# Daniel Drucker: Illuminating the GLP-1 Drug's Break Out

An episode of [Ground Truths](https://invisiblenetwork.ai/podcast/1728526108), 6 Apr 2024, 37 min.

Audio: https://api.substack.com/feed/podcast/143331647/b9311ad06523c93205d27bbd0943299a.mp3

Note: This podcast is a companion to the Ground Truths newsletter “A Big Week for GLP-1 Drugs” Eric Topol (00:06): It is Eric Topol with Ground Truths, and with me today is Dr. Daniel Drucker from the University of Toronto, who is one of the leading endocrinologists in the world, and he along with Joel Habener and Jens Juul Holst from the University of Copenhagen and Denmark, have been credited with numerous prizes of their discovery work of glucagon-like peptide-1 (GLP-1) as we get to know these family of drugs and he's a true pioneer. He's been working on this for decades. So welcome, Daniel. Daniel Drucker (00:43): Thank you. Eric Topol (00:45): Yeah, it's great to have you and to get the perspective, one of the true pioneers in this field, because to say it's blossom would be an understatement, don't you think? Daniel Drucker (00:57): Yeah, it's been a bit of a hectic three years. We had a good quiet 30 plus years of solid science and then it's just exploded over the last few years. Eric Topol (01:06): Yeah, back in 30 years ago, did you have any sense that this was coming? Daniel Drucker (01:14): Not what we're experiencing today, I think there was a vision for the diabetes story. The first experiments were demonstrating insulin secretion and patents were followed around the use for the treatment of GLP-1 for diabetes. The food intake story was much more gradual and the weight loss story was quite slow. And in fact, as you know, we've had a GLP-1 drug approved for people with obesity since 2014, so it's 10 years since liraglutide was approved, but it didn't really catch the public's attention. The weight loss was good, but it wasn't as spectacular as what we're seeing today. So this really has taken off just over the last three, four years. Eric Topol (01:58): Yeah, no, it's actually, I've never seen a drug class like this in my life, Daniel. I mean, I've obviously witnessed the statins, but this one in terms of pleiotropy of having diverse effects, and I want to get to the brain here in just a minute because that seems to be quite a big factor. But one thing just before we get too deep into this, I think you have been great to recognize one of your colleagues who you work with at Harvard, Svetlana Mojsov. And the question I guess is over the years, as you said, there was a real kind of incremental path and I guess was in 1996 when you said, well, this drug likely will inhibit food intake, but then there were gaps of many years since then, as you mentioned about getting into the obesity side. Was that because there wasn't much weight loss in the people with diabetes or was it related to the dose of the drugs that were being tested? Why Did It Take So Long to Get to Obesity? Daniel Drucker (03:11): Well, really both. So the initial doses we tested for type 2 diabetes did not produce a lot of weight loss, maybe 2-3%. And then when we got semaglutide for type 2 diabetes, maybe we were getting 4-5% mean weight loss. And so that was really good and that was much better than we achieved before with any glucose lowering drug. But a lot of credit goes to Novo Nordisk because they looked at the dose for liraglutide and diabetes, which was 1.8 milligrams once daily for people with type 2 diabetes. And they asked a simple question, what if we increase the dose for weight loss? And the answer was, we get better weight loss with 3 milligrams once a day. So they learn that. And when they introduced semaglutide for type 2 diabetes, the doses were 0.5 and 1 milligrams. But in the back of their minds was the same question, what if we increased the dose and they landed on 2.4 milligrams once a week. And that's when we really started to see that the unexpected spectacular weight loss that we're now quite familiar with. Eric Topol (04:16): Was there also something too that diabetics don't lose as much weight if you were to have match dose? Daniel Drucker (04:22): Yeah, that's a general phenomenon. If one goes from…

## Transcript

[0:06] SPEAKER_00: It's Eric Popel with Ground Truce.
[0:08] SPEAKER_00: And with me today is Dr. Daniel Drucker from University of Toronto, who is one of the leading endocrinologists in the world.
[0:18] SPEAKER_00: And he, along with Joel Hebner and John Jens Juhlholst from the University of Copenhagen in Denmark, have been credited with numerous prizes of their discovery work of glucagon-like peptide 1, GLIP1, as we're getting to know that.
[0:36] SPEAKER_00: these family of drugs, and he's a true pioneer working on this for decades.
[0:42] SPEAKER_00: So welcome, Daniel.
[0:43] SPEAKER_01: Thank you.
[0:45] SPEAKER_00: Yeah, it's great to have you and to get the perspective, one of the true pioneers in this field, because to say it's blossomed would be an understatement, don't you think?
[0:57] SPEAKER_01: Yeah, it's been a bit of a hectic three years.
[1:00] SPEAKER_01: We had a good, quiet 30-plus years of solid science, and it's just exploded over the last few years.
[1:07] SPEAKER_00: Yeah.
[1:07] SPEAKER_00: Back in 30 years ago, did you have any sense that this was coming?
[1:14] SPEAKER_01: Not what we're experiencing today.
[1:15] SPEAKER_01: I think there was a vision for the diabetes story.
[1:18] SPEAKER_01: The first experiments were demonstrating insulin secretion and, you know, patents were filed around the use for the treatment of GLP-1 for diabetes.
[1:29] SPEAKER_01: The food intake story was much more gradual and the weight loss story was gradual.
[1:34] SPEAKER_01: quite slow.
[1:34] SPEAKER_01: And in fact, as you know, we've had a GLP-1 drug approved for people with obesity since 2014.
[1:42] SPEAKER_01: So it's 10 years since liraglutide was approved, but it didn't really catch the public's attention.
[1:48] SPEAKER_01: The weight loss was good, but it wasn't as spectacular as what we're seeing today.
[1:53] SPEAKER_01: So this really has taken off just over the last three or four years.
[1:58] SPEAKER_00: Yeah, no, it's actually, uh, I've never seen a drug class like this in my life.
[2:03] SPEAKER_00: Uh, Daniel, I mean, I've obviously witnessed the statins, uh, but this one in terms of pleiotropy of having diverse effects, uh, and I want to get to, um, the brain here in just a minute, because that seems to be quite a big factor.
[2:21] SPEAKER_00: Um, but one thing I just, before we get too deep into this, um, I think, uh,
[2:26] SPEAKER_00: You have been great to recognize one of your colleagues who you work with at Harvard, Svetlana Marsov.
[2:35] SPEAKER_00: And the question, I guess, is over the years, as you said, there was a real kind of incremental path.
[2:46] SPEAKER_00: And I guess it was in 1996 when you said, well, this drug likely will inhibit food intake.
[2:54] SPEAKER_00: But then there were gaps of many years since then, as you mentioned, about getting into the obesity side.
[3:01] SPEAKER_00: Was that because there wasn't much weight loss in the people with diabetes or was it related to the dose of the drugs that were being tested?
[3:11] SPEAKER_01: Well, really both.
[3:12] SPEAKER_01: So the initial doses we tested for type 2 diabetes did not produce a lot of weight loss, maybe 2%, 3%.
[3:20] SPEAKER_01: And then when we got some aglutide for type 2 diabetes, maybe we were getting 4% to 5%.
[3:26] SPEAKER_01: mean weight loss.
[3:27] SPEAKER_01: And so, you know, that was really good.
[3:29] SPEAKER_01: And that was much better than we achieved before with any glucose lowering drug.
[3:33] SPEAKER_01: But a lot of credit goes to Nova Norris because they, you know, looked at the dose for loraglutide in diabetes, which was 1.8 milligrams once daily for people with type 2 diabetes.
[3:44] SPEAKER_01: And they asked a simple question, what if we increase the dose for
[3:49] SPEAKER_01: weight loss.
[3:50] SPEAKER_01: And the answer was we get better weight loss with three milligrams once a day.
[3:53] SPEAKER_01: So they learned that.
[3:55] SPEAKER_01: And when they introduced some magnetite for type two diabetes, the doses were 0.5 and one milligrams.
[4:00] SPEAKER_01: But in the back of their minds was the same question.
[4:03] SPEAKER_01: What if we increase the dose?
[4:05] SPEAKER_01: And they landed on 2.4 milligrams once a week.
[4:08] SPEAKER_01: And that's when we really started to see that the unexpected spectacular weight loss that we're now quite familiar with.
[4:14] Mm hmm.
[4:16] SPEAKER_00: Was there also something, too, that diabetics don't lose as much weight if you were to have meds?
[4:22] SPEAKER_01: That's a general phenomenon.
[4:24] SPEAKER_01: If one goes from either diet to bariatric surgery and certainly with weight loss medicines, we tend to see maybe two-thirds to three-quarters of the amount of weight loss in people with type 2 diabetes.
[4:36] SPEAKER_01: We don't really understand it.
[4:38] SPEAKER_01: The brain pathways are probably resistant to some of the pathways that are activated that lead to weight loss.
[4:46] SPEAKER_01: And it's really an interesting observation that needs further study.
[4:50] SPEAKER_00: Yeah, no, it's fascinating, really.
[4:52] SPEAKER_00: And it might have, at least in part, pulled up this progress that has been truly remarkable.
[4:57] SPEAKER_00: Now, recently, you published a paper among many.
[5:01] SPEAKER_00: You're a very prolific scientist, of course, physician scientist.
[5:06] SPEAKER_00: But back in December, in Cell Metabolism, it was a very important paper that explored the brain, gut, axis, feet.
[5:16] SPEAKER_00: ability to inhibit inflammation and the mechanism through toll-like receptors that you were seeing that.
[5:23] SPEAKER_00: So maybe you could summarize the fact that you saw this, you were quoted in this Atlantic piece by Sarah Zhang, the science behind Ozempic was wrong.
[5:34] SPEAKER_00: The weight loss effects of GLP-1 drugs have little to do with the gut and basically claiming that it's related to
[5:41] SPEAKER_00: The effects on the brain, which, of course, could be reduced inflammation, reduced or inhibiting centers of addiction, craving, that sort of thing.
[5:53] SPEAKER_00: So how do you interpret your recent results and ongoing studies regarding GLP-1's effect on the brain?
[6:02] SPEAKER_01: Sure, so to be clear, I don't think that was a quote.
[6:05] SPEAKER_01: I never would have said the science behind it was wrong.
[6:07] SPEAKER_01: I think that was a headline writer doing what they do best, which is catching people's attention.
[6:13] SPEAKER_01: I think what I was trying to say is that where this field started with insulin secretion first and then weight loss second, these are clearly very important pharmacological attributes to GLP-1.
[6:26] SPEAKER_01: But physiologically, if we take GLP-1 away or we take the receptor away,
[6:30] SPEAKER_01: You don't really develop diabetes without GLP-1.
[6:33] SPEAKER_01: You don't really gain a lot of weight without GLP-1.
[6:37] SPEAKER_01: So physiologically, it's not that important.
[6:39] SPEAKER_01: Why do we have GLP-1 in the distal gut?
[6:42] SPEAKER_01: I think physiologically, it's there to defend against infection and reduce gut inflammation.
[6:48] SPEAKER_01: But we noticed that GLP-1 reduces inflammation in many different places in the heart and blood vessels and in the liver and many organs where you don't see a lot of GLP-1 receptors and you don't see a lot of GLP-1 receptors on immune cells.
[7:04] SPEAKER_01: So that really led us to the question, well, how does it work and affect all these organs where we don't see a lot of the receptors?
[7:11] SPEAKER_01: And that's where we landed on the brain.
[7:12] SPEAKER_01: Obviously, the nervous system can communicate with many different cell types in almost every organ.
[7:20] SPEAKER_01: And we identified neurons that express the GLP-1 receptor, which when blocked,
[7:28] SPEAKER_01: abrogated or completely eliminated the ability of GLP-1 to reduce inflammation in the periphery, in white cells or in lungs.
[7:36] SPEAKER_01: So it's been known for some time that the brain can control the immune system.
[7:42] SPEAKER_01: So this is just the latest piece in the puzzle of how GLP-1 might reduce inflammation.
[7:48] SPEAKER_01: Sure.
[7:49] SPEAKER_00: And just to be clear, I was quoting the Atlantic headline, not you, that you reported within that article.
[7:55] SPEAKER_00: But, you know, this is something that's really interesting because obviously lip one is made in the brain, parts of the brain, our hindbrain, it's transient in terms of its half-life made from the gut.
[8:11] SPEAKER_00: But when we give these drugs,
[8:14] SPEAKER_00: these agonists, how does it get in the brain?
[8:17] SPEAKER_00: Because isn't there a problem with the blood-brain barrier?
[8:22] SPEAKER_01: Yeah, so I don't think the drugs get into the brain very well.
[8:25] SPEAKER_01: We have a lot of data on this.
[8:27] SPEAKER_01: So people have done the classic experiments.
[8:29] SPEAKER_01: They either make radioactive ligands or fluorescent ligands, and they look how much gets in it.
[8:36] SPEAKER_01: Not very much gets in beyond the blood-brain barrier.
[8:40] SPEAKER_01: And we also have big drugs that are immunoglobulin-based.
[8:46] SPEAKER_01: And they work really well.
[8:48] SPEAKER_01: So they don't get into the brain very much at all.
[8:51] SPEAKER_01: And so the way I describe this is the GLP-1 talks to the brain, but it doesn't directly get into the brain to meaningful extent.
[8:59] SPEAKER_01: It does communicate somewhat.
[9:00] SPEAKER_01: There are areas, obviously, that are accessible in the area of the stream and circumventricular organs.
[9:06] SPEAKER_01: But most of the time, we have this communication that's not well understood that results in the magic that we see.
[9:13] SPEAKER_01: And
[9:14] SPEAKER_01: You know, there are some discussions around for the neurodegenerative disease story where GLP-1 is being looked at in Parkinson's disease and in people with Alzheimer's disease.
[9:26] SPEAKER_01: Would you be able to get more benefit if you could get the drugs into the brain to a greater extent?
[9:31] SPEAKER_01: Or would you simply increase the adverse event profile and the aversion response?
[9:35] SPEAKER_01: So really important area for study as we begin to go beyond diabetes and obesity.
[9:41] SPEAKER_00: Yeah, I mean, as you're pointing out, there's
[9:44] SPEAKER_00: to ongoing trials, pretty large trials in Alzheimer's, early Alzheimer's, which may be a little bit too late.
[9:52] SPEAKER_00: But at any rate, testing, except one to see whether or not it could help prevent progression of the disease.
[10:00] SPEAKER_00: So, and as you also mentioned, diseases in Parkinson's.
[10:04] SPEAKER_00: But I guess, so the magic, as you kind of referred to it, the gut to brain axis, so that when you give
[10:13] SPEAKER_00: The GLP-1 family of drugs, we'll talk more about the double and triple receptor in a moment, but when you give these drugs, how does the message get from the gut to the brain, would you say?
[10:27] SPEAKER_01: So pharmacologically, we can give someone or an animal the drug.
[10:32] SPEAKER_01: It does reach some of the accessible neurons that have GLP-1 receptors, and they probably transmit signals deeper into the brain and then activate cell transduction.
[10:44] SPEAKER_01: So one way to look at it, if you see FOS, the protein, which is an immediate early gene, which is
[10:51] SPEAKER_01: increased when we activate neurons.
[10:53] SPEAKER_01: We see rapid activation of CFOS in many regions that are deep within the brain within minutes.
[11:01] SPEAKER_01: And we know that GLP-1 is not getting directly to those neurons, but it's activating pathways that turn on those neurons.
[11:08] SPEAKER_01: So there's probably a very intricate set of pathways that sense the GLP-1 and the accessible neurons and then transmit those signals deeper into the brain.
[11:18] SPEAKER_01: Okay.
[11:19] SPEAKER_00: Well, that makes sense.
[11:20] SPEAKER_00: Now, as this has been moving along in obesity from semaglutide to terzepatide and beyond, we're seeing even more potency, it appears.
[11:33] SPEAKER_00: And we have now double and triple receptors adding into glucagon itself and the gastric inhibitory polypeptide.
[11:44] SPEAKER_00: And there's mixed data.
[11:45] SPEAKER_00: So for example, the Amgen drug has the opposite effect on GIP.
[11:54] SPEAKER_00: as does the dual receptor, but comes out with the same weight loss, I guess.
[11:59] SPEAKER_00: How do we understand?
[12:00] SPEAKER_00: I mean, you know these gut hormones inside and out.
[12:04] SPEAKER_00: How do we get such disparate results when you're either blocking or revving up a peptide effect?
[12:13] SPEAKER_01: Yeah, it's a mystery.
[12:15] SPEAKER_01: I always sort of joke that you've invited the wrong person because I don't fully understand how to reconcile this, honestly.
[12:23] SPEAKER_01: There are some theories you could say that terzepatide may possibly desensitize the GIP receptor and that would align with what the GIP receptor blocking component is.
[12:35] SPEAKER_01: And so I think we need a lot of research.
[12:37] SPEAKER_01: We may actually never know in humans necessarily.
[12:40] SPEAKER_01: how to reconcile these observations.
[12:42] SPEAKER_01: I think we can do the experiments in animals.
[12:44] SPEAKER_01: We're doing them.
[12:45] SPEAKER_01: Other people are doing them to look at, you know, the gain and loss of function used by genetics.
[12:50] SPEAKER_01: But in humans, you'd have to block
[12:53] SPEAKER_01: or activate these receptors in very specific populations for a long period of time with tools that we probably don't have.
[13:00] SPEAKER_01: So we may not reconsult.
[13:02] SPEAKER_01: We may end up with Meritide from Amgen that's producing 15% to 20% plus weight loss, and Terzapatide from Lilly that's spectacular, that's producing more than 20% weight loss.
[13:14] SPEAKER_01: And yet, as you mentioned, at the GIP level, they have
[13:18] SPEAKER_01: opposite effect so I don't think we fully understand maybe your next guest will explain it to you and invite me on I'd be happy to listen
[13:27] SPEAKER_00: Well, I don't know.
[13:28] SPEAKER_00: I don't think anybody can explain it.
[13:29] SPEAKER_00: You've done it as well as I think is possible right now.
[13:32] SPEAKER_00: But then we have the triple receptor, which it seems like if you take that drug, you could just go kind of skeletal.
[13:39] SPEAKER_00: It seems like there's no plateau in its effect.
[13:43] SPEAKER_00: That's, I guess, is it retatrutide?
[13:46] SPEAKER_00: Is that the name?
[13:46] SPEAKER_00: Yeah, retatrutide.
[13:48] SPEAKER_00: Retatutride.
[13:49] SPEAKER_00: Okay.
[13:49] SPEAKER_00: Okay.
[13:50] SPEAKER_00: And then, of course, we're going on with potentially oral drugs or drugs that last for a year.
[13:57] SPEAKER_00: And where do you see all that headed?
[14:00] SPEAKER_01: So I think, you know, the way I describe innovation in this field is there are two buckets that we've talked about today.
[14:07] SPEAKER_01: So one bucket is the new molecule.
[14:09] SPEAKER_01: So we're going to have all kinds of different combinations that will be peptides, that will be small molecule orals.
[14:17] SPEAKER_01: You know, the
[14:18] SPEAKER_01: NIH is funding innovative programs to see if we can develop cell-based factories that produce GLP-1.
[14:25] SPEAKER_01: There are gene editing and gene therapy approaches.
[14:28] SPEAKER_01: So there are going to be multiple different molecular approaches to delivering molecules that are better and hopefully easier to take maybe once monthly, maybe every six months.
[14:39] SPEAKER_01: So that's really exciting.
[14:41] SPEAKER_01: And the other obvious
[14:42] SPEAKER_01: bucket is the disease that we're targeting.
[14:45] SPEAKER_01: So we started off with type 2 diabetes.
[14:47] SPEAKER_01: We're now firmly established in the obesity field.
[14:50] SPEAKER_01: In your field, we've seen consistently positive cardiovascular outcome trials.
[14:56] SPEAKER_01: We had a press release a few months ago in October from Novara saying that semaglutide reduces chronic kidney disease.
[15:02] SPEAKER_01: We have trials underway with peripheral artery disease, with Parkinson's disease, with
[15:06] SPEAKER_01: Alzheimer's, and a number of neuropsychiatric conditions.
[15:09] SPEAKER_01: So I think we're going to see both innovation on the molecule side, as well as expanding, if the trials are positive, expanding clinical indication.
[15:18] SPEAKER_01: So it's going to be a pretty exciting next couple of years.
[15:21] SPEAKER_00: Right, no question.
[15:23] SPEAKER_00: And as you well know, just in the past week, the FDA gave the green light for using these drugs for
[15:31] SPEAKER_00: heart failure with preserved ejection fraction, which was an important randomized trial that showed that.
[15:37] SPEAKER_00: Now, there's got to be some downsides, of course.
[15:41] SPEAKER_00: There's no drug that's perfect.
[15:43] SPEAKER_00: And I wanted to get your comments about muscle loss, potentially bone density reduction.
[15:50] SPEAKER_00: What are the downsides that we should be thinking about with these drugs?
[15:54] SPEAKER_01: Sure, so the known side effects are predominantly gastrointestinal.
[15:58] SPEAKER_01: So we have nausea, diarrhea, constipation, and vomiting.
[16:02] SPEAKER_01: And very importantly, if those side effects are severe enough that someone can't eat and drink for 24 hours, we need to tell them you have to seek medical attention because some people will get dehydrated and rarely get acute kidney injury.
[16:18] SPEAKER_01: This is rare, but it's described in many of the outcome trials, and we definitely want to avoid that.
[16:23] SPEAKER_01: Gallbladder events are probably 1 in several hundred to 1 in 1,000, and that can be anywhere from gallbladder inflammation to gallbladder stones to biliary obstruction.
[16:34] SPEAKER_01: Don't fully understand that, although GLP-1 does reduce gallbladder motility, so that may contribute significantly.
[16:40] SPEAKER_01: And then, you know, very rarely, you know, we're seeing reports of small bowel obstruction in some people, difficult to sort out.
[16:49] SPEAKER_01: We don't really see that in the large clinical trials, but we have to take people that there were.
[16:54] SPEAKER_01: We haven't seen an imbalance in pancreatitis.
[16:58] SPEAKER_01: We haven't seen an imbalance of cancer.
[17:01] SPEAKER_01: There is no evidence for clinically significant bone disease, either at the level of reduced bone densities or, more importantly, at the level of fractures.
[17:10] SPEAKER_01: And we have a lot of real-world data that's looked at that.
[17:13] SPEAKER_01: Now, muscle loss is really interesting.
[17:15] SPEAKER_01: So when the initial drugs were approved, they didn't produce much weight loss.
[17:19] SPEAKER_01: We didn't think about it.
[17:20] SPEAKER_01: Now that we're getting to 15%, 20% plus, the question is, will we see –
[17:26] SPEAKER_01: clinically significant sarcopenia.
[17:28] SPEAKER_01: And I use the word clinically significant carefully.
[17:31] SPEAKER_01: So we definitely see muscle lean mass loss on a DEXA scan, for example.
[17:37] SPEAKER_01: But what we're not seeing so far are people who are saying, you know what, my grip strength is weak.
[17:43] SPEAKER_01: I can't get up off the chair.
[17:46] SPEAKER_01: I have trouble reaching up into the cupboard.
[17:48] SPEAKER_01: My exercise or walking capacity is limited.
[17:50] SPEAKER_01: We're not seeing that.
[17:51] SPEAKER_01: In fact, we're seeing the opposite, as you might expect,
[17:54] SPEAKER_01: People are losing weight.
[17:55] SPEAKER_01: They're less achy.
[17:56] SPEAKER_01: They can move more.
[17:57] SPEAKER_01: They can exercise more.
[17:58] SPEAKER_01: So the question is, you know, buried within that data, are there some individuals with real clinical sarcopenia?
[18:05] SPEAKER_01: And as we get to 25% weight loss, it's very reasonable to expect that maybe we will see some individuals with clinical sarcopenia.
[18:14] SPEAKER_01: So you're very familiar.
[18:16] SPEAKER_01: There are half a dozen companies developing medicines to promote fat mass loss and spare weight.
[18:23] SPEAKER_01: muscle with or without semaglutide or terzopatide.
[18:29] SPEAKER_01: And this is a really interesting area to follow.
[18:32] SPEAKER_01: And I don't know how it's going to turn out.
[18:33] SPEAKER_01: We'll really have to see if we are going to see enough clinically significant muscle loss and sarcopenia to merit a new drug category emerge.
[18:43] SPEAKER_01: So fascinating to follow this.
[18:46] SPEAKER_00: I'm so glad you reviewed that because the muscle loss, it could be heterogeneous and there could be some people that really have some substantial sarcopenia.
[18:56] SPEAKER_00: We'll learn more about that.
[18:57] SPEAKER_00: Now that gets me to what do we do with
[19:01] SPEAKER_00: Lifelong therapy here, Daniel, where are we going?
[19:05] SPEAKER_00: Because it seems as though when you stop these drugs, much of the benefit can be not potentially all, but a substantial amount could be lost over time.
[19:17] SPEAKER_00: Is this something that, you know, you would view as like an insulin and other hormonal treatments or how do you see it?
[19:26] SPEAKER_01: Yeah, so it's fascinating.
[19:27] SPEAKER_01: I think the traditional view is the one that you just espoused.
[19:32] SPEAKER_01: That is, you stop the drug, you regain the weight, and people are concerned about the rebound weight and maybe gaining more fat and having less favorable body composition.
[19:44] SPEAKER_01: But if you look at the data, and it's coming very fast and furious, a few months ago, we saw data for a terzapatide trial, one of the surmount obesity trials.
[19:55] SPEAKER_01: The first officer was Lou Rohn in New York.
[19:58] SPEAKER_01: And they gave people terzapatide or placebo for 38 weeks.
[20:03] SPEAKER_01: And then they either continue the terazepatite or stop the terazepatite.
[20:07] SPEAKER_01: One year later, so no terazepatite for one year, more than 40% of the people still managed to keep at least 10% of their weight off, which is more than enough in many people to bestow considerable metabolic health.
[20:26] SPEAKER_01: So I think there are going to be people that don't need to take the medicines all the time for weight loss.
[20:33] SPEAKER_01: But we must remember that when we're excited about heart attacks and strokes and half-paths and chronic kidney disease, there's no evidence that you can stop the medicines and still get the benefits to reduce those chronic complications.
[20:46] SPEAKER_01: So we're going to have to get much more sophisticated in terms of a personalized and precision medicine approach and ask, what are the goals?
[20:53] SPEAKER_01: And if the goals are to reduce heart attacks, strokes, and death, you probably need to stay on the medicine.
[20:58] SPEAKER_01: If the goals are to achieve weight loss so that you can be metabolically healthy,
[21:03] SPEAKER_01: There may be a lot of people who can come off the medicine for considerable amounts of time.
[21:06] SPEAKER_01: So we're just learning about this.
[21:08] SPEAKER_01: It's very new and it's really exciting.
[21:11] SPEAKER_00: Yeah, no question.
[21:13] SPEAKER_00: Going back to the inflammation story in heart disease, it was notable that there were more biomarkers of reduced inflammation in the intervention trial.
[21:24] SPEAKER_00: before there was any evidence of weight loss.
[21:26] SPEAKER_00: So the anti-inflammatory effects here seem to be quite important, especially with various end-organ benefits.
[21:33] SPEAKER_00: Would you say that's true?
[21:35] SPEAKER_01: Yeah, I think that's one of my favorite sort of unifying theories.
[21:39] SPEAKER_01: If we step back for a minute and we come into this and we say, well, you know, here's a drug that improves heart disease and improves liver inflammation.
[21:50] SPEAKER_01: And
[21:51] SPEAKER_01: reduces chronic kidney disease and may have some effect on atherosclerosis and is being studied with promising results in neurodegenerative disease.
[22:01] SPEAKER_01: How do we unify all that?
[22:02] SPEAKER_01: And one way is to say all of these chronic disorders are characterized by a component of chronic inflammation.
[22:10] SPEAKER_01: And, you know, Eric, it's fascinating.
[22:11] SPEAKER_01: I get reports from random strangers, people who've been on drugs
[22:17] SPEAKER_01: or people who are on semaglutide.
[22:20] SPEAKER_01: And they tell me, and you'll be fascinated with this, they tell me, you know, my post-COVID brain fog is better since I started the drug.
[22:28] SPEAKER_01: They send me pictures of their hands.
[22:30] SPEAKER_01: These are people with chronic arthritis, and they say, my hands have never looked better
[22:35] SPEAKER_01: since I started the drug.
[22:37] SPEAKER_01: And they tell me they've had ulcerative colitis for years on biologics, and all of a sudden, it's intermission on these drugs.
[22:43] SPEAKER_01: So these are case reports.
[22:44] SPEAKER_01: They're anecdotes.
[22:46] SPEAKER_01: But they're fascinating and quite consistent with the fact that some people may be experiencing an anti-inflammatory effect of these medicines.
[22:55] SPEAKER_00: Yeah, and I think it's notable that this is a much more potent anti-inflammatory effect than we saw from statins.
[23:02] SPEAKER_00: I mean, that...
[23:04] SPEAKER_00: As you know well, they have an effect, but it's not in the same league, I don't think.
[23:09] SPEAKER_00: And also the point you made regarding this is a very good candidate drug class for long COVID and for a variety of conditions characterized by chronic inflammation.
[23:19] SPEAKER_00: In fact, so many of our chronic diseases fit into that category.
[23:25] SPEAKER_00: Well, this is fascinating.
[23:26] SPEAKER_00: And by the way, I don't know if you know this, but we were both at Johns Hopkins at the same time.
[23:32] SPEAKER_00: When you were there in the early 80s, I was there as a cardiology fellow.
[23:38] SPEAKER_00: Well, we never had a chance to meet back then.
[23:41] SPEAKER_01: So were you just ahead of Crooked Seidman and the whole team there?
[23:46] SPEAKER_00: Just before them, that's right.
[23:48] SPEAKER_00: You were there doing, was it your internship?
[23:50] SPEAKER_01: I was doing an Osler internship.
[23:52] SPEAKER_01: I think Victor McKusick loved to have a Canadian every year to recognize Osler, one of the great Canadians.
[24:00] SPEAKER_01: And I was just lucky to get the slot that year.
[24:03] SPEAKER_00: Yeah.
[24:04] SPEAKER_00: Yeah, it's wild to have watched your efforts, your career, and your colleagues and how much of a profound impact.
[24:13] SPEAKER_00: If you were to look back, though, and you were to put this into perspective, because there were obviously many other hormones along the way, like leptin and so many others that were candidates to achieve what this has.
[24:30] SPEAKER_00: Do you think there's serendipity that played out here?
[24:33] SPEAKER_00: How do you kind of factor it all together?
[24:38] SPEAKER_01: Well, there's always serendipity.
[24:40] SPEAKER_01: I mean, you know, for decades when people would write review articles on the neuropeptides that were important for control of hunger and satiety and appetite circuits, I would open the article, read it, and I'd say, darn, you know, there's no GLP-1 on the figure.
[24:56] SPEAKER_01: There's no GLP-1 receptor on the figure.
[24:58] SPEAKER_01: But there's leptin and agouti and the POMC peptides and all the malatic cortins and so on and so forth.
[25:05] SPEAKER_01: Because physiologically, these systems are not important.
[25:09] SPEAKER_01: As I mentioned, you don't see childhood obesity or genetic forms of obesity in people with loss of function mutations in the GLP-1 sequence or in the GLP-1 receptor.
[25:22] SPEAKER_01: You just don't see a physiologically important effect for having low GLP-1 or having no GLP-1.
[25:30] SPEAKER_01: And that's, of course, not the case for mutations in NPY or the melacorins or leptin, et cetera.
[25:36] SPEAKER_01: Pharmacologically, it's been extraordinarily difficult to make drugs out of these other peptides and pathways that we talked about.
[25:44] SPEAKER_01: But fortuitously or serendipitously, as you point out, these drugs seem to work.
[25:48] SPEAKER_01: And amazingly, you know, GPCRs are notoriously prone to desensitization.
[25:54] SPEAKER_01: We use that in clinical medicine to turn off entire circuits.
[25:59] SPEAKER_01: And thankfully, what goes away with GLP-1 are the adverse effects, so nausea, vomiting, diarrhea, constipation.
[26:06] SPEAKER_01: We see those during the first few weeks, and then there's tachyphylaxis, and they generally go away in most people.
[26:13] SPEAKER_01: But what doesn't go away...
[26:15] SPEAKER_01: through good fortune, are the ability of GLP-1 to talk to those brain circuits and say, you know what, you're not hungry, you don't need to eat, you don't need to think about food.
[26:24] SPEAKER_01: And that's just good luck, obviously, pharmacologically, that's benefited all of us working in this area.
[26:31] SPEAKER_00: It's extraordinary to be able to get desensitized on the adverse effects and not lose the power of the benefit.
[26:40] SPEAKER_00: What about addiction?
[26:42] SPEAKER_00: That is, whether it's alcohol, cigarettes, gambling, addictive behavior.
[26:48] SPEAKER_00: Do you see that that's ultimately going to be one of the principal uses of these drugs over time?
[26:55] SPEAKER_01: You know, the liver docs, when I give a talk at a metabolic liver disease meeting, they say, we love GLP-1 because not only might it take care of liver disease, but there are still some people that we see that are having problems with alcohol use disorders, and it might also reduce that.
[27:11] SPEAKER_01: And obviously, there are tons of anecdotes that we see.
[27:13] SPEAKER_01: If you go on social media, you'll see lots of discussion about this, and there's
[27:19] SPEAKER_01: hundred or so animal papers showing that addiction-related dependence behaviors are improved in the context of these medicines.
[27:28] SPEAKER_01: But we don't have the clinical data.
[27:29] SPEAKER_01: So, you know, we have a couple of randomized clinical trials, small ones, in people with alcohol use disorder.
[27:36] SPEAKER_01: Very unimpressive data.
[27:39] SPEAKER_01: We had a...
[27:40] SPEAKER_01: A trial in people with smoking didn't really see much, although interestingly, they noted that people drank less alcohol when they did the smoking trial.
[27:49] SPEAKER_01: So there are dozens and dozens of trials underway now.
[27:53] SPEAKER_01: Many investigator-initiated trials.
[27:55] SPEAKER_01: looking at whether it's nicotine or cocaine or cannabinoids or all kinds of compulsive behaviors, I think in the next 12 to 24 months, we're going to start to learn, are these real bona fide effects that are seen in large numbers of people, or are these just the anecdotes that we won't get a very good complete response?
[28:15] SPEAKER_01: So it's really exciting neuroscience, and we're going to learn a lot over the next couple of years.
[28:20] SPEAKER_00: Yeah, I know it's a fascinating area, which just extends the things that we've been discussing.
[28:25] SPEAKER_00: Now, let's say over time, over the years ahead, that these drugs become, because of the competition and various factors, perhaps in pill form or infrequent dosing, they become very inexpensive.
[28:42] SPEAKER_00: not like they are today.
[28:43] SPEAKER_01: That'd be great.
[28:45] SPEAKER_01: Speaking as a not pharmaceutical possession.
[28:48] SPEAKER_00: Yeah, no, that these companies, which of course, as you well know, are the council of the number one economy in Denmark and is having a big impact in Europe.
[28:58] SPEAKER_00: And obviously, Eli Lilly is now the most valued
[29:02] SPEAKER_00: biopharma company in the world from this.
[29:05] SPEAKER_00: All these effects are coming from this drug class.
[29:08] SPEAKER_00: But let's just say, you know, eventually it's not expensive and the drug companies are not, you know, gouging and pleasing their investors and we're in a different world.
[29:19] SPEAKER_00: With all these things that we've been discussing, do you foresee a future where most people will be taking one camera or another?
[29:28] SPEAKER_00: of this family of drugs to prevent all these chronic conditions that we've just been discussing, independent of obesity, type 2 diabetes, the initial frontier.
[29:39] SPEAKER_00: Do you think that's possible?
[29:42] SPEAKER_01: Yeah, I'm a very conservative data-driven person.
[29:45] SPEAKER_01: So today we don't have the data, right?
[29:48] SPEAKER_01: So, you know, if I was in charge of the drinking water supply in your neighborhood and I had unlimited free cheap gel, I wouldn't dump it in there just yet because I don't think we have the data.
[29:59] SPEAKER_01: But we have trials underway, as you noted, for Alzheimer's disease, a challenging condition for our society with a huge unmet need.
[30:08] SPEAKER_01: You know, if...
[30:10] SPEAKER_01: Like, fingers crossed, if semaglutide does show benefit for people living with early Alzheimer's disease, if it helps for Parkinson's, if it helps for metabolic liver disease.
[30:22] SPEAKER_01: There are also studies looking at aging, et cetera.
[30:25] SPEAKER_01: So it's possible one day, if we have a lot more data, that we will begin to think, okay, maybe this is actually a useful medicine that should deserve much more exposure.
[30:35] SPEAKER_01: But today, we just don't have the data.
[30:38] SPEAKER_00: Absolutely.
[30:39] SPEAKER_00: I couldn't agree more.
[30:40] SPEAKER_00: But just wanted to get you to speculate on that, a bit off script, if you will, what your thoughts were, because this will take a long time to get to that point.
[30:51] SPEAKER_00: But you just kind of wonder when you have an absence of chronic significant side effects overall with these diverse groups.
[30:59] SPEAKER_00: and relatively potent benefits that are cut across many organ systems, and as you just mentioned, might even influence the aging process, the biologic process.
[31:09] SPEAKER_01: There was another related, you know, sort of angle to this, which is that, you know, the accessibility of these medicines is very challenging, even in well-developed countries, United States, Europe, etc.,
[31:24] SPEAKER_01: And, you know, we have hundreds of millions of people in the global south and less well-developed economies that are also challenged by heart disease and diabetes and obesity and chronic kidney disease and liver disease.
[31:38] SPEAKER_01: And I think we need to start having conversations.
[31:40] SPEAKER_01: And I think they are happening.
[31:42] SPEAKER_01: just like we did for HIV and just like we did for hepatitis, and certainly we did very quickly for the COVID vaccines, we need to think out of the box and say we need to help people in other parts of the world who may not have access to the medicines in their current form and at their current pricing.
[32:00] SPEAKER_01: And I think these are
[32:02] SPEAKER_01: really important moral and ethical discussions that need to be happening now, because soon we will have small molecules and the price will come down.
[32:10] SPEAKER_01: And we need to make sure it's not just people in well-developed countries that can afford access to these medicines.
[32:17] SPEAKER_01: I think this is a great opportunity for pharmaceutical companies and the World Health Organization and other foundations to really think broadly about how we can benefit many more people.
[32:29] SPEAKER_00: I couldn't agree with you more.
[32:30] SPEAKER_00: I'm so glad you emphasized that because we can't wait for these prices to come down.
[32:36] SPEAKER_00: We need creative ways to bridge, to reduce inequities in the vital drug class that's emerged to have far more applicability and benefit than it was initially envisioned, certainly even five, 10 years ago, no less, 30 years ago when you got on it.
[32:53] SPEAKER_00: So
[32:54] SPEAKER_00: Daniel, uh, I can't thank you enough for this discussion.
[32:58] SPEAKER_00: Uh, really a candid, um, uh, discussion reviewing a lot of things we do know, don't know, we'll know someday perhaps.
[33:07] SPEAKER_00: Um, I'll, I just want to note, um, uh, I know so many people are cheering for you and your colleagues to get recognized further.
[33:15] SPEAKER_00: So like, uh, by the Nobel folks, uh, in the years ahead, I think it's pretty darn likely.
[33:22] SPEAKER_00: Um, and, uh,
[33:23] SPEAKER_00: you know, hopefully when we get a chance to visit again in the years ahead, we'll unravel some of the things that we discussed today that we didn't know the answers and that you as a really authority pioneer in the field, also I can admit that there's a ways to go to really understand the boundaries, if there are boundaries here for how these drugs are going to be used in the years ahead.
[33:51] SPEAKER_01: Yeah, it's another great story for basic science and, you know, bench to bedside.
[33:56] SPEAKER_01: And it's just another story where, you know, none of us could have predicted the outcomes that we're talking about today to their full extent.
[34:04] SPEAKER_01: And so, you know, to the extent that we can convince our governments and our funding agencies to really fund discovery science, the benefits are never apparent immediately.
[34:13] SPEAKER_01: But boy, do they ever come, you know, in spades later on in an unpredictable manner.
[34:18] SPEAKER_01: And this is just a great example.
[34:20] SPEAKER_00: Yeah, I also would say that this work, cracking the case of obesity, which, you know, has been a stumbling block.
[34:30] SPEAKER_00: You know, I ran a big trial with Remotabot, which was a failure with, you know, the neuropsychiatric side effects and suicidal ideation that had to get dropped.
[34:40] SPEAKER_00: And there's many others like that, as you know very well, Fen-Phen and a lot of lists.
[34:45] SPEAKER_00: And the fact that this could
[34:47] SPEAKER_00: do what it's doing.
[34:48] SPEAKER_00: And well beyond just obesity is just spectacular.
[34:52] SPEAKER_00: And what I think it does, what you just mentioned, Daniel, is the basic science work that led to this is, I think, an exemplar of why we should put in these efforts and not expect immediate benefits, dividends of those efforts, because look what's happened here.
[35:11] SPEAKER_00: If you can break through with obesity, imagine what lies ahead.
[35:17] SPEAKER_00: So thanks so much for joining, and we'll look forward to continuing to follow your work.
[35:24] SPEAKER_00: I know you're publishing the same pace, exceptional, prolific pace over many, many years, and I'm sure that's going to continue.
[35:34] SPEAKER_01: Well, I have a great team, and so it's a pleasure for me to go into work and talk to them every day.

Shows are listed from Apple Podcasts' charts and directory, and Podcast Index where it is used. Every show and episode belongs to its publisher and plays from the publisher's own feed; this site hosts none of them.