The Life Scientific: Jens Juul Holst

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1:03Hello, Ozempic, Wegovi, Manjaro. Just a few years ago, most of us had never heard these names. Now they're everywhere, hailed as miracle weight loss drugs that help people shed the pounds by replicating a gut hormone called GLP-1, which tells the brain that you've eaten enough and nudges the pancreas to release insulin. One of the leading researchers behind this breakthrough is Jens Juhl-Holst, Professor of Medical Physiology and Biomedical Sciences at the University of Copenhagen, whose work in the 1980s helped discover and decode GLP-1. Over the decades since then, Jens has laid the groundwork for today's wonder drugs that are changing the lives of millions worldwide by treating obesity and diabetes.

1:49This has earned Jens a slew of high-profile accolades, including the Breakthrough Prize and the Tang Prize. And he was named among Time magazine's 100 most influential people in health for 2024. But with great power come great big questions. The rise of GLP-1 drugs is not only reshaping medicine, but also sparking debate about how they should be used and exactly what they mean for long-term healthcare and healthy societies. So hopefully we'll get some of those questions answered today. Jens Juhl-Huls, welcome to The Life Scientific. Thank you very much, and thank you very much for asking me to do this.

2:28Certainly, a lot of people will have heard about weight loss jabs in recent years. How exactly do they work? The interesting new thing about them is that they inhibit appetite. So that's the principle of the slimming. And that's quite a difference to many other approaches to weight loss. And if you think about it, it is one of the key ways of regulating the problem, which is the food intake, of course. there is and always has been a lot of stigma around obesity and weight loss. Have you seen that attitude play out around these new drugs? Yes, of course. Mostly I know of it from my own country, from Denmark, where people think that it is kind of cheating.

3:09You know, you're not supposed to do this. This is not the right way. You must suffer to lose weight. And some people, you know, object to the idea that you should lose weight at all. You should be happy with your own size. And from my angle, it's a different question. The problem is the complications of obesity. I'm a doctor, so this is my interest here. And we know that there is a large number of complications to obesity. And that's what you can do something about with these new medications. And I think that's fantastic. Well, we're certainly going to talk about a lot of these hugely positive results.

3:41But concerns have been raised, including by you. You said a couple of years ago that the success of GLP-1 drugs has brought new scientific, clinical and ethical questions that the medical community needs to navigate with care. So which questions do you think should be prioritised? So these drugs were originally meant for diabetes therapy and they're now spreading out to obesity therapy also. And the problem with both of them is that you have a decreased life expectancy. And not only that, but also you run a risk of having complications during your lifetime. And that can be very cumbersome and invalidating.

4:20And this is something that the society should do something about. Now, these new drugs have been proven to reduce the mortality and been proven to improve these complications and the morbidities that are associated with diabetes and obesity. So now we know that you can do something about it. So that's where I think that society somehow has to take over. And somebody should think about how we spread these possibilities to the general benefit of the population, rather than to the few that can afford it. But let's talk about you, Jens. You were born in 1945 in Copenhagen. Tell me about your family.

4:57So my parents were dentists, both of them. My father was a professor at the dental school. And I think I'm pretty sure that that has influenced my way, my attitudes, my choices. Another thing is that my mother didn't become dentist of her own will because she had planned to become a doctor. But it turned out that my grandfather couldn't afford her studies. So he asked her to find a shorter training. And so she became a dentist instead, but met the professor, which was good. I mean, that's how the whole thing started. Exactly. Good luck. So that was the atmosphere. It was an academic atmosphere.

5:34So this kind of lifestyle was oozing through everything, I think. Right. And in your early years at school, I gather you had a bit of a tough time. That was because, you know, I was good in classes. I had red hair and I was not terribly good at sports. So, you know, I was the victim of all the bullying. Yeah, yeah, exactly. So that lasted for the first five years of schooling. But then I moved to, you know, the high school system and things became a lot better. And eventually I went to the real high school, the three years. And that was one of the greatest times in my life. So things changed wonderfully.

6:12Well, after those difficult early years, things, as you say, did improve. You were a good student academically, but initially you wanted to focus on something other than science. You were very keen on music. Yeah, yeah. For a while in school, I thought that maybe I should end up doing something with music. Today, I'm quite happy that I didn't. I think that that would have been a tough life. Fun, but tough. So no, that had to go away and it was substituted with the hard work of being a medical student. But music is still a wonderful thing for me. I was going to ask you, you know, you still play piano?

6:47I still play and always have music in my ears when I can get away with it. So, yes, music is a big part of my life. My wife, fortunately, is also musically gifted and is playing the clarinet, so we can do duets. Oh, very nice. Well, Jens, as you say, you went to study medicine at the University of Copenhagen and you really threw yourself into student life. So I qualified in medicine in 1970, which means that the last two years was 1968, 69, right? Yeah. Where we had all the revolutions and student revolutions in all over Europe and all over the world, really. And of course, I was part of that.

7:26You know, I was a young, enthusiastic socialist, and I was taking very much part in the different student activities we had, and even some of the more, you know, yeah, yeah, which we shouldn't talk too much about today. But it was a great time. And, you know, I think it cemented my attitude to health and society and things like that. So I think it was very, very, very useful. So after your studies, you started working at Bisperbjørg Hospital, which then became affiliated with the University of Copenhagen. And that meant you were encouraged to do research alongside your clinical work. Yeah, I think I was interested in research already, but the possibilities were improving as we were transitioning to university status.

8:08And so the boss, the head of the department became professor. And he was then entitled to have a scientific assistant. And I became his assistant. So that meant that I was even obliged to do research, I mean, apart from the surgery. So that really facilitated things. And that's when you first began studying gut hormones in Ernest. Yes, I was introduced to this very new field of the gut hormones because my real mentor, who's called Jens Rehfeldt, He had been to the United States to work with the hormone gastrin in Florida and came home with some hints about technology and the field as such. And he said, OK, let's join forces and see what we can make out of it.

8:49Because then we were able to create a laboratory and that laboratory was devoted to gut hormones. And for this, the big thing was the new technology of radio immunoassay, which had more or less recently been discovered or developed by two Nobel laureates. and we adopted that technology as quickly as we could because that was necessary to study these gut hormones because they circulate in very, very low concentration. So you must have a method of sufficient sensitivity and this new method had that. There were no other methods that would be able to. And at that point, you were looking at a group of metabolic hormones called incretin.

9:28Yeah, our main interest became the regulation of the gut of insulin secretion And for me, that was logical because I came from this department that had specialized in peptic ulcer disease, you know. And we had some peptic ulcer patients with too low blood glucose levels after we had been operating on them. And we wanted to find out why that was. We thought it would be a gut hormone, right? So it was absolutely natural for us to find out how the gut regulates insulin secretion and glucose levels in the body. So that became one of the key questions. We put that up as a target for us, try to find out what are the incretin hormones.

10:05And that's what actually we managed to do eventually. Well, you say eventually, because this is like a decade's worth of research to get the answers. Ultimately, you were successful in isolating and characterizing this all-important GLP-1 hormone. Talk me through that process. I was chasing this hormone that was responsible for the hypoglycemia in our patients. And then a new peptide came up. It came from Stockholm. It was called GIP. Peptides. I mean, these are basically molecular chains of amino acids. Short chains. And there was one coming up from Stockholm, which was demonstrated to be able to stimulate insulin secretion in people.

10:49But for various reasons, we could show that this was not the substance that was responsible for our hypoglycemia patients. So there had to be another one. This was clear. And we found some cells in the gut that were illuminating with antibodies against glucagon. And glucagon is a hormone from the pancreas that is normally regulating blood glucose. And it was ridiculous that glucagon should be found in the gut all of a sudden. But we eventually isolated the peptides from those cells and found out what it was. And it was a peptide that contained glucagon in the middle. Right. So we found out that this was actually the precursor of glucagon, because we could also find it in the pancreas and all the bits and pieces there.

11:31So the interesting thing was, of course, to find out what was in the rest of the molecule. That was an American who found out that, a guy called Graham Bell, who in 1983 was able to pull out a gene sequence. And we found in that DNA sequence, there was coding for something that looked like glucagon. Actually, there were two stretches that looked like glucagon, both of them. And they were, of course, designated glucagon-like peptides 1 and glucagon-like peptides 2. Which is the GLP, yes. And that's the GLP-1 and GLP-2, yeah. Right. So that opened the field, I must say. And it's a lot of technical detail there, but I think it's important because if you come to talking about these weight loss drugs, they all rely on this glucagon-like peptide GLP-1.

12:16Yes. Now, in 1993, your team provided the first clinical evidence that GLP-1 could help patients with diabetes. Now, you told us about GLP-1 itself, but how exactly was that translated into a treatment for diabetes? How did it work? So, first of all, we pulled out the natural peptide from tissues and found out that it stimulated insulin secretion directly. And the question was then, is this really interesting? And the prediction was, no, no, it's not interesting because people with type 2 diabetes, you know, they have lousy beta cells. They don't react to anything. They don't even react to glucose.

12:52And it didn't react to this first incretin hormone, GIP. It didn't react to those either. So the probability that this would make any change was very, very small. But again, we had put it on our pancreas and found out. I mean, I had a pancreas in the laboratory, you know, a living pancreas, an isolated living as a tool. It was really fun. and it also inhibited glucagon secretion. Now, there's a problem in people with diabetes that they have too much glucagon at the wrong times. And here we had something that could inhibit glucagon secretion, and this was news. So now we had two features of this hormone that could be interesting in diabetes.

13:29So I was working very closely together with Michael Nauck from Germany, and he was working in a diabetes hospital and with the big Ingridson expert in these days, is Werner Kreutzfeldt, an important professor from Germany. And together we arranged to have infusions made in his diabetes hospital. People came in with really bad glucose regulation and gave them infusions of this new peptide for four hours and were able to completely normalize their blood glucose. And that was really a breakthrough. That was really a breakthrough. But as you say, this is for people with type 2 diabetes, not type 1.

14:05Yeah, yeah, this is true. So it didn't take long before we tried on type 1 also. And it actually worked to some extent, not as well as in those with type 2, because it partly acts on the insulin. And since people with type 1 diabetes do not have insulin, that part of the activity cannot be put into practice. I see. But they do have the glucagon problem. And also there are many other things that are improved with GLP-1. So it actually works to some extent on people with type 1 diabetes. And it's very interesting today because the cardiovascular improvements that you get with GLP-1 and the anti-obesity effect, both of those are relevant for people with type 1 diabetes also today.

14:46So that's why it's come back into the picture, you know, as something that really is of interest. Right, right. Of course, as we've mentioned, all of this was the culmination of years of research and not just a single eureka moment. But in the diabetes world, this breakthrough was huge. Do you remember how you felt about it at the time? So this demonstration of the complete normalization of the glucose levels really meant that we convinced not only ourselves that this was a future therapy for diabetes, but also some of the pharmaceutical industries. And that's how Novonordis, for instance, became interested.

15:21And of course, we also demonstrated in 96 and 97, 8, that it also inhibited food intake in people. And that, of course, was also very, very interesting. So we started doing studies and tried to see what happened. And sure enough, we could inhibit appetite and we could inhibit food intake with infusions of GLP-1 in people. So things are looking very promising then. But when it came to making GLP-1 suitable for obesity therapy, there were some issues. Can you explain what these issues were? I can easily explain that. So what we found immediately was that if we gave them intravenous infusions into the bloodstream, that worked.

15:59But if we gave them just a single injection, it didn't work. Why not? Because the peptide was eliminated from the body immediately almost. So it has what we call a half-life. It means that half of what you have in the body is eliminated within two minutes. So it disappears during very, very few minutes. It completely disappears. And you can't treat people with a peptide that is eliminated so quickly. We found the reason for it, and that was an enzyme. But we also found out that if you could inhibit that enzyme, you could actually make the hormone GLP-1 survive for a longer time. But that was one of the problems, the very short survival time.

16:36Short survival, yes. And I gather, you know, you couldn't give people a higher dose because it would lead to nausea. So we tried that, of course. And it turned out, no, no, we couldn't, because the higher the doses we gave them, the more side effects there would be. There would be nausea and eventually vomiting. But we found out that you could stabilize the molecule by exchanging really a single amino acid in the chain. And that could make it resistant towards this enzyme. But it would still be eliminated quickly from the kidneys. And that would be a problem. So something special had to be done to circumvent that problem.

17:09And that's what they did at Novotis, where they attached a fatty acid chain to the molecule. And what happens is that when you inject that, it will bind to one of the proteins in the plasma, in the blood. And it has a long half-life of 20 days or something like that. So all of a sudden, this peptide GLP-1 can now survive in the body. And it turned out that the half-life of this fatty acid substituted GLP-1 was now 12 hours rather than two minutes. So that was quite a different, right? So that is the rachlotype that was developed at the Nobunortis company. So the first version of a weight loss drug launched in the UK in 2015, longer ago than people might think.

17:53So the people at Novodores created some dose response studies and could demonstrate that if they were very careful with the increasing dosing in the beginning, you could actually get to higher doses, which would give a weight loss of some 7 to 8 percent. And this was the procedure that eventually led to Saxenda, which was the first of these drugs to be approved for obesity therapy. Well, as you say, you know, this 8 % is significant. But your team and indeed others around the world were working to develop more effective versions. This is how you arrived at semaglutide, this drug that's the basis of Azempic and Mugovie.

18:31What happened was that several pharmaceutical companies were now interested in this and tried to extend the half-life by changing a few other details of the molecule, not very much, by the way, and managed to produce a molecule that could last for a week, requiring only weekly injections. So that was, of course, very nice. This was simacrotide. I was part of that process myself, so I really enjoyed it. It also was improved in terms of insulin secretion and food intake. But again, it was felt that perhaps with higher doses, you could obtain even more. And again, you know, a very meticulous, careful study was carried out.

19:09And it was found that indeed, you could increase the dose. And it was possible now to create weight losses of up to 18%. And that started the whole craze. And that wasn't the only positive outcome, was it? There was more good news from the cardiovascular trials, which you have to do with any new drug. Yeah, and it turned out to reduce the risk of cardiovascular adverse events quite significantly. It was a wonderful surprise. That's incredible. Absolutely. I want to come back to that a little later on. But in the meantime, Jens, the GLP-1 therapies developed by you and others translated into those medications that we're seeing today and within a comparatively short space of time have had a remarkable impact helping people with diabetes and obesity.

19:55Have you had any feedback from people you know about how it's changed things for them? Oh, yes. I get a lot of emails from people who are thanking and describing how this has changed their lives and how happy they are. One thing is that people are happy. Another thing is that it can be documented in hard data that it really helps. There's been a lot of discussion around other possible benefits of GLP-1 therapy. We mentioned the surprising positive results from the cardiovascular trials earlier. What possible applications are you exploring now? So there are a whole set of things. Some of them are related to the weight loss, I guess, in itself.

20:35For instance, something like sleep apnea. And there is wonderful data now that this really helps a lot. But in addition to that, we need to understand why these compounds have this effect on the cardiovascular problems. And the focus is really on inflammation and the immune system these days. And there are a lot of observations on interactions with GLP-1 with receptors in the immune system. And there is typically in obesity and diabetes, what we call a low-grade inflammation, systemic inflammation. And this is thought to contribute very much to the problems, the complications. So that is in the heart, that is in the liver, that is in the kidneys, that is in the lungs, and that is in the central nervous system.

21:27So one of the theories, and it's actually more than a theory these days because it's quite evident, is that one of the ways GLP-1s improve all these conditions, because they do, is by interfering with the inflammation, reducing the inflammation that causes these problems in the various organs so you know it's not even miraculous any longer it's it's a fact there is a mechanism behind this so that's really fantastic i think that's incredible so various positive and unexpected impacts but as with almost any new medication there are of course also concerns and one that's been covered quite recently in the media is possible swift weight regain after stopping treatment.

22:12What's your reaction to that? So first of all, it was predicted. And it also turns out to be true. Because what happens when you're in therapy is that you inhibit your appetite. And because of that, you eat less and then eventually will lose some weight. But if you regain your appetite, then you will start eating again, and you will increase in body weight. So if you stop the therapy, of course, your body weight will return. But fortunately, there is something you can do, engage in a change of lifestyle. And that should consist of two components. One is the change of diet. And the good news is that you can do this.

22:52Because now, for the first time, maybe in a very long time, you have regained your power of will here. So that's one important thing. The other activity levels. And as you lose weight, you can do it. You can actually master some increases in physical activity levels. And that's extremely important because then you can maintain your muscle mass. And we've shown that if you can maintain those good new habits, then you don't need the medication after the termination of, let's say, treatment for a year or two, where you have reached the nice plateau of new body weight. Well, it's the good habits, I think, is the important thing here, isn't it?

23:33Using these drugs as part of a properly prescribed weight loss plan with, you know, your GP support around, as you say, diet and exercise. But that actually speaks to another concern, which is about people getting these drugs from unofficial sources without any medical advice. Yeah. And I think that's probably a little bit of a risky business because you need that medical advice. I mean, otherwise you will be in a situation where you've lost your lean body mass and you come out as a weaker person after the weight loss than you were. And that is not good. So it is really the advice here that is the essential.

24:08Just like after bariatric surgery, where you have similar weight losses, and you must obey the same kind of precautions not to come out with a bad result afterwards. Another problem right now is cost. There was a BBC investigation last year reporting that out of an estimated one and a half million people using these drugs in the UK, nine in 10 are believed to pay privately. And although prices vary with doses, generally you're looking at several hundred pounds a month, which is particularly tough when you consider that diabetes and obesity rates are both higher in patients from lower income backgrounds.

24:47What could help bring down costs? There are, of course, many, many important aspects of this question. And I cannot help to say that I think that there are some societal obligations, again, that should be considered at some stage. But fortunately, there are other things happening. So the first GLP-1 to be approved of this has gone off patent, and there's now a biosimilar available. So you can buy it and it's cheaper. Now, that is the daily injection, so that's not the most super popular. But it still works, and there's no doubt that the competition, because there are many, many, many pharmaceutical companies now producing GLP-1-related agents, and some of them will be good and approved and all that.

25:29So there will be competition, and the prices will come down. There's no doubt about that. There's another development that is really interesting, and that is that it's also possible to make GLP-1 agonists that are small molecules, as we call them, small chemical entities. And they're much easier to produce and much cheaper to produce. They haven't really been approved yet, but we will have these. I don't doubt that we will have these small molecules now coming up and they will be cheaper and they will put the prices further down. But I must say, in the meantime, I think that the societies will need to think about how this should be dealt with and some support, some reimbursement for health reasons, I think would be reasonable.