I consider the most interesting question in all of medical science? How are GLP1 drugs so good at everything? And if indeed they are good at everything, should we all be on them? Several years ago, scientists took a close look at GLP1 drugs,

such as OZempic, and learned that they were pretty good at helping people lose weight. In the last few years, they've taken an even closer look and learned that these drugs are good at just about everything else. GLP-1s, technically known as glucagon-like peptide-1 receptor agonists, seem to curb alcohol, cocaine, and tobacco use among addicts. They prevent strokes, heart attacks, chronic kidney disease, sleep apnea, and Parkinson's disease. They're associated with the lower risk of several cancers, including pancreatic cancer and multiple myeloma. Arthritic patients and the drugs say they experienced relief from knee pain that was, quote, on par with opioids. A small study found that they reduced migraine headaches by 50%, and emerging research suggests that they might even slow the rate of memory loss among people diagnosed with Alzheimer's.

If you don't believe what you deterred, if you consider it fanciful, under the reasonable premise that miracle drugs don't exist, I agree with you. I can't quite bring myself to believe this either. Vaccines and other drugs seem to do one job well. They're like a key designed perfectly to open one lock. GLP1 drugs, however, seem more like a lanyard that holds your house keys, your car keys, your friend's backup keys, your CVS rewards card, your work fob, and a mini Swiss Army knife that has little tools on it

you've never actually figured out how to use. They do a zillion different things, and like some of those tiny blades in the Swiss Army knife, it's not entirely clear how some of these things actually work. Here's what we think we know for sure. GLP1 drugs stimulate the production of insulin, which reduces blood sugar. This makes it an ideal weapon against type 2 diabetes. We're also pretty sure that the drugs work by slowing gastric emptying,

which essentially means the food stays in people's stomach for longer. Patients often feel full and rarely hungry. We're also pretty sure that the drugs work on the brain. Patients frequently report less food noise, which is that constant worrying and planning around eating that's reported by many people who struggle with their diet. With the combination of full stomachs and clear minds,

calorie intake goes down and weight follows. But when I think about how these drugs work on the rest of the body, I imagine a pinball machine. When you launch a ball on a pinball machine, it pings up around the board's targets and bumpers and pockets going bing, bing, bing, bing, racking up points as it flies around. The human body is a machine with many welcoming targets for GLP1. The drugs dock with receptors in our gut, near our heart, in our immune system, and in our brain.

As a result, it moderates the activity of all sorts of systems throughout the body. The end result is a broad-based reduction in inflammation, a calmed essential nervous system, a reduction in craving that gives people the ability to ignore unwanted, compulsions and focus on what they want to pay attention to. Today we have two guests. David Delessio is Chief of Enochronology and Metabolism at Duke University School of Medicine, and Randy Seeley is a professor of surgery, internal medicine, and nutritional sciences at the University of Michigan.

We talk about how these drugs work, why they seem to do everything, why they might not do everything, and how our understanding of them could make them better, more effective, and more broadly useful. I'm Derek Thompson. This is plain English. David Dolesio, welcome to the show. Thanks very much, Derek. A pleasure to be here.

And Randy Seeley, welcome to the show. Thank you for having it. I'm really happy to be. So I want this episode to be clear, and in honor of the podcast name, Plain English, I want people to be able to follow it. I also want this episode to be a little bit nerdy. I want to understand,

much as I can, how these drugs do some of the strange and amazing things that they seem to do. So I was thinking that we would structure the conversation this way. I want to walk through some of the effects of GLP1 drugs. And I want you to first give me a simple answer to my questions, like, why are they good at helping people lose weight? And then I want to go a level or two deeper. And I want you to have the opportunity to nerd out a little bit and explain in greater detail how and what is happening to our bodies. Does that sound okay that we'll sort of, we'll start with the basics, and then my follow-up questions will sort of lead us down, down, down the rabbit hole? You've come to the right place for nerds, right? Excellent. So, David, let's start with you.

Really simple question. Why are GLP1 drugs so good at helping people lose weight? I mean, it turns out that they shut down your desire to eat food. Their satiety drugs, or they commandeer the satiety system that's baked into all of us. What does that mean? They commandeer the satiety system. What is that? Yeah. So, I mean, the reality is that at some point, even if it's your favorite meal,

you will put down your fork and stop eating. And that constitutes a control of meal size that we all have. And there's a number of factors that regulate this, including neuro loops and neuroreflexes and circulating factors like hormones. And it's a complex mechanism. And I think in terms of the physiology of GLP1, it is just a bit player in this. And my view is that there's not enough GLP signal after a normal meal to be the whole satiety effect. but if you give a large dose of a drug that will activate the glp system you can sort of drive that system drive the neural factors that are downstream of it and cause people to just eat less

and when i when i see patients in the clinic and they tell me they come back after their first three months on the drug and they've lost 18 or 20 pounds and they're just sort of a bullion that this has happened. They say, you know, I thought it was going to make me eat less. And I say, well, it is, isn't it? And they say, yeah, I guess a little bit, a forkful here or a skip dessert there. But it's not dramatic. It's not like your appetite goes all the, it goes away completely. It's just a few bits, a little bit every day. But that's how you lose weight is a few calories at a time. So I've read several explanations for what's happening here. One explanation is that it's working on the gut.

It's slowing gastric emptying, the rate at which food leaves the stomach. Another is that it's working on the brain. It's reducing food noise, the chatter that's constantly telling us, I'm hungry. Where am I getting that next food? What else might contribute to an explanation of how exactly these drugs are helping people lose weight so easily? I mean, I think you've hit on a number of them. the gastric empty and gastric motility may play a role, although these drugs work in people with bariatric surgery who don't have normal gastric function anymore.

The side effects that are common are nausea, sometimes to the point of vomiting, and that probably contributes a little bit too. In the clinical trials, there hasn't been a strong correlation between nausea and food. intake. And I don't know that that question's been asked at the right level of precision, but it doesn't, it's not just that you're queasy all the time. I mean, I think it actually makes you feel fuller or turns down the drives to get seconds or take another piece of pie or whatever it is. So it's a complex mechanism. But again, I think it's not, when we give these drugs, we're given GLP at such a high level that it sort of activates a broad range of effects.

That's always been my view, that it's not just tweaking of normal physiology. It's just putting your foot all the way to the floor and turn in the accelerator wide open. Randy, I feel like I want to bring you in to talk a little bit about the brain here. What is the brain gut access and how does the brain fit into this weight loss picture? So you can imagine that your gut's a really important part of your body, right? It's absolutely essential for your survival, which means your brain has to know what's going on your gut and be able to change what happens in your gut. And your gut is a completely adaptive organ, right?

It has to be different under different circumstances. Your turnover your entire GI tract every seven days, right? So it's a very plastic organ. So you can imagine your brain has to be intimately involved in understanding what's happening in your gut and then being able to direct it as well. And I think this goes into the issue about, like, and why is it these drugs? drugs cause weight loss. I think the simplest way to think about this is that they change the defended level of weight. So we all defend a level of weight, some higher, some lower, right,

based on both the genetics that you have and the environment that you live in. And what these drugs do is lower that weight that the body thinks is appropriate. And the magic of what happens with these drugs, right, is that people lose weight and they're less hungry while losing weight. If I taped your mouth shut, you'd lose weight. But would you be less hungry or more hungry? And the answer is you'd be more hungry. So the magic of what happens here, right, is that while people are losing weight, they're not experiencing the normal response to weight loss.

They're not experiencing what would normally make you hungry, right? And again, you talked about food noise, right? That's where it comes from, right? When you're underweight, you can imagine that all of your physiology is now oriented to all of the cues in your environment that might be related to food, right? That's what your body is now oriented to do. And what these drugs do is they lower that set point so that in fact that you can lose weight and be less hungry while it happens.

And that happens in the brain, right? So again, the direct actions of these drugs in the brain are what drive that particular weight loss. Do we know where it's happening in the brain? I think there's been two major conversations about this, two different competing hypotheses. One is an area of the brain called hypothalamus, right, which is thought to be where your body weight set point was registered and recorded. And the other place is in your brainstem. So there are areas of your brainstem that receive direct signals from your gut and direct signals from the blood. And those areas also have GOP1 receptors. And I think the modern version of

understanding how these drugs work is that they work primarily by changing those brainstem circuits that then talk to those hypothalamic circuits rather than having a primary effect in the hypokinomics. And David, back to you. If I wanted to have a clear understanding, of what parts of the gut GLP1 drugs most likely are acting on? What would we be talking about here? We're talking about the pancreas? Are we talking about the intestine? If I wanted to understand in my head, like a heat map of where GLP1 drugs are affecting stuff

inside my gut, what should I be thinking about? Well, so, so GLP1 is made in the gut. made in endocrine cells in the gun and secreted to a certain extent into the blood. And when GLP was discovered, that's what we thought happened. You ate, you secreted GLP in the blood, circulated around, hit your pancreas, and stimulated insulin secretion. And there was this elaborate model that the amount of food you ate was proportional to the amount of GLP1, and that led to a perfect amount of insulin secretion to dispose of the

nutrients in the blood. It turns out that the GLP isn't secreted that much, relatively low levels in the blood, gets metabolized quickly, and so that model is not probably accurate. GLP1 affects motility that is gastric emptying and the rate of flow through the gut, as you mentioned before, but that's done outside the gut. That's a brain effect. in the gut, in the in the in the abdomen the target tissue is the pancreatic eyelid and it's the beta cell on the pancreatic is the cell that makes insulin and secretes it that that's probably the target for the drugs that's where the drugs are having some of their beneficial effect in people with diabetes to what extent were scientists stunned by the degree to which a drug

designed for type 2 diabetes patients, was this effective at producing this level of weight loss? Was there a scientific model, for example, that said, oh, well, if you design a drug that hits pancreatic beta cells in this kind of way, you could absolutely see an enormous knock-on effect on weight loss, or did we see the results before we put together the theory? Yeah, what I would say is we had an inkling that these drugs might work in the brain. I think the majority of people in the 90s thought that this was not going to be important. The 1995 is when the hormone leptin was cloned and discovered, and everybody thought this was going to be the cure for obesity. And the GLP effect was seen as kind of phenomenological.

and oh, that just makes you feel sick, and this won't happen. This won't ever amount to much. And then in the first clinical trials, there started to be these low level of the early GLP1, exenitide, laryglotide. There started to be modest amounts of weight loss, four kilograms, five kilograms. That was a big deal because in those days, the other drugs we had to treat diabetes made you gain a few kilograms. And so patients hated that.

And now you could say these drugs will make you lose weight. I was surprised at that. I think a lot of people were surprised at that. What was just shocking was that as they refined the GLP ones, as you went from accentedide, laryglotide to the next generation, and particularly semi-glutide, you give a drug that lasts all week. You give it at a pretty high dose. And now the weight loss was well beyond what we'd ever seen for medical therapy.

And again, I was really surprised by that. And just to backfill some of that vocabulary, exanitide is the GOP-1 drug that was famously synthesized based on the proteins that scientists found inside the Gila monster, a venomous lizard. So they synthesized the Gila monster's saliva, and they turned it into exenotide. That has been overtaken by, as you said, semaglite, which most people know as Ozempic. And then leptin is a protein associated with fatty tissue. sometimes known as the obese protein, and some drugs based on leptin have also been approved.

Randy, jump in here. Yeah, just to highlight this again, inert on you a little bit, right? So the reason why you think leptin would be great is because if you build a mouse that doesn't make leptin, the animal gets really, really fat. So by the way, that's important for your normal physiology, right? If you knock out gLP1 or glporeceptors,

nothing happens in terms of the weight, right? So I always say, like, if you had gone into the chief scientific officer of your large pharma company and said, I have the great billion dollar drug for you, right? It's a hormone that lasts two minutes in the blood. And by the way, the knockout has no phenotype whatsoever. You'd be looking for a new job, right? Like, it just doesn't make any simple biological sense. And I think this points to both the serendipity, right, that Dave alluded to, but also the notion, right, that it is not physiognized, right? It is not part of what we are not mimicking something that the system, particularly the gut system does on a normal basis, right?

We are overloading the system, right, to be able to drive enough GOP1 activity in the brain, right, to overcome and change that body weight set point in a way that I don't think would have been easy to predict from the data back going back into the 90s. Randy, I think a lot of people, even with all the coverage of GLP1s, are still surprised to learn that it is, in part, a brain drug. They think they're taking a drug to lose weight, that the drug is going to parts of their gut, and that it's acting on parts of their gut. I would love you to explain a little bit about this idea that there are receptors for GOP1 drugs in the brain, like that the brain seems to come strangely pre-made for this drug. Maybe talk a little bit about how that works before we get into some of the neurodegenerative benefits. So I think this is a really important point. Lots of people want to build the model around the idea,

I eat food, I secrete gLP1 from my gut, that now tells me or my brain or my gut how much I've eaten, and therefore I stop eating. Again, that biology probably just isn't true on any level. What is true is that we do have gilpone receptors in the brain. So why do you have gLPone receptors in the brain if gut glpone isn't normally getting? The answer is your brain makes GOP1. So in addition to the GOP1 that's being made in your gut, you have a specific set of neurons in the brainstem, like I talked about before, that make GOP1. And what we're really doing with these drugs is we're hitting those GOPN receptors

that are normally listening to those neurons that make GOP1. And one of the other things about this, right, is that those GOPN receptors are all over your brain, right? They're very widely distributed. But in fact, the drugs actually only get into very small parts of the brain. So we're not actually hitting all of the places that JLP 1 acts. We're hitting very select populations. And again, that's serendipity, right? That wasn't a design feature of the drug.

It turns out it just to be something that, in fact, actually benefits its action. Turning to the brain effects, it is a little bit spooky that these drugs seem to do a little bit of everything. They reduce food compulsions. They reduce food noise. They reduce tobacco addiction. They slow the progress of Alzheimer's, according to some studies. Maybe they reduce migraines and Parkinson's, according to other research. I mean, I don't personally think that miracle drugs exist.

It's very hard for me to believe the research that I read, but it really does seem like these things are doing wondrous stuff for the brain. Why? Well, I think this is, I'll start with the big sentence here, right, which is, this is the way the arc of many of these drugs that get used widely go through, which is the idea that they only fix one thing. Then we decide maybe they fix everything. And then now we wiggle that back into what it is that they actually fix.

And we are in the process right now about GOP ones fix everything. And I think we're going to find out we're right in some cases and we're wrong in others. And that we'll eventually get trials that actually tell us what it is that it's best used for and which patients are going to most benefit from it. And I don't think we're there yet. And I think I'm happy to talk about the alcohol one a little bit because I think that's the one that I'm the least, I'm less optimistic about, right, than most of the folks that you might talk to. And I'm happy to give you a little bit about one.

And so the version of this about reducing compulsion is the idea that somehow, again, I'm reducing your drive for food. Maybe I'm reducing your drive for everything. That's sort of the simple-minded version of this, right? I'm just lowering your motivation. But again, I don't think there's any evidence for it, right? Because then the drugs would be associated with sexual dysfunction, right? They'd be associated with, again, not drinking when you're thirsty. And in fact, that's not what you see happen.

So the issue becomes, well, then why would they work? Well, I can tell you that when you set up an animal, right, to get, you can put an electrode in its brain and it will actually press a lever to get that electrical stimulation in very specific parts. It's rewarding for the animal to do. If you make the animal hungry, the animal presses the lever more, right, for that particular stimulation. So again, hunger amps up the drive, right, to be able to do these other things. So again, if you're removing some of that hunger, right, then lowering the set point, then, in fact, maybe you will lower compulsions for other things. But the problem for that is people eventually stop losing the weight, right?

Dave can attest, right? Eventually people plateau. And what you'd expect then is, in fact, that they would go back to the place they were before, right? The rest of their physiology will be the same as well. So when you hear about the very strong anecdotal data and the small amounts of experimental data around alcohol consumption, gambling, those kinds of things, it's all during the first couple months that people are taking the drug where that data is recorded. So what I worry is, again, will it be effective still when in fact they have reached the nadir, right, of the use of that drug? And where they actually put it.

And I think we just don't know that. And I hope I am wrong. I hope, in fact, these drugs are useful in that. But I have been on the record as being somewhat skeptical about whether they will have long-term effects in the way that we would. It seems like there's a lot of studies ongoing about the degree to which these drugs are neuron protective in ways that reduce symptoms of Parkinson's or slow the development of Alzheimer's disease. What are we learning about that right now? And what do you think those learning suggests about the way that these drugs act on the brain? So I think the first thing you have to remember, right, is that while GLP1 are widely spread

on the brain, they're not on every neuron by any stretch, right? So you cannot protect every neuron by simply turning on its GLP1 receptor, right? Which is sort of the simple-minded version of it. So what's likely to be true and likely to be true for lots of the things that we think that GLP1 drugs do it as a benefit is that they involve the immune system, right? So obviously there's a lot of ways to turn on and off your immune system, right? And a lot of ways that we would turn off your immune system are dangerous, right, because they leave you more susceptible to opportunistic infections, right?

So if you use a TNF inhibitor, right, you have to worry about cancers and opportunistic infections when you're using those drugs. That's not a problem for the use of the GLP1 drugs, which implies, right, that its interaction with the immune system is actually quite different. It's doing something that is much more subtle and much more targeted than what what it is that we do with these other drugs where we take on big parts of the immune system and big immune drive, big endocrine drivers of those responses. And from my perspective is the best version of that probably is it does involve the brain,

right? So the effects on the brain are actually altering the way the immune system is operating in some way. But I will tell you, that would link both the ability to help chronic kidney disease, cardiovascular disease, and the neuroprotection effects all under one rubric. of being generally anti-inflammatory. And I think that's the easiest way to think about how it is these drugs are working. But again, to nerd out on you for a minute, the wonderful thing about this, this now becomes a tool for us to pull apart the immune system in a way that we have not been able to before. And a way to be able to push and pull on it in a very unique way, again, that we had no idea what's going to happen, but turns out to potentially be clinically useful.

And the more we understand exactly what it is, then we can be more directed, right, pushing and pull. on the immune system in subtle and important ways, right, to drive more clinical benefits for a wide range of conditions even beyond the ones we're using GLP1 drugs for today. That's great. And David, before we just go back to you, Randy, what's interesting about that last thing that you said is in the piece that I wrote for my substack, I said, one of my theories for how GLP1 drugs seem to do everything they do is, I said, quote, GOP1 drugs seem to be a moderation molecule.

I went on, I said, scientists don't quite sure about how these drugs effectively moderate every system they touch, but they seem to reduce overeating as efficiently as they reduce inflammation. Like some itinerant Buddhist monk, they seem to travel throughout the body preaching a message of moderation everywhere they visit. It is really spooky and strange that, to your point, many things that act on, say, the immune system go too far, right? They shut down the immune system, like, say, chemo, in a way that makes us get sick. Or they ramp up the immune system, like inflammation in a way that makes us unhealthy. But these drugs, for whatever reason seem to be a temperate agonist, right? They seem to activate certain systems in

ways that are incredibly, I think of it like a weather, like it keeps it within like a temperate climate. Before we go back to David to talk a little bit about some of the cardio stuff that he, that he's observed and has read about. Is there any useful way to understand how these drugs seem to have this sort of consistently moderating effect throughout the body? I think what you can think about these peptides generally have sort of these sort of moderating effects, right? They're not doing the direct work, right? They are moderating the response to other inputs. That's certainly true in the brain, right?

In the brain, the biggest workhors are neurotransmit like gaba and glutamate. Gaba turns off the next neuron. Glutamate turns on the next neuron. Then you have these peptide systems that moderate. Well, how effective is the GABA and the glutamine? And GLP1 does that. If you look at the beta cell, there's a similar version of this, right? So glucose causes your beta cell to be activated and you secrete more insulin.

What does GLP1 do? It ramps up that response. And it's part of why it's a very effective drug for type diabetes because you don't put patients at risk for hypoglycemia. Because only when the glucoses are elevated, does the GLP1 have an effect, right, to produce an increase in insulin secretion? You don't just start jamming on your insulin secreting cells in discreet. So I think you're hitting on the right idea, right, that these peptide systems, right, are modifiers of other things that are going on in biology rather than direct actions of that biology. And I think that does provide in some circumstances like chronic conditions like we're talking

about, right, some real advantages in terms of long-term therapy. I'd add a couple of things to that. One, I like the idea of the moderating hormone because I do think that's part of it. And Randy's given a reasonable explanation. The other thing is the types of receptors of which the GLP receptor is in the class, with chronic stimulation, they sort of damp down their signal. So there are systems to moderate the amount of signal at a GLP1 receptor will generate. It's called desensitization.

And so that probably has a rule. But the other thing that I've been thinking about a lot is the receptors for this, are diffuse, right? They're not on all the neurons. They're not on all the islet cells. Elsewhere in the brain, they're not on all the lymphocytes. They're on small subsets of lymphocytes. They're on vascular cells, the cells in the lining of the blood vessel, but not all of them.

So just the fact that the targets are so diffuse, I think, prevents you from getting, you know, these kind of overwhelming effects that we see, as you said before, with anti-need. plastic drugs where you blast all the immune cells at once. It's a system that's built for moderation in the distribution of its receptors, in the types of receptors that it has. And again, I think I think that makes it harder to study. You can't cut out all the GLP receptor. But I think that's a, I'm going to start using moderation. I will credit you. Cool, yeah, the moderation molecule. I love this idea that the body,

that the very same thing that makes GLP1 drugs a moderation molecule also makes their mechanism hard to study, right? And that is the fact that they're only expressed on a certain share of certain cells and certain neurons. It also makes it hard if you're the CEO of a pharma company to decide to use it. Right?

In other words, if you have something that has very potent biology, right? Like you super big obvious effects, TNF alpha, IL6, or things like this, right? Then, by the way, turning those on and off, boy, those seem like a great idea, right? I can move a lot of biology around. I can move the system around a lot, right? And if you're trying to fix cancer, that seems like a really good idea, right? I want to be as potent as I can.

But in the context of these chronic diseases, sometimes being subtle, right, over the long run, is more effective than, again, taking the biggest hammer I can find and taking it to that biology. David, we've talked about the gut, we've talked about the brain. Let's talk about the heart and blood vessels. There have been some fascinating studies that show that people experience the cardiovascular benefits of these drugs, even before they experience the weight loss effects. Is it possible that GLP1 drugs aren't just gut drugs, aren't just brain drugs, they're also heart drugs?

Yeah, and that was also a surprise. So years ago, the FDA put in an edict that said, if you're going to bring a new diabetes drug to market, we'll let you take it to market, but you have to promise to do a cardiovascular safety study. And, you know, everybody hate everybody. The drug companies hated that because he cost a lot of money. And then they started not only being safe,

but showing a reduction of cardiovascular events. And then there was this whole new area of clinical medicine that opened up. And in fact, if you have heart disease, particularly if you have diabetes in heart disease, and you take one of these drugs, your risk of having a recurrent event goes down. And again, that just fell out. There was no reason to think that was going to happen. There's very few. You have to look really hard to find a GLP1 receptor on heart cells.

there's a few scattered around on some of the blood vessels that serve the heart. And so we don't know why that happens. But it's a reliable effect that you can see in these trials. Cardiovascular disease is still the number one killer in the U.S., and it's particularly so in people with diabetes. So talk about serendipity. This turned out to be a real boon to people who do diabetes medicine. Now, again, the mechanism not cancer.

clear in the trials, if you go back and do post hoc analyses of the trials, there's, or what's called a mediation analysis, that is you take a bunch of factors and say, which factor is most associated with the beneficial effect here? Weight loss never comes up positive. It's never the thing. So that your inference there that these are two different pathways, I think, is well-founded. And that's kind of the way I'm thinking about it, that it's not just another downstream effect of the brain circuits that Randy's been talking about. It's probably a different mechanism entirely. And again, we're still, the basic science, the physiology is still trying to catch these now pretty predictable clinical effects.

I was thinking it's a little bit like you can, when you're thinking about how these drugs are having all these effects in the body, you can either think of that through sort of like a domino model or a Swiss Army knife model. Like the domino model is, it caused you to lose weight. If you lose weight, it's you reduce inflammation. If you use inflammation, you're less likely to get Alzheimer's. If you're less likely to get, you know, it also, and so everything follows from one domino tipping. But the other is the Swiss Army Knife model, right? It's got the, you've got the knife and you've got the scissors and you've got the corkscrew. And that's a little bit closer to, all right, well, if there are GOP-1 receptors distributed throughout the body,

and some are in the gut, and some are in, you know, vascular lining, and some are in the brain, then you should maybe expect it to have one effect on the gut and a different effect, or a separate effect in inflammation, and a separate effect in the brain. And so that's very interesting to me. Yeah, you're hearing on the right thing, but right, I care about the brain, right?

So I'll bring this back to the brain. the notion, right, that you can push and pull on the system in the brain, and then that then talks to all these other pieces of the puzzle, right? So it's a domino, but it's not just the weight loss. And weight loss is a good thing, right? Helps lots of these disease states and improvements. But the idea, right, that I'm pushing and pulling on the immune system via the brain, then I don't have to care about whether there's geopolitical receptors in different places, right?

I can do this all by moving the brain around, right, to control the immune system in a way, again, the weeds, that it's subtle, but effective for these chronic disease conditions, right, that makes it very different, right, than the idea, oh, yeah, it's having a little effect here in the endothelial cells, it's having a little effect in the gut. Again, I think how it does that in the brain, and exactly how it exerts those positive effects, it's still very unclear. But you can imagine, right, that it's separate than the weight, right? The effect of change the immune system is separate, but again, it involves that everything starts, right, with the central nervous system. Randy, one more question for you before we talk a little bit about

the near future. Something I didn't get to is I've always been interested in the degree to which folks who study this, and particularly its effect in the brain, see this as majorly implicating the dopamine cycle. Has that been studied directly? Or are we just like, you, for example, in one of your answers, you use the word drive over and over and over again. You know, dopamine is the drive chemical. So like, to what extent are we sort of accidentally stumbling into a drug that's having like major dopaminergic effects. Is that something that we know a lot about, or is it still in the realm of

conjecture? There is definitely evidence, right, of it having indirect effects, right? So you bang on some of these neurons in the brainstem, right? They talk to other neurons that eventually have effects on the dopamine system. But the part that I think that is harder to understand is, in the dopamine system itself, right, is not drive writ large, right? That is being a interested in water is way different than being interested in food. And you don't mix those two up, right, as much of the league. So there isn't one drive, right? There are multiple drives, right, for which the dopamine system can be used, right,

to facilitate the reward function, right, that makes it rewarding to be able to fit and solve that drive. If you can't tell, right, my PhD is actually in psychology, right? And so the issue about how it is that that is organized is really important. But right, there is definitely data, right, that you're altering the dopamine system. But again, it's more subtle and more specific than the way I think it often gets portrayed or the way many people want to think about how the biology. David, when we were talking before this interview, you said you had never seen patients so enamored of a drug as they started taking it. But if you look at the data, the number of people renewing at six months or the share of people renewing at six months is like 50%.

what do you think explains the discrepancy between the passion that new patients seem to feel about this drug and the fact that the six-month attention rate is just 50%. Yeah. That, I think, is something that's been overlooked. I think that's one of the biggest questions about GLPs for clinical medicine, because it's just stark. And at first I thought, you know, it's expense, right? These are expensive drugs.

Nobody can buy them retail because they're $1,500 a month. or something like that. But even the co-pays for a lot of patients are steep. But if you look at the data, even in the UK, the adherence rates in the national health system where the drugs covered are also pretty poor. And that was really puzzling to me. So, you know, what are other possibilities? One is, I mean, what used to happen with the early GLPs is I'd say we're going to fix

your diabetes and you might lose a lot of weight. And what the patient heard was, blah, blah, blah, weight loss. And then when they lost four kilograms, I mean, if you're 104 kilograms and you lose to 100, you know, that's a little bit disappointing. I think people do have expectations for these drugs. And the people, there is a notion that the people who lose a lot of weight tend to stay on them. I've seen, I've had people come back to me and say, all right, I'm at my target now. Do I stop?

Do I taper? What do I do? I say we've got to figure this out together because there's not a guidebook on this, yeah. So I think expectation is probably a part of it. Cost is probably a part of it. Chronic side effects are a part of it. But it really should be addressed. And I think the people who are really interested in this,

besides those of us who write prescriptions, are the people who pay for prescriptions. Because insurance companies just hate for you to start down a thing. therapeutic avenue and then hit a cul-de-sac. And they've spent all this money and you're going to go back to square one. So there's, you know, that's one of the reasons that everybody keeps looking for longer-acting drugs to try and improve adherence. It just doesn't get around the question that you raised, which is pretty profound, that this is a drug people ask for by name. And then in six months or a year, they want to do, want to try something else. Well, one way to ask this question in a different way, and that was a fantastic answer, is adherence to this drug after six months low

because the drug is successful or because the drug is unsuccessful? Right? Because maybe people are getting off the drug because they're losing weight so quickly that they're hitting their target weight, and they're thinking, well, I'm at my target weight. So I don't want to be on a drug I don't need to be on, and I'm there now. So that would mean, oh, well, the drugs are ironically, maybe for the manufacturer or the pharmaceutical company, too successful to be optimally profitable. But another explanation is that, no, we need to do a lot more work because what's really happening here is that the side effect profile is such that people just don't like being on the drug that much.

And so therefore, they're dropping off after six months. What's your read? Yeah. Well, so this is something that I'm very interested in because it's something that we're actively studying. But there's a lot of gene variants of the GLP1 receptor. some of those variants affect function so that across a population, you have some people that are very sensitive to the drug and some that are not sensitive to the drug. Yet we have one paradigm

for dosing the drug. And so you could see where if you're really sensitive to the drug and your prescriber keeps amping it up the dose, you're going to get a lot of side effects. Or if you're one of the people that's relatively resistant to the drug, you may not see any effects until you get to the top dose. And I think everybody, you know, you have a common dosing paradigm. You have a common set of expectations, but then your constitutional, your genetic response to the drug can vary quite a lot. And it may be that the non-adherent people are at both ends of the bell-shaped curve, either the very sensitive or the very resistant people. And I, you know, I thought that, again, we thought that was an important question, and we're finishing

in a study on that right now. But I think that, I think you're, again, that's a reasonable inference that that patients aren't quite getting what they want or they're getting either too much or too little. I'll throw out a third version of this, right, that I think goes with the shaming of people to use these trucks, right? So, again, one of the things that has been most disappointing to me, right? Five years ago, Dave and I could see this thing come. We knew that this was going to happen.

We were going to have effective medications that were probably going to be a more way better adoption than we've had before. What I didn't anticipate was the backlash to that, right? Again, how much the influencer community right wants to pick out and shame people for using this approach to losing weight. They're going to shame them for not losing weight. They're going to shame them for losing weight using this method. And what that leads to, I think, for lots of interviews, they do not want to medicalize their weight. right? So they jump in, right? Whether it's ineffective, it's easy, right? Okay, it doesn't work for me.

This is, all these scientists are just full of bark. If it works, then what you want, right, is, oh, I know how to do this now, right? And I'm going to be able to get off of this drug, right? Because, again, the world doesn't want me on this drug. It's my fault. It's expensive. I'm spending money. You can just imagine all the things that they've talked to themselves about. Their internalization of the reasons for their increased weight are about themselves. Again, I can tell you, I have lots of family members who have said something to the victim.

Well, I don't want to take this forever, right, because I want to learn how to do this right, the right? But it's a chronic condition that needs to be treated chronically. When people go off in that first year after they go off, they regain about 70% of the weight. So the drug is still exerting in a fact, even though they're not losing any more weight, right? And you can prove that because when you take the drug away, by the way, they start regaining it. And the animal models who don't have to worry about shame as a way to think about what they're doing, right? And we don't have to blame them for being noncompliant. I know that they took the drug, right?

You can just see the fact, again, that their weight plate plate. And as soon as you get rid of it, the animals start overeating and regain the loss weight. They're hungry again, right? So I think there's a combination of things that are happening here, right, that make it, that take all the issues of trying to get people to comply with chronic disease management, whatever disease it is that's really hard. Type 2 diabetes, Dave will tell you it is hard work, right, to get people to apply. It's even worse when everybody knows whether you're being successful or not.

Nobody knows what your A1C is if you're a type 2 diabetic, right? Nobody knows what your blood pressure is. But they know when you lost weight, right? And then you know that there are some people out there who are blaming you for losing that weight. No matter how you did it. Now there's a, you are cheating somehow right to do that. And people internalize them. Again, that makes them, I think, want to get off the drug and prove that they can do it on their

own to themselves, if not to anybody else. Billions of dollars are being spent updating these drugs, customizing them, adding new targets, double agonist, triple agonist, quadruple, whatever. We'll see what comes next. Where do you want these drugs to go? I've heard, for example, that some people are worried that the drugs melt both fat and muscle. And the loss of muscle, sarcopenia, is a huge problem for older Americans. So we'd love to have drugs that retained muscle and better targeted bad fat.

How can these drugs get better? So I will give you, one I'm going to comment on the sarcopenia. That is, if you lose weight by eating less, you lose about 70% of it as fat, about, 30% is muscle. If you have a bariatric surgery procedure, that's about what you get. And as far as we can tell, that's where these drugs fall off. Now,

they haven't been studied a lot in the population you mentioned, older people. And I can tell you that the National Institute of Aging is very worried about this. And they convened a panel. They're going to put out recommendations. But the point is, nobody just loses fat with any of these modalities.

You lose some of us. So I'm going to give you two looks at the future. One is a kind of a Star Trek-E high-tech one, and one is something that I think is practical and important. The Star Techie one is that I think we're going to know, we're going to be able to genotype people. We're going to be able to know their GLP-1 receptor, and we're going to be able to customize drugs at some point. And that's not so far off in the future, as I would have said it was five years ago. So this may be a place, finally, I always say the only people that really believe in personalized medicine are

deans giving talks to rich people to raise them up. But now I'm starting to believe that we may be able to do this. And the GLP drugs, because they have a discrete target that we can identify that you could sequence for everybody and then through a library

sort of a method, you'd know which were the good and bad responders. It may solve some of the adherence problem we were just talking to. The easiest example would be if you identify that you had a sluggish receptor, then you'd know you were going to need a higher dose. And if you had a more active receptor, you could maybe stop the dose before you got bad side effects or, you know, some other untoward thing.

Yeah, truly, if you had a high risk for Alzheimer's disease, it might be that we could, you know, corroborate your GLP1 receptor variant with your APOE genotype as well. But all those things start to be possible. And again, as you start to throw in multiple receptor agonists, and know a little bit about how they work, without getting into the details, they're all going to work a little bit different. And my bet is that at some point we can pretty much target a molecule to a gene in a way that's clinically meaningful. The practical thing is that 75% of the world's population with diabetes lives in China and India. And a lot of those people, even though those are modern booming economies, they still have a distribution of people that are poorer than are going to be

able to use injectable GLP-1s that are expensive to make, because peptides are inherently expensive to make, that take little plastic carriers that need needles, that need to be stored and shipped cold, so that in fact this great drug is probably not accessible right now to the majority of the world's people with diabetes. But pills are coming, right? There is a tablet in phase three trials now that's a pretty good GLP1 agonist. And I can tell you, I get phone calls all the time from guys that have another cool idea. And I think these, I think to have drugs in tablet form where the cost of goods is way cheaper than the peptide drugs and the distribution is a lot easier, I think makes a, in terms of having a global impact, in terms of bending the curve.

It may not be quite as strong as the latest quadruple injectable agonist, but I think if they reach more people, I think now you can start to talk about, oh, yeah, we're getting somewhere. So we talked about, again, the issue about compliance, right? And we've gone from once a day to once a week, and that hasn't entirely solved our compliance issue. I do think that part of the future of innovation here is how do we get closer to one and done, right? So if you do bariatric surgery, that's as close to one and done as we have, right? You have one surgical operation, right? We have to monitor and do things with you.

But again, the event of you interacting with the medical system is a one-time event. And presumably for a lifetime event. But again, it's very invasive. Right. So the question is, how do you get between where we are today once a week, right? And not something very invasive and injection, right, to something that is mimics the one-and-done sort of version. And so what I think we're going to see, right, is drugs with longer and longer half-lives, right, so that once a month, once every other month dosing is going to be available.

I think there are going to be gene therapies, right, that are also available, right, that are going to provide ways that we can push this system in a permanent way rather than, again, in a temporary way we do with standard pharmacology. And I think there's going to be pharmacology that can have effects that last beyond the half-life of the drug, right, where you're going to see effect, right, that as soon as you come off, you do not start regaining that loss weight. And I think all of those things are going to come together where we're going to get less invasive in longer and longer periods, right, where people are going to be able to feel less

medicalized, right? They're going to have to interact with the medical system less often, right, to be able to get the benefit and still have that benefit last for long periods of time consistent with the idea that this is a chronic condition. David Delessio, Randy Sealy, thank you very much. Thanks, Derek. Convierte your passion in a new negotiation with Shopify and bathe records of with the form of

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