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Talking Biotech is a weekly podcast that uncovers the stories, ideas and research of people at the frontier of biology and engineering.
Each episode explores how science and technology will transform agriculture, protect the environment, and feed 10 billion people by 2050.
Interviews are led by Dr. Kevin Folta, a professor of molecular biology and genomics.
Kevin Folta (00:00.2)
as well. So I get home from work and I get to do work. So okay, so here we go. Let me make sure I got this here.
Radwan Darwish (00:04.597)
That must be fun.
Kevin Folta (00:11.832)
Just have to move something.
Kevin Folta (00:17.336)
Yeah, it was interesting because I just figured out why they call them Ncretins a few weeks ago. I I I talked to someone two weeks ago about an an RNA-based obesity treatment that is very interesting. So that that's a that works at the level of the adiposicity and the enzymes that maintain fat. So that limit its its lipo lipolysis.
Radwan Darwish (00:22.591)
Yeah.
Alexandra Butler (00:23.152)
Right. Right.
Kevin Folta (00:45.812)
So it's it's an it's a good alternative mechanism to GLP1 agonists. So anyway. So here we go.
Alexandra Butler (00:52.314)
Interesting. Yeah.
Kevin Folta (00:58.466)
Hi, everybody, and welcome to this week's Talking Biotech Podcast. Today, GLP1 receptor agonists like Ozembek and Wigovi, these are reshaping the global economy. They're upending the food industry. They're maybe leading to lower price flights. They're transforming obesity treatment from what's been perceived as a moral failing to really manageable biology. And it's been a really good thing in that regard.
But this billion dollar revolution, it didn't start on Wall Street. It started with a desert dwelling ghila monster. It's venom and in the 1980s, a biochemical riddle about a natural gut hormone that breaks down in just a couple of minutes. And so today on the Talking Biotech podcast, we're going to talk about the accidental history behind one of medicine's biggest recent breakthroughs. Really exciting stuff. So we're speaking with Dr. Alexandra Butler. She's a professor at
Royal College of Surgeons in Ireland and the Medical University of Bahrain. And Rodwan Darwish, he's a medical student at the Royal College of Surgeons in Ireland and the Medical University of Bahrain. So welcome to the podcast.
Alexandra Butler (02:07.452)
Thank you.
Radwan Darwish (02:08.245)
Thank you.
Kevin Folta (02:09.548)
Yeah, this is really great. I don't know that we need to give a lot of introduction to what GLP1 agonists are exactly think. Most people are familiar with what these drugs are. but let's go back a little bit further. When these were first cloned and characterized as incretants, what was the prevailing sketch skepticism around gut-derived peptides playing an actual role in glucose homeostasis when you compare against traditional insulin and and other either insulin or insulin stimulating compounds?
Alexandra Butler (02:40.166)
Right, well, I'll start and take that question. I think the skepticism is actually understandable when you look at the history. The idea goes back a long way. In the early 1900s, researchers were already showing sub that substances released from the gut could influence physiology. And by the 1930s, the term incretin had been introduced. But for several decades the evidence was inconsistent.
The early intestinal extracts were not very well characterized. Some of the results were difficult to reproduce, and the whole idea of gut hormones having an important role in glucose regulation gradually lost momentum. Then in the 1960s, the story started to change. Researchers independently showed that when you give someone glucose orally, they release much more insulin.
Than when you give exactly the same amount of glucose intravenously and produce the same blood glucose level. And that was a really important observation because it suggested that the intestine was doing something more than simply absorbing glucose. It was sending a signal to the pancreas, what we now refer to as the incretant effect. But even then,
There were several reasons why people were hesitant to see gut hormones as serious therapeutic targets. First, there were already drugs that stimulated insulin secretion directly from the pancreas. Sulfonol ureas had been around since the 1950s and they worked. So if you wanted to increase insulin secretion, there was already a relatively simple pharmacological approach. Second, peptides were not considered particularly attractive drugs.
Many of them have very short half-lives, they aren't orally bioavailable, and there were obvious challenges around developing them into practical medications. And perhaps most importantly, the first major incretin candidate didn't exactly provide a convincing therapeutic story. So GIP was identified and shown to stimulate insulin secretion.
Alexandra Butler (04:59.516)
But its effect was substantially impaired in people with type 2 diabetes. So the hormone was interesting physiologically, but the problem was that the very patients who needed treatment seemed to respond poorly to it. So then the major turning point came with GLP1. And researchers found that GLP1 could produce a very strong glucose-lowering effect in people with type 2 diabetes.
Including in patients who were not responding adequately to conventional therapies. And what made GLP1 particularly interesting was that its effects were glucose-dependent. It stimulated insulin secretion when glucose was high, rather than simply forcing the pancreas to release insulin regardless of the glucose level.
I think the broader lesson that we get from history of incretants is that the field didn't move forward simply because we discovered another hormone that could stimulate insulin. It moved forward when we understood how that hormone regulated insulin secretion, particularly the importance of doing it in a glucose dependent way.
Kevin Folta (06:18.946)
Very good. So I'm just gonna Jim. I'm just gonna my producer. I'm gonna put a little note here. I forgot to mention that if we have any kind of bandwidth glitch, we just had one. Doesn't matter, just keep going because it records, it's gonna record locally on your machine and upload. So everything comes out perfect at the end. Don't think if you have a little glitch that we have to stop or adjust. Okay. So that was perfect. Very nice answer. It was great. So we'll dive back in here. Okay, here we go.
Alexandra Butler (06:30.045)
okay. Okay.
Okay.
Radwan Darwish (06:39.918)
okay. Yeah.
Alexandra Butler (06:40.562)
I'll take
Kevin Folta (06:46.882)
Well, one of the biggest issues with the early native GLP one, it was its stability. And at the time we could have thought of ways that we would target this as a researcher. Was it targeting the degradation mechanism or was it just looking to design GLP peptides that were resistant to degradation?
Radwan Darwish (07:06.517)
Okay. So I think that's a great question. And I think researchers actually pursued both strategies at the same time. And this ultimately led to two diff very different classes of drugs. So like you said, the fundamental problem was that native GLP one simply didn't last very long in the body. And in the nineteen nineties, it was shown that GPP four, which stands for Diapeptidal Diapeptidal Peptidase IV, rapidly breaks GLP one down. And shortly thereafter,
it was also shown that injected GLP one dose was already being degraded before it reached the systemic circulation. And so there were essentially two ways of solving this problem. Number one is you know, why not stop GPP four from breaking GLP one down? And that led to GPP four inhibitors. So researchers developed small molecules that could be taken orally and inhibit the enzyme, allowing the body's own GLP one to remain active for longer.
And that eventually produced drugs such as citoglyptin and vildeglyptin. And you know that approach actually worked. It gave us a very convenient oral treatment and DPP4 inhibitors actually became a major part of diabetes treatment. You know, however, you know, there was a limitation because you're still relying on the body's own GLP1. So while you can increase its activity, you know, you can only do that to a certain extent. So you get relatively modest glucose lowering.
And importantly, you don't get the dramatic weight loss that we you know typically associate with the newer GLP1 drugs. The other approach was almost the opposite. So instead of protecting GLP1, why why don't we redesign the peptides so that DPP4 can destroy it? And that's where things like semiglutide come in. And you know, one of the key modifications there was replacing one of the amino acids with a slightly larger amino acid.
And that small change makes it significantly harder for DPP4 to recognize and you know break down that peptide. And there's a really important distinction here is that liriglutide, which is one of the GLP1 agonists, isn't actually resistant to being broken down in the same way. It has a longer duration because it attaches itself to a fatty acid, which allows it to bind to albumin.
Radwan Darwish (09:29.625)
And sort of form a depot after injection. So like you said, there are essentially you know two philosophies: either protect the body's own GLP one or build a GLP one molecule that can survive on its own. And ultimately the second strategy is what gave us the very long acting drugs that have essentially transformed the field.
Kevin Folta (09:49.999)
Well, one of the really fun aspects of this entire story is gila monster venom and it was my favorite lizard as a kid. how is cross reactivity with human GLP one receptors first received by the endocrine community?
Alexandra Butler (10:05.456)
Okay, so this is a fun question because it's probably one of the most unusual stories in modern drug development. And we have to go back to the 1980s, and researchers were studying the gyla monster venom for reasons that had nothing to do with diabetes. Jean-Pierre Raufman and colleagues were interested in its effects on pancreatic secretion. And Zhong Eng, who was an endocrinologist at the Bronx VA, followed that work and isolated a peptide.
From the Gila Monster venom called Ixendin 4. And he published his work with Ralphman in 1992. What made IXendin 4 so interesting was that despite coming from a lizard, it was remarkably similar to human GLP1 and could activate the human GLP1 receptor. But it had an enormous advantage. It was naturally resistant to DPP4.
So suddenly nature had given researchers something that they had been struggling to design themselves: a GLP1-like molecule that lasted much longer. Okay, so to your question, the initial reaction was very mixed. There was certainly some amusement around the idea of developing a diabetes blood drug from lizard spit, but beneath that there was also a very legitimate scientific concern.
This was a non-human peptide that would have to be given repeatedly to patients. And would the immune system react to that? And that concern wasn't completely unfounded. I mean, a substantial proportion of patients did develop antibodies to a xenotide, although most were low-level and didn't have a major clinical effect. But physiologists such as Jens Holtz, Michael Knock,
And Daniel Drucker recognized the significance fairly quickly. Excendin IV had solved one of the central problems in the field. How do you make a GLP1 molecule that survives long enough to be useful as a drug? So, funnily enough, John Ang actually had to work surprisingly hard to get anyone to take the discovery seriously.
Alexandra Butler (12:27.578)
And the VA initially declined to patent it, so he filed the patent himself and eventually licensed it to amylene. That molecule eventually became a xenotide or Bieta, which was approved in 2005. So I think the broader lesson we can take away from this is fascinating. The one of the most important molecules in modern diabetes and obesity treatment came from studying the venom of an animal that has nothing to do.
With human medicine.
Kevin Folta (12:59.116)
Yeah. And then, you know, in the in kind of the good subtext, there are a couple things. One, it's why we never see obese lizards, then maybe that's there. But the other thought is is that when we talk about the funding of basic research, and people would say, why would we possibly look at lizard spit? You know, the it just underscores why it's so important for us to have the NSF and NIH fully funded and exploring avenues that people may find questionable if they're not experts in these areas and and and
Alexandra Butler (13:27.92)
And grew you entirely.
Kevin Folta (13:30.262)
It's it's it's in in these days especially. But I I guess the other real interesting subtext there is is that maybe we can learn more from what Mother Nature has made for us. I mean, is it what what else can we learn about pr natural product exploration and peptide drug design from examples like this? Like here, you know, gila monsters got this in its saliva, you know, mistoperins and wasp venom. There's all of these peptides that
are biologically active and can they actually inform better drug design when we do it in the laboratory?
Radwan Darwish (14:05.877)
I think the bigger and broader lesson here is that nature can sometimes solve pharmacological problems for us before we even know that that they are actually problems. And the important thing about Exentin four here wasn't that it was simply another version of human GOP one. In fact it was quite different. It was only about fifty percent identical to human GOP one. But those differences gave it properties that were extremely useful therapeutically.
particularly its resistance to DPP4. And so, you know, rather than look only looking for molecules that, you know, are almost identical to human proteins, there's a strong argument for looking at divergent molecules from other species. Evolution has experimented with an enormous chemical library that we haven't even begun to explore. And you know there are plenty of other examples in medicine on this. You know, Captopril came from work on snake venom and
Zycomatide came from const nail venom. And you know, these molecules aren't necessarily finished drugs, but they can give you a very good starting point. And I think there's another important lesson here. It's that the natural molecule isn't necessarily the final product. So in this case, exendin 4 gave us the starting point. But the drugs that followed required a huge amount of medicinal chemistry and pharmacology to improve duration, tolerability, dosing.
and manufacturing. And so I I wouldn't necessarily say nature gives you the drug, but it certainly gives you a very interesting starting point.
Kevin Folta (15:41.015)
It gives you a a hint of how nature can intergress with biology. Like how does it make a molecule that fits the machine? And it's it's kind of fun. What my laboratory did for a long time. We made a library of 800,000 random peptides that we can express in any organism and and interfere just and this was before this was a major story with GLP1 agonists. And we were able to identify molecules that would disrupt spike protein ACE receptor.
interaction, you know, all kinds of fun things like that. But but your point is extremely well taken. when we look at these drugs themselves, how was that transition from a once daily, unstable or less stable, and what once weekly dosing modifications, how did they change the farm or what were some of the pharmacokinetic challenges that really had to be balanced with albumin binding and receptor potency?
Alexandra Butler (16:39.258)
Very good question. And actually the basic idea came from insulin. Researchers at Nova Nordis could already shown that by attaching a fatty acid to insulin, it could make it bind to albumin in the blood. And albumin, as you know, is a very large and abundant protein. So if your drug binds to it, effectively it gives you the drug a much longer circulation time. So the challenge was then how do you
Attach a fatty acid to GLP1 without destroying its ability to activate the receptor. And laraglide was one of the first successful solutions to this. A fatty acid was attached to the GLP1 molecule through a spacer that allowed laraglide to bind albumin and remain in the circulation for much longer. It had now had a half-life of roughly 13 hours.
Symaglotite took the same basic concept much further. It combined several modifications: greater resistance to DPP4, stronger albumin binding, and a longer, more flexible spacer connecting the fatty acid to the peptide. And this is where the chemistry gets really interesting because you want the fatty acid to bind albumin very strongly because that gives you duration.
But if you make the molecule bind too tightly or position the fatty acid incorrectly, you can interfere with the part of the molecule that needs to interact with the GLP1 receptor. So you're constantly balancing two competing objectives. You want the molecule to bind albumin strongly, but you also need enough of the drug to remain available to activate its receptor.
And the spacer that I mentioned is particularly important because it acts almost like a flexible leash between the peptide and the fatty acid. And there are parts of the GLP1 molecule that you really don't want to touch. The N terminal region is critical for receptor activation. So much of the successful chemistry has involved modifying other parts of the molecule.
Alexandra Butler (18:56.006)
While leaving the receptor binding machinery intact.
Kevin Folta (19:01.514)
very good. So really receptor binding and and availability, all the questions that are there, that's the first part that leads up to receptor binding. But once you're binding, now the system starts to maybe acclimate to the fact that the receptor is bound. And so early studies were showing that there was a rapid desensitization and internalization of the GLP1 receptor. And so how did research navigate the issues of resistance to the drug when designing these more continuously active, longer acting agonists?
Radwan Darwish (19:32.67)
You know, this was actually a very interesting case where the biology looked concerning on paper, but the clinical experience was much more reassuring. so I'll preface this by saying GLP1 receptors are actually G protein coupled receptors. And when you continuously stimulate a G protein coupled receptor, you would normally expect that receptor to become less responsive, like you said. And then you know the receptor can be phosphorylated.
and then subsequently internalized. And so the obvious question was if we're giving GLP one continuously, won't the receptors simply stop responding? but the clinical data really didn't really show that. And in 2002, there was a study in which patients with type two diabetes received GLP1 continuously for six weeks, and the glucose lowering effect had persisted and they didn't see any kind of progressive loss of effect that people had initially feared.
And this was not very well understood at the time, but over time researchers started to understand why this is happening. Internalization doesn't necessarily mean that the receptor has been switched off permanently. It can be recycled back to the cell surface, and there's also evidence that it can continue signaling from inside the cell. And there's also a very important distinction here, and it's that not every effect of GLP1 behaves in the same way.
during long-term treatment. So that's to say, for example, the effect on gastric emptying tends to become weaker with continued exposure. But the effects on glucose control and body weight persist. And that's actually very clinically informative because it tells us that gastric emptying can't be the main explanation for the long term weight loss produced by these drugs. And at the same time, you know this also influenced how the drugs were designed clinically. Long acting drugs
were origin when initially introduced, they were given sorry, long-acting drugs are generally introduced gradually and titrated upward, which helps patients adapt to the GI effects that they may have. So rather than trying to completely eliminate receptor internalization, the field slowly learned that receptor trafficking is more complicated than simply on and off.
Kevin Folta (21:57.463)
I see. So that makes it makes a lot more sense when you think about it as a continuum. Well, we're speaking with Dr. Alexandra Butler. She's a professor of pathology at the Royal College of Surgeons in Ireland and the Medical College or Medical University of Bahrain. And Rodwan Darvish, who's Darvish, who's still a medical student at the same institution. This is the Talking Biotech podcast, and we'll be back in just a moment. And then we take a little break here where they do everything okay? And it's
Alexandra Butler (22:25.061)
Everything's good. Yeah.
Kevin Folta (22:26.71)
Rodwan Darwish. I gotta I I I gotcha. Okay, I gotta make sure I s pronounce that correctly. I all right, here we go. And I I should just say both at the same institution. All right, here we go.
Radwan Darwish (22:31.722)
Yeah.
Kevin Folta (22:42.742)
And now we're back on the Talking Biotech podcast. We're speaking with Dr. Alexandra Butler. She's a professor of pathology at the Royal College of Surgeons in Ireland and the Medical University of Bahrain. And Rodvon Darwish, who is a medical student at the same institution. And we're talking about the history of GLP1 receptors or and GLP1 drugs and their interactions with receptors and many of the factors that really were found out along the way from their discovery and the way in which.
They have been changed and decorated of the r of their interactions with receptors and how this all dictates their action, because it's such a black box to watch the commercials on TV. There are magical peptides that do their job and so much more to it. So we left off talking about the receptor interaction and ways in which this was potentially internalized and some of the desensitization issues that were described, but
GLP1, it was first pursued almost exclusively for glycemic control via insulin secretion and gastric emptying, as we kind of discussed. But when did the community recognize that the action was really starting to also hit the central nervous system? And when this was the primary driver of weight reduction, and how did that really kind of adjust the pipelines that were developing the drugs?
Alexandra Butler (24:06.632)
So this is a really interesting topic because in this case the biology was recognized much earlier than was its clinical importance. Way back in 1996, Turton and colleagues published a study in Nature showing that giving GLP1 directly into the brains of rats suppressed their food intake. And around the same time, Tang Christensen and colleagues reported similar findings.
So the idea that GLP1 could influence appetite wasn't new. The problem was figuring out what it meant. At first, there was a reasonable concern that animals were simply eating less because they felt sick. And clinically, weight loss was often interpreted as a consequence of nausea, reduced gastric emptying, or simply eating less because of the GI side effects. There was also a broader problem.
Because obesity drugs had had a difficult history. And so pharmaceutic a lot of them had failed, the situation had ended badly. So pharmaceutical companies were understandably cautious about investing heavily in obesity drugs. But the field started to change when researchers realized that the effects of GLP1 on gastric emptying and body weight could actually be separated.
The slowing of gastric emptying becomes less pronounced with continued treatment, but the weight loss continues. And that suggested that something else was driving the sustained reduction in food intake. And that something else was the nervous system. And what's particularly interesting is that these large GLP1 molecules don't need to cross the blood-brain barrier extensively.
They can act at areas where the barrier is more permissive, such as the area plastrema, and then influence broader neural circuits involved in appetite and energy balance. And there is also, interestingly, a population of GLP1 producing neurons in the brainstem, particularly in the nucleus tractus solitaris, which adds another layer to this system. And then came some very
Alexandra Butler (26:32.506)
Elegant genetic experiments. Studies from Jeff Seely's group, including work by Sisley and colleagues, showed that disrupting central GLP1 receptor signaling could eliminate the weight loss effect whilst preserving much of the glucose lowering effect. And this was a major conceptual shift, meaning that GLP1 wasn't simply a pancreatic hormone that happened to make people lose weight.
It was also acting on neural circuits that regulate appetite and energy balance. And once the field understood that, obesity stopped being viewed simply as a problem of willpower or calorie arithmetic. It became much clearer that body weight is actively regulated by the brain.
Kevin Folta (27:27.816)
That that was a real really important breakthrough, a really important understanding and really good. So, but but for every upside, there's a downside, right? So, you know, during the late 2000s, I guess about there, there were a lot of concerns regarding pancreatitis and thyroid tumors and also cardiovascular safety that were associated with with these drugs. And how did the cardiovascular outcome trials really change the clinical perception and adoption of GLP ones?
Radwan Darwish (27:57.962)
I think the cardiovascular outcome trials were one of the biggest turning points in the entire history of this class of drugs. And the interesting irony here is that these trials weren't originally designed to prove that GLP one drugs protected the heart. Instead, they were largely designed because regulators wanted to make sure new diabetes drugs weren't causing cardiovascular harm. And that came after the controversy around Rosyclitazone, which raised major concerns about cardiovascular risk.
And the FDA subsequently required large cardiovascular outcome trials for newer diabetes drugs. And so companies went into these studies essentially asking, you know, are these drugs safe from a cardiovascular perspective? And that was when you know something unexpected happened, that some of them actually appeared to reduce cardiovascular events. So liriglide in the leader trial showed a reduction in major cardiovascular events, senoglide showed a benefit in sustained six.
And subsequent trials with deligatide and other agents continued to reinforce this signal. And that sort of changed how clinicians think about these drugs. They were no longer simply medications that lowered HBA1C. You could now choose a GLP GLP1 drug because a patient had cardiovascular disease or was at high cardiovascular risk. And then in 2023, the Selectray trial came out, which was particularly important.
Because it studied semiglide in people with obesity and cardiovascular disease without diabetes, which hadn't been done before, and it showed a significant reduction again in major cardiovascular events. And again, this was a major moment in the history of these drugs because it changed their identity. They weren't just diabetes medications that happened to cause weight loss, and instead they were becoming therapies for obesity and cardiovascular risk in their own right.
and of course, at the same time, these outcome trials helped address some of the safety controversies. And just to shortly comment on the issue of pancreatitis and you know thyroid cancer that you mentioned, you know, as for the pancreatitis issue, I think it's important to separate the early safety signals from what we know now. When these drugs first became widely used, there were concerns about pancreatitis and by extension whether they might increase the risk of pancreatic cancer.
Radwan Darwish (30:23.369)
Those concerns understandably generated a lot of attention, but much of the early evidence comes from spontaneous reports and observational studies, which are of course useful for detecting signals, but can't reliably establish causation. And as larger y trials and longer term observational studies accumulated, the evidence became much more reassuring. And now there's no convincing evidence that these agents cause pancreatic cancer, and whether they produced any meaningful increase in pancreatitis.
Is it just remains uncertain? But if there is a risk, it appears to be small. And as for thyroid, that has a completely different origin, actually a preclinical one. So in animal studies, particularly in rodents, GLP1 receptor agonists caused a certain type of thyroid cancer called medullary thyroid cancer. And that finding led to a boxed warning that still remains on these medications today. And we haven't necessarily seen that in humans.
so I think the fairest interpretation here is that the thyroid warning reflects a genuine, unresolved safety signal that originated from the animal data rather than concrete evidence that these drugs are known to cause thyroid cancer in in people.
Kevin Folta (31:41.839)
Yeah, there's a lot of the labeling as a precautionary approach based upon, you know, just rodent studies with huge doses and these legacy findings, you can't get rid of them. Look at red dye 40, you know, same concept. But you know, just kind of progressing over to the evolution of this, these compounds, that the modern therapeutics really have evolved from individual peptides into triple and dual receptor agonists, you hit targeting like GLP1, GI GIP and glucagon.
And from a physiological standpoint, how does this synergistic multi receptor targeting resolve the metabolic sealing that you get from pure GLP1 antagonism?
Alexandra Butler (32:22.63)
Right, and to your point, I think it's useful to start by asking the question: what is the limitation of GLP1 alone? Why not just use a single drug? And to answer that, at some point, increasing the GLP1 dose doesn't simply give you proportionally more weight loss. You start running into tolerability issues, particularly nausea and vomiting. So the question becomes: rather than pushing
One pathway harder, can we activate several complementary pathways at the same time? And that's the thinking behind drugs such as terzepatide. And terzepatide activates both GLP1 and GIP receptors. And the important idea was to put multiple activities into a single molecule rather than simply giving two separate drugs.
Now, GIP may contribute in several ways. There's evidence that it can influence adipose tissue and insulin sensitivity. And there's also an interesting hypothesis that GIP signaling may help offset some of the nausea associated with GLP1 signaling. So GIP may not simply add another appetite suppressing signal, it may also change.
How much GLP1 activity can you tolerate. And then there's glucagon. Glucagon is interesting because it affects a different side of the energy balance equation. GLP1 mainly reduces energy intake. Glucagon can increase energy expenditure and promote processes such as hepatic fat oxidation. So in theory, a GLP1
Glucagon combination could do two things at once. Reduce how much energy you take in while increasing how much energy you use. The challenge is that glucagon itself can raise blood glucose and heart rate. And that's where combining it with a GLP1 becomes attractive because the two activities can counterbalance one another. And I think the broader principle is that obesity.
Alexandra Butler (34:43.034)
Is a highly defended biological system. In other words, the body has multiple mechanisms trying to bring weight back towards its previous level. So if you target only one pathway, the system can often compensate. And that's why the field is increasingly moving towards combination therapies of GLP1, GIP, glucagon, amylene, and potentially other pathways.
But there's an important caveat here, and that is that more mechanisms do not automatically mean proportionally more weight loss.
Kevin Folta (35:25.71)
Yeah, it's an important point. It's one plus one does not always equal two, right? Well if we think about things like from DN like milestone discoveries, whether it's DNA or CRISPR Cas9, there's these really milestones we think about in biology. And in this particular case, when you think back over all the decades that this peptide's been studied, now a multi-billion dollar industry that everybody knows about.
which early experiments or overlooked contributors maybe deserve a little more of a gold star in the history of metabolic medicine?
Radwan Darwish (36:04.403)
Let me first let me start by first saying that many, many people contributed to the story of GLP one. So this is by no means an exhaustive list, but there are a few contributions that I think are particularly important. And one of the earliest is one by Svetlana Mostov, and I hope I'm saying that correctly. She actually did she had very important work identifying the biologically active form of GLP one.
Which was fundamental to understanding what the hormone actually does. And then you have John Eng, for example, who Professor Alexander already mentioned, whose discovery of exendin four in gila monster venom provided the basis for a xenotide, the first GLP one receptor agonist. And if we kind of shift to the medical side, to the clinical side of things, Michael Knox studies were really important because they showed that GLP one could
produced powerful glucose lowering in people with type 2 diabetes, which essentially turned what was an interesting physiological observation into potential therapy. And then of course there's Carolyn Deakin's work that showed just how rapidly GLP1 is broken down by GPP4 and helped explain why the native hormone itself wasn't going to make a very practical drug. And then later
you know, people like Richard DiMarchi and Mate Matthias Matthias Chop helped take the fields in different direction, towards combining activity at multiple metabolic hormone receptors, which is the concept that Professor Alexander just explained behind drugs such as terzepatite and retatritite. And you know what I find most interesting is that almost none of these researchers set out to develop this blockbuster obesity drug.
They were studying peptide chemistry, venom, physiology, or basic biology. And the eventual therapies emerged from a chain of discoveries spanning you know decades. And I think that's one of the great lessons of biomedical research. You rarely know which basic scientific observation is going to become transformative medicine one day.
Kevin Folta (38:20.332)
No, very true. I I yeah, we that's a really important point and and such an endorsement for why we need to keep going on basic science. You know, there's there's been a lot of people who said that the way we could affect national health care more than anything else would be to get everybody who's overweight on GLP one type drugs. And that, you know, then other people have said that this will have a profound effect from everything from the stock of McDonald's through you know, American Airlines ticket price.
And how big do you think this will be? I mean, do you think that as they begin to understand these therapies better and then combine them with others, do you really see this as being a major part of managing the comorbidities of weight that really have been a substantial burden on our healthcare system?
Alexandra Butler (39:09.778)
So I think to start with, the best comparator we can look at is probably statins. And statins gradually became one of the most widely used classes of drugs in the world, and over decades they have changed cardiovascular prevention and mortality. GLP one drugs could have a similar trajectory because we're increasingly seeing benefits beyond glucose control.
Cardiovascular disease, kidney disease, heart failure, sleep apnea, and obesity-related liver disease. And we're already seeing an enormous economic impact. The US spending on GLP1 drugs reached roughly between 65 and 72 billion in 2023, up many fold from a decade earlier. And around 90% of that spending was still.
For diabetes. So we've arguably only seen the tip of the iceberg of the obesity market. Now, the problem with these drugs is that they're extremely expensive. List prices can approach like $1,000 a month, and out-of-pocket costs are a major barrier to access for many, many people. And at current prices, some cost-effective effectiveness analyses.
Actually consider them poor value compared with inexpensive treatments like our standard metformin. But that could change dramatically as patents expire, competition increases, and oral GLP1 drugs become available. And if manufacturing costs eventually come down from hundreds of thousands of dollars a month to tens of dollars, you're talking about a completely different.
Public health proposition. And then there are the wider economic effects, which you alluded to earlier. If people consistently eat less, particularly less high-processed and calorie-dense food, that could eventually affect the food industry. I think I'd still be a little more cautious about claims that GLP1s will determine things like airline ticket prices, but who knows? So
Alexandra Butler (41:34.843)
I think the really important question here isn't whether GLP ones will be big, they already are. The question is whether we can make them affordable and accessible enough to have the kind of population impact that statins ultimately had. And if that happens, I think we're looking at one of the most important public health interventions of our generation.
Kevin Folta (42:02.29)
absolutely. That's a it's a really optimistic look going forward on this. But one of the big problems is you know the disinformation system that's out there these days that we have to navigate and especially in social media. So if people wanted to identify the most trusted sources of information about this class of drugs, you know, either on a website, social media, where would you recommend they look?
Radwan Darwish (42:25.973)
Mm-hmm. So I for the public, I'd start with institutional sources rather than social media. The FDA approved prescribing information is probably the most important resource if you want to know what a drug actually does and what its established risks are. The ADA, the American Diabetes Association, is another good resource for both healthcare professionals and the public.
And for people who want more accessible and readable information, the NIH and NIDDK have useful patient oriented material. And I think the bottom line here would be look for sources that cite the actual studies, disclose their conflicts of interest, and are willing to discuss both what the drugs can do and what they can't do, as opposed to either.
Kevin Folta (43:20.782)
Yeah, well this has been a really fascinating walk through this. And I learned a lot just from the discussion with you. And I I really appreciate your time today. and I'll put a a link to the your review paper inside the episode here. So pr Professor Butler and Rodwan Darwish, thank you so much for joining me today. Rodw Rodwan, what do you want to do next? I mean you're you got a year before you're done with medical school. What's your next plan to work in obesity or somewhere else?
Radwan Darwish (43:51.061)
So my plan currently is to pursue internal medicine residency in the US, which is three years long, and then hopefully pursue a career in endocrinology, which would be another two years, and then hopefully find myself somewhere in obesity medicine. But you know, who who knows? Who knows where I'll be in in in in in the next you know five to ten years.
Kevin Folta (44:13.934)
Well, I I would recommend Florida for your residency. So it it's it it's awfully nice here. It's it's a good place to do a spend a few years. No, it's a great place it's a wonderful place to to pitch a tent for a couple of years and a a really nice medical campus. Well, thank you very much for joining me today and best wishes going forward.
Radwan Darwish (44:16.691)
Yeah.
Radwan Darwish (44:23.102)
I agree.
Radwan Darwish (44:27.946)
Yeah.
Alexandra Butler (44:33.658)
It's been my pleasure. Thank you, Kevin. Bye bye.
Kevin Folta (44:36.29)
And then I'll wrap up here all right, and then I'll wrap up here real quick.
Radwan Darwish (44:36.725)
It's been a pleasure. Thank you.
Alexandra Butler (44:40.699)
Okay. Great.
Kevin Folta (44:42.55)
And so this is a really exciting example of how a billion dollar drug that we didn't really talk about a decade and a half ago is a major part of healthcare and will be bigger going forward. It also underscores the importance of basic science in continuing to support and fund efforts like the National Institutes of Health, National Science Foundation, and other institutions that today are eroding in their trust as well as their financing from federal sources.
It's never a better time to invest in science. And the world is doing it, our US is kind of falling behind. But this is just a great example when someone asks you why we should possibly spend federal money on science, because for every dollar you invest, you get quite a few back, and the industries that it supports are pretty substantial too. This is a talking biotech podcast, and we'll talk to you again next week. And then I hit stop and