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In December 2017, the FDA approved a new injectable drug to treat type 2 diabetes called semaglutide, which you likely know by its brand name: Ozempic. A few years later, during the pandemic, Wegovy, a drug with a higher dose of the same active ingredient, was approved specifically for chronic weight management. Soon after, people taking Ozempic started reporting a dramatic, even “life-changing�� weight loss. Ozempic is now a bona fide blockbuster. So what’s the science behind these “wonder drugs�� that apparently 1 in 10 of us could end up using? They have the potential to have so many positive effects on our lives, from treating Alzheimer’s disease and addiction to changing our relationship with consumption but, like with most things, they also come with risks.

Transcript of this Episode

Sam: In December 2017, the FDA approved a new injectable drug to treat type 2 diabetes called semaglutide. You probably know it by its brand name: Ozempic. A few years later during the pandemic, Wegovy, a drug with a higher dose of the same active ingredient, was approved specifically for chronic weight management. Soon after, people taking Ozempic started reporting a dramatic, even “life-changing�� weight loss. Then celebrities weighed in and sales skyrocketed.��

Deboki: Ozempic is now a bona fide blockbuster. Novo Nordisk reported more than $40 billion in revenue in 2024. And with more than 100 million Americans being obese, you can only imagine those numbers will grow. A bold projection from JP Morgan says that by 2030, 9% of the total US population could be using this class of drugs.����

Sam: Today, we’re getting into the science behind these “wonder drugs�� that apparently 1 in 10 of us could end up using. These drugs have the potential to have so many positive effects on our lives, from treating Alzheimer’s disease and addiction to changing our relationship with consumption. But, like with most things, they also come with risks.

Welcome to Tiny Matters, a science podcast about the little things that have a big impact on our society, past and present. I’m Sam Jones and I’m joined by my co-host Deboki Chakravarti.��

Deboki: To start, we have to clear something up right off the bat.

Sam: Totally. So these drugs got a ton of news coverage, especially with all of these celebrities talking about whether or not they were using them to lose weight. There’s an estimate that some 30,000 news outlets reported on it. And I guess this makes us roughly number 30,001.

Deboki: A common thread in the reporting is that these drugs were being developed for diabetes, and the weight loss effect was a serendipitous discovery. Another example of a happy accident in science like penicillin.��

Sam: Yes exactly, and I thought that was the case as well, but after doing some research, we found out that’s not actually true! We spoke with Lotte Bjerre Knudsen, Chief Scientific Advisor for Research & Early Development at Novo Nordisk. She says she and her colleagues spent nearly two decades trying to develop a drug that would go after both indications: type 2 diabetes and obesity.��

So where did this rumor come from?����

Lotte Bjerre Knudsen: Yeah, I do think I know where the misconception comes from. I think the first medicine that was approved didn't have that much weight loss.

Sam: She’s referring to the drug Exenatide which was prescribed for type 2 diabetes and came on the market in 2005.

Lotte Bjerre Knudsen: The big surprise that we got with the second generation medicine was that it was so much better with weight loss.

So it took a little bit more time before we saw that there were newer molecules that had much more weight loss. So because it took time, I think that story started to spread, like, “Oh, it was just a side effect that people saw in people with diabetes.�� Then it just kind of became a story that was told again and again, and it's a little bit hard to stop those stories. And also it seems that people really kind of like these kinds of stories.��

Deboki: I had no idea, and I know you didn’t either Sam. I mean falsehoods do have a way of spreading on the internet. A not so fun fact: researchers have found that false statements reach people 6 times faster than the truth.

Sam: At least in the case of Ozempic it’s a relatively harmless misunderstanding. Okay now that we’ve set the record straight, let’s get to the really fascinating science of how these drugs work.

Deboki: Ozempic is part of a class of drugs that mimics a natural molecule in our body called glucagon-like peptide one or GLP-1. GLP-1 is both a hormone and a neurotransmitter, meaning it’s released into your blood and acts as a signaling molecule between your neurons. It does a lot of helpful things in the body �� something to keep in mind for later when we talk about its unusually broad potential effects.�� ����

Lotte Bjerre Knudsen: In physiology, GLP-1 is part of what needs to happen after you've eaten. So there are all these things going on in people's bodies after they eaten. Something needs to happen to glucose, something needs to be told to the brain, something needs to be messaged to the heart and the kidneys and the vasculature.��

Sam: Chemically-speaking, GLP-1 regulates sugar in three main ways: First, it triggers the release of another key hormone: insulin. Insulin helps convert your food into energy. Without enough insulin doing its job, you end up with too much glucose in your blood. People with type 2 diabetes lack insulin or can’t use it properly. This can lead to serious damage all over the body, to the heart, eyes, kidneys, and nerves.

Deboki: GLP-1 also blocks another hormone called glucagon. This hormone is responsible for raising your blood glucose levels, keeping it from dropping too low. Lastly, GLP-1 slows down the emptying of the stomach so glucose is taken up more slowly.�� ����

Sam: So drugs like Ozempic treat type 2 diabetes by acting like GLP-1 to modulate blood sugar levels. But, remember, GLP-1 is also a neurotransmitter, involved specifically in the brain’s reward systems.��

Lotte Bjerre Knudsen: And then when it comes to obesity, we are in the brain, where when people are taking these medicines, they eat less and they do that because they both feel an increase in satiety, a reduction in hunger, and they also feel a better control of cravings and some change in what they choose to eat.

There's a good understanding on what they do at the clinical level, both when it comes to satiety and hunger and having effects also on the reward system. But of course, there's not the same molecular knowledge as there is in the mouse models. For example, I think I have a total of six papers that describe the mechanisms in animal models. And we do know that the brain GLP-1 receptor is the one that is mostly involved. And we also know some of the neuronal networks and cell types very well, for example, in the hypothalamus, which is a key area for appetite regulation. And we also know some in the hindbrain and further up. So I think we have a fairly good understanding with the limitation that it's in animal models. And that's a general thing with the field of obesity, that we really haven't had that much knowledge from the human brain.

Deboki: For decades, scientists suspected that there was a hormone in the body that was responsible for boosting insulin production. But it wasn’t until the mid-1980s when GLP-1 was identified that the science really took off. By the 1990s, there was a lot of interest in trying to make drugs inspired by GLP-1 for both diabetes and obesity.��

Many of the companies including Novo Nordisk went after classic small molecules that would mimic GLP-1 �� a standard drug development strategy to find a drug that can be neatly packaged into a pill. Small molecules can easily get into cells because, well, they’re small�� they have a low molecular weight. That makes them attractive potential drugs. In fact, over 90% of drugs on the market are small molecules.

Lotte Bjerre Knudsen: We had actually kind of three attempts that didn't work out before the one that ended up working out.��

Sam: They didn’t find any small molecules that would work, so they took a different approach. They came up with the novel idea of creating a GLP-1 mimicking peptide �� a molecule made of a chain of amino acids. The first couple of attempts there also didn’t work, but then attaching it to a fatty acid chain made the difference. Creating a peptide-based drug was unheard of at the time.��

Lotte Bjerre Knudsen: They're not a protein, they're not a small molecule. They have a size that in between, and people just did not believe that those could be medicines. When I got the Science Breakthrough Award last year together with Richard DiMarchi, he was head of research at Lily, and he said, I could not convince Lily to take these peptides into obesity. Svetlana Mojsov, one of the people I shared the Lasker Award with, she said she was also met with the same, and actually both of them came from the lab of Bruce Marrifield, who was got the Nobel Prize for the peptide synthesis. So she was also being faced with these kind of molecules are not medicines. So that was just what people were saying, but it was not based on knowledge. It was just fear of something new, I think.

Sam: Fortunately for Lotte, she wasn’t exposed to that conventional thinking.

Lotte Bjerre Knudsen: So I never heard that kind of challenge. I heard a lot of challenge to people saying, oh, why do we need new injectables? I did hear that, but I think not to the same extent as others, not this thing, which these peptides cannot be medicine. I didn't hear that. So I think being in a biotech company, maybe more than a big pharma company, I think made a difference.

Deboki: Their team’s persistence paid off big time. But it wasn’t an overnight success. Lotte and her team spent more than a decade modulating peptides before striking gold.��

Lotte Bjerre Knudsen: Well, I'll have to credit GLP-1 for that, right? Because it was clear actually very early on that there were clinical data that supported its use in diabetes and also a little bit later in obesity. So there were always data that supported that this was relevant for humans. And maybe I'm just happily naive, but I always thought that we can solve, we can take the time.��

We were the only large pharma that were working to progress anything in obesity. Now everybody wants to do it, but I'm just telling you, we were alone in it for 20 years, and I didn't find that demotivating. I found it inspiring.

Sam: And Lotte is still at it. She says the company is now testing their GLP-1 drugs in clinical trials for treatment in heart, liver, and kidney conditions and a phase three trial for Alzheimers�� disease.

Deboki: Several other big pharmaceutical companies like Eli Lilly, Amgen, and Pfizer have GLP-1 drugs for diabetes and obesity on the market or in the pipeline, hoping to tap into the insatiable demand for these drugs. But because these drugs are fairly new, scientists are still trying to get a handle on all of the side effects and their potential uses.��

Sam: In January, researchers at Veterans Affairs St. Louis Health Care System released the largest-ever study of the effects of GLP-1 drugs �� looking at close to two million patients. Led by Ziyad Al-Aly, the team looked at 175 different health outcomes.

Ziyad Al-Aly: It was surprising in the sense that you don't land on a new drug every day that has this really broad beneficial profile and also broad risk profile, right? Usually drugs are designed for a reason to be very specific, to target a one specific pathway. Subsequently, they have an effect. It's not unusual for drugs to have what we call off target effects, but usually one or two off target effects. And obviously it's also not unusual for drugs to have a few side effects. I think what distinguishes GLP-1 here is that there is really, we saw the breadth of effects across multiple organ systems.��

Deboki: The team found that patients commonly had adverse gastrointestinal issues, including nausea, diarrhea and vomiting, which have already been widely reported. These negative health effects are one of the reasons why people stop taking GLP-1 drugs. One report found that almost 60% of people quit the drug within 12 weeks.�� ��

Sam: But what really caught Ziyad’s attention were several risk reductions linked to the drug. One of them was an 11% reduced risk of Alzheimer’s disease.

Ziyad Al-Aly: And 11% is not really a huge risk reduction. But if you put that in the context where we are in a landscape where we don't have good therapeutics for Alzheimer's disease, well, I'll take 11% reduction any day when there is no alternative, there is no better reduction. In addition to that 11% reduction, these GLP-1 drugs could be by sheer serendipity teaching us about the biology of Alzheimer's disease and giving us breadcrumb clues.��

Deboki: Clues that Ziyad says could inform what brain pathway to target that could have an even stronger effect in reducing the risk of developing Alzheimer’s. The other standout risk reduction is for substance abuse disorders, another condition for which there are few pharmaceutical treatments.

Ziyad Al-Aly: It was really a big aha because it wasn't really only reduced risk of alcohol problems or cannabis problem or smoking or stimulant use disorders or opioid was all of the above, was literally all of the above. And that tells us that these drugs, the GLP-1 drugs, are actually acting on the brain to suppress craving for these substances.

Sam: To Ziyad, this suggests that perhaps we should adjust societal thinking to see obesity as a possible addiction to food. This would challenge a pervasive, harmful idea in popular culture that sees overeating as an individual moral failing.

Deboki: And suppressing our cravings for things beyond food could have major implications for the way we live now.

Ziyad Al-Aly: The grocery store chains are worried about this because it has been labeled almost like the anti-consumerism or anti-consumer sort of curbs our addictive drive to consume more and buy more and do more, right? And it's not only food, it's tobacco, it's alcohol, it's other things, expensive items. It also curbs that sort of impulsive gambling and other things. So it may be that, and definitely we live in a world of abundance and we live in a world where we have become almost like addicted. Excess is kind of like the word that describes our life.��

Sam: In 2023, Walmart was one of the first national chains to link Ozempic with consumer habits. According to internal data, they found that people on GLP-1 drugs bought less food, especially sweets. Morgan Stanley is predicting a 4% drop in soft drinks, alcohol, and snacks because of Ozempic.

Deboki: It’s wild that these drugs that are meant to change our bodies do it in a way that actually might affect our whole economy.

Ziyad Al-Aly: And food companies, the people who engineer food are actually taking notice. They engineer the cereal to be addictive. They engineer the pizzas and pizza doughs to be addictive. The chips and the salsas and all these things that you buy at the grocery store, they actually are engineered, they're not made fully with natural products.��

They're engineered and they actually engineer to make you like them, to make you crave them, gravitate towards them and buy more and more and more of them. So you keep eating more and buying more. And they make money off of this and they realize that GLP-1 are curbing this addiction. So now there is a movement. There's almost whenever there is something that is a counter movement, right? There is a movement that is actually research and development at these big food corporations trying to figure out, like, how do they design things to circumvent the GLP-1 effect and curbing addiction.

Sam: Apparently the food science industry is scrambling to defend their stronghold on snacking. A few months ago, the NYT published a feature that we’ll link to on a food innovation company that has been tasked with cooking up industrial foods that can break through and appeal to GLP-1 users.��

Deboki: We continue to see reports about the unexpected ripple effects of these weight loss drugs, impacting everything from hair loss to so-called Ozempic face, to upending people’s marriages.

Sam: But one of the biggest and as of right now unknowable side effects from these drugs are their long term health effects.

Ziyad Al-Aly: This is really a very important question. So we really don't know if people are taking these medicines for let's say 10 years, what will happen at 10 years. The things that we worry about is that when people lose weight as a result of GLP-1, they don't exclusively lose fat. They lose fat but they also lose skeletal muscle.

There's no magic that's like, oh, the body is going to exclusively get rid of the fat and preserve everything else. That doesn't happen. That's not how it works. And we worry about these things, especially in older adults who may not be able to regain muscle mass and then regain bone mass. For 20-year-old people, maybe they'll go to the gym and they'll exercise again and they build their muscles back up and they feel good again. So maybe it's for 20 or 30 years old, it's a bit different than people who are in their fifties and sixties and seventies where loss of bone and muscle mass could actually be detrimental for long-term longevity and health.

Sam: We’ll have to wait and see what other effects arise down the line. But it’s clear that GLP-1 drugs are changing the game for a lot of people right now.

Ziyad Al-Aly: I think they are because a. The disease that they treat obesity is really a significant disease that affects a lot of Americans. We've tried as a nation, we've tried everything under the sun. So people did the Atkins diet and it worked for a while, and then failed, and then it did the Weight Watchers and did all these different diet fads. I mean, if you've been attuned to anyone who looks at American culture and you'll see that there is really failure after failure, after failure, after failure of fad or ideas or hypotheses or ways of things, and nothing has really worked.��

And now there is this new kid on the block that actually works to treat obesity. And in addition to this, it could have this broad beneficial profile while there is some risk, but there really the broad beneficial profile. So I think these are a new dawn in the management of obesity or a new chapter. And I definitely think that there are some people calling them medical drugs or game changers. It may not be an exaggeration. It may be that this is exactly what's happening with these drugs.

Sam: All right. So Tiny Show and Tell. Deboki, do you want to go first? Do you want me to go first?

Deboki: I can go first.

Sam: Okay, perfect.

Deboki: So I have a recommendation for a general article. It's from the Smithsonian and it's titled, “For Some Women With Serious Physical Ailments, Mental Illness Has Become a Scapegoat Diagnosis.�� And I think it's just a really important and also interesting look at the tension between two things that are really hard to grapple with medically. The first is women's health and the other is mental health. I think these are both areas where it's really easy to go without a good diagnosis. And so it was really interesting to me to see them kind of not clash. It's not a clash because they're both realities for people, but it's interesting-

Sam: And underserved.

Deboki: Exactly. And so it's interesting to me to see them play out in this way here. And also frustrating because yeah, it can be hard to take conditions that fall under any one of these umbrellas, seriously. So the article follows how patients with conditions like endometriosis often have their complaints not taken seriously, which is a very common and terrible aspect of medicine. I feel like if you know anyone who is a woman who has gone to a doctor and faced any kind of issue, they have probably had a frustrating experience. I guess I shouldn't generalize, but.

Sam: It's common.

Deboki: Yeah. And so the patients that this article is following are talking about how instead of getting the actual diagnosis that they needed physically, they were usually given a diagnosis of anxiety or something else that was more mental health related. And so for the patients, it was really frustrating because it felt like the doctors were saying the pain is in your head, but it was like there was actually something real and underlying that explained why they were experiencing the symptoms they were experiencing physically. And so the article explores some of the culture of medicine that makes this the case, like doctors having a tough time expressing uncertainty. So that's magnified by how difficult a lot of these conditions are to diagnose.

But also there's a long history of attributing issues that women face to a tendency supposedly to just be more emotional, to be hysterical. And also talks about the consequences, obviously for the patients in the immediate moment of not getting the diagnosis they need. But also as they see more doctors, like how having this diagnosis can make it continue, like how having this diagnosis rooted more in their mental health rather than their physical symptoms can end up affecting the way they're treated kind of down the road. So yeah, I just thought it was a good read to kind of better understand these issues.

Sam: Yeah, that's really interesting. It sounds fascinating. I'm excited to check it out. All right, so I'm going to do a big pivot. Typically, how we do things on Tiny Show and Tell, which is great.

Deboki: Yep.

Sam: So Deboki, I want to tell you about a research group in Japan that has shown that a new device that stimulates the inner ear by sending out a specific sound wavelength can significantly reduce motion sickness.

So in terms of the wavelength, they identified 100 hertz as the optimal frequency for reducing motion sickness, which is a safe limit for the human ear. This is pretty common in urban environments or essentially just being out in the world, you're going to have stuff that's around 100 hertz. So it's not like they're blasting your eardrums and saying, do you feel motion sick now? Okay. So-

Deboki: Yeah, they're not like, oh, you know the cure for motion sickness is just unbearable pain.

Sam: Yeah, exactly. So to test the device, what they did is they recruited volunteers. They also tested this in mice as well, but I'm just going to talk about the human aspect. So they recruited volunteers, they exposed them to the sound, and then they induced motion sickness. So they defined motion sickness as lightheadedness and nausea, and they took a few approaches to try to induce motion sickness. So they had people get on a swing and have it start shaking. And that went for about a minute.

They did a driving simulator, and then they also had people ride in a car where they had to read something, which for me is that is my motion sickness thing. I cannot look at my phone for more than 30 seconds before being like, oops, I'm going to get sick if I don't stop. And so yeah, none of these things lasted that long. It was between one and 15 minutes. But what they found was that with inner ear stimulation ahead of time, it significantly reduced reports of motion sickness, but was not clear, and what I don't think they did, I looked through the methods, but I didn't spend a ton of time. But it didn't seem like they were trying to do this inner ear stimulation when someone was already feeling motion sick. And for me, that's like sometimes, I don't know. I mean, I know if I'm riding in a car I should not be reading a book or looking at my phone.

Deboki: Yeah.

Sam: But I feel like motion sickness often sneaks up on people or they don't realize it. So it's sort of, like would this also help? It seems like it would also help after the fact when it's beginning. But just a caveat.

Deboki: That's a good question though.

Sam: Yeah. So why does this seem to work? There are some theories. Nothing has been definitively proven at this point, but apparently vibrations at 100 hertz will stimulate organs in the inner ear that are the ones that detect linear acceleration and gravity. And so the idea is that this sound could more broadly activate the sensory system in the inner ear called the vestibular system that controls balance and spatial orientation. And so essentially you are activating the balance system to try and keep someone from then experiencing motion sickness, so.

Deboki: I see.

Sam: I thought this was really interesting. And as someone who, I'm not someone who, like I do well on boats, I do well in most things. Don't even talk to me about a spinny carnival ride.

Deboki: I agree.

Sam: Since I was very young, I'm like, no, no, no, no, no. I do roller coasters.

Deboki: I don't understand the fun of them.

Sam: Me either. Me either. But some people love getting spun around. I'm like, I like heights, I like drops, I love a roller coaster.

Deboki: I hate it all.

Sam: That's so funny. But I can't do spinny stuff. But I feel like if this worked and they have this device, they've patented the device. If this really does work, I feel like especially if it works once you're already feeling a bit of motion sickness, it could be a real game changer because I feel like a lot of the options available, they don't work for a lot of people, or they make you really tired or, so anyways, I just thought this was kind of fun.

Deboki: Yeah, that is really cool. It still wouldn't make me get onto a spinny ride, but that's really cool.

Sam: For science, maybe I would.

Deboki: No, I was like, before you even described how they were testing it, I was like, no, absolutely not.

Sam: You have to know your limits.

Deboki: Yes. Well, thank you Sam. And thanks for tuning into this week's episode of Tiny Matters, a podcast brought to you by the American Chemical �й�365bet���Ĺ��� and produced by Multitude. This week’s script was written by Tien Nguyen and edited by me, Michael David, and by Sam, who is also our executive producer. It was fact-checked by Michelle Boucher. Audio editing was done by Jeremy Barr. The Tiny Matters theme and episode sound design was by Michael Simonelli and the Charts & Leisure team.��

Sam: Thanks so much to Lotte Bjerre Knudsen and Ziyad Al-Aly for joining us. We’ll see ya next time.

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