ZOE Science & Nutrition - Obesity and the new science of weight loss | Dr. Louis J Aronne

Episode Date: June 27, 2024

Obesity is a physiological condition that can be managed with the right education and treatment. In today's episode, Dr. Louis J. Aronne, a leading expert in obesity research, sheds light on the science behind weight management and obesity treatment. Dr. Aronne dives into groundbreaking weight loss medications. He also explores how lifestyle and eating habits affect long-term health and why medications combined with dietary changes can unlock transformative results. Louis J. Aronne, M.D. is a leading authority on obesity and its treatment. He’s a former president of The Obesity Society, which publishes the peer-reviewed scientific journal Obesity, of which Dr. Aronne is an associate editor. He has also authored more than 60 papers and book chapters on the topic.  🌱 Try our new plant based wholefood supplement - Daily 30 *Naturally high in copper which contributes to normal energy yielding metabolism and the normal function of the immune system Learn how your body responds to food 👉 zoe.com/podcast for 10% off Follow ZOE on Instagram. Timecodes 00:00 Introduction 01:01 Quickfire questions 03:51 What is obesity? 05:06 What’s the difference between overweight and obesity? 07:38 Why has there been such a quick rise in obesity? 10:55 Why it’s not just a lack of willpower 13:50 The complexity of weight regulation 15:54 What is Leptin and why is it so important for weight control? 19:51 The brain’s role in weight regulation 20:36 Curing obesity in animal studies 22:29 Why hunter-gatherers did not gain weight 23:58 Natural experiments in weight gain and loss 26:01 How medications can cause weight gain 28:42 The impact of calorie restriction diets 30:13 Reducing diabetes risk through weight loss 34:10 Research into medications as a tool for weight loss 38:36 How well do weight loss drugs work? 41:38 The future of weight loss drugs 43:51 Will you regain the weight if you stop taking weight loss drugs? 48:08 Can obesity be avoided without the use of drugs? 49:42 Concerns about weight loss drugs Books by our ZOE Scientists: Every Body Should Know This by Dr Federica Amati Food For Life by Prof. Tim Spector Fibre Fuelled by Dr Will Bulsiewicz Mentioned in today's episode: Persistent metabolic adaptation 6 years after "The Biggest Loser" competition in Obesity  The Finnish diabetes prevention study (DPS) in Diabetes Care The National Diabetes Prevention Program of the Centers for Disease Control and Prevention (CDC) Have feedback or a topic you'd like us to cover? Let us know here. Episode transcripts are available here.

Welcome to ZOE Science and Nutrition, where world-leading scientists explain how their research can improve your health. Today we're learning all about obesity and weight gain. When I was growing up, the common belief was that if you gain weight, it's your fault. And if you can't lose that weight, it's also your fault. Those beliefs are not just harsh, they're untrue. Today's guest has been studying obesity for 35 years. And he'll explain why the recent science means that today we are more able than ever to treat obesity. Dr. Lu Erron is one of America's leading authorities on obesity and how to treat obesity. Dr. Lou Aron is one of America's leading authorities on obesity

and how to treat it. He founded the Comprehensive Weight Control Center at Weill Cornell Medicine. And in this episode, he shares his most exciting breakthroughs on long-term weight management. Lou, thank you so much for joining me today. Pleasure. So we have a tradition here at Zoe where we always start with a quick fire round of questions from our listeners, which means we ask you to give us a yes or a no or if you absolutely have to, a one sentence answer. You up for that? Yeah.

Fantastic. All right. If I can't lose weight despite trying, is it my fault? No, never. Is exercise likely to lead to weight loss? Exercise rarely causes weight loss. Can gaining weight trick my body into gaining even more weight? Yes. Do these new weight loss drugs work? Absolutely work. If I am using a weight loss drug, can I eat whatever I want? No. And finally, you have a whole sentence on this. What's the most surprising thing you've learned about weight gain in recent years? Probably the most surprising thing is that we can control weight completely.

So as I was thinking about this, I was talking with the team who was doing the research, they're basically sharing these extraordinary numbers about the rise in obesity over the last 30 years. And apparently the latest numbers show that more than half a billion people worldwide are living with obesity. And we had a lot of questions from our listeners about weight loss, like why is it happening and how to maintain weight loss if you can achieve it over a long period. And many of these people felt that it was sort of inevitable that it would put on a pound or two of weight every year as they age, and there was sort of nothing that you could do to reverse it. So I think if we look at that sort of epidemic of obesity,

it's clear there's a lot that as a society we have to learn about our body's own weight management system. And so that's something I really want to get into with you. But actually, can we start with like that big picture? What is obesity? Obesity is not what people think it is. Obesity is not what people think it is. Obesity is a disease. When I say a disease, I mean that there is physical damage that occurs in the process of gaining weight that makes it very hard for people to lose weight.

And we've never really thought about that before. I've thought about it, and people who are researchers in this area have thought about it a lot. But if you think about it, why don't people just eat less and lose weight? And the reason that it gets so difficult to lose and why your set point, your weight set point keeps getting higher and higher, is that the nerves in your brain that receive hormonal signals from your fat cells, your stomach, and your intestine that tell your brain how much you've eaten and how much fat is stored, these nerves get damaged in the process of eating highly processed foods, overload those nerves, and as a result, they can't sense how much you've eaten, how much fat is stored. And the default is to keep

raising your weight and filling up fat cells more and more. Could you help to understand that? What's the difference between being overweight, which is I feel a word that people use a lot when I was growing up, and obesity? And how could someone, maybe if they're listening, find out which category they're in? Sure. The difference between overweight and obesity is the magnitude of excess fat stored. And we have formal definitions that are based on the body mass index, which is the weight in kilos over the height in meters squared. You may think it's good or bad. There are clearly

better ways to measure how much extra weight somebody has on them. But the BMI right now is the standard by which we determine a lot of the care we deliver and the risk associated with it. And what are the cutoffs that you use as a doctor there for? For overweight, a BMI of 25 up to 30 is overweight. A BMI of 30 and above is obesity. And then there are subcategories of obesity. There's class one, class two, class three. BMI of 30 to 35 is class one. 35 to 40, class 2. And above 40, class 3. You said that there are better ways to measure obesity, but this is what's being used at the moment. And that's because that's not a direct measure, actually, of the excess weight. Is that why the BMI is not? Sure. I mean, the best example is that people with extra muscle mass may have a high BMI,

but they're not really at risk. And very athletic people, for example, sports figures, have a high BMI, but it's because they have so much muscle mass. Because it's not distinguishing between the weight of your muscles and the weight of the fat that you're storing. That's right. But for the average person, that is true. A way to modify the BMI to get a more careful characterization is looking at waist circumference. In women, if waist is bigger than 35 inches, in men, if it's bigger than 40 inches, then we see that there's additional risk. So if someone has a high BMI, but their waist is very low, let's say a man has a BMI of 32, but they're an athlete, their waist would be less than 40 inches. Got it. And I know Zoe, we often look at waist circumference as one of the

measures to see whether or not health. So I know this is used quite a lot in science. So I'd love to come to that sort of rise in obesity, you know, half a billion people worldwide. This is an enormous, you know, you can't get your head around that number. What's going on? How can that have shifted so much and so fast? People ask me this all the time. I'm sure. The genetics haven't changed. So what's going on? Aren't people just eating too much? And the answer is they are eating too much. But if you look at what happens when you eat food, which is highly palatable, so it is definitely driven by the hedonic urge to eat good tasting food,

meaning it's enjoyable to eat this food. Everybody knows. This is a food that is like, we all know is that every cornucerone just tastes great, even though we know it's not good for us. That's right. Okay. So you think about how hard it was to get food 100, 200, 300 years ago, no less, 1,000 years ago, to find good tasting food was virtually impossible. To find food that wasn't spoiled.

If you wanted to eat meat, you had to go out and kill an animal and then you had to fight off other animals who were trying to eat it before you got it. I mean, really think about what it took to eat food. And a lot of food was spoiled or partially spoiled. So you had to have a very strong drive to eat to overcome that. That is why these systems are so robust. And we joke around and say that Darwin got it wrong, right? He said his theory was it's survival of the fittest. It's actually survival of the fattest.

Help me to understand that. So in a wild environment, the fattest are often the fittest. They will live the longest during a period of famine. Because basically they've got stored energy in this body fat. They have stored energy, even if they have the exact same energy stores as another animal, animals with genes that predispose to obesity will live longer if they go through a period of starvation because they use those calories more wisely, if you will. I want to get into that whole weight management approach. Just one final question, maybe before digging into that in more detail, because you already talked about diet and the sort of ultra processed food and things like that. Is that the entire explanation

for this rise in obesity in your view? Well, we recognize that a lack of physical activity is also associated with it. And so if you can imagine that we have highly palatable food that is readily available and is inexpensive. And then we're not doing much physical activity to burn those calories off immediately. And so we go through periods of calorie excess. And again, what happens? The key step is that the periods of calorie excess damage the critical nerves that regulate body weight. That's what happens. It's not a passive process, which is what people always used to believe.

So it's not under the same kind of willful control that we once thought. And can we talk about that for a second? Because I was definitely brought up that weight was simply a measure of willpower. And I think I was surrounded by all these ads from Coca-Cola about, well, if you just went and did some more exercise, you can drink as much of this fat Coke as you want. In fact, I seem to remember they might have sponsored all sorts of kids' exercise. That was a story that I was being sold. Now, I think the science now says something completely different. Is that right? That's correct. Again, while you could potentially prevent obesity with enough physical activity, it's difficult. And having a diet that focuses on foods that we recognize as healthy, lots of vegetables,

healthy proteins, that makes it a lot easier to regulate weight. So there's weight gain in society is one issue, and then trying to lose weight, those are slightly different issues. Could you just help us to understand a bit, maybe for someone who's not living with obesity, so in a way in this system that you're describing is working as it would have done in the wild. What's going on as I'm eating food that causes me to, I guess, you know, stop eating and what is it that helps me to actually stick to the same weight over time? Because I remember speaking to another scientist who explained that if I even ate just like a few extra teaspoons of sugar every day, then by the end of the year,

I might've put on, I can't remember, like 10 pounds or something. So actually somehow, you know, I'm not measuring how many, I don't believe in measuring calories. I don't, but somehow actually my weight is pretty stable throughout this year. So what is going on there, Lou? Right. So the point that the doctor was making is that if you do the math, eating just 10, 15, 20 calories more per day than your body needs will make you gain a significant amount of weight every year. I mean, 10 calories per day over 365 days is roughly a pound a year. Wow. It's just 10 calories to make a pound, so. Approximately.

So the point is, do people whose weight remains stable actually do that? Do they add up how many calories they've eaten? And the answer is no, they don't. The system regulates itself. It makes you hungrier. It makes you burn up more calories in your muscle. It does something to keep your weight under control. And obesity is caused by a difficulty with that regulatory

pathway. I'd like to share something exciting. Back in March 2022, we started this podcast to uncover how the latest research can help us live longer and healthier lives. We've spoken to leading scientists around the world doing amazing research. And across hundreds of hours of conversations, they've revealed key insights that can help you to improve your health. If you don't have hundreds of hours to spare, no need to worry. At the request of many of you, our team has created a guide that contains 10 of the most impactful discoveries from the podcast that you can apply to your life. And you can get it for free. Simply go to zoe.com slash free guide or click the link in the show notes and do let me know what you think of it.

Okay, back to the show. Could you help us to understand a little bit, maybe starting with it working, which is describing and then helping to understand how it's stopped working. So maybe in my case, I'm not living with obesity. What is going on and where is it driven by? Because you mentioned something about the brain. Well, it's actually incredibly complicated. If you look at pictures that we've drawn, other people have drawn of the weight

regulating pathways, a key point is that there are multiple overlapping systems, multiple hormones and nerves that are all trying to regulate body weight one way or another. And as a result, if one system fails, there's another system to back it up. And this has been part of the problem in getting people to lose weight and maintain that weight loss. So you go on a diet, you eat fewer calories, your body recognizes it, and it sends messages to parts of your brain that make you not feel full. And this is your set point thing that you were saying a minute ago. Like if my set point is 150 pounds, in the short term, I reduce my calories.

I start to lose some weight. I'm at 140 pounds, but my body is desperately trying to push me back up to 150. Sure. That's exactly what happens. But if you ask, how does it happen? I'll give an example. There's a key hormone that comes from fat cells. And it's been shown that with a 10% reduction in body weight, 10% reduction in body weight. So if you weighed 150, if you got down to 135, the level of this hormone goes down 50%. 10% weight loss, 50% reduction. That would be like you're driving around in your car. You're just driving around a little bit and your gas gauge goes way down. You can't tell how much gas is in the gas tank. You may stop and get gas sooner rather than later. We've joked around and said it's like having an electric vehicle and range anxiety.

That's what happens when people lose weight and they have obesity is that they get range anxiety much sooner. And the point is it's hormonally based. It's hormonally based. And so what happens when you run out of this hormone is that you don't feel full. All the other hormones that regulate body weight depend on this one hormone that is a critical co-factor in the brain. It's called leptin, L-E-P-T-I-N. And in the absence of leptin, massive obesity can occur. But normally, in the normal course of living, its role is that with weight loss, gets down to this critically low level,

and all of a sudden, you can't feel full. Circuits in your brain that activate craving, they start getting activated. And so does the leptin make you hungry or the leptin makes you feel full? So leptin is necessary to feel full, but it doesn't actually make you feel full. So it's part of the process. It's part of the weight regulating pathway. But if you're not creating it then, then you can't get full. That's right. So when you think about why don't people just

stick with a diet? Okay, you lost 15 pounds. Things are going great. Why don't you just stay there? Just stick with it. Now we hear this stuff all the time. The reason people can't stick with it is they don't feel full and their brain is telling them to eat fattening food. Those are the kinds of things that can happen. But the key point is it's not a lack of willpower. It's something physical. Something physical is going on. And I'm talking about leptin. It's the best studied example, but there are many hormones. There are literally a dozen hormones and nerves that are all focusing on the same process, and that is to increase how much you eat to restore equilibrium.

So that's completely different from the story that we were all told by everybody around weight loss and nutrition until quite recently, isn't it? Which is that you should just count your calories. You can lose any amount of weight you want if you just make sure that you have fewer calories than you used to. But you're actually describing all of these real physical processes, which are just cutting into basically block this from being able to work. That's correct. What's not correct, though, is we've known about this since the mid-1990s. Okay. That's a long time. People like myself have been working on this. I worked at Rockefeller University where leptin was discovered in another lab.

And so initially we tried to give more leptin to people who lost weight and ran out of it. And it took us 10 years or so to figure out that in addition to not having enough, you're also resistant to it. So if we tried to give it, it just does not work. Could you help me to understand the resistance that you're just describing? So the resistance we think is because of the damage that occurs in nerves. When you think about this set point going up, people develop resistance to a number of the hormones that are regulating body weight. And we think that resistance to this key fat cell hormone, leptin, is part of that process. So your fat cells are trying to tell you that there's

plenty of fat stored. Don't eat anymore. But the nerves are resistant to the hormonal signal. And Lou, when you talk about these nerves, is this specifically in your brain that you're saying this is damaged or is this? This is in your brain. Okay. So there's a very robust, complicated, overlapping system in your brain that regulates your weight. And you were saying that we don't understand it very well in human beings because it's hard to do these studies in human beings,

but there have been a lot of studies in animals that have helped to, I think you called it the hypothalamus. Is that where this is happening or is that? It's a key part of it. It's kind of like the grand central or time square of weight regulation. But there are many other areas of the brain that are also critically important. So it's very complicated. It's not like it's just like one single thing that is in charge of all of this. That's one of the reasons why it's taken so long to understand it, because there are so many different parts of the brain that are responsible for regulating

weight. But again, by looking at what goes on in the hypothalamus, we've been able to see that it's very clear that the damage that occurs there, it can occur in other parts of the brain, but we can actually, by the way, fix it. The reason why I'm so confident that what I'm saying is correct is that obesity has been cured, C-U-R-E-D, by giving certain compounds to animals. What happens is you give it over a period of time, you stop giving it, and the animals maintain their weight. And if you look

at what's going on in the part of the brain where damage was previously seen, the hypothalamus, all of a sudden, they have new healthy nerves in that part of their brain. So the normal signaling pathways have been restored by giving these compounds. And maybe that's the future of treating obesity. But this has been done now again and again. Are these medicines that they're giving to animals now medicines that we're giving to people? Is this the same as the...

This is not the same as these new wet drugs we're talking about. It's not the same as the medicines that we have now, but eventually I'm going to guess that someone will come up with a version that will be successful, will be safe and effective in humans. One thing I'm struck by is I do feel that we all generally feel that some weight gain is inevitable as we age, that we're used to this idea that as we get older, we will put on some weight. I suspect there are a lot of listeners out there who are not living with obesity, but definitely feel that they've been sort of slowly and steadily putting on weight. Is that, in your view, also a consequence of sort of the, you know, the bad food environment and

other things we're living in? Or is there also some sort of underlying shift in this set point that you're describing as we get older, even if we were living as hunter-gatherers in East Africa? Sure. Well, if you look at hunter-gatherers, they don't gain weight over time. They do not. Okay. That's a pretty strong answer. People in Asia, Japan, they gain very little weight over time. It's really Western countries, the UK, the United States, Australia, and now increasingly around the world. So it's the same process.

So that's interesting. So somebody who's just putting on some weight may not even reach your definition of overweight in the sense they're still in that same process that you view as a sort of damage to this natural system. It's not just a natural thing that happens in the same way that, I don't know, menopause might happen. No, that doesn't happen. But when you think about it, so there's a tremendous variability from person to person. And so when we talk about the set point shifting up,

there's variability around that set point. So you could have someone whose set point is normal, but they gain weight for one reason or another. They gain 10 or 15 pounds, but then they are able to get back to where they were. That's entirely possible. I'm not saying that doesn't happen. But then you have other people whose set point shifts up. And virtually no matter what they do, they could not get back to that ideal world. And do we have any understanding about that? Like is there a time or element or something?

So if you put on your 10 pounds for two weeks, then it's easy to still get back. But if you've had it for, you know, a year, then suddenly it's that set point has been reset. Do we understand this? We don't completely understand it, but there actually are some, what I would call natural experiments. So one of the best, it's not studied, but anecdotally has been recognized that if you look at actors who are preparing for a role where they have to gain weight, and there are a number of examples of this in history. So they gain weight for a period of time, and they overeat, and they're told to overeat. They're forced to gain 10, 15. I mean, in one case, an actor gained 30 or 40 pounds for a roll. When they stop eating, all of a sudden their weight goes down.

So when they stop paying attention to that, what happens naturally is they don't eat as much and they lose weight and go back to where they were. And in fact, a number of experiments have been done over the years where that has been done. Overfeeding experiments were done 30 or 40 years ago. We don't do them now because they're seen to be unethical because there's risk associated with gaining weight.

But what would happen when you'd stop the experiment and say to people, okay, go ahead, you're fine, leave the lab. And over a period of three, six months, a year, their weight would go back to where it was before. So if your body doesn't want to gain weight, if it doesn't have the setup to gain weight, if it's resistant to weight gain, then even though you may for a period of time be able to maintain a higher weight, your will come back down again and i guess the counter examples of this that you were talking about is with people living with obesity you were describing i think that um the system is now damaged so what happens in this case so medications can cause weight gain. There are a number of medicines that we recognize cause weight gain. And there are several different categories.

But we have cases of patients who will come in and say, I've been eating the exact same thing. And for some reason, I just started gaining weight. And we'll ask them about their medical history. And we'll find that one of the medicines that we know is associated with weight gain has been prescribed for them. And almost to the day the medicine was prescribed, their weight has been going up, up, up. And they'll tell us that they're eating exactly the same way. In some cases, however, their appetite is increased dramatically or they'll never feel full. Those are other variants.

But the most interesting ones are where people say, I am eating absolutely the same thing, but for some reason, I keep gaining weight. We've seen cases of people gain 20, 30, 50 pounds in one year by being prescribed a medication. That, to me, is a good example of the physical aspect of this. That person, if they had not been prescribed the medicine, I doubt they would have gained that much weight. Maybe they would have gained a pound or two. I understand there's been quite a lot of research into the impact of trying weight loss and that actually trying weight loss with calorie restriction type diets can potentially actually have a negative long-term impact. Can you tell me about that?

So I'm not a big believer in the idea that losing weight for a period of time and then regaining is unhealthy. And again, this is my opinion based on reading of the literature. Why is that? So I understand the counter argument that you can lose muscle mass in the process of losing weight. And then when you gain back weight, you may gain more fat mass initially than gaining muscle mass. If you look at it over very long periods of time, the best study ever done was done in people who were in a television show called The Biggest Loser. And over a six-year period of follow-up, their body composition, they gained back a tremendous amount of weight from their low, but their body composition was basically the same. So muscle came back, fat came back, and it was equivalent. So I believe that over time, these factors re-equilibrate, but fat could come back faster. But if you look at studies

looking at prevention of diabetes through weight loss, there are studies going out 20 years showing that a period of weight loss will prevent diabetes 20 years later. So you go through a period of losing 15, 20 pounds, 7% of your body weight, and then you're out of the program and then you just get followed for 20 years, you're less likely to develop diabetes than if you were in an arm of the study where you didn't do that. So to me, that shows profound long-term benefit. And this has been seen again and again and again. Now 10 years, 15 year, 20 year benefit. And just to make sure I understand that this is because you've managed to reduce your weight significantly. And then even though it may end up going up a bit, it's sort of over this time, it's lower than would

have been otherwise. So you're not saying that because your weight is lower for eight weeks, I think, are you? No. That is giving you the help. So there are studies looking at whether or not you can prevent diabetes with weight loss. And the answer is very clear that you can. And just to give you some milestones, a 5% weight loss has been shown to reduce the risk of developing diabetes over the next five years by 50%. So let me just make sure I've got that right. So if you could reduce your weight by 5%, you reduce your chance of getting diabetes by half. That's right. If you lose 10%, you reduce it 80%. If you lose 15%, you reduce your risk by 95%. So that's amazing. Now, obviously, the challenge of this is actually keeping this weight off. And

I guess that was a bit where my question was coming from, where I understand that in general, the evidence behind just calorie reduction as a way to reduce weight and keep it off is like it works for some people. But on average, most people bounce straight back and many of them bounce back higher, in fact, than where they started. So the evidence is about one third of people can lose 5% or more of their body weight with a dietary intervention. So no matter what study you look at, while there may be some that look a little better, a little worse, in general, one-third of people with any type of dietary intervention will lose 5% or more of their body weight. And what I've always said is,

well, what do you do with the other two-thirds of the population? Tell them, too bad, you're just going to develop diabetes. But I just want to point out, going back to the point I was discussing before, is that if you lose the weight and then you regain weight following that, there's still a reduction in the risk of developing diabetes if you go out 5, 10, 15, 20 years. So if you look at studies, one is called the DPP, the Diabetes Prevention

Program. Another study was done in Finland, another in China. Weight loss occurred over generally a one-year period. Attempts were made to maintain the weight. But in general, over the next year or two, weight was regained by the majority of people in the study. But despite that, there's limited periods of weight loss. And now with medications, we're seeing numbers that go even beyond that. And I'd love to sort of maybe transition. I think you've helped us to understand that obesity is really a disease, that it's having this effect on our brain and how we respond to these different hormones. Now, I know you've done a lot of research on weight loss

medications. I think a lot of listeners will recognize some of these new names like Zempik and Wegovy. And I know there's also a lot of more medications emerging to market. Could you maybe start by just helping to understand how those medications fit into this description of what's going on? So what these medications do is they simulate a hormone known as GLP-1. That's the primary effect of these medicines. It's a hormone, it's short for glucagon-like peptide. It was discovered in the 1980s, and it was shown to regulate body weight much, much later, in the late 90s and early 2000s. But later on, it was shown that it was possible to control appetite as well. One of the key findings in the history of the research on GLP-1 was the recognition

that a lizard that eats once or twice a year had high levels of a version of GLP-1 in its saliva. That's amazing. Yeah, it's amazing. So, you know, researchers wondered, how could this animal just eat two meals a year? So, this all started with some lizard scientists. That's right. Okay. How do you, how does this animal just eat two meals a year? And what they found in the saliva of that lizard was a version of GLP-1 that was very potent and long-lasting.

And that gave the researchers and then pharma companies a path to figuring out how to make a more potent version of GLP-1. GLP-1, by the way, lasts for 30 seconds. The one that we naturally make. The one you naturally make lasts for a minute, something like that. So you eat food, it's released, it's gone very quickly. But a Zempik is basically sort of lizard saliva, is that what you're saying? It's an amplified version of lizard saliva GLP-1.

That's one way to look at it. What does it do? What does it do? What does it do? So there are many areas of the brain that have GLP-1 receptors. And these may be areas of the brain that the GLP-1 that we make does not really affect because the signal is not there for a long enough period. So it may be that these are areas that are not things that are involved in weight regulation normally. But in any case, when you make a very potent and long-acting version, as the new drugs are, all of a sudden, they can access different parts of the brain, different receptors,

and they can overcome the resistance that may exist in the hypothalamus, the key regulating part of the brain as well. And so the recognition now is that these medicines are working throughout the brain in areas where naturally occurring GLP-1 probably couldn't get to before. So it's working, but it's even doing it in a different way. And the net result is that it switches off hunger? It makes you feel like you've eaten. So if I asked you to eat dinner, and then I brought out another dinner and said, have dinner, you would say, I can't. I just ate dinner. Yep.

That's kind of what people describe. But we're now recognizing that it works on other aspects of weight regulation. It may work in some people on the hedonics, on the interest in food. We've seen it work on alcohol intake. And we have patients where when we first started using semaglutide, which is ozempic for diabetes or we go for weight loss, they would say, I don't know what's happening, but I don't feel like drinking. I have two drinks a day every night. Now I don't feel like drinking at all. Hi, I have a small favor to ask. We want this podcast to reach as many people as possible

as we continue our mission to improve the health of millions. And watching this show grow is what motivates the whole team at Zoe to keep up the really hard work of creating new episodes each week. So right now, if you could share a link to the show with one friend who would benefit from today's information, it would mean a great deal to me. Thank you. I know you've been doing a lot of research on this as well as being a physician. So how well do they work? How good do you feel about them for people living with obesity?

You know, like anything that's new, there's a lot of controversy. I think there'll be a lot of people listening to this who feel that they can't really be a good thing because you're ending up in this situation where people are getting so sick because of the food they're eating. And then you're sticking them with a medicine afterwards, but you're not really solving the underlying cause. But what's your experience? So first of all, I've been doing this for 35 years. I did the first study looking for anti-obesity medications in 1989. More than 60 trials of obesity treatments in my career. And it's pretty clear that these are a breakthrough. And this is the beginning of the breakthrough. This is not the end. This is just the beginning. So the breakthrough is not only the level of efficacy, which it's clear people

find is terrific and enjoyable and changes their lives, but also the tolerability of these medications. So we've had medicines that are not quite as effective, but they are effective. The problem was, in many cases, the side effect profile and the risk associated with those medications. But now we have things that are not only effective, but easy to use. One shot per week is pretty well tolerated. And I think that this is a pivoting point in the treatment of chronic metabolic disease, that people are choosing to treat their obesity, which is the cause of their diabetes,

their hypertension, their high cholesterol, their sleep apnea, their knee arthritis, and the list goes on and on. And lecturing these days, I have a slide I made where I've characterized treating obesity as the superman of treating metabolic disease. Literally 200 illnesses can occur as the result of increased body weight. And treating obesity makes them all better to a certain extent. It may not cure them all. Your blood pressure may stay up. Your

cholesterol may not go down. All of those things can occur, but there is no treatment for any of the others that treats something else. But by treating the obesity, you get them all. It may not go away, but it tends to get better. And so I think that we're going to see people choosing to treat their weight rather than wait until they develop all of these complications. And Lou, I know you're also researching a whole set of sort of new weight loss drugs that are not yet available for prescription. What can you tell us about those? Because I understand that they may be better still than the drugs that are available today. Yes. I think that what we're going to see is, on one hand, increasing levels of efficacy.

If we look at the second drug that has been approved in the United States, terzepatide, which is known as Munjaro for diabetes, and in the U.S. for weight loss, Zepbound. That produces even more weight loss than semaglutide, Ozempic, or Wegovi, where those drugs produced about 16, 17% weight loss in the highest dose, terzapatide produces 22, 23% weight loss. I mean, that's amazing. These are enormous numbers. If you look at the next generation of medications, they're going to produce between 25 and 30% weight loss. And in some cases, you know, we haven't finished these studies yet, but I bet they're going to produce even more than 30% weight loss. So these next generations are dramatically better than the sort of

Zempik that we're all hearing about. If this is going to cure this disease of obesity, does that mean that everyone should just continue and can continue to eat sort of all this ultra-processed junk food and they're now going to live as many healthy years as they would do if they were on a different diet? So the short answer is I don't believe so. But when you use these medicines, it helps people to comply with a diet. I think that's really powerful. It's one of the things that I've been wondering a lot about because we know how much challenge there is for a lot of people to be able to manage what they're eating. Right. So not everybody is going to do that. But we work with registered dietitians. They love these medicines because they say, finally, my patients listen to my advice.

I tell them to eat healthy proteins, vegetables. We work out a plan. And they're like, oh, yeah, I can do that. It's not a problem. And Lou, one of the things I understand is basically you have to keep taking these drugs forever. If you stop, then you will go back to that set point you were describing. Is that right? And is there any evidence that you might be able to shift your diet while you're on these drugs towards something much healthier and that then you might, you know, for example, you know, be able to come off them and not sort of shoot back to where you were before? Not everybody gains all the weight back.

About one in six people can maintain at least 80% of the weight loss. So if they lost 20% of their body weight, they could maintain at least 16% or greater weight loss. And if you look at the rate of weight regain when you stop a medicine like this, it's roughly 1% to 2% of the initial body weight regained each month. We just published a study where we got patients on terzepatide. They lost 21% of their body weight over nine months. And then we either continued the medicine for a year, in which case they lost another 5% of their body weight,

or we stopped it for a year. And over that one-year period, they regained 12%, 1% per month of the initial body weight. So they were still down between 9 and 10 percent one year after stopping the medicine. So what my conclusion from studies like that is that you could use it intermittently, perhaps. Take it for a month on, a month off. I think that those kinds of strategies will be used. There are studies now showing that semaglutide, as Wegovy, reduces the risk of a heart attack, a stroke, and death by 20% in people who have heart disease. That's just like using a statin drug. But in addition, it also reduced the risk of developing diabetes by 73%.

And that's because these were people who were living with obesity, and then that was such a high risk, and you'd take that away. That's right. So they did not have diabetes. They didn't have diabetes when the study began. So in addition to getting the reduced risk of heart attacks, strokes, and death, you also got a reduced risk of diabetes. You also got a reduced risk of diabetes. You also got a reduced risk of developing kidney failure. And so they sound pretty magical when you describe this. I think a lot of people listening to the same, well, that's great, but I can't get it right now.

Either it's not available in my country or it's, I can't afford it or whatever. How do you imagine accessibility? Imagine we're in five years from now. What's your guess about accessibility? And in 10 years, is every single adult human being going to be taking these? There are more than a dozen compounds that we will see within the next five to seven years that are in development, in later stages of development, and will become available. That should reduce the price and increase the availability.

If we look at examples of other chronic diseases, hypertension being the first. Back in the 1970s, we knew that hypertension could give you heart failure, strokes, etc., but the treatments were not very good. They had a lot of side effects, and they weren't used very regularly. But in the early 1980s, a whole group of drugs was discovered that were very accessible. Primary care physicians could use them because they were very tolerable and not very complicated. And since that time, hypertension has become treated everywhere. What we've learned with chronic diseases like this, cholesterol being the second big example, is that if we treat early and prevent things from getting worse,

that's really the best way to go. And so, Lou, one way of saying that would be you would give these drugs to everybody as soon as they were, you know, two pounds heavier than they were when they were 21. I guess personally, it feels bad to me. I feel like we haven't been living with obesity forever. This is a consequence of our environment, I think in particular the food. Let's say you're listening to this and you're like, that's not what I want to do. Are we in a world where sort of this living with obesity is inevitable? Or actually, do you believe that if you hit it before this damage is done and you sort of above all change your diet, that you can avoid that? What is your perspective? Sure, you can avoid that? What is your perspective? Sure. You can avoid it. So if you do that, and if you want to do that, you are welcome to do it.

So when people come to see us, we do not make them take medicine. It's entirely up to you. But if it doesn't work, and you develop these kinds of complications that we see, my advice would be to take the medicine rather than to wait until things get worse. So I don't want you to think that I'm advocating for everybody. This should not be in the water supply in high schools. But changing the food supply is more difficult than you may think. And I would urge you to try it if you think it's possible. Very final question. There are clearly a lot of people who are taking even these first-generation drugs, who are not living with obesity, who I think don't fit your medical definition of overweight. Do you have any concerns about that? Because you

were describing in general how well tolerated this drug is. What are your thoughts about that? So I just saw on the way over, an actress was using the medication, was talking about Ozempic, but she had no weight problems. And so my feeling is we should not conflate the misuse of these medicines by actors and actresses and other well-known people with the incredible benefit that is being seen by people with the disease of obesity. I mean, I can't tell you how grateful our patients are and how freeing it is to have something that finally works. I mean, it's just amazing because we train doctors at all levels and they're thrilled seeing patients with us. They cannot, so, you know, the young doctors, the residents or fellows or students are like, this is unbelievable.

I never saw anything like this. I've never seen people who are so grateful for relief from what they had to endure. You know, those are the kinds of things that we see. So I think that that is being obscured by people who don't need to lose weight taking these things. But make sure that those are not confused. That's not the use of these things. That is what I would call misuse, which we do not encourage. If you look at people who really need these medicines, this is liberating. This is like the biggest change in their lives that has ever occurred. Lou, I love that. I think it's a wonderful place to stop. I always do a little wrap up at the end of the show. So I'd like to try and do that. And please correct me if I get anything wrong. So then we started by explaining that obesity is a disease, and that's a really important thing for people to understand. We talked about its definition that

you can use this BMI scale. It's not perfect, but it is the way that it's used as a definition. And so being classed over 30 classes obese, there's been this enormous rise in obesity in the US and the UK and everywhere around the world over the last 30 years, that you said that sort of highly palatable, ultra-processed, cheap food is sort of what you believe is in underneath it. But ultimately what's happening is it's actually causing damage to our brain. And you mentioned particularly sort of the hypothalamus as a part of the brain, which is this key regulating part of our brain for hunger. And basically, we become sort of resistant to actually understanding our own hormones. You mentioned leptin as an example of this that tells us when we've had enough to

eat. Normally, we now understand we have this thing that you call sort of a set point. So we have this ability, our body knows like the weight we're meant to be. It's part of why it's so hard to lose weight because your body tries to pull you back to that level. But it also normally stops us from putting on weight. And you said fascinatingly, this idea that we just put on weight every year is like a modern fallacy. So in theory, it should be keeping us, but it's not. In the last few years, this has accelerated with all of this food. So there are all of these people that you're seeing in your clinic and everywhere else who are living with this terrible disease.

And this is not about willpower. There's nothing you can do about it. This causes damage. And that it's important because losing even a small amount of weight can have a profound impact on your health. And I think you said that if you could have weight loss of 5% and have kept it that way for, I think you said two years, you reduce your risk of diabetes by 50%. And if you reduce your weight even more, that fell away

in a way away. So this is a really big deal. This is not just about how you look, it's about your quality of life, even your number of years. You've been looking at this field for quite a long time. I think you said it started in the late 80s, there's been this massive breakthrough, which is this discovery that there are these sort of artificial versions of this GLP-1, which is based on lizard saliva, which I think is brilliant, which is much more sort of long lasting than anything we create ourselves. And it makes you feel as though you've already eaten. So it just profoundly shifts your desire to eat. And suddenly it means that for people

who've been living with obesity, they are actually able to reduce the amount they're eating. And so you see these sort of immense amounts of weight loss and that there are a whole series of new versions of these GLP-1, which is sort of more and more effective and that you're doing in your trials. And so you were talking, I think, about getting up to maybe like 30% weight loss. Is that what you said? Which is a lot more than the sort of a Zempik we've heard about. And already you're seeing in these trials that there's a big reduction in heart disease and diabetes and all the rest of it. So it's not just about weight. You're actually seeing these are beneficial. You're a bit frustrated, I think you said, about the way in which in the media it's sort of represented by actors who don't need to

lose weight because actually you feel like there are so many people for whom this is transformational in how they feel in terms of their health. And that, yes, in general, people are going to have to stay on this. But there may be, you know, you said, I think you said maybe one in six people can keep the weight off without it. Maybe there's ways to come on and off. But above all, you're quite excited by the idea that for the first time, many of these people can engage in improving the quality of their food once you've treated sort of the source of this disease. And so there may be a really great pathway to improving their health further as a

result of taking this drug. So it's not like it's necessarily one or the other for people who are living with obesity. Actually, potentially these GLP-1 drugs could really unlock an ability to then improve their food. That was amazing. Well, I was listening very carefully. I think this is really exciting. And I know that there'll be a set of people listening to this podcast who feel, well, you know, if you could just eat the food that we now understand is really right for you, you would be fine. But I think you're talking about the reality of so many people who have just got this physical damage at this point. We're very much a science-driven podcast and a science-driven company. So I think if this is a way that actually might enable people to then be able to embrace much better food, that actually is, I think, very exciting for me. It absolutely is. I mean, if there's a final message that I would like people

to hear, it's that it's not their fault. If you have obesity, it is not your fault. Everybody is not eating very well, but only some people gain weight. And the stigma, the bias, the blame that has gone in to damaging the psyche of people with obesity, we now see people being freed from that. I think there is something great about understanding that it isn't all your fault. This is not just about self-control. And we see through Zoe itself that when people shift from the diets they were having to the diets they start to follow as they become members, profound shifts in things like energy. And so you see that this is not just calories, as we've been told. This food is having this profound impact on our body. Yes. Lou, I know you need to go back to your patients.

Thank you so much for coming in. It's really a pleasure. Thank you so much. You're very welcome.