Liraglutide

Medicines based on glucagon-like peptide-1 (GLP-1) have revolutionized the treatment of diabetes and obesity. On Saturday, five scientists involved in the discovery and characterization of the peptide and its translation into therapeutic drugs were awarded one of the $3 million Breakthrough Prizes in Life Sciences, an award sometimes considered a precursor to a Nobel Prize. The five winners are: Svetlana Mojsov of The Rockefeller University; Lotte Bjerre Knudsen of Novo Nordisk; Jens Juul Holst of the Novo Nordisk Foundation Center for Basic Metabolic Research and the University of Copenhagen; Daniel Drucker of the University of Toronto and Sinai Health; and Joel Habener of Harvard University. Ahead of the announcement, Endpoints News spoke with Holst, the co-discoverer of GLP-1, about his career so far, and about future work. The conversation has been substantially edited for length and clarity. Another Breakthrough Prize went to the gene editing pioneer David Liu, who spoke with Endpoints’ Ryan Cross. Elizabeth Cairns : Congratulations! How does it feel to get this recognition? Jens Juul Holst : To tell you the truth, I didn’t know much about the Breakthrough Prize until I was notified some months ago. They forced me to wear black tie, which is something that I never have worn before. So it’s a bit of a surprise all the way through. Cairns : At least you’ve had a little while to get used to it. Are you proud? Holst : I’m extremely happy about these awards, not for my personal satisfaction, but because of the general appreciation of the work we’ve done. I’m a medical doctor and it’s fantastic to see these incredible results coming up in front of my eyes. It was something we hoped for, of course, but it was completely unpredictable many years ago when we uncovered this hormone. Cairns : You discovered GLP-1 in 1986. Did you realize how significant it was going to be? Holst : No. We found this insulin-releasing peptide, but there were many insulin-releasing peptides from the gut. Eventually we found out that it was the peptide that was responsible for low glucose levels in some of the patients we were helping. It turned out that compared to all the other insulin-releasing peptides, it did something else: It also inhibited glucagon secretion. That was really something. And we found that it was a very strong inhibitor of gastric emptying, and also intestinal transit. We also found that it was a neural mechanism, which turned our attention to the brain. Because this was a gut hormone and we knew that the gut would play a role in the regulation of food intake and appetite, we also looked at that, and sure enough, it also inhibited appetite. Cairns : How long did it take you to get from the discovery of the peptide to initial human research? Holst : That key step was in 1993, so it took quite some time. Cairns : What were the challenges you faced? Holst : That’s simple: money. Like most researchers we were relying on external support for our research, and throughout the early years, we were really short of support, forcing us to use old-fashioned, secondhand equipment and cheapest possible reagents, etc., and wages were kept at a minimum. But we got by, collaborating with friends who had been lucky to get better equipment. Cairns : Why do you think this recognition is coming now? Holst : That has to do with a development that nobody could have foreseen. That is the tremendous weight loss that the higher doses of the modern, long-acting agonists had. The effect on food intake was recognized early on. The question was how to harness this without having too many problems with side effects. People were brave. “OK, if we slowly up titrate, then maybe we can get to higher doses and get a greater weight loss.” And that was published in 2009 in The Lancet . That led to the approval of liraglutide [Saxenda] for obesity. This was a sensation. And in the meantime, a second generation GLP-1 had been launched for diabetes, and that was semaglutide [Ozempic/Wegovy]. I was there when it was developed. The weight loss was, again, something like 8%. Nothing sensational about that. But people did a new dose-response study this time with very small daily doses, and it turned out that you could get as high as something like 0.4 milligrams per day, and that would result in a 15% weight loss. And then the world went crazy. Cairns : It did indeed. This prize has been split five ways — were you all working in separate groups towards a similar end? Holst : Completely separately, yes. Although Lotte Bjerre, the chemist, she was a kind of a partner with me, we knew each other very well. What she did was to create liraglutide on the basis of the long-acting insulins Novo Nordisk was doing in those days. They were doing insulin detemir, which is long-acting because they attached the fatty acid to the molecule. She did that as well to GLP-1, and it worked. So she was responsible for the liraglutide part of it. Cairns : Where do you think research in this field might or should go in the future? Holst : People that are prescribed a GLP-1 agonist do not stay on therapy. One of the ways whereby GLP-1 agonists inhibit food intake is by inhibiting the reward mechanism, and this is very important because that is the same mechanism that is responsible for its effects on addiction — alcohol, opioids. Apparently there are fantastic effects on this. But the reward system also takes away some of the pleasure of eating. This is something that should be looked at in detail. Maybe it’s not fun to be on a GLP-1 receptor agonist. If your greatest pleasure in life is to eat good meals and that pleasure is taken away from you, what is left? In the meantime, there are other major problems to look at. One is to provide sufficient amounts of the GLP-1s, and get them to affordable prices. But they will be solved, there’s no doubt about that. There’ll be lots of producers of them, and that means that the prices will really fall and there will also be more products. Cairns : Are prizes like this becoming more important as a source of funding for this kind of research, especially with cuts to agencies like the NIH in the US? Holst : That’s a sneaky question because in principle, they’re personal, those prizes. I mean, it’s my money. Cairns : Yeah, absolutely. Sorry. Holst : I actually wanted to transfer some of the money for research, and it turned out that the part I wanted to transfer for research is being taxed. So it was quite expensive for me to transfer money for research from my personal prize. And frankly, the family didn’t think it was a good idea. They wanted the money. Cairns : So would I, I have to say. What do you intend to do with the money you’re keeping? Are you going to have a holiday, buy a car? Holst : A holiday? Christ, what is that? No. We have work to do. Cairns : The Breakthrough Prize is sometimes thought of as a harbinger for the Nobel. Do you think that GLP-1 research might win a Nobel in the future? Holst : They don’t apparently accept more than three recipients. That precludes a Nobel Prize for all the five of us. The scientific advance made by GLP-1 is big enough and suitable for the regulations of the Nobel Prize. But I have absolutely no idea what they’re going to think of in Stockholm. And it’s good enough as it is already. Cairns : If you do win, they’ll make you wear black tie again. Holst : Not even black tie, but white tie. It would be even worse!