SPENCER: Katherine, welcome to the Clearer Thinking Podcast.

KATHERINE: Hey Spencer, thanks so much for having me. I'm really excited to be here.

SPENCER: Are GLP-1s the most effective weight loss drug ever invented?

KATHERINE: They are actually. We've had GLP-1s since 2005, and earlier versions were not as effective, and they also had more side effects. But the technology has advanced in such a way that the versions we currently have now are producing more weight loss than anything we've seen before.

SPENCER: And they're peptides, right?

KATHERINE: Peptides are just small proteins. I feel peptide now has sort of a negative connotation because there's a lot of unregulated business happening, but yes, technically, certain versions are peptides. Certain versions are what we call small molecules.

SPENCER: It's funny because maybe in your world there's negative sentiment, but you see all of these influencers being like peptide, peptide, peptide, buy my peptide, and I imagine most of them are not nearly as well proven as GLP-1s.

KATHERINE: That's definitely an understatement. Medications in order to be FDA-approved have to go through multiple rounds of randomized control trials, and what's happening right now with some supplements and compounds is that there hasn't been any sort of testing even remotely close to the rigor of what happens in the FDA approval process.

SPENCER: Yeah, it's funny because people will critique the whole FDA system, and there's money in medicine and all these kinds of things, and a number of those critiques are valid. But on the flip side, in the supplement world, that's 100 times worse. So yes, we should critique the FDA. We should critique the way medicines are practiced, but at the same time, we have to think about what we're comparing against.

KATHERINE: Yeah, a hundred percent. There is a lot going on right now that has very significant safety concerns. It's an important conversation that's not happening enough, unfortunately.

SPENCER: I also know people who don't have easy access to GLP-1s, and so they've been buying them on websites, on the gray market, on the black market. Do you think this is a bad idea? Do you think it's hard to say?

KATHERINE: I understand the impetus to do that because we have a huge access problem right now. On one hand, we have these amazing new tools that can help so many people, and only a small fraction are able to access them in a way that is safe and effective. I definitely understand the drive to go through these alternative pathways, but there are tremendous safety concerns with medications that have not been through the FDA approval process.

SPENCER: Sometimes people think they're buying what has been FDA approved. They're just buying it from some kind of sketchy manufacturer, right? Do you think there's a reasonable reason to believe that they're actually getting what they think they're buying?

KATHERINE: No, I think they're not getting what they think they're buying, unless a medication is brand-name FDA-approved coming from a regular pharmacy, or there are different ways to get the real stuff. There's a huge confusion right now about what a compounded medication is. People think that compounded medications are the same as generic, but that's definitely not the case. A generic medication still has a whole approval process, and it's regulated in a way that compounded medications are not.

SPENCER: So, what does it mean for a medication to be compounded?

KATHERINE: These medications are basically versions of the real FDA-approved medications that are sort of like knockoff versions. They typically are produced in a powder form, come from different countries, and generally come from outside the United States. They are reconstituted in some kind of liquid. The issue is the way safety works. One, we don't know exactly what the compound is because it's some knockoff version. Maybe it's using a different salt, maybe there are different vitamins included, so there's no consistency. You don't know that you're getting the dose you think you're getting. Two, you don't even know what you're getting. I can go into many of the details if you're interested about how this came to be and why we're in this situation right now. But to answer your question, it's basically in a powdered form coming from outside the U.S. that is not the same as the actual medication.

SPENCER: I feel really conflicted about it because, on the one hand, if there's a cheaper way for people to buy it and they can't afford it or their insurance doesn't cover it, great, get it. I don't feel that bad about them going around the patent. You can make an argument that maybe it's bad for the patent system, so there's an argument to be made there. But on the other hand, there's just a real safety concern. Are they even getting what they think they're getting? Are they going to be poisoned, etc.? So, how do we get here where we are now?

KATHERINE: Yes, it's an interesting story, and I've done a lot of writing on this. I've done a lot of speaking. I actually did a briefing for Congress last year about the safety concerns, so I learned quite a bit in that process. Basically, the whole way this came to be is that when these medications came to market, there was so much demand and not enough supply. When medications are in shortage, that means that other ways of manufacturing are okay during a period of shortage. These medications are no longer in shortage, so this should not be happening anymore. But what is happening to get around the regulation is that these medications have to be different from the real thing, and they have to be personalized. What personalized means is, if you think about a kid needing a personalized dose because a medication's weight-based, or if you think about someone who has an allergy to one component of a medication and they need it to be made up specially without that component, that's personalization. The manufacturers making these products are saying that they're personalized to get around the regulations that large-scale manufacturing and distribution of compounded knockoff versions of the real medications are not supposed to be happening.

SPENCER: Got it. So effectively, there was a time when it was legal what they were doing. Now it's not legal. They're trying to use a loophole: if we personalize it, then it's technically legal, but it's really just a way to sell these things.

KATHERINE: Exactly. Yes, you said that much more eloquently than I did. Yes, that's exactly what's happening.

SPENCER: Before GLP-1s, what was the most effective weight loss approach?

KATHERINE: It's bariatric surgery — metabolic and bariatric surgery.

SPENCER: So that was used just more for extreme cases, right?

KATHERINE: Yes, but if you look at the whole spectrum of treatment options for obesity, on one end of the spectrum, bariatric surgery is associated with 25 to 33% total body weight loss. Medications historically — well, if you look at the other end of the spectrum, lifestyle interventions. The best diet long term is going to produce about 3 to 5% total body weight loss.

SPENCER: People will lose more temporarily, right? They'll dip down, but then they'll come back to, and you'll just get 3 to 5%.

KATHERINE: Yeah. Well, to get into that point, Spencer, if you take a look at randomized controlled trials of the best dietary approaches out there, the average weight loss is 3 to 5%. Some people may lose way more. Some people may actually gain weight with any diet, but the average number is 3 to 5%. And then if you look at what happens over the next five years, 80% of that weight is regained. Yes.

SPENCER: So, even in the short term, it's only 3% to 5% and then they regain that. It's not like they're losing 20% and going back up.

KATHERINE: Within five years — yeah, depends if you call that short term. So, the bottom line is that for people with obesity, most people will require some kind of medical intervention to help them achieve clinically significant weight loss and health improvements. The medications we had before these newer, highly powerful GLP-1 medications were associated with about 5% to 10% weight loss. It was three to five for lifestyle and 25 to 33% for bariatric surgery. There are some GI procedures and things like that. But for us, going from the ability to prescribe one medication and achieve 5% to 10% weight loss to prescribe one medication that can achieve 15 to now 23% has been absolutely revolutionary.

SPENCER: There's such a funny contradiction here, where we know basically if you eat fewer calories, you're going to lose weight. If you're able to maintain eating fewer calories, you're going to probably stay at a lower weight. Okay, maybe there's metabolic effects and other effects, but at the end of the day, if you do calorie restriction and you maintain it, you will lose weight. At the same time, we know from numerous randomized controlled trials that giving people that advice, or even trying to help them do it, or even trying to give them healthy foods or whatever to do it, it just doesn't seem to work very well. How do we resolve that contradiction?

KATHERINE: It's actually not as simple as eat less, exercise more, and you lose weight and keep it off. That does not happen for 99% of people who have obesity. If you're someone of normal weight, go on a diet and maintain that. Maybe you can keep off 5 to 10 pounds. But for most people with obesity, to really lose a clinically significant amount and keep it off long term, it's just not possible without some kind of medical intervention. What happens is our bodies have evolved to be in this situation where when you go on a diet, when you are restricting, your body thinks you're starving, and these are evolutionary adaptive responses to help people stay alive. Anytime somebody goes on a diet, you go into this sort of anti-starvation mode, and I'm happy to get into the biology of what happens hormonally and everything. But basically, that counteracts people's best efforts, and they just start gaining and gaining. For most people, all that weight comes back, and maybe even more.

SPENCER: So, I just want to get really clear here. Suppose someone was in prison. They didn't get to control what they ate, and the prison guards only gave them X calories a day. And that was way below their base rate. Am I correct that they would then lose weight and stay at that lower weight in that controlled environment where they have no ability to eat more food?

KATHERINE: Yeah, Spencer, I love your questions. I love how you know this is so hard to understand. It's so hard to understand, and that's why this idea of eating less, exercise more has persisted for so long. It's also part of our world's diet culture. But yes, let's say you cut your calorie number and your body starts losing weight...

SPENCER: Let's use me as an example. Let's say I eat 2,500 calories a day. Let's say I went down to 1,500 and I literally never broke it. I always ate 1,500. I never deviated. What would happen?

KATHERINE: It's fascinating. Several things happen. When your body starts losing weight from that calorie deficit, the hormones that control your metabolism and the hormones that control your hunger and cravings adjust in a way to promote weight gain. Leptin is one of those hormones. It's at a certain level when you're at your baseline weight, and then let's say you lose, Spencer, you go on this diet in a controlled environment. You lose 10% of your body weight. Your leptin level actually goes down by over 50%, so it's totally out of proportion. Your leptin tells your brain about how much fat you're storing and how hungry you are, and you've only lost 10% of your body weight, but your leptin level is telling your brain that you've actually lost 50%. The purpose of that is to make you more hungry, make you think about food more. If you're physically unable to eat those calories, it's a little bit different. But in a real-world environment, you will start eating more calories. What else happens is that your metabolic rate slows down, and your body becomes much more efficient. So, let's say you exercise after you've lost this 10%. You're going to burn way fewer calories at this lower weight with a lower metabolic rate than when you started.

SPENCER: That's so interesting. I thought it was just a small metabolic difference. You're saying it's a really substantive one.

KATHERINE: Yes, exactly, and it's out of proportion to the calorie deficit to make you more hungry, make you think about food more. Your metabolic rate changes to basically not starve. These are literally evolutionary anti-starvation responses that now in our environment are helping people gain weight and develop obesity.

SPENCER: So to make sure I understand this, if my base rate is 2,500 calories and I was in a controlled environment where I could not eat more than 1,500, I would lose weight and I would keep it off. But in a real-world environment, what's going to happen is I'm going to get hungrier and hungrier, thinking about food more and more often. Exercise is going to become less effective. My general emotion throughout the day is going to become less effective. So while in theory I will lose the weight and keep it off, in practice I won't. Is that accurate?

KATHERINE: Yeah.

SPENCER: Because it does seem to be this deep contradiction. Yes, you can in theory just eat less, right? But it doesn't work, and this is a very strange thing, and I think a lot of people have trouble wrapping their heads around it.

KATHERINE: I think this is one of the hardest concepts to really understand. Honestly, most healthcare providers don't. Most patients have gone to their doctors for different reasons, in different ways, at different times, and have been told over and over again, just eat less, exercise more, by a range of healthcare providers, and it's so defeating. Because it just doesn't work, and this is such a hard concept, and I love that you're very quickly getting to the bottom of it and really understanding it in a way that is so important. This is the crux of what the issue is and why people need more than just a diet. Think about it. Diets just don't work in and of themselves for the vast majority of people.

SPENCER: How does the body decide what weight to defend? For me, if I get up to 190 pounds, I feel like that's just not that hard to lose weight below that. But I do think it's increasingly difficult. I have this sense that my body wants to be a certain weight in some way. So, do we know that? Does that depend on the maximum weight you've gotten to?

KATHERINE: Yes, I love your question. It's basically called fat mass set point. Everybody has a set point, and that set point throughout your life can basically get ratcheted up for different reasons. I'm happy to go into the details of everything that pushes your set point up, but it doesn't really go down unless you take away some of those contributors that can be reversible, if that makes sense. As people get older, they tend to gain more weight — about a pound a year on average for an adult, literally — different things happen during life. I know you love talking about mental health and behavioral health, and most medications used to treat psychiatric conditions are actually weight-gaining. Most people are taking one, two, sometimes five or more medications that are actually weight-gaining. So that's a huge contributor. Family history is a huge contributor. Lifestyle is a huge contributor. Diet, exercise, all of these things basically just keep pushing weight up and up. If you lose weight, your body always wants to get you back to your fat mass set point, which is basically the highest weight you've ever been.

SPENCER: Maybe this is not known, but I'm wondering if you spike up quickly, you suddenly gain a bunch of weight and lose it. Would that immediately set your set point at the higher level, or does the body have to get used to a certain weight or something like that?

KATHERINE: That's such a good question. We talk about this all the time. There's a lot we don't know, first of all, and then there are exceptions. Pregnancy is an exception where that doesn't really count as much. I think the duration, as you're alluding to, likely does make a difference. If someone gains a certain amount of weight and is able to lose it pretty quickly, they have a higher chance of keeping that off. Whereas if someone gets up to a high weight and they're there for a really long time, it's likely going to be harder for them to lose that weight as easily.

SPENCER: One thing that's always baffled me is it seems culture has some impact here. If you look at Houston versus Austin, I haven't checked the numbers recently, but my understanding is there are huge differences in obesity, and it's how a whole city has a different obesity rate. Is anything known about that and the effect of culture on obesity?

KATHERINE: A hundred percent. It's so incredibly multifactorial. There are so many different factors. The environment is huge. The way I explain it to my patients is that everything in medicine really is a combination of genes and environment. If you have a genetic susceptibility, it just means that it takes less environmentally to get things going, and obesity just keeps getting worse as people have it. Honestly, it's like feed-forward loop, and there are genetic factors at play. There are absolutely all environmental factors. I'd have to research a little bit more about Houston versus Austin, but genetically maybe people are different in terms of maybe there's less opportunity to walk as much, maybe the nature of food, maybe the chemicals in the environment. There are so many different factors that would make that the case.

SPENCER: I would love to see a study where they take people who move from Austin to Houston and people who move from Houston to Austin and see what happens to their obesity. Does it change to match the city, or does it just reflect what they started with? I'd be fascinated to see the effects of that.

KATHERINE: What you can compare to is people coming from other countries. Many of my patients were born in other countries and they were fine, and then they tell these stories of getting to the United States and they'd never had a weight problem before, and now they just can't stop gaining. Clearly, there's a huge environmental trigger. I think everyone likes to blame it on food. It's not just food though. It's everything else. It's differences in physical activity, the chemicals in our environment, and prescription medications. All of these things.

SPENCER: Are there specific chemicals in the environment we know are implicated in obesity?

KATHERINE: Yes, anything that you can think of as a hormone disruptor. This is an area that there's still so much we need to learn about. It's a lot of different chemicals in our environment. Talking about plastics in the food that we're eating — microplastics, pesticides — all of these things have been implicated, and everything probably contributes in a way that's not good.

SPENCER: My understanding is that today, about 11% of U.S. adults are currently on GLP-1s, and 15% report having tried them. That's mind-blowing.

KATHERINE: Yeah, it is, but it's really understandable. They have been such a medical breakthrough, one of the biggest medical breakthroughs of our lifetime, literally. They have only been studied in people with obesity or people with diabetes. They haven't been studied in people of normal weight who want to lose five pounds. I think a lot of what we're seeing right now is people who are taking them off-label. So people without obesity, people without diabetes, who are not necessarily getting them in appropriate medical ways. I would argue that the majority of that may actually be off-label use.

SPENCER: Oh, well, 11%. But we do have a huge obesity epidemic. How bad is that problem, and why is it a problem? People talk about obesity causing health issues, but how big an issue are we talking about here?

KATHERINE: Yeah, huge problem. We're at about 42% of the U.S. population, and the estimate is that by 2030 we'll be at 50%. The worldwide numbers are going up as well. It's not just an aesthetic thing. It's not just a physical issue. Obesity, in and of itself, is a disease that's incredibly hard to treat. Additionally, obesity is related to at least 200 other weight-related health complications. Think of all the leading causes of death. Heart disease, many types of cancer. Literally, in every single specialty or every single organ system, there are many different conditions that are either caused by obesity or worsened by obesity.

SPENCER: When we learn more about things like cholesterol, often at first, we kind of have a simple model of cholesterol being bad or something like that, and then science studies it more and gets a more nuanced model. Well, maybe it's not the cholesterol per se or different types of molecules or whatever. It evolves. And what has happened with our understanding of obesity? Is all obesity equal? Are there certain types that are actually worse in terms of health outcomes?

KATHERINE: Oh my gosh, I love talking about all this, Spencer. I could literally talk to you for hours. You have such good questions. Yeah, so we're still learning more. There's a lot we don't know. The old kind of simplified definition of obesity was body mass index, which basically takes a ratio of height and weight squared, and that gives us a number. That number doesn't tell us anything about body composition and someone's metabolic profile. It just gives us a very crude estimate of putting someone in the overweight category or in the obesity category. But there's been a long debate in our field about whether there is such a thing as healthy obesity. This is still hotly debated. We know obesity is not just a disease. There are different types of obesity. It's like cancer. It's not just one kind of cancer, and you don't use the same medication on every kind of cancer. Obesity is really different from person to person. Part of it is where people store their fat. Sometimes fat is much more what we call metabolically active or dangerous than other kinds of fat. If you think about people who are more apple-shaped, they have more fat in their upper body. That's much more dangerous than people who are more pear-shaped. It's mostly that the fat around organs, what we call visceral fat, is more metabolically active, and that leads to greater amounts of or greater burden of disease.

SPENCER: Is the issue of fat around the organs more so than fat that's near the skin?

KATHERINE: Yes, in general, yes, absolutely. So visceral fat is more metabolically active and dangerous, but then there are other nuances too. Some fat is more inflammatory than other fat. It's really healthier fat versus sicker fat. We call this adiposity, adipose tissue, and obesity is when adipose tissue leads to other medical problems. It's not just having adipose tissue. You can have tons of adipose tissue and be in the obesity range in terms of BMI, but maybe you have zero health complications from that. That's a very different picture than someone who has the exact same BMI, but their adipose tissue is in more dangerous places, and it's more metabolically active, and it's releasing more cytokines or what we call adipokines that cascade and lead to other diseases.

SPENCER: Is it basically our genetics in the body, where you store your fat and how bad your fat will be, or could someone who gains fat eating healthier food have healthy, less dangerous fat? What controls this stuff?

KATHERINE: Such a good question. It's multifactorial. Yeah, genes play a huge role. Think about families. A lot of families have people with the same shapes. But many different aspects in terms of genes and environment play into this.

SPENCER: So actually, your behavior could change where the fat is stored. Are different foods stored differently? Does exercise cause fat to be stored differently with the same amount of fat, or maybe the answer is it's not known? I don't want to put you on the spot.

KATHERINE: No, I just don't know if we know that.

SPENCER: Yeah, yeah.

KATHERINE: But I love that. I just don't know if we know.

SPENCER: Because you sometimes will hear from people, influencers and stuff who might be more on the heavier side, but they exercise a ton. They're clearly very active, et cetera. And they're like, "I'm healthy. I go to the doctor. They give me a clean bill of health. I don't need to lose weight." It sounds like there can be people like that, depending on the way their fat is stored. But maybe you don't — you're kind of lucky if you get that, if it happens to be stored in that way, is that right?

KATHERINE: Absolutely. There are, again, taking two people with the same body mass index. Think about someone who has a lot of unhealthy fat and someone who has that high body mass index because they're all muscle. Football players are all in the obesity category. So it really comes down to the health of your fat and the location and all of those other characteristics.

SPENCER: Can you compensate for being obese with exercise, or are you still going to be bearing all the risk from obesity?

KATHERINE: I love talking about exercise. Exercise in and of itself doesn't really help so much with weight loss. The average number is about 1% or 2%. What exercise does, and why exercise is so important, is that it helps in many different ways metabolically and in many different ways when it comes to muscle. If you take a look at insulin resistance, which is another topic I'm happy to discuss, exercise actually makes your body more sensitive to insulin. It's one of the treatments for insulin resistance, which is a vicious cycle with obesity. Also, exercise really helps with the health of your muscles. Everyone talks about how with weight loss, "Oh, you lose so much muscle mass." We don't care as much about the muscle mass for different reasons. We care about the health of the muscle. If you lose all this volume but go from having unhealthy muscle to healthier muscle because you're exercising, you may be in a way better position than without the exercise. Exercise is such an important part of any weight management, cardiometabolic plan.

SPENCER: I don't know if I've ever even heard of someone talking about the health of a muscle. Is that different from the strength of a muscle? What is the health of a muscle?

KATHERINE: Think about when you eat. This isn't a great metaphor, but think about when you eat steak and you have steak that's really marbled with fat and steak that doesn't have as much fat. Muscles are the same. Fat is stored in muscle, and that's not a great thing. If you go from your high weight and have less healthy muscle, meaning it doesn't work as well as it should, it's metabolically different from muscle that doesn't have that fat. That's sort of what we're talking about. There's a big study going on right now out of the University of Kansas. Researchers are John Jakicic and Renee Rogers. They are brilliant. If you want to have them talk about exactly this topic, they would be wonderful. They're doing a study to see what exactly happens with muscle as people lose weight because right now there's almost fearmongering, "Don't go on GLP-1s because you're going to lose all your muscle mass." That happens no matter how you lose weight; it's just that GLP-1s generally lead to more weight loss than other ways of losing weight. What we're looking at more now is function and health rather than just mass.

SPENCER: Yeah, some people have expressed concerns that maybe people lose more muscle mass on GLP-1s. Is that unfounded? Is it basically just any weight loss you lose muscle? GLP-1s are just a form of weight loss. That's it.

KATHERINE: We think, yeah.

SPENCER: Yeah. And should people even worry about that muscle loss? Some people say, "Well, you should eat a higher protein diet. You should do more strength training when you're losing weight, whether on GLP-1s or any form of weight loss." Is that a smart thing to do to help compensate for that muscle loss, or does it not really matter?

KATHERINE: No, it's always a smart thing to do for health. I would say most people are talking about it wrong, and there are a lot of nuances. We talk about exercise with our patients not in terms of weight loss, but in terms of two main benefits. Exercise is really important to help keep weight off. When people lose weight, the metabolic rate slows down. All of these things. Doing more exercise really helps people keep weight off long term.

SPENCER: Is that because of burning calories during exercise, or because it somehow changes their metabolism, or something else.

KATHERINE: Both. It's changing the muscle itself, but also helping with the metabolic rate. Exercise is really important for keeping weight off, but also just for overall health. I'm not encouraging my patients to exercise as they lose weight because I want them to hold on to as much muscle as possible. We used to talk about that a little bit, but you're going to lose this much muscle. We want to make sure that your functional ability, think about grip strength, think about daily function, is still preserved as much as possible instead of thinking about not losing all your muscle.

SPENCER: Who should be on GLP-1s?

KATHERINE: So I love this. Right now, there is this belief that it's GLP-1s or nothing. Every single patient who comes to see any of our healthcare providers comes in and says, "I want this. This is exactly what I want." We have to do a fair amount of education to explain that yes, GLP-1s are these amazing medications and for the right people in the right circumstances, they can be wonderful, but it's not GLP-1s or nothing. We have a whole armamentarium of different obesity treatments. It's so much more than just getting a prescription for a GLP-1. It needs to be an appropriately selected patient. The medication needs to be managed appropriately, and it needs to be part of comprehensive care because obesity is so complex. If you are a healthcare provider and see someone who's like, "Hey, I have obesity, I want to be on a GLP-1," and you write a prescription, that's a tiny fraction of what constitutes good care. It's important to understand all the different factors and address those factors. Another is to try other medications first. We have other medications, and most of the time, people are just jumping right to GLP-1s without even seeing if they're a responder to something that may be way less expensive or have secondary benefits. It's a much bigger topic than just putting everyone on a GLP-1.

SPENCER: Got it. So on the one hand, sometimes they come in, and actually GLP-1s are not the best treatment for them. They could be on another medication that maybe helps with some other issue they're experiencing. On the other hand, you're saying in addition to GLP-1s, they might need other care. Maybe they have other issues that need treatment, that kind of thing. Is that the idea?

KATHERINE: Yeah.

SPENCER: So who should make the cut though? Okay, they should be on a GLP-1? Can you talk about what kind of criteria you think about?

KATHERINE: Yeah, you're right. That was a very nice way of saying, "Oh, you didn't answer my question." Yes. Who should be on a GLP-1? People who we think of as more appropriate for GLP-1s are maybe people who've tried and failed other treatments first. People who have a much higher body mass index. If you think about someone who needs to lose 30 to 40% of their body weight to improve their health, that's someone who's likely not going to be able to do that with a couple of medications that lead to 5% body weight loss. The numbers just don't add up. So people with diabetes, and then there are all of these other indications now that we have seen come through as FDA approvals, and that will be coming. For example, sleep apnea. GLP-1s have been proven to be the best treatment for sleep apnea, which is really revolutionary. Cardiac disease: we have what we call cardiovascular outcome trials, and we now know that we can reduce someone's cardiac risk when they have established cardiovascular disease by a very significant amount. So it's really obesity that's a bit more complicated in terms of the extent of the obesity or the medical complexity of the obesity, and then these other certain indications where we have clinical trials that have proven that GLP-1s are really good for that condition.

SPENCER: So suppose a woman in her 20s was 130 pounds, and then she kind of ticked up over the years, and she's at 145 pounds. She has tried diet and exercise and hasn't been able to keep it off. But it's only 15 pounds. She's in good health; she doesn't have any bad health indicators, but she just wants to get back down to 130 pounds. Suppose she can afford it; she doesn't mind paying for it. Should that woman be on GLP-1s, or is there a reason she shouldn't do it?

KATHERINE: The way I talk about this is that with any medication, there's a risk-benefit. With any medical treatment, there's a risk-benefit. If you take one of my patients who has obesity and multiple weight-related health complications, on average, the risk-benefit profile looks very different. If you take someone who is young and healthy and only needs to lose five pounds, and is doing it more for appearance than for health outcomes, then the risks associated with these medications, which generally aren't so significant, but that risk-benefit profile looks very, very different when they're not getting massive health gains. The other thing is that the medications haven't been studied in that population, so we just don't even know.

SPENCER: Let's talk about the risks. So let's start with the most common risks. They're not so severe. So gastrointestinal stuff. What kind of issues do people have, and how common are they?

KATHERINE: The most common side effects are gastrointestinal. Patients will describe that being on a GLP-1, they fill up much faster. It takes a smaller amount of food to get them to feel really full, and sometimes feeling extremely full can end up feeling like nausea. Sometimes that can feel like heartburn. Think about eating a huge Thanksgiving dinner. It's that kind of discomfort that is the most common and can generally be controlled by starting with a very low dose and increasing very judiciously, slowly as tolerated and as needed. Most of the time, we're seeing these side effects when people start on a dose that's too high and titrate up too quickly, or aren't given the education to eat differently to tolerate the meds. Sometimes people have diarrhea. Sometimes people have constipation. Those things happen, but yeah, mostly gastrointestinal.

SPENCER: My understanding is in drug trials, you occasionally have people quit the trials from these symptoms, but not that often. Is that right? They're annoying, but they're not so severe that many people quit from them.

KATHERINE: It's a really interesting topic. With clinical trials, they have to follow a protocol where even if somebody is losing weight really quickly or having side effects, the way the trials have been designed is that you have to get up to the highest dose and then stay on that dose.

SPENCER: That's not a good indicator of how often people want to stop taking them because they feel pressured in the trial.

KATHERINE: People have dropped out of trials because they're literally losing too much weight with some of the newer meds, or they're just so powerful they're having side effects. The trials are now kind of designed differently because of all of that. People dropping out, if someone has mild diarrhea or they're constipated and they can control that, people are generally just so happy that they're finally losing weight if they've never been able to. The bigger issue with clinical trials right now is the placebo arm. People know they are not getting the active drug and they drop out. It's really hard to do these trials these days because why would people want to be in a clinical trial and be on placebo if they can be on a real GLP-1 and not waste their time with that? So that's been a big issue.

SPENCER: Interesting, but in your experience, do most people, few people who take these drugs drop out from the side effect profile? Is that right?

KATHERINE: I would say in my patient population, that's true, but when you look at the numbers after one year, maybe 30% to 50% of people are still taking them, and there are many reasons for that.

SPENCER: Yeah. Why? Is it costly? What's going on there?

KATHERINE: It's everything. So cost issues, loss of insurance, side effects, many of which can be avoided or mitigated with proper education and support. It's not having the education that once you lose the weight, you need to stay on the medication, and people think, "Great, I lost all the weight, I'm stopping," and then they regain it eventually. So many reasons, but that's been a huge issue that people aren't talking about enough. This idea of adherence and persistence are really important numbers to look at in terms of the success of a practice or a program, so we do so much to make sure that we don't start medications until someone really understands they have to be on them long term, and we do everything possible to avoid side effects and keep educating people that they need to be on them. So yeah, the numbers are really bad though when you look at the general population.

SPENCER: What about more serious side effects or rarer?

KATHERINE: Pancreatitis is a serious side effect. Pancreatitis is basically an inflammation or infection of the pancreas, and that can be life-threatening. People often need to be hospitalized, and it can be very severe. That is a rare thing that happens, and usually people have other risk factors for pancreatitis. So we would screen people for, have you had pancreatitis before? People who drink a lot are at higher risk. People who have very high triglycerides. So those people would not be great candidates. Otherwise, I would say the most severe side effects you hear about, and there's so much GLP-1 side effect hype that's happening right now, are diverticulitis or small bowel obstruction. Those are often situations that would lead to someone being hospitalized. Those kinds of things, though, don't just come out of nowhere. Somebody needs to be constipated, not going to the bathroom for several days before they have a bowel obstruction. So again, it comes back to the education that this could happen, so try not to get constipated if you are starting to do this and this and this, and reach out to your healthcare provider if you're having these issues. So I would say those are most of it. Sometimes people get really dehydrated, and if they're not eating...

SPENCER: They eat less food and just so take less moisture.

KATHERINE: So it's a variety of different things. Sometimes, when people are much less hungry, they also feel less thirsty. So people may not be keeping up with enough water intake. But if people are having diarrhea from the medication, and that's often because of certain things they're eating, then they could become so dehydrated that that could impair their kidneys, or there could be other complications of the dehydration.

SPENCER: What about gallbladder issues? I thought that was happening for some patients.

KATHERINE: It's more a factor of just the weight loss itself. In fact, when people have metabolic and bariatric surgery, they take medication for the first six months to prevent gallbladder issues because that's just kind of what happens in your body when people lose weight. We're seeing more gallbladder issues now because people are losing so much more weight, and they're sometimes losing faster. So that's a bit less to do with the GLP-1 itself, and more the weight loss.

SPENCER: People hear these different words, like tirzepatide versus semaglutides. Help us understand the difference. My understanding is Mounjaro and Zepbound are tirzepatide. Is that correct?

KATHERINE: Yes, tirzepatide, not -tides. When you get into the "s" at the end, semaglutides, that means peptides compounding stuff generally.

SPENCER: Okay, that's a different thing. Okay, and then Ozempic would go by semaglutide.

KATHERINE: Yeah.

SPENCER: So what's the difference between those classes of medications?

KATHERINE: Semaglutide was the first really effective kind of weekly GLP-1 medication that we've had. It was approved in 2017 or 2018 for diabetes as Ozempic. Ozempic is the exact same thing as Wegovy. Wegovy is the same semaglutide, but with a slightly different dosage. It was FDA approved in 2021 for obesity. So the same thing, but different indications. The indication for obesity is associated with 15% total body weight loss. So when Wegovy came out, it was like, "Oh my God, this is mind-blowing. What tirzepatide is, is not just the GLP-1 like semaglutide. It's actually two of these gut hormones, GIP and GLP-1, and they work together to create even more weight loss and generally fewer side effects. So tirzepatide, which was FDA-approved in 2022 as Mounjaro for diabetes and in 2023 as Zepbound for obesity, is associated with over 22% total body weight loss.

SPENCER: So it seems like it's an improvement on the older drugs. Is there a reason to take Ozempic or Wegovy today, or should you just always be doing Zepbound instead?

KATHERINE: Oftentimes, honestly, it comes down to insurance coverage.

SPENCER: Okay, got it.

KATHERINE: People ask this question a lot. We don't yet have a cardiovascular outcome trial for tirzepatide for obesity, and we do for semaglutide for obesity.

SPENCER: The better, basically, the older drugs have better data — so we can understand them better. Something people worry about is what it's like long term, because, as you mentioned, if you go off the drug, you tend to regain the weight. I was talking to one doctor about this, and she said that she's been experimenting with maybe after they hit their goal weight, they can reduce their dosage. What is current evidence for this? Can you go off completely? Can you reduce your dosage, or do you basically have to stay on the same dosage once you hit your goal weight?

KATHERINE: Yeah, that is also a hard pill to swallow. Obesity is a chronic disease, just like other chronic diseases, where if you're on medication for depression, if you're on medication for blood pressure, if you stop that medication, you expect that what you're treating won't be treated anymore. We now have clinical trials showing very clearly that when you stop a medication when you get to your goal weight, you regain most, sometimes all, sometimes even more than that. Sometimes it starts happening right away. Sometimes it doesn't happen for a little while. But I would never start medication for someone who is like, "Oh, thanks. I'm not going to take this long term. I'll get to my goal weight and then stop," because they're going to have problems.

SPENCER: Have there been studies that tried lower doses once they hit their goal weight, or is that just an experimental thing that we don't know much about?

KATHERINE: So, the short answer is no. Certain things work for different people, but if someone is adamant that they want to stop or reduce the dose, I'm happy to support them through that. But I give them very strict guidelines on if you gain this much weight, if you're this hungry, let us know, and we're increasing the dose or restarting it. So it's not something that I generally recommend unless a patient really wants to do it, and we don't yet have studies showing that different protocols, whether reducing the frequency or reducing the dose, actually work.

SPENCER: So basically, then it sounds like it's a lifetime commitment for these patients if they want to stay at a goal weight.

KATHERINE: Yeah, but it's a chronic disease, so of course it is. The way I talk about it is, if you have high blood pressure and you go see your primary doctor, they put you on medication. Three months later, when your blood pressure is beautiful, and you go see your primary, they're not going to say, "Oh, great! We've solved the problem. Stop your blood pressure med." They'll say, "Great, the medication's working. Keep taking it."

SPENCER: Yeah, I think a lot of people, and maybe this is just unrealistic, but they dream about, "Okay, yeah, I'll start the blood pressure medication, but then I'm going to do more exercise, and I'm not going to need it anymore." But maybe it often doesn't pan out that way. Maybe the same is true of obesity. They say, "Oh yeah, I'm going to start eating differently now that the drug helped me have better eating habits." But you're saying in practice it doesn't really work.

KATHERINE: For most people. That being said, if someone goes off the medication and they spend their life eating nothing and exercising all the time, sure.

SPENCER: What about long-term health? Obviously, it's a relatively new drug. Is there a fear that if someone's on it for 10 years, 20 years, something could manifest that's really bad that we just don't know about? Is there any reason to think that it could be the case?

KATHERINE: Yeah, we don't have reason to suspect that, but anything could happen. And this is another reason why I talk to every single patient before I start a medication like this about the risk-benefit profile. For someone who's taking medication to lose five pounds, it doesn't look so good. But if somebody really needs this medication to resolve their sleep apnea, improve their cholesterol, improve their arthritis, reduce their risk of heart disease, is it worth it if they have some kind of mild side effect in 30 or 40 years? Maybe it's really such an individual decision.

SPENCER: You hear all these silly gossip things about, "Oh, that person has an ozempic face," or whatever, as though these drugs are doing something different to the body. Do we have any indication that it's doing anything different than normal weight loss? Do we see biological changes that suggest, "Okay, no, this is putting you in some different kind of state?"

KATHERINE: Yeah, I would say that it's most likely mostly the weight loss, but there could be things that we learn that we don't know right now.

SPENCER: Oh no. It's like you just can't tell for sure. But it does seem like for people who are in the high obesity category, it's so dangerous being in that category from a heart health and other health standpoints. As you point out, this possible unknown is not that big a fear relative to the very well-known fact that you're shortening your life basically unless you find a way to lose weight.

KATHERINE: Yeah, I love talking about how when people ask, "Oh, what are the risks of GLP-1s?" It's like, "Okay, well, what are the risks of not treating obesity?" I think people don't factor that into their decision-making.

SPENCER: Are you familiar with good data on the number of years that people are losing from being in the high obesity category on average?

KATHERINE: Yes, I can't remember the exact numbers, but it's something like with a BMI over 40, I think people live maybe five to 10 years less. But yes, there's definitely well-studied data showing that at different BMI categories, people live shorter lives by X amount.

SPENCER: I wonder if the health span numbers are even worse, where it's one thing to reduce the number of years, but another thing the number of healthy years, where you can be in good health and can function well. That's a whole other factor.

KATHERINE: Totally.

SPENCER: Since the tirzepatide has come on the market, that kind of suggests this technology is advancing. Do we have reason to think that it's going to be even better in a few years? Are there going to be even more effective drugs with fewer side effects and so on?

KATHERINE: Oh yeah. So there are hundreds of medications in development, literally, probably thousands, but hundreds that we know of. Yes, there is so much going on right now, and the pipeline is just so exciting. So what to look out for is other mechanisms and combination mechanisms. Just like I said, trizapetide is two different gut hormones, whereas semaglutide is just one. There's a new medication coming out that's three different ones, and then different hormones in different combinations. So that's one thing that will potentially help tolerability, so fewer side effects, and improve efficacy, so greater amounts of weight loss. Other developments are more oral options as opposed to injectable options, longer half-lives. So we're looking at monthly. Maybe at some point we'll have quarterly shots, or maybe we'll have a shot that can be given every year. So those are the kinds of meds that will be coming out in the next several years, and we're really excited about.

SPENCER: Some people who take them have reported psychological effects. One of the most common that I've heard, just anecdotally, is that their food noise goes down. Where throughout the day they might be thinking about food all the time, and now they kind of stop thinking about food. What do we know about the psychological effects of these drugs?

KATHERINE: Yeah, it's really interesting. So many of my patients will say to me, "Oh my God, I just didn't even realize how much of my brain capacity was taken up by food. You wake up, you think about what you're eating for breakfast. While you're eating breakfast, you think about what you're eating for lunch," and so we kind of coin that food noise. People will literally describe that they have so much more brain capacity to do other things, and they feel such a sense of freedom. In terms of generally more psychological effects, I would say more often than not, people's mood improves, but sometimes we see people get more depressed. There was a question about suicide, but I think that's largely been debunked. But it's tricky. When you take a look, we have much more data on the bariatric surgery population because it's been around for so much longer. You do sometimes see more depression after people lose weight because there are so many complex feelings about body image. People think that when they lose weight, everything is going to get better, and then they lose all the weight. One, people treat them differently, and they're trying to grapple with what that feels like. And two, it doesn't make everything better. So there's a lot of data in terms of depression after bariatric surgery or alcoholism after bariatric surgery is a little different, but we screen all of our patients for mental health conditions, and we track how people are doing before, as they're losing weight, and then afterwards, when they're maintaining. Just because everything is so interrelated and so complex, it's important to really individualize how we're treating our patients.

SPENCER: Some people have made the speculation, or maybe there's data now to suggest that these medications may be acting on the reward center of the brain in some way, so that it's not just merely about food, but it could influence other rewards. Is there data to support that?

KATHERINE: Yes, really exciting. I can tell you in my patient population what I see, which is kind of fun. But yes, these medications are being investigated for all sorts of different indications. One of which is addictive behavior, so alcohol and other forms of addiction. That would be huge because we just don't have great treatments for many forms of addiction.

SPENCER: Got it. So, would you say it's still in the speculative stage where we don't quite know whether it will work for these kinds of other indications? But maybe it's promising.

KATHERINE: Yeah, I would say we don't have the data right now to say yes, but we're seeing a lot of signals that things are looking promising.

SPENCER: Is there a concern that if it's actually in the reward center, it could make people enjoy things less broadly or produce anhedonia?

KATHERINE: Definitely. I've seen a lot of articles in the news about that. I see that in my patients. Some patients are so happy that they don't have all this food noise and they're finally losing weight that it doesn't bother them as much, but some people are really bothered by the fact that they find less pleasure in eating, and so that's a big one that comes up. I would say the most, but there is a lot of hype right now about what else is less rewarding, from shopping to any kind of pleasure, a lot of different things. I think we just don't have the data on this as much, but absolutely, the pathways in the brain are totally overlapping with all of this.

SPENCER: Are there any other indications that people are testing for that are promising?

KATHERINE: Yeah, Alzheimer's, Parkinson's. There's one trial that's looking at multiple medical outcomes. That's the tirzepatide trial. Yeah, fatty liver. So what we call MASLD or MASH. There's a medication that likely will be approved very soon that has a MASH indication. Actually, Wegovy has a MASH indication. Kidney disease, different kinds of heart failure, arthritis, as we talked about, addiction. So yeah, tons of different indications.

SPENCER: And are most of those operating through weight loss. Because we know weight loss improves lots of health outcomes, or are they actually saying no? Even in a population that's above and beyond the weight loss, we think that it's going to help with these things.

KATHERINE: So above and beyond, When you look at the cardiovascular outcome trials, you see improvements in other markers before people even really start to lose weight. Some of that is inflammation. We know that these medications are anti-inflammatory, and then there are other pathways.

SPENCER: If we turn to this, this research needs to be done. There's still a lot of data we don't have, but if it turns out well, it almost feels like these are wonder drugs. You always want to be super skeptical and be like, no, there's no drug that's really that good. But if there was a drug that worked on all these mechanisms at once, should a third of the population be on these things?

KATHERINE: Maybe, yeah. I can definitely see that happening in the next decade or so.

SPENCER: If we just consider obesity alone, just that indication. What percentage of the population could benefit? We talked about 40% being obese. Does it make sense that a substantial fraction of those people would be on it just for the health benefits?

KATHERINE: I think right now, as we talked about, one of the biggest barriers is access and coverage cost. So many more people could benefit from these medications than actually have access to them. As I said, there are other medications that treat obesity and other treatments for obesity. It's not that everybody with obesity needs a GLP-1, but I would say way more people could benefit than those who are actually receiving treatment right now. And it's also not just obesity. If you take a look at the indication from the clinical trials, it's changed a little bit now, but historically and classically, it's been a body mass index over 30 or a BMI over 27 with at least one weight-related health complication. When you take a look at our population with overweight, that's about 80% of the population, and most of those people have at least one weight-related health complication. So it's like everybody.

SPENCER: That's wild to think about that we could be living in a world where eventually a large fraction of the population is on these. Should we expect that the cost will fall a lot? If there are 100-plus drugs in the pipeline, will that create a ton of competition? And then, in a few years, maybe the cost is a tenth of the price. What do you think?

KATHERINE: Yeah, a hundred percent. In the next couple of years, I think we'll be seeing quite a bit of movement. Unfortunately, not as quickly as we would like, but yes.

SPENCER: Yeah, because it takes so long to do this research. Is it 15 years to market from drug development, or 10 years to market?

KATHERINE: Something like that, and billions of dollars. Yeah.

SPENCER: One thing we didn't talk about that might be good to discuss before we wrap up is just the effects on society when it comes to beauty. I know this is outside of the medical realm, but in a world where you can take a drug and get thin, what do you think that does to the perception of beauty? Do you think that we already have people saying, "Oh, someone's obese, that's their fault," and people think badly of them? If all it takes is a pill, how does that change people's perception?

KATHERINE: Exactly. There are new forms of bias that we had never had before. There's always been a tremendous amount of weight bias, stigma, and discrimination, and it's mostly been, "Why is this person not losing weight?" Now that we have highly effective, powerful medications, the question is often, "Why is that person not taking a GLP-1?" It's changed quite a bit. Yes, I think we're seeing this in media and Hollywood. Everyone is taking these. People are so skinny now. If you walk on the Upper East Side in New York City, people look different. It's pretty crazy the extent of the effect of this.

SPENCER: I've seen some people have a really negative reaction against these drugs, not based on potential side effects, which is understandable. You could hurt yourself accidentally with them, or you have to buy them on the black market, or just from the regular side effects of the drug. But it's more of a visceral reaction, like this is cheating or it's an unnatural way to achieve this outcome. Do you hear that?

KATHERINE: All the time. That's been any form of obesity treatment because there's this false idea that people can just eat less and exercise more and actually lose weight and keep it off, which we know is a false idea. Our society has promulgated that, and we have our whole diet industry that promotes quick fixes. Absolutely, people always say, "Oh, I feel like this is the easy way out, or it feels too good to be true, and I shouldn't be cheating." You're right. It's like the word cheating, but that's where all the education comes in. I explain to all my patients when I first meet them that obesity is a disease, and it's not a matter of willpower. It's not people's fault, and when someone starts to gain weight, it just leads to more and more weight gain. As we talked about, when people try to lose weight, it's really hard, and our bodies don't let us lose weight. It's really just education.

SPENCER: That model would suggest that it might be extremely worrisome if children get obese because it might make their set point at an unhealthy level, and then the rest of their life they might struggle. Now, okay, GLP-1s can help a lot with that, but is that true? Because my understanding is that more and more children are getting obese when they're quite young, so do you think that might be kind of metabolically messing them up for adulthood?

KATHERINE: So childhood obesity is a huge problem, and it's getting worse. Early intervention is incredibly important. Sometimes people will see a child who has excess weight and just say, "Oh, they're going to grow out of it," but childhood obesity — you don't grow out of it. Childhood obesity is very, very, very strongly correlated with adult obesity. So early intervention is so incredibly important, and even medications. A lot of the medications are FDA-approved down to the age of 12, and it sounds crazy to think about giving a kid an obesity medication, but if you have a child who is 50 pounds overweight and they've tried every diet and they have sleep apnea and they have arthritis and they have heart disease or diabetes, what are you going to do? It's a risk-benefit.

SPENCER: What do we make of the rare but existing people who are, you know, I was way overweight for years and then I got my act together, I totally reformulated my diet, and now I've kept the weight off ever since. I lost 70 pounds, I've kept it off ever since, and it's been 10 years, 20 years. Should we just think of them as unusual outliers, that they're the rare person that can do this and everyone else is sort of stuck? Or how do we think about this?

KATHERINE: Exactly, outliers.

SPENCER: Yeah, they're just unusual. And would you say it is really different? Some people, you know, because there are a lot more people who are, "Yeah, I was 10 pounds overweight. I lost it. I kept off that 10 pounds." That seems like a much more common scenario, right?

KATHERINE: Yes, a hundred percent. So what you're alluding to is that there is a distinct pathophysiology with obesity that basically leads to greater levels of obesity. So weight gain kind of leads to weight gain, leads to weight gain, and it's really the pathophysiology of obesity that makes it so much harder for people to lose weight. So if someone puts on 10 pounds and then they lose that 10 pounds, that's not what we're talking about. Whenever people ask me what I do, and I tell them, they're like, "Oh, I don't believe any of this stuff. I once gained all this weight and lost it, and I've kept it off." It's like, okay, well, you don't have obesity. It's totally different.

SPENCER: We're talking about people whose set point has been set at a much higher weight from years of being at that weight, and now their body's kind of fighting it. Is that view controversial, still being debated, or is that settled science from your point of view?

KATHERINE: From my point of view, this is what I've devoted my career to, and what I understand so well. We've really proven this, especially, the new medications have helped to prove our point. That we actually have a treatment that can target these dysregulated hormonal pathways with something that actually works. So yeah, it is. I think that there's, again, so much weight bias in our society that some people will just never wrap their heads around it. But when people have experienced this themselves, or when they have family or friends who they're watching just struggle so much, trying every way to lose weight and have spent a lifetime losing and gaining and losing and gaining and blaming themselves. This education comes in different ways for different people at different times, but there will always be people who are like, "That's just, you know, why don't your patients just eat less? And why are there all these medications that are cheating?"

SPENCER: Is there a competing scientific theory to the kind of set point theory that we've been describing?

KATHERINE: Not really. This is understanding the biology of obesity. This is how it works.

SPENCER: That's fascinating. It's very different than most people think. I want to research it more. Before we wrap up, Katherine, what do you want people to remember from this conversation?

KATHERINE: Oh my gosh, hard to sum it up in a sentence or two. Really, just that obesity is a disease that requires medical treatment for most people. It's not people's fault, so don't judge people. And if you're struggling with obesity, there are effective treatment options when lifestyle interventions haven't worked.

SPENCER: Thanks so much for coming on the Clearer Thinking Podcast.

KATHERINE: Thank you so much for having me, Spencer. I really enjoyed talking to you.