…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 Massachusetts General Research Institute. 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.

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 Juul 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.
W: 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.
J J 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. [cf. Sadri2023]

W: [re: lack of commercial interest from Novo Nordisk] …But by the early 1990 things started to change?
J H: 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 4 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.
W: At that point, did you have a sense of how much potential these drugs might have, for treating obesity as well as diabetes?
JJH: 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 10–15% of adults in the world who have a BMI at or above 30; in the US it’s around 40%. And obesity is clearly a very serious metabolic disease.

W: …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% 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?
JJH: 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.
W: And a 15% weight reduction is pretty remarkable too, right?
JJH: 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% decreases in 8 weeks, you could do that. But you can’t continue that kind of low-calorie diet. But now to have 15% or perhaps even up to 20% 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% of their body weight in that study had 86% diabetes remission. If you can lose 15% 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.

…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.

W: …So there might be a problem with getting people to stay on GLP-1 drugs?
JJH: …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…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.