JG: Jane Godsland, Clinical Director, Springer Medicine.
NW: Natalie Wood, Senior Clinical Content Manager, Springer Medicine.
CG: Claire Greenhill, Chief Editor, Nature Reviews Endocrinology.
DD: Daniel Drucker, Professor of Medicine, Division of Endocrinology, University of Toronto.
JG: Hello and welcome to Medicine Matters, the Springer Medicine podcast. I'm Dr Jane Godsland. You are going to be so glad you made time for this podcast today. I urge you to stop whatever it is you're doing right now, maybe grab a cup of tea, but relish the next half an hour as we delve into what's arguably the greatest medical story of this century.
It's been 20 years since US FDA approved the first GLP one medicine for type 2 diabetes, and in the past few years these new drugs have exploded into mainstream medicine across the developed world. They're now set to disrupt treatment pathways and options across a dizzying variety of clinical specialties. And I'm so excited because today we have the absolute honour of talking with Professor Daniel Drucker, the pioneer of GLP-1s, about his life’s work developing these wonder drugs. We're also delighted to have Claire Greenhill, our esteemed colleague and Chief Editor of Nature Reviews Endocrinology, join us to add her insight into the latest and emerging research in the field. Together we will explore all that these treatments have to offer, from diabetes and obesity to substance use disorders and dementia. So come on, let's get started.
NW: Hello, my name is Natalie Wood and I'm a Senior Clinical Content Manager with Springer Medicine. I'm thrilled that today we're going to be talking about GLP-1 based therapies and that there are going to be three of us having this conversation. I'd like to start by handing over to my co-host for this episode so that she can introduce herself.
CG: Thank you, Natalie. So, my name is Claire Greenhill and I'm the Chief Editor of Nature Reviews Endocrinology. Also really looking forward to diving into this topic that's so interesting.
NW: Thanks, Claire. Before you do the honors and introduce our guest, you know I really wanted to have this conversation because it seems that GLP-1 based therapies are everywhere right now. It must have been exciting to see the developments over the years you've worked on the journal.
CG: Yeah, absolutely, because I've been working on the journal for about 15 years now and obviously not been there since the beginning, because it's been a long story, but it's been very fascinating watching the early findings coming out and then watching it grow into clinical application and watching all of those developments happen actually really fast over the last few years as well. It feels like there's been new major advances almost every week, and on my journal we do an article type called Year in Review where we ask experts to summarize the findings from the previous 12 months in a particular field, and we actually late last year asked our guest today to do that for us based on these drugs and the advances that have happened over the last year, and that was an amazing opportunity to have such a leading expert in the field to synthesize all those findings for us. And so that brings me on to introduce our expert. So, we're joined today by Professor Daniel Drucker, who is an endocrinologist and clinician scientist based at the University of Toronto. Welcome and thank you so much for joining us today.
DD: Thank you.
CG: And also congratulations on the Breakthrough Prize. That result came out in the last couple of weeks, that's really wonderful to see that recognition for your work.
DD: It was a, it was a different weekend, that's for sure, yeah.
CG: No, I'm sure. Could you tell us a little bit more about that early work and sort of what made you interested in that area of research and just what it was like at that time, what was happening?
DD: Sure. So, you know, I trained in endocrinology and in the early 1980s set out to learn some research, and landed in the lab of Joel Haffner at the Massachusetts General Hospital, actually intending originally to do thyroid research. My mentor was a thyroid specialist. I thought I was going to learn how to do thyroid molecular biology, and the lab at the time had some thyroid projects. When I got there, they were winding those down, and Bill Chin, who’s turned out like a leading investigator, he established the thyroid program at the Brigham across the way in Boston. And so they told me, well, Drucker, with our projects, you know, not viable for you here, you have to work on the glucagon chain. And at that time, I said to myself and my brain, what? Like, what are you talking about, I'm supposed to work on the thyroid? But in those days, we did what we were told, actually. We didn't have cell phones to complain to other people, and it was hard to reach out and you know, figure stuff out, so I just started to work on the glucagon chain and there were these unidentified sequences there called glucagon-like peptides. And nobody knew if they were made, where they were made, what they did, and that became my project.
CG: And, at the time, did you think, as you were in those early days, did you have any inkling of sort of what the implications could be, like to predict sort of what's happened now with those early findings?
DD: So, the first experiments that we did were showing GLP-1 stimulates insulin secretion and so there was a clear vision that maybe this would be useful for diabetes, particularly the aspect that was interesting was that the insulin secretion only happened when the blood sugar was elevated. And that was different from the drugs that we had at the time, the sulfonylureas, that continued to stimulate insulin secretion even when the blood sugar was low, so people are at risk for a low blood sugar. But none of us imagined that there would be an obesity chapter, and a heart disease story, and kidney disease, and sleep apnea, and liver disease, and substance use disorders, and neurodegenerative disorders. This has been an unbelievable journey of science and anyone who tells you that in 1985 they had a glimpse of this is maybe using a bit more imagination than he or she should.
NW: As you say, you envisaged they may have a use for diabetes and look where we are now, and I just wondered if, out of all the indications that are coming out, if there are any of that have really sort of surprised you?
DD: So, the really interesting conversations that we tend to hear are, and I hear very smart people say this all the time, that when we have a clinical result, people say, well, no-one could have predicted this. The reality is though if one looks at pretty much every single really cool clinical trial result that we've seen in the last couple of years, those trial results were predicted by preclinical studies. And so, whether it's cardiovascular disease that we got the first outcome trial in 2016, you know we and others had done experiments in small animals a decade before showing that GLP-1 reduced heart attacks, reduced strokes, was cardioprotective, and so the same thing for lung disease, the same thing for kidney disease. So, I think when people say, wow, this is totally unexpected, we never predicted this, I think what they really mean to say is we couldn't have imagined that this preclinical science would have translated so beautifully into humans. But almost every indication, even the stuff that we're excited about now, the substance use disorders, alcohol use disorders, smoking, cocaine, neurodegenerative disease, Parkinson's Disease, Alzheimer's, there's just a lot of basic science, preclinical science, suggesting that GLP-1 has actions on these diverse disorders. And what we're excited to learn is, you know, is this going to translate in humans? If so, what is the effect size? What's the risk–benefit ratio? But I, I sort of smile when I hear people say we never would have predicted this. What they really mean is well, the clinical trial results were better than we thought but consistent with the basic science that came before.
NW: Brilliant. Thank you. That is interesting.
CG: I'm going to take a slightly different tack now, because I think one of the things I find quite interesting is personalized medicine and tailoring treatment to patients, and I think now that there are so many more of these types of drugs available, I wondered what your thoughts were in terms of where we're at with making sure that patients with diabetes and obesity are getting the right drug for their particular risk profile, their particular background, and all those sorts of aspects.
DD: Yeah, this is a fantastic research opportunity for the young people coming into the field now. There is tremendous interindividual heterogeneity in how people respond to a GLP-1 medicine, and there are going to be tremendous differences between the new medicines that come out, with respect to some might be better for liver disease, others might be better for heart disease, others might be particularly good for weight loss in some people, others might be better tolerated for some people who have trouble with the medicines. But we're just starting this journey, you know, there's a very lovely paper in Nature Medicine that was published in April that looked at the genetic determinants of the response to weight loss, either in people with bariatric surgery or in people with GLP-1 medicines. And disappointingly, it was very difficult to find meaningful genetic variation that would predict the extent of weight loss. And yet in the clinic, we have some people who say, you know, wow, I lost 15–20% of my body weight, I haven't weighed this much since I was a young person. And other people come back to the clinic and they say I'm really disappointed, I've only lost 3 or 4% of my bodyweight, I wanted way more. So, why is that? What explains that interindividual heterogeneity? How we how do we begin to figure that out so we can make better, as you mentioned, personalized recommendations? And there may be similar recommendations about side effects. Half the people don't complain of side effects, this nausea, vomiting, diarrhea stuff. Other people do and it's very difficult for them. Could we figure out in advance who those people are, and could we figure out whether one drug might be better tolerated than another? So right now, we can't do this. It's a lot of trial and error in the clinic, but I'm sure as we go forward and study this in greater detail, we will begin to get a better grasp of this heterogeneity and response, lack of response, and be able to practice medicine in a wiser manner.
CG: Yeah, it's such an interesting field because obviously obesity itself is such a varied disorder as to why people develop it, so, of course there’s going to be variation in how people respond to the drug.
NW: Yeah, you mentioned that, Claire, about how varied it is and just thinking about patients, particularly, perhaps those with who are living with obesity, there's been a lot of stigma around obesity and it kind of feels like with the development of these medicines, it's going hand in hand now with changing attitudes and viewing obesity as a chronic disease. And so the impact that it has on patients, it must be very sort of freeing for them, in terms of the narrative changing from being one of personal responsibility. So that must be also a nice thing to sort of see as a consequence of these drugs being developed.
DD: Yeah, it's a really important point, I'm glad you raised it, and I would say this is the journey. There is still tremendous stigma in society at large as well as among healthcare professionals regarding obesity. There are almost no diseases we blame people for, I never hear conversations if someone has rheumatoid arthritis or Crohn's disease or multiple sclerosis, I never hear anyone say you should have looked after yourself better. But when it comes to people living with obesity, there is a substantial proportion of the population who tends to feel this is totally under the control of the individual and that they're not making the right choices, and they don't have enough willpower, and they need to use these medicines as a crutch to substitute for their own lack of agency. And you know, even though we have very good conversations now, we say listen, obesity is a disease, your brain does change, you rewire your defense of a certain bodyweight, even healthcare professionals don't accept that. And often when I do TV or media appearances and I have this conversation, I have colleagues who are professors of medicine write to me and say oh, come on, Drucker, you, you surely can't mean that no-one has influence over their ultimate destiny or their ultimate body weight. So, I think the power of these medicines has allowed many people who have been following diets, who have been exercising, who have literally been depriving themselves of calories and doing their best, but not sufficiently successful to reduce their body weight, now we help them. And they can be spectacularly successful, and they can turn around to the rest of us and say I just needed help, just like someone with 150 other chronic diseases needs help to control their disease. We now can help people, and they can turn to the world and say I did want to get back to a healthier weight, now I did, I just needed help. And I think that's a powerful message, but it's going to take a lot of conversation with members of society, because everyone eats, everyone drinks, everyone is an expert in the control of bodyweight, and many people have very rigid opinions about this.
NW: Yeah. Again, I just think it's fascinating and you know, following the sort of the story and how things are changing, but you're right, there's still a lot more work to be done at that level. And ultimately the things that we eat and the exercise, they’re things that we control, but there are a lot of other things about obesity that are out of our control, some at a societal level, when we look at our food environment and as we say, the obesogenic environment, and genetics and everything. So, as you say, there's still work to be done.
DD: Yeah. I mean, our population has not changed their genetics in 50 years. But when I was growing up, you know, we had Malthusian predictions of starvation as the number one health challenge related to food availability. And that is completely flipped over now, so that across the world, even in the global south, we're now challenged with obesity and not starvation. So, it's clearly not the genetics. And what is it? Is it, as you mentioned, is it the environment? Is it chemicals? Is it pollution? Is it ultraprocessed foods? Is it the way we build our cities? Is it infectious agents? So we don't know, these are very important questions to ask, but I don't think it's helpful to blame individuals, who have not changed their genetics, for this global shift in challenges with bodyweight.
NW: Brilliant. Thank you.
CG: I've just wanted to pick up on the point about obesity being a chronic condition, a lifelong thing, that people are going to be facing. And there's a there seems to be a bit of a division in the field as to whether patients are going to need to be on these therapies in some form or another for their entire lives, or if they'll be some other way of managing it, sort of like treatment windows and off periods and things, and I wondered what your perspective was on the long-term care of patients who have taken the GLP-1 based medications.
DD: Yeah, so there are some diseases in medicine, and particularly the infectious diseases, where you can say to someone take this antibiotic for 3 weeks and you'll be fine. Or even with hepatitis, we've had spectacular cures, now we can cure certain types of hepatitis, we can say take these antivirals for a defined period of time, you'll be fine and then you won't need the medicine anymore. Per hundreds of other chronic diseases, whether it's blood pressure, or cholesterol, or arthritis, or multiple sclerosis, or IBD, I can just go on and give you a hundred different diseases. When you stop taking the medicine, your disease comes back because we haven't cured the reason you have the disease we're just controlling the symptoms, and everyone accepts, no one says I'm going to take my high blood pressure pills for 6 months, and then I'm going to be fine, or I'm going to take my, you know, type 2 diabetes pills for 3 months and then I'm gonna be fine. Or I only need to take my Crohn's disease immunotherapy for 4 months and then I'm gonna be fine. Everyone understands that these are chronic, serious diseases. Because we have not had effective therapies for obesity that are medical beyond bariatric surgery, there hasn't been this concept of well, oh how long do you have to treat people with obesity, and what are the goals, and why are we treating them? And we now have compelling data from the SELECT trial that says you know what, if you treat people for a little over 3 years and they are at risk for heart disease they're going to reduce heart attacks and strokes by 20%. That's not likely to happen if we treat people for 4 months, they lose, you know, 5% of their bodyweight and then they come off it because they're a little happier with their bodyweight. So, this is an ongoing process of education. There will be some people, if you're just healthy and you're just trying to lose a certain amount of weight, some people can maintain their new lower weight by themselves for some periods of time after they’ve stopped the medicine. Other people cannot. But if we're trying to reduce serious complications, heart attacks, strokes, kidney disease, death, sleep apnea, etc., we don't really have good evidence to suggest, well, you just take the medicines for 6 months and then you stop and you're good to go. And this is a process of education. Most people who take GLP-1 medicines, the majority of that, after a year or so, they're not taking the medicines regularly if they started the medicines for weight loss. So, we have to make a greater effort at education, saying it's not just the weight we need to look at, it's the complications that are challenging when you're living with obesity, and they’re serious complications, those complications will be diminished if we continue taking the medicine. So, this is a brand-new field, right. Semaglutide was approved for obesity 3 years ago. Tirzepatide was approved for obesity a year and a half ago. So, we have a lot of work to do to educate healthcare professionals and the community with regard to the benefits of the medicines and the need for sustained therapy for many people.
CG: Do you think that the development of the oral formulations might help with that? Because I would imagine that a weekly or a monthly or a quarterly whatever injection is quite a barrier for some people, but maybe a pill might be an easier option for somebody.
DD: Some people like to take pills and don't favor injections. Endocrinologists who have being treating people with insulin their entire professional careers are so used to the use of these very nice pens now and you really can't feel the needle, and many endocrinologists would themselves say I'd rather take a pen-delivered injection once a week or, or soon even once a month, than take a pill every day. But the key point is, let's have options for people, and so that the person who prefers the pill a day, we have something for that person, the person who prefers an injection once a week or once a month we’ll have something for that person. And the pills also, we hope, will be less expensive, and when I say we hope, you know from my lips to the ears in Indianapolis and other centers that are making these medicines for us, but that's a big barrier now, right? So many people can't access the medicines, they can't afford the medicines, they're very expensive. And pills will not need a pen, they will not need expensive plants to make relative to the peptides, they will not need a cold chain, and the cost of goods and the ease of manufacture is much less, and so one would hope, I certainly hope, that the pills will be a more affordable option to improve access for many millions of people that can't otherwise afford them today.
NW: I've, you know, been reading how a lot of the quite adverse side effects have been when people are taking sort of some of the compounded GLP-1s and so kind of, I wonder if a lot of it goes back to the issue of cost and access, and then obviously we have all the counterfeit GLPs that are out there. So, do you think that the developments with the drugs will address some of that problem?
DD: Yeah. As I said, options are fantastic for people, right? If you, if you went to buy a car and, and someone said, well, here's the one car we have, I hope you like it, because if you don't, that's the only car we have. You say, well, that wasn't a very, you know, pleasant experience. Whereas if you went to buy a car and they said, well, you know, depending on what kind of person you are, we have six different types for you, they'll all work, but some might be better for you than others. And ways to deliver GLP 1 is really, I think, the same thing. Some people might like a once daily injection. Some people might like a once weekly or monthly injection. Other people might like a pill once a day. We have other technologies being developed as well for even more-extended delivery. And, again, the more options we have for some people the better. If you were a truck driver and you were not home for 2 months of the year because you were driving all across the continent, having an injection, you know that you needed to take once every 3 months would be amazing. You wouldn't even need to take your medicine with you, etc. So, I think we're going to see a lot of new options come forward in the next 3 to 5 years, and it will broaden access and be, I think, useful for many people.
CG: And talking of those options that are coming out, I know there's been a lot of work with different compounds adding in different things to try and for instance, adding in amylin analogues to try and address some of the adverse effects. Are there any of those things that are in the pipeline that you think are particularly promising or particularly exciting?
DD: Yeah. So, we just, I just wrote a an overview of this pipeline that appeared in Nature Reviews Drug Discovery, and if you had told me 10 years ago that there would be dozens and dozens and dozens of new GLP-1 medicines, not only peptides or oral small molecules, or weekly, monthly, but also, you know, amylin and FGF-21 and glucagon and GIP, and other bits and pieces that we’re sticking on to GLP-1 to produce benefits, whether it's more weight loss or better targeting of certain disorders, or less nausea etc.. If you had told me that 10 years ago, I’d have said, oh, come on, like maybe we'll get a few better GLP-1s, but the progress in this field is staggering. There are, you know, 60, 70 medicines in clinical trials already and I don't know how all of these medicines are going to be able to differentiate. I think some of them will not make it all the way. At some point, the later stage clinical trial results will not be as appealing as the sponsors would like. But, you know, today I can show you all the GLP-1 medicines on one slide and they're all quite big and visible. In 5 or 6 years, I'm either going to need five or six slides or I need to shrink the size of the GLP-1 medicines to get them all on one slide. So, again, this innovation will serve patients. But you know, is amylin going to be the secret sauce, or is GIP–glucagon gonna be fantastic, or should we think about adding some of these new muscle-sparing agents to make people living with obesity healthier and stronger? So, there's so many different ways people are trying to add on to GLP-1 to make the, you know, option more appealing, and it's very exciting, great trials are underway, and you know I think it’ll make you very busy as journal editors for the next little while.
CG: Oh, that’s good, good to hear.
NW: A nice problem to have, hey. In terms of going back to sort of talking about different populations and taking the drugs, and we're talking about it being lifelong. What do you think about, you know, because we see this burgeoning of adolescent or childhood obesity, do you think that holds true for the younger population? I know it's much more difficult to do the trials in children. I know there has been some work. I'm wondering if it's something if we treat it early before there have been these years of disease that have built up, whether that you think that that might be a possibility, or if there's anything sort of we need to be particularly careful about.
DD: Yeah, fantastic question. One of my favorite areas to focus on in terms of an unmet need for data is pediatric and adolescent obesity. In fact, I was reading a review that came out this morning that did a meta-analysis of all these trials, whether it was liraglutide, semaglutide, tirzepatide, in this patient population. There might be just around 700 people that are being studied, who are young people in these trials, and these are young people who are growing, they're going through puberty, their minds are developing, their organs are changing, their, their bones are growing, so many different things are happening to young people, and yet not treating them, they’re getting very unhealthy, and they’re developing type 2 diabetes and heart disease and they're at increased risk for cancer. So, we can't just stand back and say oh, you know, carry on with diet and exercise, which for many people is not helpful alone. But we don't, in my opinion, we don't have enough data for answering these critical questions, if I was a parent or a young person and I want to know, well, what's going to happen to me in 5 years? Is it going to affect my, you know, reproductive capacity? Are there any effects on maximal height that I'll change? Will it change my personality as I go through my adolescent years, which can be sometimes challenging to observe in any event without GLP-1 medicines. So, having only given these medicines and trials to 700 people, I think we have a huge obligation to study the consequences of these medicines, not only in bigger, longer trials, perhaps real-world trials, but also follow these young people in a registry and try and learn as much as we can. Because I always remind people, we've had 20 years of GLP-1 medicines in the clinic and 10s of millions of people treated with type 2 diabetes. April 28th was the 20th anniversary of the first approval, but, in contrast, the use of these medicines in young people, we’re just starting to learn. So, I think we're obligated as a community to invest more resources in understanding the benefits and potential risks of this medicine in younger people.
NW: Yeah, and I guess at the opposite end of that scale, as you say, we now have the experience of people using these medicines for some time and that population is aging. And I'm thinking, you know, with reference to obviously there’s sarcopenic obesity, but obviously, we know as people age, you know, frailty and sarcopenia are an issue. So, I guess we'll learn more about that as well over time if these patients are being followed up.
DD: Yeah. So, again, very important issue that's being actively studied. Most older people with frailty and sarcopenia are not studied in the conventional clinical trials where we used to register the medicines, yet they appear in our clinical practice every day and very rapid weight loss in someone who's a little bit fragile to start off with is often not healthy, and you know many of our patients have gained weight over 10, 15 years and gradually evolved a less healthy state. Yet we're sometimes trying to reverse this level of obesity in 9 months or 12 months, and that doesn't need to happen. We don't need to up-titrate the dose to the maximum dose and have people lose all of their desired weight in 12 months. We can go much slowly. We can start at lower doses. We can make sure people feel well. We can emphasize diet and resistance exercise, and you know, traditional maneuvers to make their musculoskeletal system as healthy as can be. So again, I think this is a really important opportunity that wasn't well studied in clinical trials, but it's starting to be looked at much more carefully now. And just the whole business of GLP-1 and aging in the older population, you've seen many articles written, I think, that you know are people in California who seem to be in the leading edge of taking stuff for aging, you know, have not only become fond of metformin and low-dose rapamycin, but many are now asking should I take GLP-1, you know it seems to prevent many of the chronic diseases of aging and prevent people from getting a little bit overweight, etc. So, these are populations we need to study. We don't have good data in people who are older and fragile. We don't have good data in people who are 75 and 80 years old. So, tremendous opportunities for investigation.
NW: Brilliant. Thank you.
CG: And building on that, do you think there are any other major gaps in the in the research that need to be filled over the next few years? Anything that's been missed?
DD: There are always major gaps. As a self-serving scientist who thinks we need to learn more. You know, so on the basic science side, we still don't understand how these medicines work. It's embarrassing to me, people ask me. I'm having a 45th class reunion for medical school graduation next month and I know people are gonna say to me, Drucker what are you doing now like? And I'm gonna say I'm still trying to figure out how GLP-1 works. I've been doing it for 40 years, I still don't understand this, and this is absolutely true. You know, if you look at all these new indications and you know we have the clinical trial experts from the SELECT trial saying, well, the 20% reduction in heart attacks, strokes, and death probably wasn't related to weight loss and happened very quickly. And so how does this happen? We don't understand. And then all of the new medicines, if we're adding GIP, or blocking GIP, or adding glucagon, or adding amylin, what's going to happen to the health of these people? Is it only going to be better, or are there some issues that maybe some of these other medicines might somehow mitigate the benefits of GLP-1, and, if so, what's that interaction going to be? So, we need a lot more study. And just as we've had 20 years for the GLP-1 class, every time we have a new class and every time we have a new patient population that's not just type 2 diabetes, we need to remind ourselves of how little we know, and we need to really study these medicines carefully to understand the benefits and the risks. We owe that to people.
NW: I was going to take it back to a really practical question, if I may. So, if you have someone who's coming to you and they're saying that they really want to take these drugs. What questions do you ask them? What is your advice to them and what do they need to know? And you know, when would you rule out giving someone these drugs? I'm thinking about any of our healthcare professionals that are listening would appreciate some advice on this.
DD: So, I'm a very conservative person. Umm. That's probably why I don't worry too much about when the stock market goes up and down, or I don't gamble and do things like that. But, you know, I stick to the clinical trial data. So, I look at what is the medicine registered for? What are, what were the clinical trials that were studied? Does that person in front of me meet the clinical criteria for benefit or meet the approved indications that NICE, or the FDA, or Health and Welfare Canada have stipulated guide the use of these medicines? And that's how I practice medicine. Now, I understand there are people in the community who say, you know, maybe I don't look like that person in the clinical trial, but I really want to lose 15 stone because Uncle Harry's wedding is coming up and there's a beautiful dress and I used to be a size 6 and I'd love to get into it. So that's an individual conversation between a patient and a healthcare provider, assessing what we know, what we don't know, and you know, I don't, I don't make opinions about that, but myself, in terms of being a practicing physician, I'm very conservative.
NW: Thank you.
CG: I kind of wanted to talk a bit about the flip side as well. We've talked a lot about the, the benefits and the potential of these drugs, but there are obviously some associated adverse effects which you mentioned, some of the gastrointestinal ones that are, are there any indications that there could be any major roadblocks with these drugs or groups of people who just are never going to be able to take them?
DD: Yeah, there, there are always going to be people who are at the, you know, borders of tolerability and say I just can't take them, the medicines don't make me feel well, I've tried all the different medicines at very low doses, and I just have a persistent feeling of malaise and don't feel well. And we should acknowledge that, it's not for everyone. For most people, these gastrointestinal symptoms appear when we start the medicine and when we increase the dose. And if you look at the data, 95% of the time, after a few weeks, these gastrointestinal complaints go away. But I respect lived experience. I have people tell me that they don't feel well, or they don't feel right, or they have noise in their brain, or their headaches are worse or they're tired, etc. and we should listen to people who are telling us these stories. And, even though we know from clinical trial data and real-world experience that most people can tolerate these medicines, not everyone can. And you know, last year, after 20 years of GLP-1 in the clinic, I wrote this pretty large, I think it was 20-page, review in Diabetes Care, on the side effects of GLP-1 medicines and it's become extremely popular, and you know it's one of my lifelong passion, scientifically, is not just to focus on the benefits but also to say what can go wrong? And what do we have to worry about? And what are the rare side effects that we should think about? And I think that's very important as medicines become more widely used, you know, even if a side effect is a 1 in 1000 side effect, if 20 million people are taking the medicine, you're going to see a lot of those side effects. So, I think this is something we must always study. And again, particularly as we introduce new medicines, we need to start all over without any assumptions and study those very carefully.
CG: Absolutely. That's so important.
NW: Yeah, I guess that is part of the thing, isn't it, it might be rare, but when so many are taking it, then it comes to the attention, doesn't it?
DD: Yeah, I think good physicians always respect what we don't know and there's a lot we don't know, so we should always remain vigilant.
NW: Brilliant.
CG: I just had one final thing I wanted to ask you about actually because I remember when these drugs were first approved for obesity that there was quite a lot of chatter around. Is this the end of bariatric surgery? Are all the surgeons going to be out of jobs? And obviously that has not transpired, and I guess that's again, because there need to be options for patients, but do you think that that's a fair summation? And I guess we might see that bariatric surgery rates decline slightly, but that it will always be a part of the treatment arsenal.
DD: Yeah, you know, I'm of a certain age that I have seen very busy cardiovascular surgeons who were doing open heart surgery and coronary artery bypass grafting and replacing valves. Very few cardiovascular surgeons do that kind of volume anymore other than in very, very difficult scenarios. We put in stents now, we can switch valves in and out through veins, and, you know, have amazing results. And I remember when the lineup for the urologists to have a transurethral prostatectomy if you were a 55- or 56-year-old man, there was an unending need for that type of surgical procedure. That's extraordinarily rare now. Now, we still have cardiovascular surgeons, we still have urologists, but they're not doing the same volume of procedures they used to. And we will always, I think, have a need for bariatric surgeries. They are colleagues, it's an extremely useful operation that has many advantages compared to potential lifelong GLP-1 medicines. This can, for some people, be a one and done procedure. It does have some side effects that need to be thought about. So, yes, there is now a reduction in volume of surgeries done, and there is actually some sense of some of the centers that are closing because they don't have enough volume to remain profitable in healthcare centers where profit is a key driver. But I think we all work together, the bariatric surgeons and the endocrinologists and the obesity specialists to make people healthy, and now we have complementary tools. We can use GLP-1, in essence, before bariatric surgery or after bariatric surgery. We can use bariatric surgery if the person is living with extreme obesity and has not had a good response to medicines, or we can use them if medicines have failed, etc. So, most of us view these options as tools and options to help people get in a better, healthier state, not as the, you know, either this or that or this one should go away, etc. Now we just have more options for people.
NW: We could talk to you for much longer, I'm sure. There are so many interesting questions. Given the way that the field is developing, I think it's probably a little bit unfair to ask you exactly what you think the future holds. But perhaps we could just finish with you telling us what you're most excited about in the short and long term.
DD: So, I think the most exciting new actions of GLP-1 that we're going to learn quite a lot about in the clinic are those in the brain, and you know we have a lot of trials now underway looking at substance use disorders. These are very challenging to treat. They can be very costly to people’s health and to society, and we have a lot of these anecdotal reports that people say I don't want to smoke as much, I don't need to drink as much, I'm not using as much of cannabinoids or opioids, etc. But what we're really lacking is a definitive large clinical trial with a good effect size saying, wow, a substantial number of people who took this type of GLP-1 medicine did or did not have a benefit. So, those trials are underway. Now, I think they're really exciting. I don't expect all of them to work. I don't expect GLP-1 to, you know, cure all substance use disorders, but let's see, you know, what we learn. And then neurodegenerative disorders. We've had five trials in Parkinson's, three looked like they were helpful, two looked like they were not. We have two large trials with oral semaglutide that will report out at the end of 2025. What a huge unmet need in our society, neurodegenerative disease and Alzheimer's, and so let's see what the results of GLP-1 show. And then probably the final one that I'm very interested in because we studied this in the lab, are the inflammation-related disorders. So, you know, we've seen some preliminary results look good in, in people with knee osteoarthritis. We have other trials underway now in, in psoriatic arthritis, or trials planned for rheumatoid arthritis and probably systemic lupus, and people are now starting to think again about inflammatory bowel disease. So, GLP-1 does reduce inflammation. Where might it be helpful? And, and we don't know, and so the clinical trials I think are going to be very exciting to learn more about this.
NW: There is lots more that we could talk about there. Thank you. So, I'd just like to finish by saying thank you so much, Professor Drucker, for taking your time out to speak with us today. I've really enjoyed our conversation, and I've learned so much. And many thanks also to my co-host, Claire Greenhill, and to those of you listening for joining us. Thank you.