Should you take Ozempic? 5 things you need to know before starting GLP-1 drugs with Dr Ania Jastreboff

GLP-1 drugs like Ozempic and Mounjaro are now everywhere. But what do they actually do beyond weight loss? And what do you need to know before starting them?

In this episode, we’re joined by Dr Ania Jastreboff, a world-leading researcher at the forefront of GLP-1 treatments and writer of the New York Times bestselling book Enough: Your Health, Your Weight, and What It's Like To Be Free, co-authored with Oprah Winfrey.

We also explore why weight often returns after stopping, and what you need to know about Ozempic side effects and long-term use.

If these drugs can change how your brain controls hunger, what does that mean for willpower, weight regain, and how we treat obesity long term?

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Jonathan: Ania. Thank you so much for joining me today.

Ania: Thank you for having me.

Jonathan: Now we always start the show with a rapid fire Q and A, and we have some very strict rules, very difficult for scientists. So you can say yes or no, or if you have to, you can have one sentence. Okay. Are you willing to give it a go?

Ania: I'm willing.

Jonathan: Have new clinical trials of GLP-1 drugs in the last couple of years changed our understanding of what they can do?

Ania: Yes.

Jonathan: Can GLP-1 drugs offer benefits beyond weight loss?

Ania: Absolutely.

Jonathan: Once you stop GLP-1 treatment, will the weight stay off?

Ania: No.

Jonathan: Should everyone who is overweight take a GLP-1 drug?

Ania: No. It's up to the patient.

Jonathan: Is it safe to microdose a GLP-1 to stay thin as I age?

Ania: Small doses for people who have obesity are appropriate. So it depends how you're using the term.

Jonathan: Is there evidence that long-term use of GLP-1 medications can lead to unwanted side effects?

Ania: All medicines have side effects.

Jonathan: And finally, what's the most common misconception about GLP-1 medications?

Ania: One common misconception is that these are weight loss drugs.

Jonathan: Over just the last couple of years I've watched these GLP-1 medications like Ozempic go from like promising research breakthrough to viral sensation, and now just sort of medical mainstream in this incredibly short period of time. And what I know is that while all that's been happening sort of in the public view, scientists have been quietly progressing our understanding of how these drugs work, who they can help, and trying to increase their effectiveness. And so there's a huge number of people talking on social media about GLP-1s. But on this podcast, you know, the core of the idea is that we allow our audience to actually hear from the scientists who are carrying out the research. It's really wonderful to have you here. And I would say the other thing that's nice is you're not just a research scientist, you're also a practicing physician. That's right. And so I think you also have that experience, not just of studying in the lab, but actually working with patients and understanding what it means. I guess the question I'm gonna start with is sort of quite a simple one. What are these GLP-1 drugs and how do they work?

Ania: Yeah. So the medications are medicines that treat obesity. And so in order to answer that question, I'm just going to share a little bit about what obesity is. Our bodies are super. They figured out forever ago that we needed to store energy. And they figured out, well the most efficient way to store that energy is to store it as fat. So fat is a good thing. It enables us to survive as a species. But now how much fat are we gonna store? Well, our brain decides that, and our brain is informed by hormones in our body. We call them nutrient-stimulated hormones. So GLP-1 is a nutrient-stimulated hormone. GIP is a nutrient-stimulated hormone. Amylin is a nutrient-stimulated hormone. So these hormones communicate with our brain and they say, I'm hungry. I'm full. I need to eat more. I'm good, I'm full. And basically they help our brain set what we call a body fat set point, or in the book that we recently published, the enough point. So body fat set point or enough point. And so you might say, okay, great, well. Our bodies set this awesome biology. Why in the world do we have obesity? Well, we have obesity because of our obesogenic environment. So an environment that is filled with ultra-processed food, lack of physical activity, lots of stress, lack of sleep, all these different things basically push up our body fat set point or enough point on a population level. So what does that mean? That means that anything that we use to treat obesity has to recalibrate or reset that set point, and that's what we think the medicines do. They work in the brain to recalibrate that body fat set point or enough point.

Jonathan: I think that's one of the clearest explanations that I've heard of, like a very complicated topic that has come up. You know, quite often on this podcast, whenever you speak to somebody who's on one of these medicines, the big thing they talk about is this profound shift in appetite. And also, I think they often talk about being full, very fast. What's going on there?

Ania: So you raise hunger. A lot of people talk about food noise, which is different than hunger. It's appropriate to be hungry as humans. If we had no hunger, we would die. We wouldn't have any inclination to eat. Food noise is what patients talk about now that they stop experiencing it when they're on the meds. Food noise is disruptive, persistent, intrusive. People would go about their day and they would constantly be pulled towards, what am I gonna eat next? What's gonna be for lunch? What's for dinner? I need to plan it out. I have to make sure I don't eat too much or just enough of something, or not something else. Food noise is something though that we didn't know existed. Until people started taking the medicines and then they experienced the silence. So we did not know food noise existed until it didn't, until it was quieted. So I think it's really important to consider that the medicines are teaching us about that. Now, what is food noise? It's a manifestation of our bodies or our brain's biology, making sure that we have enough. Making sure that we don't starve. Making sure that our body fat set point or enough point is high enough that we survive. Now, we don't understand why our bodies would set a defended fat mass or a fat mass set point that is higher than what is healthy long term, right? All that excess or extra fat ends up leading to detrimental effects on our health because the fat spills over into our organs or organs end up moonlighting as fat storage facilities and they can't do the job that they're supposed to do. But what we do think is that that food noise is what is one of the things that keeps pulling people back up in terms of carrying more weight or more fat. So we don't know exactly how the medicines change that, but we do know that. As they recalibrate that defended fat mass or that set point as they recalibrate it down, that food noise quiets, your body says, Hey, your brain says, Hey, I have enough. I don't need to finish what's on my plate. I don't need more. I'm good.

Jonathan: Are these drugs doing anything beyond impacting our sort of appetite and food noise?

Ania: We knew for over 20 years that specifically GLP-1 receptor agonists, they of course work on the islet. They work in the pancreas. They increase the secretion of insulin. That's how they were discovered. They were developed for the treatment of type two diabetes. So we already knew about those peripheral effects, but now there's additional effects. So the weight effects we think are specifically in the brain, but other effects in the body, whether it's the pancreas or the vasculature or inflammation or other things, those are peripheral effects, but they're still effects of the medications.

Jonathan: If I take this drug, it's not only acting, you know, in some specific part of my brain to do with appetite, actually it's acting in many places across my body, and one of those has an impact on my blood sugar control.

Ania: Yes. So anywhere there's receptors for that specific hormone, whether it's GLP-1, GIP, amylin, what have you, the medicine will work there. It will work in the brain to regulate weight or specifically fat mass. And it will work in the periphery, for example, the pancreas, as you mentioned, to regulate blood sugars, and that's why these medicines were developed specifically for diabetes. And then it was noted as a side effect that these medicines also helped. In terms of weight and then that was followed. And this is how the development continued in terms of looking at these medicines not only as ways to treat type two diabetes and improve blood sugar control, but also for weight and obesity treatment.

Jonathan: That's really interesting. So actually, sort of the biggest thing it's now being focused on, it is almost like a complete unexpected, beneficial side effect of drugs that were originally trying to solve for bringing down your blood sugar if you had diabetes.

Ania: Yes. So 20 years ago was when the very first GLP-1 receptor agonist was approved by the FDA for the treatment of type two diabetes. And one of the things that was noted was that our patients were not only not gaining weight, right, 90% of people who have diabetes are overweight and have obesity. And it was noticed, oh, they're losing weight. Whereas something like insulin, giving someone exogenous insulin usually causes weight gain. And so we wanted therapies that would not cause weight gain. Right? Because why would you give someone a therapy that ultimately may actually contribute to the progression of their disease as the root cause of type two diabetes is obesity. So here we had this therapy that not only improved the blood sugars and not only improved the blood sugars without causing hypoglycemia, but also led to weight loss.

Jonathan: That is fascinating. So our body is naturally making these hormones.

Ania: Yes.

Jonathan: What I guess is happening in like a normal, you know, healthy state in terms of what's going on with these hormones and then what's different. Yes. If I go and inject myself. Yes. With one of these.

Ania: Great question. I love it. And this comes to another myth which I'll hopefully circle back around to at the end. Let's take GLP-1 as an example. So GLP-1 is stimulated when we eat food. Okay. So it's nutrient-stimulated. We eat food, it gets released. The hormone helps to signal to our brain, Hey, I just ate, I'm good. The medicines are GLP-1 receptor agonists, meaning that they target the receptor for the hormone, wherever that receptor might be in the brain, the pancreas, different parts of the body, so it targets that receptor. It is not the hormone, the medicine is not the hormone. It is an analog of the hormone. It works on the same pathways as the hormone works, but our body would never make this much of this hormone. So these are much higher doses in a way, which, here's the myth. A lot of people, and colloquially these medicines, people refer to them as GLP-1s. They're not GLP-1s, they're not the hormone our body makes. They're synthetic, they're a medicine. They work on the same pathway, but they are not the hormone. And so they basically target the same pathways and they signal to our brain and various tissues in our body, whatever it is that they're signaling.

Jonathan: So, is there an analogy? Think about this. Like all over my body, there are sort of all of these little locks. Yes. Is the key into which I can put a key. Yes. And the GLP-1 is naturally made after I am eating food, it

Ania: gets made, it gets secreted in your gut, it gets secreted from your gut and they act differently in different parts of the body, depending on where the receptor is. When they work in the pancreas, they help us secrete insulin, so that brings down blood sugars in the brain. They help the brain know, Hey, I'm full. They give you satiety signals.

Jonathan: And so if I am living with obesity. Is it that my body is no longer making the same levels of GLP-1 that you'd expect? That means that I'm not hungry, or is it that my brain somehow isn't like responding to the normal amount?

Ania: Yeah, it's a really good question. I don't think we have enough information to know the answer. People with obesity make GLP-1, they secrete GLP-1. People with type two diabetes do as well. There's some question of whether people with type two diabetes may secrete less after a meal. You're not replacing something that your body doesn't have. You're giving your body a lot more of something than it would naturally make. But it is using the natural pathways or communication systems that your body already has in place.

Jonathan: So could we talk maybe about those? Yeah. Those different drugs now? Yeah. Because I think a lot of people listening will have heard of Ozempic, Mounjaro. And I know that you just completed a new study. The latest, I think one, I'm gonna pronounce this wrong, retatrutide

Ania: Retatrutide, we did a phase two and that was published in 2023. And

Jonathan: that is not the triple yet, I think licensed in the States or elsewhere.

Ania: No, we're doing the phase three trials.

Jonathan: So we can talk, I'd love to talk a little about that. But there's like this series of these drugs. Yes. And so my question I guess is how are they different from one another and what's different between that and just the GLP-1 that I am producing right now? 'Cause I had lunch just before this podcast. Yeah.

Ania: So each of these medicines is very different. They are different molecules. They can target one receptor. For example, GLP-1 receptor.

Jonathan: Right? When you say a receptor is, I'm thinking still again, like the lock.

Ania: The lock. Yep, exactly. It's the lock. They can target one lock, they can target two different types of locks. So two different types of keys for two different types of locks, even though it's not actually two different types of keys. 'Cause if it's one molecule, it's one key that fits both locks.

Jonathan: Clever.

Ania: Yes. So you have molecules that target one receptor or one lock. So that's something like semaglutide, which is Ozempic or Wegovy. You have medicines that it's one molecule or one key that targets two locks. So that's tirzepatide like Mounjaro or Zepbound. It targets GLP-1 and GIP receptors. And then you have medicines like you mentioned, retatrutide, retatrutide targets three receptors. It targets GIP, GLP-1 and glucagon. So one molecule that targets all three of those locks. And those are just some examples. There are many other molecules in medicines in development that target 1, 2, 3. There may be some down the road that are in development that are targeting maybe more.

Jonathan: The first version of these drugs basically targeted these GLP-1 receptors. Yes. That's like this lock. And that was the simpler explanation that you were giving to me about hunger. However, in my body. There's actually a number of different hormones that are related to this process that affects hunger. Yes. And the set point you're talking about. And so these newer drugs are starting to say, oh, I can create a molecule that doesn't just hit one of these hits, two or even three of these sort of locks in my brain. Yes. And so these are three slightly different in my natural, in my body. Naturally I'm actually creating like three different hormones that affect my hunger somehow. And so these latest drugs are starting to hit more of them in order to try and get me to lose more weight.

Ania: Well, it's not only about weight loss, weight reduction is just part of the story. Treating obesity is about optimizing or improving health.

Jonathan: Okay.

Ania: That's the goal. I think the more interesting aspect or thing to think about is how can targeting these different receptors also impact other parts of our health? So first I'll just start with GIP and GLP-1 were actually discovered around the same time. GIP was actually discovered before GLP-1, and they both are hormones that help our pancreas secrete more insulin. Okay. Glucagon is a different type of hormone. It uniquely, there's receptors in the liver and so it may impact liver health. So for example, with retatrutide, which targets GIP, GLP-1 and glucagon and there's other medicines, for example, survodutide, which targets GLP-1 and glucagon. Both of those have a glucagon component. They may have, and it looks like they do have, beneficial impacts on liver health. So they help remove fat from the liver. And I'll give one more example because this is part of the next wave, amylin analogs. So. Amylin is a hormone that is co-secreted with insulin. When we release insulin, we also release amylin. It looks like amylin also helps with satiety. It also acts in similar ways to GLP-1, but also in different ways. And so the question will now be, well, what are the additional potential impacts of creating amylin analogs, and pairing these, for example, with GLP-1 receptor agonists or using amylin analogs by themselves.

Jonathan: I had understood that the health benefits that came from taking these drugs was as a result. Of the weight loss

Ania: part of it. Yes, absolutely.

Jonathan: But I think you're saying that isn't the only way in which these drugs can help your health. And so potentially you might have a new drug that gave the same amount of weight loss as an old drug, but might be better for health because it actually affecting these other parts of my body.

Ania: Well, different aspects of health. So let's say that you are a person and you have cardiovascular disease, you have heart disease, right? And let's say that the beneficial effects are specifically from GLP-1 receptor agonism. And we don't know, right? But there is evidence, for example, in the SELECT trial, which was this very large, more than 17,000 individuals in this trial, most of these trials, and this is one example, look at individuals who have had a heart attack, a stroke, something. Before they're looking at preventing, can we prevent a second heart attack, a second stroke, a second cardiovascular event. And so semaglutide reduced the risk that you would have another event. And so the investigators were interested in looking at, well was that all because of the amount of weight they lost or was it something else?

Jonathan: And can I confirm that if you are living with obesity or indeed overweight and you lose a significant amount of weight, you would expect to be healthier and reduce your risks of, you know, the heart attacks and all of these sorts of things. So

Ania: it's a combination of the two. So we did another trial. This was with tirzepatide, looking at individuals who have pre-diabetes and we treated them for three years and we saw very interesting things. First of all, tirzepatide compared to placebo, significantly decreased the chance that you would develop type two diabetes. So it was a 94% risk reduction. Nearly 99% of people who received tirzepatide did not develop type two diabetes over the course of the three years of the trial.

Jonathan: And how would that compare with the people who didn't take the trial,

Ania: the placebo group? There was a higher incidence of development of type two diabetes. And the question was, and a lot of people ask this is what happens if we stop tirzepatide? And people started to gain back weight. On average, they gained back about 7% of their body weight within about a four month time span and more individuals started to develop type two diabetes. The bottom line was in order for the beneficial effects of the medicine to be seen, whether that was maintenance of the weight loss, whether that was prevention of type two diabetes, improvement of blood pressure, improvement of cholesterol, the medicine needed to be continued. So it's not just for the weight. It's for the weight, and it's for all of these other downstream obesity-related beneficial effects. And we shouldn't be surprised, right? Obesity is a chronic disease. Chronic diseases require chronic treatment. If you are taking a blood pressure medicine and your blood pressure improved, what would happen if we stopped that blood pressure medicine? Your blood pressure would go up. With medicines to treat obesity. It comes back to what we talked about at the beginning, which is that what do these medicines do? They recalibrate the body fat set point. They recalibrate the enough point. So if a medicine is stopped, that set point goes back up and the weight follows.

Jonathan: That's clear. There's something rather depressing about it, of course, at the same time that you need to keep taking this thing forever. So we've had this obesity epidemic, we've now got this drug, which is magical. But I think a lot of people feel like, well, I ought to be able to sort of take this thing and be cured. And you're saying that's not really the case, not this is like an ongoing treatment

Ania: that's not, but is it depressing that if somebody has high blood pressure, that they would have help from a blood pressure medicine? Or is it wonderful that we have treatments for people, that we have options for people, whether they have high blood pressure, whether they have diabetes, or whether they have obesity. And the added difference with obesity is that obesity is related to over 200 obesity-related diseases. And so if we treat obesity effectively and safely. Then in essence, aren't we preventing mitigating or treating over 200 other diseases? And that has an incredible impact on the health of our world.

Jonathan: So I totally agree with that. I think that what probably quite a lot of people listening will say is, yes, but why are we in that situation in the first place?

Ania: Our obesogenic environment, we have to work on our obesogenic environment. There's no debate. So as we are hopefully changing and reshaping that obesogenic environment to be a default healthy one, that will help prevent obesity and those who don't yet have it. But for the people who have obesity, if they are seeking treatment, we would like options for them.

Jonathan: I love that and I love the passion comes through really strongly. So I would love now to talk about like our latest understanding, you know, we're here in 2026 and this is obviously, you know, I think you paint a picture of how fast this has been moving and you've been at the center a lot of this research. Before we do that, I think there's an important topic that I'd like to touch on briefly. Most drug studies are funded by the drug manufacturers. And I know that this has been true for like all four of those studies in New England Journal of Medicine. And I think the question that, you know, a number of listeners are gonna have is, well, does that mean that I can't trust the results? And does it mean that I can't trust you?

Ania: Yeah, I mean, it's a really great question and I think that for any disease, this is how we develop new therapies. It's working together. A company may not be seeing patients in clinic. They may not know what the patient is asking for, what the patient is experiencing. In the same way that I'm not in the lab making the medicines, nor are my colleagues. So I think it's really working together just as we would for any other disease, any other complex chronic disease.

Jonathan: Will you just talk me through for a minute how science makes sure that these results are in fact true. Because clearly there's an enormous amount of financial interest from a pharmaceutical company to prove that like this drug is safe, there's no side effects, and it works really well because then they make billions of dollars of revenue. How as science and scientists do we make sure that we don't just get fake results?

Ania: Yeah, absolutely. It's incredibly important. So there are multiple steps that these studies have to go through. There is constant communication with the FDA, the EMA to ensure that the steps are taken and that the trials are conducted in such a way that they demonstrate are these medicines safe? Are there toxicities that we would be worried about? Are they effective? And that there has to be a balance. So this actually brings me to one thing that you asked about in the very beginning, which is this microdosing, all it means is little dose. Now we use little doses for our patients all the time. Maybe the patient only needs a little dose, right? Maybe they don't need the larger dose, which is very common for any disease, including obesity. But the medicines haven't been studied in people who don't have obesity, right? Maybe overweight with an obesity-related disease, but not without that, right? And so the FDA doesn't have the data. It needs to know whether the risk to benefit ratio is a good one for someone who doesn't have obesity, who doesn't have overweight with an obesity-related disease. That is exactly why we do the trials.

Jonathan: People listening may be wondering, are you employed by one of these pharma companies? And do they get to just write the paper and then it gets published? What's the actual situation?

Ania: Yeah, no, I'm not employed by any of the companies. I do serve as a scientific advisor to many companies, as many of my colleagues do in every field of medicine. In terms of the papers I write, every word you have authors that are academic and you have authors that are from the companies, and we work together. But for the papers that I lead as a first author, everyone knows. I'm gonna write that first draft. I'm gonna integrate all of the different feedback from all the authors, the academic authors, the authors who are sites for the trials and from the companies themselves. So integrating all the comments and then working with the journal and getting feedback. We get peer reviews, right? So external experts who are reviewing our papers. I love that rigor.

I don't even wanna say long ago because it wasn't that long ago, but the threshold that the FDA set for these medicines was losing at least 5% of your body weight, right? So if somebody weighed, let's say 200 pounds, that would be 10 pounds. Let's say somebody weighed a hundred kg, it would be five kg. That was the threshold that was set. Now that seems like a pretty low bar. Why was that threshold set? It was set because with diet and exercise, if somebody lost between three and 7% of their body weight, there would already be metabolic benefit. For example, if they had diabetes, it may improve their blood sugars. If they had pre-diabetes, it may help prevent it. So with that degree of weight reduction, there was already health benefits. Right. And the FDA wants to know what are the health benefits of what we're doing. Right? So that's why that was set. Now with the newer medications, we started seeing weight reduction of more than 15%, more than 20%. And now the medicines that are to come, we're looking at weight reduction that's 25%, maybe 30% we'll see 30%

Jonathan: of body weight.

Ania: And then you're approaching what you would see with bariatric surgery, with weight loss surgery. And not only that, if the medicines are targeting different mechanisms, you can use them in combination. So if a medicine has a GLP-1 receptor component, you don't wanna pair it with a medicine that also has that component. But if you have a medicine that, for example, targets GLP-1 receptor, GLP-1 GIP receptor, and then you have an amylin analog. Or it's targeting some other receptor. You can pair them for additional weight benefit. And we did this, and we still do this with older medicines. There were medicines and there still are medicines for obesity treatment that are not GLP-1 based or not nutrient-stimulated, hormone-based medications. And we use them in combination. But I'm gonna just come back to one very important point, which is that it's not just about the weight reduction. Yes. Weight reduction is important for health. Treating obesity is about improving health. It's about optimizing health, so it's weight as well as some of the direct peripheral effects of these medicines.

Jonathan: And can you tell us what the latest data tells us about the impact of these drugs on actual health conditions?

Ania: So, one, we of course see that these medicines result in weight reduction in treating obesity and reducing adipose, right, reducing fat mass. We also see improvements in heart health, kidney health, improvements in lipids, improvements in blood pressure. I'll give some examples. So with semaglutide, we already know that it can improve heart health in terms of preventing a second heart attack or stroke in somebody who's had a heart attack or stroke. And now semaglutide is approved for people with cardiovascular disease. Obstructive sleep apnea is another common obesity-related disease. And now tirzepatide, there's a trial that was conducted with tirzepatide, SURMOUNT-OSA or SURMOUNT obstructive sleep apnea, that demonstrated improvements in those who have obstructive sleep apnea. And now tirzepatide is FDA approved for the treatment of obstructive sleep apnea. The medicines are being looked at for kidney outcomes, for blood pressure. Another aspect of health is liver health. So basically these medicines are helping to remove fat from the liver. That can have a lot of detrimental effects on our health.

Jonathan: Are these likely to end up being drugs that we start to think of as being valuable, not just in order to either lose weight, as many people listening to this will think about, or to deal with health conditions that are direct result of obesity.

Ania: The short answer is yes. As an example, tirzepatide is FDA approved for obesity treatment. The FDA calls it chronic weight management. It is also FDA approved for obstructive sleep apnea. Semaglutide is FDA approved for obesity treatment. It is also FDA approved for cardiovascular disease as well as MASH, a form of liver disease. So I guess to your question about will they be used for people who don't necessarily have obesity? I think the one caveat would be that if they don't have obesity and they're taking a medicine that causes weight reduction, we'd have to balance that, right? Because then you'd want a medicine that maybe targets those things but doesn't lead to that significant amount of weight reduction. And the older medications that were GLP-1 receptor agonists, they didn't result in as much weight reduction. What actually happened was that the scientists wanted to extend their half-life, meaning help them to last longer in the body. So instead of taking them multiple times a day or once a day, those were the original ones, how do we make them last longer, a week or maybe a month? Right? And as they were trying to make them last for longer, they found that they led to more weight reduction. And part of the thought is by them acting longer, do they have more opportunity to do whatever it is that they're doing in the brain to act on those receptors in the brain? But by making them last longer, they also happen to have more impact on weight. We are in our infancy of understanding.

Jonathan: Can we talk about side effects now? Anything that's new? I think there's always this question like, how safe is this? In the long-term, what do we know about the potential long-term side effects of GLP-1s and like what level of concern should somebody have as they're thinking about that?

Ania: Yeah, so the most common side effects are gastrointestinal, nausea, diarrhea, constipation, and in some instances vomiting.

Jonathan: These are quite short term effects, right? Like I'm gonna get that side effect quite rapidly after I start to take the drug.

Ania: Yes, usually. Usually if people have side effects, it's at the start and when the dose is increased.

Jonathan: Are there any known long-term effects that maybe you don't feel at the beginning, but you know, are risks that will build up if I keep taking these drugs for years?

Ania: Well, there are rare side effects that we talk about with our patients so that they know and they can look out for them. One is increased incidence of gallbladder disease, so with any form of weight reduction, whether it's bariatric surgery or diet and exercise and these medicines. There can be gallbladder disease. And so we counsel patients if they have abdominal pain, that they shouldn't ignore it, right? That they should get treatment for it. Most often patients can resume taking the medicines right? Once their gallbladder is removed. We also continue to monitor for pancreatitis. So pancreatitis is increased in people who have type two diabetes versus people who don't have type two diabetes. So we don't use these medicines in people who have pancreatitis or acutely are having pancreatitis, or if they develop pancreatitis, then we stop using the medicine. Again, we counsel our patients on abdominal symptoms so that they know there are other things that patients come to us after they've lost a significant amount of weight. So hair loss is one, and we saw this with bariatric surgery when patients were losing a significant amount of weight very rapidly. They would experience hair loss. And we can see this with these medicines as well. Other things that have come up and questions are muscle loss or bone loss. Again, these are things that we see with any form of weight reduction. And now they're coming up with these medicines because people are losing a significant amount of weight. And this brings me to a very important point, which is that when these medications are taken or prescribed, they need to be paired with healthy diet and physical activity because the goal of obesity treatment is improving health. And there's no medicine out there that can help us eat more healthfully or move more. And so really for optimizing health, it's pairing both. It's pairing the medicines that help recalibrate the amount of fat that your body wants to store with the healthy diet and physical activity.

Jonathan: One thing I'm struck as I'm listening to that is the risk of taking the drugs for a short period of time, losing a lot of weight, then coming off the drug for whatever reason. Getting back, you're saying you should stay there and then getting back. And I think about this, 'cause we've talked a lot about the problems of doing this through yo-yo dieting, right? That's come up often on other podcasts. Yeah. But here you can do something really extreme, right? You're saying you could lose 30% of your weight and then come off it. Are you potentially in a worse place if you do that because you've sort of lost the muscle through this? Then you go back on and so you really wanna make sure that if you're going into this you're describing, you know, you need to be aware. You're gonna have to stick with it.

Ania: There's one study with liraglutide and exercise, it was published in 2021, and the people who paired liraglutide with exercise did better in terms of maintaining their lean mass and obviously the medicine was helping in terms of the fat loss.

Jonathan: So I'd love to pull all of this together now and say, okay, we've talked about all the science. What does this mean for like a real person who's considering starting out on one of these new therapies? We talked a lot about living with obesity. How do I translate that to me saying, well, I weigh this amount. Like, is this relevant for me?

Ania: The studies have included participants who have a BMI, a body mass index of greater than or equal to 30 or a body mass index of greater than or equal to 27 with an obesity-related disease like high blood pressure, like high cholesterol. The studies have also looked at people who have type two diabetes, irrespective of BMI.

Jonathan: And could you just paint me a picture? So if I have, for example, a BMI of 27 or 30, what does that mean?

Ania: Greater than or equal to 25 is overweight. Greater than 27 was a midway point that was chosen within that overweight range. But if you look at the labels, so the FDA labels for semaglutide, tirzepatide, if you look at the labels for these medicines, what they actually state now is overweight or obesity. They don't state the BMI criteria for the indication, right? So it's looking at the whole individual and seeing where's the data in the trials and then what is the risk to benefit ratio for that person.

Jonathan: And so are these just sort of slightly arbitrary cutoffs that you know, you and others using in trials to decide who's in here and we don't know that it won't work great if your BMI is 26 or 25, or do we know like this really only makes sense as you are starting to get into those levels.

Ania: So it's not arbitrary. It's based on morbidity and mortality. So it's based on older studies. But again, BMI is not a great measure. It was designed as a screening tool, not a diagnostic tool. And so we really need to, if we're gonna continue, which I think we're gonna continue using BMI, we need to revamp it by age, sex, and race ethnicity.

Jonathan: Amazing. That's what we need to do. Yeah. So let's say you go and see your doctor. They say, yes, this makes sense for you. We wanna start what you should you think about as you're about to begin treatment. And I'm particularly thinking that a lot of people drop off these drugs quite quickly. So what do you need to do to maximize your chances of this succeeding? Because after all, you told me, I need to be on this forever. Right. So I need to make this work.

Ania: Yeah. So I mean, my approach with patients is I like to see where they are, what their expectations are, what their goals are for their life, not just for this, but in general. And I always start with the biology, so there's a shared understanding of what the disease is and what we're trying to accomplish and do. And then I invite them to ask questions, right? So I invite them to ask me questions about side effects, about potential other things that may happen beyond weight reduction, right? When somebody loses a significant amount of weight, there's a lot of things that change in their life. So we start to have that conversation, and a lot of that first visit is focused on what are the side effects and what are ways to mitigate those side effects. We learned very quickly not to go up on the dose quickly, and most of my patients do not go up once a month. Also, even if they're not having side effects, if a patient is losing weight on a certain dose, we don't increase that dose is working for that patient. There's no need at that moment in time to quickly dose escalate. The weight did not come on overnight. Why would we want it to come off overnight? Now, what are ways that you can help mitigate side effects besides start low and go slow? So there are several things that I talk about with my patients. One is not eating past the point of fullness. So you're going to feel full earlier. Tracking which foods may exacerbate your symptom. That's the second thing. So our patients tell us that fatty foods tend to exacerbate their symptoms. For some people it's spicy foods or carbonated beverages, but fatty foods seem to be a common theme. So eating less fried foods, less french fries or chips, right? Eating less of those foods while you're dose escalating. You can always come back to those once you're at a stable dose and you plateau. Sometimes I have people just keep a diary, right? It's hard to keep track of what foods you may have eaten. Then the third thing is eating more frequently but smaller amounts. And then the final thing is staying well hydrated. So being dehydrated can actually exacerbate people's nausea. And when people are less hungry, they also tend to be less thirsty and food has water. So if somebody's eating less food, they are also taking in less water. So that's the final thing.

Jonathan: Could we talk about the quality of the food now and of course on this podcast?

Ania: Absolutely.

Jonathan: There's to be so something we think quite a lot about, there's been a lot of discussion around the fact that you're suddenly eating much less than before and that many people on these drugs probably haven't been on the best diet anyway because part of the challenge of, you know, the obesogenic environment as you're talking about, it's like all this ultra-processed food and all the rest of it. But certainly if you suddenly reduce the amount you are eating, then what, if any, other challenges around getting the nutrients that you need? And I guess on the more positive side, what do you see about the opportunity in this moment to actually change what you're eating and improving the quality of what you're eating?

Ania: It's almost like putting yourselves in the shoes of someone who has obesity, someone who has experienced food noise, or just they finish their day and they have followed this plan that they laid out of this perfectly healthy breakfast, lunch, dinner. And then after dinner they are hungry. They are pulled towards the ice cream in the freezer or the cookies or the biscuits in the pantry because their body wants them to get more energy. Their body wants that to get them to that higher set point and now they take the medicine and all of a sudden their brain says, you have enough, you don't need to eat more. Now, we have not gotten to the state yet where we can have medicines that change food preference, although there's a caveat there. Maybe some of these will, we don't know yet. We have to do that research, but the freedom that patients now have, and so that freedom could be okay. Well, they also impact, for example, alcohol intake. Right? Some of these medicines. So somebody doesn't want another glass of wine. Right? And instead they'll have the water. Right. Or they don't want another bite of the chips.

Jonathan: Is there anything that you would be saying, look, I think it's really important you focus on these couple of things in your first

Ania: Yeah.

Jonathan: You know, six months say on these drugs.

Ania: Absolutely. Number one, hydration. Very important. Prioritize protein, vegetables, fruits, all the things that we talk about, whole foods to the extent that is possible within that person's sphere, within what that person has available to them. In terms of your question about protein and other things, because people are full earlier, what I advise is try and eat those foods first because you're going to get full earlier, and we want your body to get all the nutrients that it needs in order to be as healthy as possible. If the dose is escalated too quickly, what we don't want is somebody to be eating very little and not to be able to get in all of those healthy, nutritious foods. That is rare, but this can happen in some patients if we're going up too quickly on the dose. So it's super important to not go up on the dose too quickly.

Jonathan: If I'm going up on this dosage a lot faster than you're describing, you do inpatients. I would note that. And you know, I think there's a lot of people who get these drugs, you know, online in some way with quite limited amount of physician support. I think that is the reality for a lot of people around the world. Are there any particular risks that they should be aware of to watch out for in that situation?

Ania: Yeah. These are not weight loss drugs. These are not weight loss aids. They are medicines just like a blood pressure medicine or a medicine to treat your heart disease. These are medicines. Would someone take a medicine for their blood pressure or for their diabetes without the compassionate care of a provider? There are absolute detrimental effects. There are negative things that can happen if the dose is escalated too quickly, if it's escalated inappropriately, if a higher dose is taken than is needed or a higher dose is taken at the outset. Somebody doesn't dose escalate, maybe because they don't know, or because the person who's providing them with the medicine didn't know. So it's incredibly important to make sure that the medicines are treated as medicines and they're provided in a very safe way as we would any other medicine for any other disease.

Jonathan: It's really interesting to hear you talk about that because I think there's so much noise about this. People find ways to get this without ever physically seeing a doctor, and I think it is treated almost like taking a vitamin supplement that you might be able to take. It's not treated with the sort of seriousness that you are describing. What is your message to someone who is thinking about it like that?

Ania: Talk to your healthcare provider. Talk to your primary care doctor. Ask the questions. This is new. The healthcare field is catching up, but find healthcare providers that can help you along this journey.

Jonathan: I feel like that naturally pulls me onto a question I asked right at the beginning about people so-called microdosing on these drugs, because as they're getting older, they want to stay as thin as they were when they were 25. What would you say to people who are doing that or thinking about doing that?

Ania: We don't have the evidence yet. We need to know what the risk to benefit ratio is, and in the same way that anytime somebody comes to us who has obesity, there's a choice to be made. You ask me very early on about should everyone take these? Well, if somebody is seeking treatment, we should give them options, but we need to present them with the risk to benefit for those treatments as we would for any other disease.

Jonathan: Are there any natural ways to increase your levels of these GLP-1s to sort of manage your hunger? You know, long before you end up in the situation where you're with this, you know, this disease of obesity,

Ania: we don't have a way to do that at this point. There are ways to help prevent obesity from developing, and those start early on before the onset of obesity, right? So being physically active, moving, eating a healthful diet, all those things help prevent, but just let's not forget that there is a strong genetic component to obesity, and it's not just your parents at this point. It's your parents' parents. We don't know when those changes, those recalibrations of this setpoint occur. Do they occur in utero? Are they generational? And I would argue that they are.

Jonathan: There is one other topic that I really wanted to make sure that I got your answers on, which is around exercise while you're on this drug. That's another area where there's been a great deal of discussion. What is your view?

Ania: It's very important. It's very important. So at that first visit we talk about side effects and we talk about healthful diet and movement, whether that's to maintain muscle mass, muscle function, which is even more important than muscle mass. Any incorporation of physical activity or movement into the day. And let's not forget about resistance exercise, right? So it's cardiovascular and resistance, but meeting the patient or the person where they are, right? Wherever they are. Adding a little bit, and then along the way as they lose weight, adding in more and more.

Jonathan: We're at time. But I'd like to ask one final question. Imagine that you are sitting here again with us in, let's say five years time. What do you think might be the most exciting next new thing that you might be talking about? Which is like a dream of a study in front of us, but you could be sitting here talking about the results today.

Ania: In the next five years, I'm hopeful that we'll have more than one class of medicines to treat obesity. There's more than one type of obesity. Not everybody responds to these medicines, so I'm hoping we have different choices, different classes. What we will have, we already have oral. So daily oral, weekly and monthly options, maybe even less frequent options. And most importantly, I think we will be five years farther in our understanding of how these medicines impact health, of how treating obesity impacts health. And I think that's the most exciting thing, is how can we help our patients lead healthier lives?

Jonathan: Amazing. And yeah, I'd like to do a summary of, you know, just maybe a few of the things that we've covered because we've covered a lot of things today. I mean, the first thing that's obviously striking, as you said, you know, when you went to medical school, you didn't even study obesity. None of these drugs existed, and now you are saying that, you know, the latest version of these drugs that are just gonna come through can potentially deliver 30% weight loss, and then these extraordinary set of health benefits that follow. So this is really a sort of transformation in terms of this whole new class of drugs and the impact they have. The second thing I'm struck by is you know, I thought of these as being GLP-1 drugs and you've corrected me and said, well, actually that's not even right. You know, GLP-1 is almost like one lock in my brain, in my body that a drug can unlock and have benefits. But we've already found at least three of these different locks as I was thinking about them. I think you described these as nutrient-stimulated hormones. And that basically there's probably loads more that we don't even know about. Yes. So potentially we're gonna continue to have impact. And that interestingly, although the weight loss is driven by the fact that these drugs change something in our brain, that mean that basically we stop being hungry. We stop being surrounded by this food noise. We actually have these receptors, these lots of all around our body and that as we're expanding these drugs, they're having a lot of impact on other areas. It in fact started originally in terms of managing blood sugar. There's all of these new sets of drugs that are doing things around the liver, which seems really exciting. And there are already a set of studies, a number of which you've been involved with that show that, for example, I think it was semaglutide, you said if you've already had some sort of heart attack or stroke and you take this drug, it like dramatically reduces the chance of a second one, which is pretty magical. And that another drug, I think it was tirzepatide,

Ania: tirzepatide,

Jonathan: tirzepatide, these are tricky names. You said a 94% risk reduction in getting diabetes. So these are like really big impacts outside of weight loss. You've also emphasized that all of these trials are about people living with obesity or who are overweight, and this impact can be life changing. That because of what's happened in their brain, like this isn't something that, you know, traditional approaches were able to solve because. You know, we haven't talked a lot about it, but this whole like, you know, just count your calories, like none of this works.

Ania: Well, it doesn't recalibrate

Jonathan: because it doesn't change the set point. That's right. That is in your body, but you're very cautious about what that might mean for people who are using these drugs who aren't in those categories with that level of weight. Yeah, and I think really emphasize that this is, you know, it's a serious medicine. You wanna make sure you have a physician looking after you, and you're quite cautious about this. In terms of like what does it mean to actually be taking these drugs? The first is the main side effects are sort of gastrointestinal. So this is like nausea, diarrhea, constipation. And the key approach that you take in your clinic and your colleagues is start low and go slow, which means, you know the amount that you're taking is not very high to start with and you don't ratchet it up really fast. Yes. And you're saying if people are losing weight, actually you don't need to increase that. Whereas for a lot of people, if you're ratcheting up the levels very fast and getting this very high weight loss, you're also increasing the chances of the symptoms. And that's a problem. 'Cause what you're also saying is you've gotta be on this for life. So if you do it for a bit and then you have bad symptoms, you give up, actually, you're just gonna go back to where you were at the start. So you need to get past all of these initial symptoms and you need to think about this like taking your blood pressure medication, you're just gonna take it for life. But you did have a bunch of other tips. The one you kept talking about was being hydrated, which is really interesting. Like you really need to drink with this. You need to rethink how you eat because suddenly you're gonna eat much less. So you need to prioritize. Like the good stuff first. So all the things I think that we talk about on this show, you mentioned, you know, whole foods and vegetables and protein, like get that first because suddenly you're gonna be full up much faster than before. And then finally, you know, I think on exercise it was like a very positive message rather than being very anxious about this 'cause you're losing weight. And what will this mean for muscle mass? Actually many people feel able to do a lot more exercise on these drugs. And so almost as you are making progress on them, then suddenly you can do more. But of course it's really good for your health and that is something that you want to encourage all of your patients to do as they're on this journey.