← Plain English with Derek Thompson
Plain English with Derek Thompson
If GLP-1 Drugs Are Good for Everything, Should We All Be on Them?
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- [00:02]
Brian Raft
As the 21st century was getting underway, Hollywood released a series of films that were daring, entertaining, and absolutely unmissable. Films like 25th Hour, Bring It On, Zodiac, and no country for Old Men. They arrived during the George W. Bush era, a chaotic time in America. Think 9, 11, Katrina, the mortgage crisis. After the Bush years, the country would never be the same, and neither would Hollywood. I'm Brian Raft, and in my new limited series, Mission Accomplished, we're gonna dive into some of the biggest movies of the Bush years and look at what they said about the state of the nation. We'll go behind the scenes with filmmakers and experts and relive some of your favorite movies from the early 2000s, from Donnie Darko to Michael Clayton, from Anchorman to Iron Man. So slip on your sketchers, dig out your old Nokia, and join me for mission accomplished starting Aug. 12 on the big Picture Feat.
- [01:04]
Derek Thompson
This episode was brought to you by ServiceNow. We're for people doing the fulfilling work they actually want to do. That's why this was written and read by a real person and not AI. You know what people don't want to do? Boring, busy work. Now, with AI agents built into the ServiceNow platform, you can automate millions of repetitive tasks in every corner of your business, it, HR and more. So your people can focus on the work that they want to do. That's putting AI agents to work for people. It's your turn. Tap the banner to get started or visit servicenow.com AI Agents this episode is brought to you by KPMG. Making an impact is how KPMG helps make the difference. KPMG applies advanced tools and strategic thinking to convert data into actionable knowledge and deliver value by improving Improving performance through transformation, modernizing processes with technology, harnessing the power of data, navigating complex MA transactions and enhancing trust among stakeholders. Go to KPMG US Advisory to learn more. KPMG make the Difference Today what I consider the most interesting question in all of medical 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. GLP1s 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 a lower risk of several cancers, including pancreatic cancer and multiple myeloma. Arthritic patients on 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. Like 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 central 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 d' Alessio is chief of endocrinology 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 d', Alessio, welcome to the show.
- [06:39]
David d'Alessio
Thanks very much, Derek. A pleasure to be here.
- [06:42]
Derek Thompson
And Randy Seely, welcome to the show.
- [06:45]
Randy Seeley
Thank you for having me. I'm really happy to be here.
- [06:48]
Derek Thompson
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 as 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.
- [07:38]
Randy Seeley
You've come to the right place for nerds, right? Excellent. So no problem.
- [07:41]
Derek Thompson
So, David, let's start with you. Really simple question. Why are GLP1 drugs so good at helping people lose weight?
- [07:49]
David d'Alessio
I mean, it turns out that they shut down your desire to eat food. They're satiety drugs, or they commandeer the satiety system that's baked into all of us.
- [08:01]
Derek Thompson
What does that mean? They commandeer the satiety system? What is that?
- [08:06]
David d'Alessio
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 neural loops and neural reflexes 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 see patients in the clinic and 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 bullian 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 that dessert there. But it's not drama. It's not like your appetite 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.
- [09:46]
Derek Thompson
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?
- [10:11]
David d'Alessio
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'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 GLPs 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 turning the accelerator wide open.
- [11:30]
Derek Thompson
Randy, I feel like I want to bring you in and talk a little bit about the brain here. What is the brain gut axis, and how does the brain fit into this weight loss picture?
- [11:39]
Randy Seeley
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 in your gut and be able to change what happens in your gut. And your gut is a completely adaptive organ. It has to be different under different circumstances. You turn over your entire GI tract every seven days. 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. I think this goes into the issue about why is it these drugs cause weight loss? I think the simplest way to think about this is that they change the defended level of weight. 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 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. The magic of what happens here 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. It's 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 can the direct actions of these drugs in the brain are what drive that particular weight loss?
- [13:15]
Derek Thompson
Do we know where it's happening in the brain?
- [13:18]
Randy Seeley
I think there's been two major conversations about this. Two different competing hypotheses. One is an area of the brain called the hypothalamus, which is thought to be where your body weight set point was registered and recorded. And the other place is in your brain stem. 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 GLP1 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 hypothalamus.
- [13:56]
Derek Thompson
And David, back to you. If I wanted to have a clearer understanding of what parts of the gut GLP1 drugs most likely are acting on, what would we be talking about here? Are we talking about the pancreas? Are we talking about the intestine? Right. 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?
- [14:24]
David d'Alessio
Well, so GLP1 is made in the gut. It's made in endocrine cells in the gut 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. It's relatively low levels in the blood, gets metabolized quickly. And so that model is not probably accurate. GLP1 affects motility, I.e. 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 abdomen, the target tissue is the pancreatic islet, and it's the beta cell on the pancreatic islet, the cell that makes insulin and secretes it. That's probably the target for the drugs. That's where the drugs are having some of their beneficial effect in people with diabetes.
- [15:45]
Derek Thompson
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? Like, 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?
- [16:21]
David d'Alessio
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. 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, exenatide, liraglutide. There started to be modest amounts of weight loss. 4 kg, 5 kg. 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 GLP1s, as you went from exenatide, liraglutide to the next generation, and particularly semaglutide, 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.
- [17:49]
Derek Thompson
And just to backfill some of that vocabulary, axanatide is the GLP1 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 exenatide. That has been overtaken by, as you said, semaglutide, 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.
- [18:23]
Randy Seeley
Yeah. Just to highlight this again and nerd 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 GLP1 receptors, 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 physiology. 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 to be able to drive enough GLP1 activity in the brain to overcome and change that body weight set in a way that I don't think would have been easy to predict from the data back going back into the 90s.
- [19:35]
Derek Thompson
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 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 GLP1 drugs in the brain like that, the 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.
- [20:14]
Randy Seeley
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. That biology probably just isn't true on any level. What is true is that we do have GLP1 receptors in the brain. So why do you have GLP1 receptors in the Brain if gut GLP1 isn't normally getting. The answer is your brain makes GLP1. Right. So in addition to the GLP1 that's being made in your gut, you have a specific set of neurons in the brain stem, like I talked about before, that make GLP1. And what we're really doing with these drugs is we're hitting those GLP1 receptors that are normally listening to those neurons that make GLP1. And one of the other things about this, right, is that those GLP1 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 GLP1 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 actions.
- [21:26]
Derek Thompson
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?
- [21:59]
Randy Seeley
Well, I think there's. I'll start with the big sentence here, 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 whittle that back into what it is that they actually fix. And we are in the process right now of a GLP1s 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 can happy to give you a little bit about why. And so the version of this about reducing compulsions 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 that. Right. Because then the drugs would be associated with sexual dysfunction. Right. They'd be associated with again, not drinking when you're thirsty. Right. And in fact that's not what you see happen. Right. 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, very specific parts of the brain. It's rewarding for the animal to do that. If you make the animal hungry, the animal presses the lever more for that particular stimulation. Again, Hunger amps up the drive to be able to do these other things again. If you're removing some of that hunger and 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. Dave can attest, 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've actually plateaued? 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.
- [24:35]
Derek Thompson
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 learnings suggest about the way that these drugs act in the brain?
- [24:55]
Randy Seeley
So I think the first thing you have to remember is that while GLP ones 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. So what's likely to be true and likely to be true for lots of the things that we think that GLP1 drugs do as a benefit is that they involve the immune system. 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 it is that we do with these other drugs where we take on big parts of the immune system and 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, right, 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 from it, 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, right? In a way to be able to push and pull on it in a very unique way, again, that we had no idea was going to happen, but turns out to potentially be clinically useful. And the more we understand exactly what that is, then we can be more directed at pushing and pulling on the immune system in subtle and important ways to drive more clinical benefits for a wide range of conditions, even beyond the ones we're using GLP1 drugs for today.
- [27:03]
Derek Thompson
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 GLP1 drugs seem to be a moderation molecule. I went on, I said, scientists aren'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 like, think of it like 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'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.
- [28:25]
Randy Seeley
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 workhorses are neurotransmitters like GABA and glutamine. 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 glutamate? Right. 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 2 diabetes, because you don't put patients at risk for hypoglycemia because only when the glucoses are elevated does the GLP1 have an effect to produce an increase in insulin secretion. Don't just start jamming on your insulin secreting cells indiscriminately. So I think you're hitting on the right idea that these peptide systems are modifiers of other things that are going on in the 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 some real advantages in terms of long term therapy.
- [29:43]
David d'Alessio
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 a GLP1 receptor will generate. It's called desensitization. And so that probably has a role. 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 these kind of overwhelming effects that we see, as you said before, with antineoplastic 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 that makes it harder to study. You can't go and cut out all the GLP receptors, but I think that I'm gonna start using moderation. I will credit you.
- [31:22]
Derek Thompson
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.
- [31:46]
Randy Seeley
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.
- [32:29]
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- [33:59]
Randy Seeley
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- [34:22]
Derek Thompson
Learn more@WhatsApp.com 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?
- [34:51]
David d'Alessio
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 everybody hate everybody. The drug companies hated that because these 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 and 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 US and it's particularly so in people with diabetes. So talk about serendipity. This turned out to be, you know, a real boon to people who do diabetes medicine. Now, again, the mechanism not clear in the trials. If you go back and do Post hoc analyses of the trials, there's 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. The thing. So that your, your inference there, that these are two different pathways, I think is well founded. And, and that's kind of the way I'm thinking about it, that it's not, 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.
- [37:07]
Derek Thompson
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 it 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, 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 GLP1 receptors distributed throughout the body and some are in the gut and some are in 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.
- [38:02]
Randy Seeley
Yeah, you're hitting on the right thing. But I care about the brain, right? So I'll bring this back to the brain. The notion 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? It 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 GLP1 receptors in different places, right. I can do this all by moving the brain around to control the immune system in a way. Again, the weeds that is subtle but effective for these chronic disease conditions. That makes it very different, right, Than. Than the idea. Oh, yeah, it's having a little effect here on 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 is still very unclear. But you can imagine, right, that it's separate than the weight. Right. The effect to change the immune system is separate, but again, it involves that everything starts right with the central nervous system.
- [39:03]
Derek Thompson
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 used the word drive over and over and over again. Dopamine is the drive chemicals. So 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?
- [39:42]
Randy Seeley
There is definitely evidence, right, of it having indirect effects. Right. So you. 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 is not drive writ large. Right. That is, being interested in water is way different than being interested in food. And you don't mix those two up as much. So they're not. There isn't one drive. Right. There are multiple drives. Right. For which the dopamine system can be used to facilitate the reward function. 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. And so the issue about how it is that that is organized is really important. But you're 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 works.
- [40:44]
Derek Thompson
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%.
- [41:16]
David d'Alessio
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 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 within the national health system, where the drugs covered, are also pretty poor. And that was really puzzling to me. So 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 4kg, I mean, if you're 104kg 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. 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 got to figure this out together because there's not a guidebook on this yet. 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, you know, but it's, it really should be addressed. And I, I think the, 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 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 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 raise, 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 try something else.
- [43:29]
Derek Thompson
Well, one way to ask this question in a different way, and that was a fantastic answer, is, 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 need to, 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?
- [44:19]
David d'Alessio
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 and 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 till 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 the, 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 you know, I thought that again, we thought that was an important question and we're, we're finishing a study on that right now. But I think that, I think you're. Again, that's a reasonable inference that, that, that patients aren't quite getting what they want or they're getting either too much or too little.
- [45:40]
Randy Seeley
I'll throw out a third version of this. Right. That I think goes with the shaming of people to use these drugs. 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 coming. We knew that this was going to happen. We were going to have effective medications that were probably going to be way better adoption than we've had before. What I didn't anticipate was the backlash to that. Again, how much the influencer community 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 individuals, they do not want to medicalize their weight, right? So they jump in, right? Even whether it's effect, whether it's ineffective, it's easy, right? Okay. It doesn't work for me. All these scientists are just full of bunk. If it works, then what you want 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, all the things that they've talked to themselves about their internalization of the reasons, right. For their increased weight are about themselves. Again, I can tell you, I have lots of family members who have said something to them. Well, I don't want to take this forever, right? Because I want to learn how to do this the right way. Okay? 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, right? So the drug is still exerting an effect 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 weight. This is in 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 non compliant. I know that they took the drug, right? You can just see the fact then that their weight plateaus and as soon as you get rid of it, the animals start overeating and regain the lost 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 comply. 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 Dan, 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 will internalize it 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.
- [48:31]
Derek Thompson
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?
- [49:02]
David d'Alessio
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% as 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 follow. 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, worried about this and they just, 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 muscles. So I'm going to give you two, two looks at the future. One is a kind of a Star Trek 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 GLP1 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 money. 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 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 identified 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 some other untoward thing. Yeah, truly, if you had a high risk for Alzheimer's disease, it might be that, that we could 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, 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 then are going to be able to use injectable GLP1s 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.
- [52:50]
Randy Seeley
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 of benefit. 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 with not something very invasive, an injection, right. To something that is mimics the once a 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 that are going to provide ways that we can push this system in a permanent way rather than again in a temporary the 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 effects as soon as you come off, you do not start regaining that lost weight. And I think all of those things are going to come together where we're going to get less invasive and 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.
- [54:22]
Derek Thompson
David d', Alessio, Randy Seely, thank you very much.
- [54:25]
David d'Alessio
Thanks Derek.
- [54:26]
Derek Thompson
Thank you for listening. Plain English is produced by Devin Beroldi and we are back to our twice a week schedule. We'll talk to you soon.
- [55:07]
Randy Seeley
And Doug, here we have the Limu Emu in its natural habitat helping people customize their car insurance and save hundreds with Liberty Mutual.
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David d'Alessio
Fascinating.
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Randy Seeley
It's accompanied by his natural ally, Doug Limu.
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Derek Thompson
Is that guy with the binoculars watching us?
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Randy Seeley
Cut the camera. They see us.
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Brian Raft
Only pay for what you need@libertymutual.com Liberty.
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Derek Thompson
Liberty Liberty Liberty Savings Ferry Unwritten by Liberty Mutual Insurance Company and affiliates excludes.
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Randy Seeley
Massachusetts Trip planner by Expedia. You were made to outdo your holiday, your hammocking and your pooling. We were made to help organize the competition. Expedia made to travel.