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THE HISTORY OF weight-loss drugs is littered with failures. Some were outright dangerous: In the 1950s and ’60s, amphetamine-based diet pills were popular, but their prominence faded after being linked to addiction and other severe side effects. In 1997 the drug cocktail fen-phen was removed from the US market after it became clear it caused heart valve damage. Other attempts at treating obesity with drugs hit scientific dead ends. The history of anti-obesity drug discovery is for the most part “a bottomless pit into which people shove money and time,” wrote Derek Lowe in Science.
The new crop of much-hyped weight loss drugs seems to be different. These work by mimicking a hormone called glucagon-like peptide 1 (GLP-1), which regulates blood sugar levels and slows down the rate at which food leaves the stomach, making people fuller for longer. GLP-1-mimicking drugs seem to be a powerful tool for weight loss: Some people lose 15 percent of their body weight or more after 68 weeks on semaglutide, which is approved in the US for weight loss as Wegovy and for type 2 diabetes under the brand name Ozempic.
But the history of GLP-1 goes back more than 40 years—before obesity became the health crisis it is today. To get a sense of where these drugs came from—and where they might go next—WIRED spoke to two scientists who did some of the earliest work on the GLP-1 hormone, and who have played an important role in the development of these drugs.
Jens Juul Holst is a professor in the Department of Biomedical Sciences at the University of Copenhagen in Denmark. Joel Habener is a professor at the Mass General Research Institute in Massachusetts. In 2021, Habener, Holst, and Daniel Drucker were awarded the Warren Alpert Foundation Prize for their work discovering and developing treatments based on the GLP-1 hormone.
Holst and Habener were interviewed separately. This interview has been edited for length and clarity.
WIRED: Jens, you got involved with this research in the 1970s. Rather than diabetes or obesity, the history of GLP-1 starts with a completely different disease. Tell us about that.
Jens Holst: This was duodenal ulcer disease—people have forgotten about that disease completely. Diabetes was just something for old people, and you couldn’t do a lot about it anyway, and it was not interesting. So people were talking about duodenal ulcer disease—that was the problem.
And this meant looking at the hormones that are secreted when people eat. You started taking GLP-1 from pigs and pumping it through pig pancreases to see what it did—and that’s when you realized GLP-1 seemed to be a particularly powerful hormone.
Holst: We found that not only did GLP-1 stimulate insulin secretion, it also inhibited glucagon secretion. This was interesting, because people with diabetes have too much glucagon and that glucagon causes high blood sugar. So by stimulating insulin and inhibiting glucagon, you could have a double mechanism on the blood glucose. And now it was beginning to look like something interesting, and we were beginning to think of diabetes.
That pig pancreas study was published in 1988. Were drug companies paying much attention then?
Holst: I have always had friendly relationships with [Ozempic and Wegovy manufacturer] Novo Nordisk. It’s in Denmark, just up the street, and we were interested in the same things, so I kept telling them about what we were doing.
They were obviously interested in anything that could stimulate insulin secretion, but I must say that when we showed Novo Nordisk that [a different but related hormone] does not stimulate insulin secretion in people with diabetes, they withdrew some research support we had received because they said it wouldn’t work.
This is true. This is what happened. They were listening politely, but they weren’t really interested.
But by the early 1990 things started to change?
Holst: The real turning point was a study by Michael Nauck in 1993. We worked together, and we finally infused GLP-1 into people with type 2 diabetes and could show that the blood glucose came to completely normal levels in four hours, while insulin was stimulated and glucagon was inhibited. This demonstrated to everybody that this was really doing something in people with type 2 diabetes, completely unlike other hormones.
At that point, did you have a sense of how much potential these drugs might have, for treating obesity as well as diabetes?
Holst: We were finding these things out step by step. First, it was stimulating insulin secretion. That’s interesting but not really exciting. Then it’s stimulating glucagon secretion—that’s more interesting, put that on top. Then it’s also inhibiting the GI tract and gastric emptying.
Then we find out it’s inhibiting food intake as well. Wow, amazing. Amazing. It’s building up on top of each other all the time.
Joel Habener: We thought this might be a potential treatment for diabetes, type 2 diabetes. But we and others were finding with treating human subjects with GLP-1 in the very early days that you had to be very careful to keep the dose low, because many patients felt ill when they were eating. They were supposed to eat a meal, and then within 30 minutes we’d measure the blood insulin to check how effective it was.
Many of the subjects noted they were unable to finish their meal. It was messing up the experimental protocol because they were getting full and feeling nauseated and saying they didn’t want to eat any more food. Today, we’re between 10 to 15 percent of adults in the world who have a BMI at or above 30; in the US it’s around 40 percent. And obesity is clearly a very serious metabolic disease.
And that means a huge number of people will meet the FDA’s requirements for Wegovy treatment. Some projections put the future value of obesity drugs at $100 billion annually. Did you ever suspect that your work on GLP-1 could make you rich?
Holst: I’m so old, you know! I’m from ’68 and all of that; I was walking around in the street with signs saying: “Research for the people, not for the profit.” We didn’t even think of patenting or getting money out of this or anything. We were interested in publishing, doing something and moving this ahead.
Right, but you have close links with Novo Nordisk—it supported some of your research on GLP-1—and you also work at the metabolic research foundation it established at the University of Copenhagen. The company must be pretty grateful for your work?
Holst: I have been treated very nicely by them. I’ve been hired as a consultant [by Novo Nordisk] for some years, but otherwise I’ve never received a penny from them. Actually, when we found GLP-1 inhibited food intake and demonstrated this in 1998, we tried to make a patent with Novo Nordisk on the treatment of obesity. We were very interested in appetite regulation and treatment of obesity.
They said yes, and we thought we’d have a good patent, together with Novo Nordisk’s experience. Of course, eventually it turned out that the things we patented were not the things that they developed, so nothing came out of that after all.
The wider world really started to realize the potential of these drugs for weight loss in 2021, when The New England Journal of Medicine published a study showing that weekly semaglutide injections led to an average 14.9 percent weight loss in overweight and obese people. A lot of people in the industry were really impressed by this result—did it come as a surprise to you?
Holst: We already knew since 2001 that the dose of GLP-1 you were able to give people would determine its effect on food intake, so you could make the deduction that this would work. The problem was the side effects. Throughout the development of these GLP-1 drugs, the main problem has been finding a balance between the two. One of the really important observations was when Novo Nordisk created a fixed combination of long-acting insulin and GLP-1 called Xultophy. That was given to people with severe diabetes and it worked beautifully, but it turned out that to get to a steady dose with Xultophy it took 14 weeks of [gradually upping] the dose. And the more carefully you can up these drugs, the less side effects you can get eventually.
And a 15 percent weight reduction is pretty remarkable too, right?
Holst: It’s exceptional for two reasons. One is that it has not been possible with any other means to make a similar drug-induced weight loss. It’s simply not been possible; you can’t do it. This in itself is remarkable.
With low-calorie diets you can make 12 percent decreases in eight weeks, you could do that. But you can’t continue that kind of low-calorie diet. But now to have 15 percent or perhaps even up to 20 percent weight loss in a year or so is really remarkable.
The other reason is shown by studies like the DIRECT studies from Scotland, where they managed to make people lose weight by dieting and lifestyle interventions, and they could look at weight loss in categories. Those who were able to lose 15 percent of their body weight in that study had 86 percent diabetes remission. If you can lose 15 percent body weight, then a lot of people can get rid of their diabetes, apparently. If they can maintain it, the same is true. And this, of course, is supported from bariatric surgery results—they show exactly the same results.
But one of the problems is that these drugs aren’t always being taken by the people who are most in need of them—just look at Ozempic’s popularity as an off-label drug among celebrities. Derek Thompson in The Atlantic has written that these drugs could be a public health revolution, but in early 2023 they represent “an elite cultural makeover more than a medical intervention.”
Holst: I am a doctor. I am an MD all the way through. And my interest is in the complications of diabetes and obesity, and so I’m thinking constantly of people with obstructive apnea, and people with arthritis who can’t move, and I’m thinking about all the cardiovascular disease in these people. This year we will have the results of the SELECT study looking at semaglutide’s effects on heart disease and stroke in patients with obesity.
There are so many terrible problems. Have you ever visited a diabetes hospital? It’s really deplorable. People come in with amputated limbs and compromised cognitive functions and heart problems or they can barely move—they’re miserable and depressed. It’s really serious. There is so much you can improve with a drug that is not only a weight-loss drug but is also an anti-diabetic.
Habener: I think it’s important at this stage that the use of GLP-1 drugs is under medical supervision. The drugs should not be available over the counter, for example. It needs to be a prescription carefully followed by a physician who will be looking for troublesome side effects. But it’s hard to know where it’s gonna go.
I’d say the most satisfying thing right now about the drugs is the fact they are very effective at controlling type 2 diabetes for the most part.
Activists have warned that the rise of weight-loss drugs could deepen social stigma against fatness; that it will entrench the idea that anyone could—and should—have a skinny body. Does this worry you?
Holst: I don’t consider the shape of people at all in this. I only talk about complications. If people are completely healthy, I’m not interested. Let them be, that’s not a problem for me. But if they start to develop cardiovascular disease or cancer or depression, then there’s something to do. Then I’m a doctor or a surgeon and have to do something about it.
And this also underlines the importance of making sure the right people have access to the drug.
Habener: It’s not going to be available for poorer people unless things change. And currently a lot of insurance companies won’t cover [Wegovy] because obesity is still seen as a cosmetic problem, and they think that people are obese because they eat too much or don’t exercise enough or don’t have any willpower. But obesity is a disease, a metabolic disorder that has genetic and environmental inputs. It’s a complex trait.
It’s also partly to do with big problems with our food system: access to healthy food, poverty, the dominance of big corporations over our diets. Drugs like Wegovy can’t address any of these root causes, so I wonder if there’s this dynamic where we have this terrible food environment, but we also have these drugs that undo some of those effects, so we end up ignoring all of these fundamental problems with our diets.
Holst: I don’t think it works that way, actually. What happens is that you lose your appetite and also the pleasure of eating, and so I think there’s a price to be paid when you do that. If you like food, then that pleasure is gone. The craving for food for some people is taken away when they take GLP-1 drugs.
So you don’t eat through GLP-1 therapy because you’ve lost interest in food. That may eventually be a problem, that once you’ve been on this for a year or two, life is so miserably boring that you can’t stand it any longer and you have to go back to your old life.
So there might be a problem with getting people to stay on GLP-1 drugs?
Holst: GLP-1s have been on the market since 2005. Do people stay on them? No, they don’t. It’s just like every other drug, they don’t stay on it for many reasons. One of the reasons, as I said, is that once you have tried it and you realize you’ve lost interest in food, then that may be enough. We don’t know why people stop taking these drugs, but we know for a fact that they do stop. They do that all over the world.
It’s not the question of money. It’s simply because something happens that makes you uninterested in going on. Maybe you think everything is alright now, and then it turns out later that it is not alright and maybe you come back on the therapy. But I don’t see that a huge part of the population will be put on Wegovy and will stay on Wegovy for the rest of their lives—I simply don’t see that picture, because this hasn’t happened with other GLP-1 drugs.
Source: WIRED
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