Latest / Art of the Question / Ozempic, GLP-1s and the Future of Obesity - Prof. Carel Le Roux - #26

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Ozempic, GLP-1s and the Future of Obesity - Prof. Carel Le Roux - #26 · Art of the Question

• Julius Moorman: GLP once. it's something that I feel like ⁓ if you were not in the space, ⁓ it kinda came out of nowhere. ⁓ that might not be the case if you are in the space. ⁓ but first of all, I was kinda wondering when did you first get interested in in GLP ones and what sparked that that moment? Yeah, so it was really when I was doing my ⁓ PhD. Because we were interested in how the gut talks to the brain. So we wanted to get these hormones that's made by the gut after you eat food and then see what action they have on the brain. ⁓ so as part of my PhD, we took GLP1, but also peptide YY, oxyantomodulin, pancreatic polypeptide, all this sort of natural concert of hormones that you and I produce every time we eat, and we purified them. And we were able to give them back to humans. And when we gave them back to humans, what we saw is patients reported that they felt ⁓ less hungry, they felt more full, they were eating smaller portions. but then we also saw that these medications had weight loss dependent benefits and weight loss independent benefits. ⁓ so now, you know, this is now twenty five years later, ⁓ you know, ⁓ these are now medications that we can use in clinical practice. So I still think of them as peptides, I still think of them as natural hormones that you and I make. And what we've been able to do is amplify them ⁓ by giving them to patients. And and I think that's been the revolution as you commented on. Yeah, and it started out like I think most people know it as of course ⁓ the drug that was used for diabetic patients, right? So how did we go from strictly using this drug for for di for treating diabetes to what it is right now? Because ⁓ I think I know it has something to do with the Gila monster. I don't know if you're aware with the with the history that goes far back, but I just thought that was super interesting and and happy to discuss again. So so because this is a natural peptide, what it does is it binds a receptor. It's almost like an antenna. ⁓ that's a receptor and the peptide sort of binds it. But these antennas, these receptors, are spread over the body. So the first place where they excuse me. where they are. ⁓ so the first place where they are ⁓ could be on the pancreas. And that's where it was described first. So that's so so-called incretin effect. So if you bind that receptor on the pancreas, the pancreas will make more insulin and ⁓ and that will help you to have better g ⁓ glycemic control for diabetes. So that's why it was targeted first for people with diabetes. But that same receptor is situated inside the brain And that's the part of the brain that has the disease of obesity. So if you treat that, the disease of obesity gets better. We now see that those receptors are also in the kidney. And if you bind that, you get better blood pressure control. and ⁓ so what we are seeing is that these peptides are binding, they're just doing their natural work. They go where they're supposed to go. Now the Gila monster is interesting because these natural peptides only have a half life. So they only live in your bloodstream and my bloodstream for about two minutes. And then the body breaks them down. They have like little it chops them up with peptidases and ⁓ and therefore it can't hang around much longer. But the Gela Monster, when they discovered that the Gela Monster made something in its saliva that looks Almost 50% to 60% like this natural peptide, but the normal peptidesis on humans can't break it down. So that's why they took that ⁓ peptide from healer monsters and were able to give that to humans, and that's called xenotide. and that was the revolution because suddenly now we could have these benefits for more than two minutes. Because remember when I said, you know, I did this as a PhD student. But we had to infuse it. We had to run the f infusion into the bloodstream all the time. But now with what the benefits with the Heli monster and subsequently, now we can give it once a day or once a week or even now once a month. ⁓ so they therefore it becomes much more convenient. But the jump from diabetes to obesity, that was a very natural change because it's just binding the natural receptors. in ⁓ in different parts of the of the body, different organs really. Yeah. And ⁓ I think for for for reference for the people who had never heard about the Gila Monster, the Gila Monster is a lizard ⁓ that lives, I believe, around in the US, around ⁓ Mexican desert area. And they started studying this lizard because it only had to eat like three times a year or something. At least it was able to fast and go on about its day for very, very long periods of time without eating. And researchers I believe were just fascinated by like, hey, that's interesting. How can this animal function so well without eating? And then it turns out it had something ⁓ yeah special happening inside ⁓ its body, which ultimately led to the discovery of ⁓ of these ⁓ GLP1 like medicines. So I just thought that was was super ⁓ super interesting. so yeah, we've we've briefly ⁓ talked about ⁓ the mechanics all already, but maybe if we can go ⁓ a little deeper into how these ⁓ drugs work. ⁓ so for example, what normally happens when I consume food? and what happens when I consume food while using I don't know, ⁓ Ozampic or or any other ⁓ GLP one. like drug. Yeah, I and I think, you know, you need to zoom out a little bit. It's like, you know, why do some people have a higher weight than other people, right? We all live in the same environment. We, you know, there's no difference in motivation or intelligence, etc. But yet some people are much heavier than other people. And what we're now under starting to understand, the science of the brain, is that there's a middle part of the brain that controls how many fat cells your body wants to carry. Now, say for example, you want to carry a certain number of fat cells and you then decide to go on a super duper diet, your calorie restrict yourself, what will happen is you will become more hungry and you'll think about food more often. Doesn't matter what weight you are, if you go below that weight, you know, that's a natural response. Now, what we've understood is that obesity ⁓ is not a problem Of eating too much or, you know, not doing enough exercise, we now understand that obesity is a fundamental dysregulation of the amount of fat cells that your body wants to carry. Now, it's interesting just to go back to that point. The body doesn't regulate weight. And we know that because if astronauts go to space, they don't balloon up, they don't change their weight, because of course, you know, there's no gravity. But the body regulates mass. And the mass that is regulating in this instance is a dipocyte mass, fat mass. So if you are at the same level of a depoisite mass where your body wants you to be, it's comfortable, then you feel a little bit hungry, you feel a little bit less you know, f full after you've eaten, but it's it's controlled. But it's when you change that that the body reacts. And what we now understand what these medications do is Is they fix the problem where the problem lies, you know, inside the brain, inside the hypothalamus or area postrema, these are the very specific parts of the brain that has the disease. And then what happens is the body comes under the impression that it is maybe fifteen or twenty or twenty-five percent too heavy. Now, say for example you weigh 125 kilograms and you take ⁓ such a medication and your body has decided that it's 25% too heavy. Then what it's naturally going to do is you're naturally going to come down to one hundred kilograms. And that has to be without effort. So you don't have to try because the body wants you to be at this new level. And of course by doing this in the first couple of weeks you feel less hungry, you feel more full, you're thinking about food ⁓ less often, you're eating smaller portions, but you still enjoy the food you're eating. But now when after a year, because it takes a human about a year to lose weight, after a year when you actually reach this new level state where you're supposed to be, now you just become normal again. Now you feel more hungry, you feel less full, you're eating more food, you're thinking about food more often, you still enjoy it, but your weight does not change. And that's really strange for people. So in the past, you're correct to point that out. In the past we thought that these drugs Make you feel less hungry. We thought these drugs make you eat less food. But now we understand actually what the drugs do is they treat the disease. If the disease comes under control, that change in the disease, that's what's making people eat less food. That's what's making people lose more weight. And that's now becoming apparent because when you actually continue the medication in the long term, your weight comes down and stays down, but it doesn't continue to lose weight. You know, so so we don't talk about these drugs as weight loss drugs anymore. We talk ab ⁓ talk about them either as weight change drugs or treatments for the disease of obesity. And that's fundamental because people, you know, won't you know, I won't take a medication if it's not working, you know, and why should anybody else take it? And if we say this is weight loss drugs or it makes changes you know how hungry you feel, once that stabilization happens at one year, people stop the drug. ⁓ because it's not they're not losing weight anymore and they're not feeling less hungry, but the minute they stop it, the body goes back to exactly the place where it was. So it goes back to that reg that dysregulated state. So I I I I wanted to emphasize that because that is so important that we now understand these are just chronic medications that need chronic treatment in the long term. Yeah, and I really appreciate the fact that you did ⁓ emphasize that. ⁓ because it's one of the points I wanted to touch on, discussing obesity as as being a brain disease. how is it possible that how does this disease occur? Like w how does it start in people? Because I believe if we look at pictures of the beach from fifty years ago, sixty years ago, nobody was overrate, right? So something must have changed in those fifty to sixty years. In our diets, I I know when I walking when I'm walking through the supermarket and I see what's in all these products, it's terrible, right? So ⁓ what role does processed food ⁓ have in this gigantic change of of the way we look and the amount of people that struggles with obesity? Yeah, it's you know and I think we also need to remain a bit humble and say that we don't know ⁓ exactly what causes the disease of obesity. In the past we thought that overeating caused obesity. And if you think overeating causes obesity, then what you're going to do is try to make people eat less. But that hasn't worked for the last two thousand years. now we actually understand the disease of obesity makes people overeat. And if I treat the disease of obesity, then people naturally eat less. Another good example of this is that ⁓ nobody would think that eating sugar Causes diabetes. Okay? Because we know diabetes is a disease that is, you know, two things that drive it. It's a reduction in insulin secretion and an increase in insulin resistance. That's what causes the disease of type 2 diabetes. But if you have type 2 diabetes, then your blood sugar levels are high. Okay. And that's a little bit the same. We don't think overeating causes obesity, but we think if you have the disease of obesity, you overeat. And of course, then you eat. you know, high calorie dense foods, et cetera. ⁓ so we need to do a lot more research in understanding what causes the disease of obesity, because once we can do that, we could really help prevent it. Because whatever we've done in the last 10, 20 years, and you know, your government, lots of governments across the world have spent an enormous amount of energy thinking about preventing the disease of obesity, and they've all failed. Every government in the world have tried about doing the same thing, and none of it has worked. All right. And so we didn't change the the incidence of the disease of obesity. So but we will. We will understand it. We just need to think of it in a in a new way. So I think ultra-processed foods may play a very important role. Not so much in how much people eat, but it may be that it changes inflammation in the brain. You know, that's a very early story, you know. ⁓ but there's a lot of new there's a lot of, you know, evidence to say that, you know, it's it's about how what we eat changes what happens in the middle part of the brain. So ⁓ but understanding that link I think is going to be important. But I must say to you right now, I don't think we're good enough and we need to do a lot more. Yeah. No, I I think I think you're you're you're completely right. ⁓ but if I look at some of the foods like the flavor some of the foods have these ultra processed foods. We weren't evolved, like millions of years of evolution. ⁓ we had like very bland diets, if you will, and then all of a sudden in the span of maybe fifty years, we start to go into the laboratory and we come up with all these exciting new flavors, all these synthetic flavors that mimic stuff or or supercharge Some of the flavors introduce new flavors we've never been exposed to. ⁓ to me it's very logical. Like if you want to sell your product, it has to be tasty. People want to buy it. Well, how do you make people buy your product? Make it super good, make it extremely tasty. ⁓ and I think in a way we we somehow ⁓ over overshot that and and made it addicting at times. Because I I think our our systems, our brains. weren't evolved to to taste something with with four different types of flavors thrown into one thing. So I I mean to me it makes it makes a lot of sense. Like why this happened. If you want to sell your product you ⁓ gotta make it super tasty. If something is so super tasty that we weren't evolved to handle it, it ⁓ yeah, maybe addicting to to some people. So yeah, I don't blame you know I I I think I think you're right. But but also You know, can we put the genie back in the box? You know, can we go back? You know, can we ask people to eat the bland food that your grandparents and my grandparents ate? You know, and and I I don't I don't know that that's going to be possible. ⁓ and that's why, you know, now when it comes to the treatment of obesity, we have made massive progress. And when it comes to the treatment, ⁓ you know, and it's pretty revolutionary to say that, is that The treatment has to be without effort. Because for many years people thought that obesity, if you want to treat obesity, you must try really hard, you must be super motivated, you must be ready for change, you know, all of this stuff, right? But none of us will say that if we treat asthma, or if we treat high blood pressure, or if we treat high cholesterol, right? You say, well, listen, you have a disease, this is really bad luck. You know, you didn't deserve to have this disease, but now you have it. So let us help you and you have a responsibility to take the treatment and I have a responsibility as a doctor, you know, to give you the right treatment. But if I treat your asthma or I treat your high blood pressure or your high cholesterol, it really has to be without effort. Otherwise, it's not sustainable. And I think that's gang that's what's happening now with these medications, is it's a little bit of a ⁓ you know, a social challenge to say to people, listen, if if this works, it has to be without effort. ⁓ because I want it to be sustainable. I think that's the issue because people are so used to having short-term weight loss. I try really hard, I do my super diet, my super exercise, ⁓ but I can't sustain it for the long term. Or there's very few people that can sustain it. ⁓ but now we actually have treatments that's very safe, that's very effective. And that can be sustained in the long term. And and I think that's gonna be our challenge, you know, moving forward. Yeah. And I think that's part of the reason why this is so so groundbreaking, right? Because for people that have struggled with obesity, like I I used to be overweight. It was during my uni years and I was drinking too many beers and I didn't exercise all that often and I was living in the student house and I was eating a lot of ⁓ unhealthy foods ⁓ every day. ⁓ so I I lost like I don't know like fifteen kilos when I ⁓ came back from uni, but it was difficult, you know. I had to like I was in my fitness bell every single day, tracking my calories and yeah, just torturing myself. Basically, if someone next to me was having ⁓ a nice ⁓ pizza or or ice cream or whatever, I remember that being very difficult. ⁓ but then like as soon as I moved out of that environment, ⁓ started drinking less, ⁓ started exercising more, yeah, was able to cook for myself. So all of these factors contributed to to me now being able to sustain a healthy weight. ⁓ but I remember it being very, very difficult. So now that we have something that makes it a lot easier and and ⁓ removes a lot of that friction. I think that's ⁓ yeah, many people don't realize how how groundbreaking this is in order to treat obesity. Yeah, ⁓ but but I also think what you touched on is that we want everybody in the world to have a healthy diet and everybody in the world to do healthy exercise. It doesn't matter what your weight is, if you're overweight, if you have obesity, if you're normal weight, you know, even if you're underweight, we need you to have a healthy diet, healthy exercise. And I think that's also what these medications are doing. So now it's allowing patients to have a healthy exercise and healthy diet ⁓ routine, not for weight loss, but for health gains. Because when you do exercise and you do eat healthier, you feel better. You may not lose any weight. And I mean you had a great example where you were able to make those changes and lose a substantial amount of weight. But that's the exception to the rule. ⁓ it's a good it's a good thing that it that it happened to you. ⁓ But there's many people that do the same as what you've done and actually don't have the benefit. ⁓ and that's also why we're talking about ⁓ that lots of people are now saying, ⁓ a diet and exercise doesn't work. Of course it does work, ⁓ but it only works in about two in every ten people. And we call that a nutritional therapy. So it's not a calorie restriction, you know, it's that a nutritional therapy that allows also the disease of obesity to come under control. And ⁓ and I and I and that's why we want people to do more exercise. We want them to have a healthier diet, because ultimately it's going to drive the health gains, even if it doesn't cause weight loss. Yeah, and how big of a problem is obesity globally? Because it is my understanding that we now have more people that struggle with obesity than ⁓ with ⁓ hunger, basically. So obesity is officially ⁓ a bigger problem than yeah, the the the lack of of food is. Yeah, absolutely. And and you know, that's a again a testament to good farming techniques, you know, and the fact that there's fewer people with hunger, that's a fantastic thing, you know. ⁓ you know, and I that's ⁓ that's really, really and I mean I I I just, you know, applaud the the scientists and the and the farmers, you know, for doing such a great job. ⁓ however, ⁓ what you are now seeing is probably part of it is that There were people that would live in constant states of famine and therefore if you're constantly hungry, you know, you cannot express ⁓ excessive adipocytes because you know you're constantly starving. And now what's happening is there's a lot of people that are no longer starving, but they always had obesity. ⁓ but now the obesity is just coming forward and is as presenting itself. ⁓ so we are seeing these shifts. But The problem is not so much obesity because nobody's going to explode, gonna keep keep growing and becoming bigger until they explode. But people die from complications of obesity. And there's more than two hundred and twenty complications. And these complications could either be mechanical complications like I can't move, I can't pick up my kids from the floor, I can't buy my shoelaces, ⁓ or I can't go for a walk or a run because, you know, I'm just too short of breath. ⁓ Also ⁓ metabolic complications, as you say, developing diabetes or heart disease or liver disease or kidney disease. ⁓ so what it does is obesity causes these complications that make you live shorter and make you live worse. So your quality of life is down, and how long you live is down. So when we are now treating obesity, I don't think many people get excited about, ⁓ you know, I'm gonna get people to lose a lot of weight. No, it's not that exciting. But most doctors would say to you. I'm pretty excited about helping people l ⁓ become healthier. And now we see these drugs, yes, they do people do lose weights, but it's the health gains that's really valuable. The fact that people come back and say, This is amazing. I can, you know, pick up my kids, I can go out with my friends, I can play with my grandkids, right? Or, you know, my diabetes is now gone backwards, I don't have ⁓ I don't have high blood sugar anymore, or my heart disease is reduced, or My kidney function is much better. So so we want to shift the focus away from weight loss to health gains. Both because, you know, you and I will have to pay more tax ⁓ you know, to to pay for these medications. But we're not going to pay more tax for people to lose weight. But we will pay more tax if it really makes people live longer and live better. Right. and ⁓ equally so doctors are not excited about treating weight. But they are excited about treating health. ⁓ so so so you can see how ⁓ that th these medications have revolutionized how we think ⁓ about obesity, no longer as a weight problem but as a health problem, ⁓ and also now as something that we can really address without effort. Yeah, no, totally. And I also it's it's a it's a downward or upward spiral, right? Because if you gain a lot of weight, every movement you do every single day takes more effort. And if something takes more effort, there's more friction. If there's more friction, you tend to do less of it. So if you wanted to go outside to to go for a walk or go for the run and and you are overweight, it's like it's harder to do. It's literally harder to do. So therefore you're less likely to do it. And therefore you move less and if you move less you you may even gain more weight. So it's like a a a a negative spiral. You definitely don't wanna wanna get sucked into. Yeah. Yeah. And it I don't know. It's but but but it's also another thing that, you know, if if you didn't like exercise before you take these medications, you're not going to like it afterwards. And if you like it before, you're going to like it before you're afterwards. So so these medications don't change the color of your eyes either. You know, so it's not like a complete revolution like everything suddenly becomes wonderful. And that's important because people come to us in good faith because they want to be thin and they want to be happy. And the two things we cannot do is we cannot make them thin and we cannot make them happy. So when we ask people, even when they've lost twenty five or thirty percent of their body weight, ⁓ and we ask them what do you see when you look in the mirror, most of them will say, Yeah, you know, I look a little bit older, I've a bit more saggy skin, you know, I don't see a big difference in the mirror. Other people say I look very different, or when I look at photos, I can really see the difference, but they don't see a big difference when they look in the mirror. Of course there's exceptions to that rule. I I I accept that. ⁓ but the other thing is also true, when we measure quality of life after these medications, we see quality of life dramatically improves. But the reason why quality of life improves is because quality of life have two domains, the physical domain and the mental domain. And the physical domain is dramatically better. People say I can walk up three flights of stairs carrying the shopping. You know, I'm not getting short of breath. I don't have any pain. You know, my functionality is so much better. But when we measure their mental quality of life, ⁓ it's absolutely unchanged. Right? So ⁓ so again, just coming back to that, people come to us in good faith because they want to be thin and happy. The two things we cannot do is we cannot make them thin, we cannot make them happy. But what we can do is we can make them healthier and more functional. And what you do with your health and functionality, that's your business. but it's important that we set expectations ⁓ so that we don't oversell these treatments, so that people really understand how to use them in an optimal way. Yeah, sure. And it depends from from person to person, right? But I I do think like health ⁓ and mobility and and wellness are are strongly correlated. ⁓ with happiness because if ⁓ it starts it starts with your health, right? I mean the the the saying is is it's a cliche but it's very true. ⁓ a healthy man wants a thousand things and a sick man wants just one thing, which is their health. So I think it's a good starting point if you wanna become happier ⁓ to ⁓ to at least ⁓ yeah be be healthier or try to be healthy. So no I think it's very important. Let's talk about potential side effects, right? Because there's a lot of misinformation out there, I believe. I noticed that to me what's interesting is this this drug, at least if we're just specifically talking Ozempic, it's been on the market f forever to treat diabetes. It's been used on millions of millions of people before we even started using it to treat ⁓ obesity. And now I see some I yeah, I wouldn't say lesser campaigns, but it's like it it's it's it seems pretty similar. So there's people saying that ⁓ from what I've seen, for example, that that bone bone loss may occur. And then they they introduce some of these ⁓ pictures I see from from from all these bones that look messed up and as like I don't know what to believe anymore. So maybe we can just clear the air around some of the known side effects ⁓ that may be applicable to some people and and some of them that we're seeing that are just complete and utter BS. Yeah, so so the good news is that we have been using this class of medication ⁓ for more than twenty-one years. And you're correct. We started by treating people with diabetes. Now, of course, people with diabetes have higher risk. than people that don't have diabetes. So we've had 21 years of treating patients and understanding what are the long-term side effects of these drugs. And what we see is their short-term side effects. And we always say it's not the dose, ⁓ rather I I misspoke. I we say it's not the drug, it's the dose of the drug that caused the side effects. So what I mean with that is the classical things is people may feel nauseous when we start the medication. Or even if you make them nauseous enough, they may even vomit. ⁓ or other people may develop constipation and others again can have diarrhea. So those are all the gut classical ⁓ effects. And what we now understand is that we in the past were too aggressive when it came to increasing the dose. And now what we're doing is we're increasing the dose slower. So if you start the medication and you have some nausea, ⁓ then I keep you on that dose until the nausea subsides, and then I go to the next dose. And I keep you on that until you have no nausea and I go to the next dose. So there's no rush in increasing the dose. We can go much slower. And if you go slower, you have far fewer side effects, but you have all the benefits. So there's no downsides of going a bit slower. Now, of course, some people don't have any side effects and they can just go up as per usual. So they don't have to slow, but no, we don't have to slow everybody down. ⁓ but as I said, I say to my patients, if you have side effects, it's my fault. Because I have gone too quickly. So I think that's the common thing. But the long term effects of these medications are very interesting because if we do these three year studies or four year studies, especially in the sickest patients, patients who are older, patients who have heart disease, ⁓ or patients who have heart disease and diabetes, and we follow people for three, four years, what you then see, because remember in these clinical trials, what we do is we we we pull your name out of a hat. And half of the people get the placebo treatment, ⁓ a dummy treatment, and half of the people get the active treatment. Then when we measure the serious adverse events, this bad things that really happen, it turns out that the people on the placebo arm have more serious adverse events than the patients on the active treatment arm. That doesn't mean there's no serious adverse events on the active treatment arm, but on balance, The riskiest thing to do is to not take the medication, you know? And and a reason is because the medications reduce heart attacks by 20%, kidney disease by 25%, reduces diabetes by 80 or 90%. So those are the long-term things. But now we're also seeing these rare things that happen. And I and these things are real, right? And and we need to, you know, understand them and be able to explain. So for example, if you lose weight very quickly. Then we can cause gallstones. So gallstones can happen in about three in a hundred people. ⁓ now we know that people that have the disease of obesity they are more prone to gallstones anyway. ⁓ and now if you make them lose weight faster, you really make it worse. So so that's why you know you take a group at high risk and you can make it worse by losing weight too quickly. So so we need to work out how to do it better. We think by slowing it down. ⁓ will make it better, but but we need to prove that. Now of course if you get a gallstone, ⁓ it can come down a little tube, and that tube is called a common bile duct. And if that gets stuck, if that little stone gets stuck, then you can have pancreatitis. Now that's a terrible pain, right? It's a pain in the middle of the tummy. And we always say first you worry that you're going to die and then you worry that you're not going to die because the pain is so bad, right? ⁓ but ⁓ But no, but but ⁓ but that's a very bad pain that that people get. and that could it can happen if the gallstone gets stuck. Now that's very rare. It's less than three in a thousand. Right. ⁓ but again we're doing everything in our power to actually reduce that risk. And and in lots of the new medications like semaclytide or tazepatide, we haven't seen that signal, right? ⁓ but we need to be vigilant. We need to look because if we're gonna cause enough gallstones, we're gonna see more pancreatitis. So so there's no point in pretending that these things don't happen. It's like how how can we manage it? Can we inform people? And what what do they need to do when when this does happen? And then of course we're now seeing this very rare ⁓ trouble in the eye where you have an optic neuritis. ⁓ you know, and and and that that also appears to be real, but it's very rare. So for example, if you have diabetes, your chances of getting this rare problem in the eye. Is typically one in 10,000. Now if I give you these medications, I double the risk. Now it's two in 10,000. But if you now imagine your chances of having a heart attack if you have diabetes is maybe 600 in 10,000. And if I reduce that by 20%, I bring your risk down to 480 in 10,000. So you understand? So sometimes when you talk about relative risk and Absolute risk, we need to be able to explain that better to patients. So the overall benefits is far superior than the risks, but the risks aren't zero. And we need to understand it. But finally, you know, just to come back to your point about bones, ⁓ so because we've done these studies now for or we've used these medications for 21 years, you know, we do not see a massive epidemic. of people with osteoporosis and fractures, you know, that been using these medications. Remember, some people have been using it for twenty years, right? So so so but we do see in bariatric surgery, we do see ⁓ some increases in fracture risk. ⁓ it's very small. The the absolute risk is small, but but it's real. And of course bariatric surgery also works partly through these gut hormones. So so I think that just comes back to the excuse me. to the point that you make, that's why we want exercise, that's why we want a healthy diet, is to help reduce these risks. ⁓ you know, but but ultimately we see massive functional improvements and and we don't see these long term problems being a massive epidemic. But we need to be vigilant and keep an eye on it. Yes, of course. And of course w one of one of them w one of the ⁓ side effects we often hear about is muscle loss, but I'm just curious to understand. Like, let's say I would st stop eating right now for for a week. I stop eating any any type of food. I will lose muscle. You know, like like I if the so it's I believe I'm not an expert by any means, but there's a good chance that this muscle loss side effect is more because people may have overdone the dose, stop eating altogether just because they aren't hungry anymore and that the muscle loss is triggered by a lack of nutrition, a lack of food, a lack of protein perhaps, ⁓ rather than an actual side effect of the drug itself, so that it can very easily be offset by just working out, doing a strength training and trying to keep at least get enough calories in ⁓ that is on par with your your BMR. ⁓ is that correct or or is ⁓ am I completely off here? No, you you're spot on. And I think there's some it's a couple of components. ⁓ exactly to what you said is if we increase the dose too quickly and people eat so little, you know, that there's not enough space to meet their protein requirement, then you're correct. Then people will start burning muscle for their protein requirement. And that's why we want people to have a high protein meals when they're having these medications. So they they they Get the proteins in first. So that's the first thing. The second thing is we don't want to increase the dose so rapidly that they eat almost nothing. There's no value and they they should not feel nauseous. So you should be able to eat the foods that you enjoy, prioritize your protein, ⁓ but ⁓ you know, then you were going to meet your protein requirement. Now, there's another thing that's just like, and you said you said what was the heaviest that you weighed? You you made a comment earlier. What was the heaviest that you weighed? I think on my ⁓ the the highest I've weighed and probably also the lowest I felt ⁓ was around hundred and four hundred and five kilos. Okay. ⁓ which is about around twenty kilos heavier than I currently am. And also I I wanna add that I am more I have more muscle mass now than I have ⁓ had back then. So the the difference was probably even bigger because we all know muscle is heavier than than fat, right? So let's say it was around twenty to twenty-five kilos of excess fat that I carried. But when you were a hundred and four kilograms, your body had to have enough muscle to carry a hundred and four kilograms around. True. And so because you know, as you said, it was just like it was an effort to go from place A to place B. So you your body had to be strong to do that, right? Now If you just lose the weight ⁓ and you don't go to a gymnasium, you don't exercise particularly, you know, what happens is say for example your body comes down now to eighty-four kilograms. Then your body will have the amount of muscle it needs to carry eighty-four kilograms around. Right? So if you of course do extra exercise, then the body needs extra muscle to cope with the exercise load that you're giving it. But if you're not doing exercise, your body will just come back to say, look, you know, I don't have to carry enough muscle for 104 kilograms, I'll carry enough muscle for 84 kilograms because I just need to move around and do my daily things. So we do see that there's a reduction in muscle as we actually lose weight. But that is what is supposed to happen. But what's fascinating now is when you were 104 kilograms, and if I took your your muscle out and I looked, I cut it and I looked at it, you would have looked like a rib eye stick. Right. They would have been fat inside the muscle. You know, that marbling, you know. That that's that's inside. And now what we see when people lose weight, what happens is that fat that used to be inside the muscle, that fat goes out. So of course the muscle looks smaller, but that's because the fat has left. And and of course fat inside the muscle that causes inflammation. So the muscle doesn't work so well. So even if the muscle has a bigger volume, the muscle function isn't quite as good. So so what you hear, the classical thing, and you have heard it and I hear it all the time. Anybody that says, you know, I've had bariatric surgery, or I've good done a good nutritional therapy, or I've done the medication, ⁓ and that have lost weight, they say, I'm so much more functional. My muscles move so much better. So they there may be less volume of the muscle, but they certainly work better. Yeah. And and what about people who aren't obese but still use ⁓ GLP one like drugs. ⁓ of course ⁓ we've had the whole body positivity movement in in Hollywood. You're perfect just the way you are and everyone is is as as beautiful as they as they feel. And then boom, Ozempic hits the market and ⁓ within a few months ⁓ the entire ⁓ red carpet, everyone is now skinny and and yeah it turns out body positivity movement was kind of a scam. My words, not yours, but ⁓ I just thought that was super interesting, right? so what we also see, like some of these people were actually obese, right? Some of these people were actually overweight. So good for you, use use the Ozambig. But what about people that weren't obese? Like they could lose some weight. Maybe they were just like they they were they were five kilos to heavy and they just want to look extra good this summer in their in their swimming suits. Maybe there's people out there that just want to have a six pack or whatever. ⁓ what is your vision on ⁓ those people? So using it ⁓ recreatively, I suppose, like non obese people using GLP one like drugs in order to look better and not treat obesity. Yeah, it's a difficult question because we don't have enough data, you know, and this is a a real example where the real world is exceeding ⁓ what is happening in the science. And the science need to catch up to really give people information, you know, so they can make informed decisions. My ⁓ just arguing from first principles, my biggest concern is that if you take the medication, say for example, for three months or six months before the summer. And now you stop it. Okay. What will happen is you will go back to where you were and you may even be a little bit worse than where you started. Right? So w whether or not you take the medication because you have the disease of obesity with all the complications of obesity, it has to be taken for the rest of your life. And and I think when we speak to people who come and say, Well, you know, I'm not that heavy, but you know, I'd like to lose some weight. ⁓ we say to them, look, this is a treatment for the disease of obesity. If you have the disease of obesity, we should treat this, right? ⁓ but if we treat this disease, it has to be for life. And I think once you explain to people those two concepts that look, this can be a dise a treatment for the disease. And you don't have to have a very heavy weight to have the disease of obesity because people say, I'm thinking about food all the time, I'm hungry all the time, I can't feel full. You know, ⁓ that could that could be the classical symptoms of the disease of obesity, even if your weight isn't that high. But ⁓ when you explain to people that you have to take it for the rest of your life, then people go, well, maybe, you know, I'll try the exercise and diet a little bit more, you know. So so so I I think it's about giving people choices, giving people the right information. you know, but but I understand and I I said to you before, people come to us with good faith because they want to be thin and happy. ⁓ but even if you h use this medication and you do lose the five kilograms, ⁓ there's no suggestion that you're going to be thin or happy, you know, even if you if you do fit into the bathing suit, you know, because your your body image has very little to do with your body weight, you know. And we know that from people with anorexia nervosa, you know, they're very underweight, but they see themselves as very ⁓ as being overweight. ⁓ so so we just wanna make sure that these medications are incredibly safe. ⁓ because they're naturally natural peptides that we've just modified slightly. So but, you know, if people make themselves vomit or they don't eat enough, ⁓ then they can cause trouble. And and we want to make sure the first rule in medicine is always do no harm. So let me put it together by saying that nobody nobody should use these medications if they're not prepared to take it for the rest of their life. If it works, then you we need to take it for the rest of their life. And that is a really a That that decision allows people to come up with quite sensible sensible you know final judgments. Yeah. No, I think that makes sense. And ⁓ from from ⁓ what we have seen so far, there there is no indication ⁓ apart from from the if if we ⁓ mono apart from the the side effects we we discussed, ⁓ there there seem to be relatively They they seem to be very manageable. So the the is there any way to if you if you have the d disease of obesity and and you're thinking about food all the time, maybe you've lost the weight already, but still y you the entire day you're just thinking about food and every day is a struggle because you feel like you have to contain yourself and have to have a very high discipline in order to maintain this healthy weight, which is an indicator that you are still struggling with the disease of obesity and not necessarily the physical yeah appearance of it. so taking such a a GLP one like drug for for life, ⁓ there there are at this point, ⁓ also because we've done have a lot of ⁓ research that we've been giving this drug for ⁓ diabetes, for example, that that is in principle safer than going back to physically being obese. Absolutely. And you know, so say for example, somebody has used a nutritional approach, right? And they've actually brought their weight down. But ⁓ now what they have is exactly what you say. You've activated the food noise, you're thinking about food, etc. If we use the medication and all we do is we dampen that process, we put you back into balance and homeostasis. That's a really good outcome of the medication. And that's why we're now talking about using these medications as we would any other chronic medication. We talk about minimum effective dose, not maximum tolerable dose. Not everybody has to go to the top dose, right? You go to the dose that sorts your problem out. And maybe in this instance, you know, somebody has gone from 100 kilograms to 80 kilograms with the diet, and all we do is we give them a lower dose of the medication and we keep them at 80 kilograms, right? ⁓ and suddenly they can just live their life, you know, and people say this is amazing. I've like thirty percent more brain space. I can just do things. I'm not thinking about food every living moment. ⁓ so that's a really good example of how to use medications in a sensible way. Yes. And what about ⁓ let's say we we we use this ⁓ medication, we have to use it for the rest of their life of of our lives. ⁓ what about dosages? Do we ⁓ get ⁓ any tolerance from from this drug drug or do we not fascinatingly no. It doesn't so when we look at long term studies, so this amount one three-year extension study or the select, which is a four-year study, that was one was done with the zepatite, one was done with semaclitite, what you see is people lose weight and then they flatline. It's like a pancake. It's incredible, right? So ⁓ and I would have predicted, I would have thought what will happen is the weight will come down and then drift up slowly, but actually it's absolutely flat. That is on average. Now there's eight percent of people on these medications that will slowly gain weight. So one in twelve people, right? And we do not understand why that is. There's also another ⁓ eight percent of patients that will actually slowly drift down and continue to lose weight over time. ⁓ so therefore we can adjust the dose. ⁓ and that's why we're having even better medications that's coming out now. ⁓ so if you d excuse me if you don't respond, then we can change the the we can change the dose up or we can reduce the dose. So I think you know, we will use this. This is just another hormone. And we will use it like we use any hormone. We will adjust it so it's just right for you, for the patient. You know, we don't it doesn't matter what I want as the as the dose. It matters what is the right dose for you as the patient. Yeah, and that right dose, how how how do people figure that out? Is that something that just how do you feel? How how are your cravings? How what does that look like finding your Well, we don't know yet, again, and there's a lot of work being done in the space at the moment, because what we're saying is we don't know what the target should be. ⁓ so for diabetes, you know, we we don't need to make you Normal, we just need to bring you into a low risk state. So the targets for diabetes could be a hemoglobin amid C of seven or six point five. That's the blood test we're taking. Or even for blood pressure, ⁓ it could be 130 over 85. So that's not normal, but it gets you to a low risk state. We don't know yet what that number is in obesity, but what we do know. is some people will go and lose 50% of their weight with these medications. And some people will gain weight on these medications. It is not the smart people that listen to us that lose a lot of weight and the people that don't listen that don't lose weight. It's biology. So if you are somebody that is a super responder, you're going to lose 50% of your weight. But we don't need you to lose 50% of their weight. We just need you to lose 25% of your weight, then we will give you a much lower dose. Right? And So so we would like the targets to be attached to health outcomes. You know, ⁓ how much weight do you need to lose to walk up the flights of stairs without any problems? Or, you know, for you not to have diabetes, or for your heart attack risk to be as low as possible. So so those are the targets that's meaningful to people, rather than the the weight on the scale. Yes. And w what about This is super interesting to me. Wha what about positive side effects or different treatments than obesity? Because it is my understanding that we are now also researching ⁓ the use of GLP one like drugs to treat addiction, for example. w what's happening there and and how does that work? It was it was fascinating, you know. And ⁓ we have a very good ⁓ general practitioner and you know, I was working with him ⁓ Morris Offarrell and he was He's just very good at documenting alcohol intake. He always has documented it for everybody. And he came to me in the beginning and he said, Look, I think people are drinking less alcohol. I'm like, no, why would they do that? You know, no, that's not a good thing. I don't think you're right. I said, okay, but let's go and look because your your notes are so good. And we actually analyzed it, and lo and behold, it was exactly right. And it was the people that drank the most that had the biggest change, right? But everybody said that they still liked. You know, if they have a beer, they still enjoy a beer, but they don't have to have four beers. Or if they drink wine, you know, they enjoy a glass of wine, but they don't have to have the bottle of wine. You know, ⁓ and and that was that was very interesting. So we are seeing in the brain multiple things. So addiction, but especially alcohol, I think is now at the forefront. ⁓ but we're also looking at other diseases. For example, heart disease. We now see that that is affected, that's independent of the weight loss. So the medications have a direct effect. Or the kidney. The ⁓ the medications have a direct effect on the kidney to protect it. and ⁓ and I think inflammation. So so I think we're gonna learn a lot about these medications and it's very exciting. It is very exciting. Finally I wanted to talk about some ⁓ new players in town, if you will. ⁓ we everyone knows Ozempic. ⁓ but one ⁓ I keep seeing is redatutrite. And it's supposed to work even better because Ozempic works on one receptor where ⁓ redatutrite works on three receptors. ⁓ can yeah, how how how how is it different and and why does it work so well? Yeah, and and I think this goes back to the bariatric surgery days, because if you actually measure the gut hormones that are elevated after surgery, it's exactly that. You know, it's GLP1 and that's ⁓ you know, somaclitide or Zempic. ⁓ but it also is this drug called opsintimodulin that's elevated after bariatric surgery. And that drug now is is a new drug called Civudutide. And it's also another drug called or another hormone rather called GIP. So what rtatritite is is it's three hormones. It's GLP1 plus GIP plus glucagon receptors that it binds. and you know we're learning from surgery that, you know, if you can allow the concert to play ⁓ perfectly together. So it's a little bit like if you've got a beautiful violin, you know, you can listen to that. But if you add a cello and you also add a viola, you know, now suddenly you have a string quartet. ⁓ you know, and ⁓ and I think that is, you know, where we're going with these drugs. Is we're using the natural pathways ⁓ that the body has created and we're optimizing them. And you know, so so the data is only available in ⁓ press release form at the moment, but it will be presented at the American Diabetes Association. And that's incredibly exciting. You know, because now we're talking in people with the body mass index above thirty-five, so these are people who have a very severe form of the disease of obesity, they lose more than thirty percent of their weight at two years. ⁓ and people with lesser forms of obesity, they lose twenty eight percent. And that's average. You know, so some people lose more, some people lose less. But that's very remarkable. So I I think the future is very bright, you know, when it comes to treating the disease. Yeah, and and if we look at the different ⁓ receptors, so ⁓ technically how how does that work? Because it is my understanding that one of them has something to do with the actual f feeling of hunger, but then the other two are more have more to do with how if we ingest calories or or carbohydrates, how those are being treated by the body and ⁓ how much ⁓ glucose ⁓ is spiked in in your blood. But as you hear, like I'm not an expert on this stuff. So I would like to No, no, no, no, no, no. Your understanding is excellent. No. No i it you so effectively you have like Imagine now you have all these different antennas in the in the body, like a glucagon antenna, a GIP antenna, and a GLP1 antenna, and they sit on different organs. And now you have this one compound and it can choose. You know, it can bind the glucagon receptors in the liver and for example reduce the liver fat. It can bind the GIP receptor on the pancreas and increase the insulin secretion to bring your sugar down. It can bind the GLP1 receptor in the brain and And bring the disease of obesity down. Now of course the brain also has GIP and GLP one and glucocone receptors. So that's why it's so powerful when it comes to the disease of obesity. But it's also going to be and that's the hypothesis and that's what's being tested right now, it's also potentially going to be very powerful when it comes to heart disease or kidney disease or liver disease, you know, and again driving that quality of life but also making people live longer. Super interesting. And finally I wanted to touch on something I will probably butch the pronunciation of, which is surfodutite, because you are personally leading the trial of one of the the new drugs in the space. Can you maybe explain what surfodutite is and ⁓ yeah what your trails are are are looking like currently. No, and your pronunciation was spot on. And I know and and that's also one of these new drugs that's based on a classical hormone called oxintomodulin. And what it does is it it binds either the GLP receptor or the glucagon receptor. So what we see is substantial weight loss, but we also see, especially the liver, ⁓ we see this reduction in fat in the liver, reduction in fat in the visceral space. That's the bad fat that causes trouble that sits inside the tummy. But also fat on the outside underneath the skin. So I think these drugs are, you know, they are and to me as a clinician, we just have more choice, you know, now and our patients have more choice. ⁓ so ⁓ and of course, you know, the more drugs they are, the lower the prices will be because there'll more competition in the system. So so I think this is a win win for all. Great. And ⁓ w what is what is ⁓ something that is is there something Most people get wrong about about GLP ones. There's a lot of ⁓ writing messaging about GLP one like drugs in the media. Is there something that you wish everyone would get right or everyone would know about these ⁓ these drugs? Yeah, these drugs are not magic and they don't work randomly. They just are biologically predictable. And therefore we can actually use them as chronic medications. And I think that is the key. We are discovering so many things, but ultimately we need to come back and say that if we want to have the benefits, we have to be able to make these drugs sustainable so people can take them in the long term without effort so to have the optimal health gains. Perfect. And is there ⁓ is there anything ⁓ we haven't touched on ⁓ that you think is is still important ⁓ to to mention when we're discussing ⁓ GLP one like drugs? Yeah, I I I think the final thing is that so many people are gonna have incredible responses. But there will be maybe ten, fifteen, twenty percent of paper people who will take these medications and will not respond to it. That's very important to say. That is not their fault. It's not because they've done anything wrong. But even these medications cannot connect to all the diseases of obesity. So if you don't respond, it's not because you've done anything wrong, but just go back to the doctor because there may be another treatment, you know, that may be suitable for you. So we don't want to increase the stigma of obesity in those people that biologically don't respond to the treatments. Of course, of course. And yeah. Carol, this was incredibly, incredibly interesting. I learned a lot today. So ⁓ thank you so much for for enlightening me on ⁓ on this topic. ⁓ I had a blast. ⁓ where can people go if they want to keep up with your work and and your research? Yeah, so ⁓ so our website where we actually put a lot of information on is ⁓ you know mybestweight dot ie. ⁓ and that sort of gives people, you know, all the new news and and also how we actually are thinking about obesity, not for weight loss, but for health gain. Perfect. I'll make sure to ⁓ to put those ⁓ in the show notes. ⁓ yes, again, Carl, thank you so much. ⁓ this was ⁓ incredible. And ⁓ yeah, if there's any new groundbreaking ⁓ news in this space, I'd ⁓ I'd love to ⁓ to talk to you ⁓ again someday. Thank you.