This piece is part of our first-annual Health Care Heroes series, where we spotlight people doing amazing things in the health care and medical fields. Read the rest of the stories here.
IN 2002, NOVO Nordisk chemists Thomas Kruse and Jesper Lau were studying small molecules in the global pharmaceutical company’s Denmark lab (over 90 percent of marketed drugs are made from small molecules) when they got a call from their bosses. Novo Nordisk wanted to pivot research efforts into peptide chemistry with the goal of creating a long-acting GLP-1 receptor agonist—a class of drugs that mimic the natural GLP-1 hormone in our bodies.
To Kruse, it felt like moving from carpentry to plumbing—two totally different trades—since the molecules are about 10 times bigger in peptide chemistry. After reluctantly joining the team full-time, he started working alongside Lau (the project lead) and laboratory technician Paw Bloch to create the next big GLP-1 receptor agonist. At the time, only two existed: exenatide (developed by Amylin Pharmaceuticals in collaboration with Eli Lilly) and liraglutide (developed by Novo Nordisk), so they began by applying learnings from the liraglutide project.
Two years and 216 failed attempts later, in November 2004 the team found success when they attached a fatty acid chain to the GLP-1 molecule. That fatty acid allows for stronger binding to a protein called albumin, which prevents the kidneys from breaking down the drug. In other words, it extends the drug’s half-life in the body. This new molecule would become known as semaglutide, the active ingredient in Ozempic (FDA-approved in 2017 to treat type 2 diabetes) and Wegovy (FDA-approved in 2021 to treat obesity).
A little over two decades since its discovery, semaglutide has become the catalyst for widespread GLP-1 use and has reshaped how we treat diabetes and obesity. Ahead, Men's Health spoke to Kruse and Lau about the challenges of creating semaglutide, their reactions to how popular GLP-1s have become, and how their beliefs about obesity and body image have evolved after working on this project.
Men’s Health: Several GLP-1 receptor agonists were developed and approved for type 2 diabetes and weight management before semaglutide. How did those inform your work?
Thomas Kruse: A big problem for all drugs is that we have a kidney with a size filter (imagine a seed with holes of different sizes). Molecules that are big stay in the blood. Molecules that are small are filtered out of the kidney and into the urine. The other problem specific for the GLP-1 class of peptides is that normally the GLP-1 hormone is produced in the intestinal wall and is degraded very quickly by an enzyme called DPP-4. It cuts off the first two amino acids of the peptide chain and makes the molecule completely inactive. So we had to take care of two degradation processes: the filter in the kidney and the enzyme DPP-4.
When it comes to the enzymatic degradation, you can make changes in the peptide sequence. In this case, we needed to add an unnatural amino acid, something our body cannot produce, and introduce the amino acid in position number two in the molecule to obtain complete stability. [Additionally, you need to] make the molecule permanently or reversibly bigger [to avoid renal excretion]. So you can piggyback on a very big protein abundant in the blood called albumin, which is so big that it’s not filtered in the kidney. If we could chemically bond albumin to GLP-1, it would help with the issue of kidney filtration.
This was the knowledge from the previous GLP-1 project [at Novo Nordisk in the ‘90s] that led to liraglutide. There was also knowledge from our insulin area about putting fatty molecules onto other insulin or GLP-1. But the binding that comes by adding fat to a peptide was at this stage not optimal. It was too weak. The major achievement in the semaglutide project was to increase this binding.
MH: Can you share the "aha moment" when you successfully engineered a potent GLP-1 receptor agonist? What were your reactions at that point in time?
Jesper Lau: You have to remember that you’re talking with science nerds that are used to many failures. You have to celebrate every little good result to keep your motivation high. But of course, the first moment was when we saw the phase I result in humans [in 2008]. That was a great day.
TK: We had the goal given to us from management that this [drug] should be suitable for a once-weekly injection. Since a week is 168 hours, it was almost spot on when we learned that semaglutide has a half-life of 160 hours. At the time, it was completely unprecedented to take a peptide and give it such a long half-life. People actually didn't consider peptides very good drugs because they typically disappear too fast out of the body.
MH: So once you invent something like this, what happens next?
JL: Projects have to run through different phases, starting with early discovery and ending with FDA approval. In those days, we had something called milestones. The first milestone was when you feel you have something that you will be able to develop into a treatment. The first human dose was a celebration, and so were the phase I results. The phase II results were a thumbs down because we overdosed the patients, so there were a lot of side effects. The biggest celebration before approval was phase III’s sustained results. As our scientific executive said, the results are flabbergasting.
MH: Did you encounter any challenges during the drug development process?
TK: The exercise of using animal data and predicting what would happen in humans is one of the most difficult tasks in drug development and also in this project. The animals are much smaller than humans [and the drug] typically has a much shorter half-life than it is in humans.
JL: It's not only a matter of extending the half-life that's key to success, but you can easily destroy all the activity of the peptide if you glue too much to albumin so it becomes inactive. It’s the balance of getting the right half-life without destroying the biological activity. On top of that, you also had to be sure you had a molecule that was stable enough so you could make a drug product as a liquid in a vial because the native hormone has very little stability. If you make a formulation in a buffer of a [native GLP-1], then it will become a gel within 24 hours if you leave it at room temperature. We also had to fix this biophysical issue. So there were three things: half-life, potency, and biophysics in order to have success. It was not simple, and it was really a lot of trial-and-error.
MH: Millions of Americans are now on a GLP-1 and Ozempic was a big catalyst for this. Did you two anticipate the cultural impact the drug would have on weight and body image?
JL: Not to what we see today, for sure. I think it's also important not to focus only on obesity. Semaglutide will be a game changer for people with type 2 diabetes.
TK: I never expected that I would be involved in making something that Elon Musk, the Kardashians, and Oprah Winfrey would speak about. That was weird.
MH: How did working on this drug change your own views on obesity and willpower?
TK: I honestly was not telling people that I was working with obesity. I was actually telling people that I was only working with diabetes because I thought that sounded less controversial. There was this idea that if you are obese, you basically just lack willpower to eat healthy and not eat too much. I have changed my mind on that by learning a lot about it over the years. So today I actually do say that I work with diabetes and obesity, and I'm fairly proud of it. If people say that, well, this is just a lifestyle drug for people who are lazy and do not want to go on a diet, then I have all the scientific arguments to say that is not right.
JL: I'm very much aligned with Thomas. I was also skeptical of semaglutide's [initial impact], but I'm very convinced now that [semaglutide] has a good effect on society. I've even heard that there is a change in the average weight of a U.S. citizen.
MH: Did you anticipate the potential role semaglutide can play in health outcomes like reducing the risk of heart disease back when you invented the molecule?
TK: No, there was a lot of uncertainty about how big this could really go. Some people said that if you can come up with something that can put more than 5 percent of people's weight off, then it can become quite big. Semaglutide was able to take 17, 18 percent of the body weight on average, and for some people, more than others. I think it's fair to say that the very large number of what we call comorbidities—diseases that are associated with being overweight like heart attack and stroke—can be reduced with semaglutide. You can measure that fewer people get cardiovascular deaths and probably also a lot fewer people will get type 2 diabetes.
MH: Were you both involved in the making of the semaglutide pill Rybelsus? If so, how did that process differ from the development of the injectable?
JL: We were part of that, but that’s launched so now we are out of it.
TK: The process of making the pill is quite different from the injectables. It's a solid pill that you mix with some chemicals that allow uptake in the stomach. So it was actually lucky that semaglutide could be also used as a pill, because it was not designed for that from the beginning.
JL: At the end of the day, it's the same treatment. You can choose whether you want to inject yourself or take a tablet. It's the same active molecule, and the same clinical efficacy.
MH: What would you say to the people out there who are hesitant to start Ozempic or Wegovy due to the lack of long-term research on the drugs?
JL: They should discuss these things with their private physician. We cannot really go into that kind of discussions as scientists. There’s a reason why it’s a prescription drug. You have to talk with your physician and get a personal insight on what’s best for you.
MH: Do you think Ozempic and other GLP-1s have the potential to completely eliminate diabetes and obesity?
TK: If we are talking specifically about semaglutide, it’s not as efficacious as bariatric surgery in terms of lowering people's weight. On average, you can expect to lose about 17 to 18 percent of your weight. Some people more, some people less. But 9.4 percent of the U.S. population needs weight loss to get a BMI below 25 into the normal weight range. There's a long way to go. There's also a significant group of obese people who do not want to be treated and are happy with their life. So I don't think that we will ever get to a complete elimination of obesity and type 2 diabetes.
JL: There's one more parameter. In reality, it's not only about how many [pounds] you lose, it's more about the quality of life you get afterwards. It will take years before we have enough data, and we'll maybe one day figure out that there are many types of obese people; different segmentations that need different treatments. It can be dangerous only to look at body weight because it's not the body weight that is a problem. It’s all the inflammatory and whatever other things that happen in your body when you are too big.
MH: Are you both still involved in GLP-1 research or have you all pivoted to another drug development project?
JL: Thomas is, I’m not. [Lau is currently serving as a Scientific Vice President of Novo Nordisk.]
TK: We saw the success of semaglutide and this method of attaching a fatty acid to a peptide. That could be potentially used in other hormones too. There's also so many ways semaglutide can be improved. There will be more than enough for me to keep being in this area until I retire somewhere between two and 10 years from now.
MH: What’s the next frontier of GLP-1 agonists?
TK: When we were still working on the semaglutide program, we looked through the literature and looked at other peptide hormones that are involved in appetite regulation. I looked into a hormone called amylin. Amylin turned out to be a good supplement to GLP-1 in terms of strengthening bone, making a more smooth blood glucose level, and further reduction in body weight.
We have come a long way, but we have only scratched the surface. When competition increases, then you get better drugs, lower prices, and more people can get access to the drug. I think that we have only begun to see what actually can be gained from these molecules and the research that’s still ongoing.
JL: We have inspired the rest of the industry to go into this, but I still feel that we paved the way on how to handle this kind of technology and how to make a change on treatment…not only in obesity, but also in type 2 diabetes. My personal guess is that semaglutide will probably be the only once-weekly, clean pure GLP-1 agonist forever. Most others are into dual activity with another hormone. Of course, there is a non-peptide small molecule GLP-1 drug available [known as Foundayo]. But so far, it seems they are not as efficacious as peptides.
TK: I speak to friends who have actually tried to take semaglutide. In most cases, people are very happy about it. I've also come across people who say that they have had quite a lot of nausea. I believe understanding why patients are so diverse and tailoring treatments would be a huge thing in the future.
This interview has been edited for length and clarity.
Describe your job in three words.
TK: Playing soccer on a team in Champions League.
JL: That was more than three words.
TK: *Laughs.*
JL: It’s really nerdy.
Favorite medical show to watch?
JL: I do not watch any drama of that category.
TK: I enjoy watching my wife watch Grey’s Anatomy.
Best career advice you’ve ever received?
JL: I have aways been told to follow my beliefs and interests. That will make your life better.
TK: Specialize, but keep your eyes open outside of your subject.
Robotic surgery: Yay or nay?
JL: That is already ongoing.
TK: Yay, but hopefully not on me.
Describe the future of AI in health care in three words.
JL: Better solutions to patients.
TK: After hype, reality.
Jocelyn Solis-Moreira, MS is the associate health & fitness for Men's Health and has previously written for CNN, Scientific American, Popular Science, and National Geographic before joining the brand. When she's not working, she's doing circus arts or working towards the perfect pull-up.
