Plain English with Derek Thompson - How Weight-Loss Drugs Could Impact U.S. Healthcare and Food. Plus, the Biggest Problems With GLP1s.

Episode Date: December 15, 2023

Today’s episode is our second in a series on the weight-loss drug revolution of the last two years. On Tuesday, we talked to endocrinologist Beverly Tchang about the science of glucagon like peptide 1 receptor agonists—also known as GLP1s, also known as Ozempic, Wegovy, Moujargo, and Zepbound. If you haven’t listened to that show, I think you’ll feel safe and entertained within the bounds of this episode. But if you want to know more about how these drugs work, their effect on insulin and glucose and the brain’s reward center, or the questions they raise about obesity and the nature of willpower and free will, I’d encourage you to queue up that show.  Today, in Part 2, we have two guests: Zach Reitano is the CEO and cofounder of the telehealth platform Ro. He is here for a couple reasons. He has a bird’s-eye view of the GLP1 marketplace, the rise in demand, the supply chain, the economics of pricing and insurance. He’s also written several revelatory essays, pulling in research from think tanks, medical experts, and investment banks, that have helped shape my understanding of these drugs and the effect they could have on the population and the economy. Our second guest is Dr. Robert Lustig, an endocrinologist who spent years as a pediatrician and researcher at the University of California-San Francisco. As you’ll hear, he is much less optimistic about the ability of these drugs to revolutionize obesity medication in America. If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek Thompson Guests: Zach Reitano & Robert Lustig Producer: Devon Baroldi Learn more about your ad choices. Visit podcastchoices.com/adchoices

What's up everybody? It's Austin Rivers from Offguard, and I've got some exciting news. Offguard hosted by me and my guide, Pasha Gigi, is officially moving to our own podcast feed. We are now dropping two shows every week. Me and Pasha go way back and talk so much hoops already that we figured it was time to fire up the mics and let you in on these conversations. Every week, Pasha and myself will hit on the biggest stories happening around the league. Tap into the show twice a week on our new Offguard feed on Spotify or wherever you get your podcast. Today's episode is the second in our series on the weight loss drug revolution of the last few years. On Tuesday, we talked to the endocrinologist Beverly Chang about the science of glucagon-like

peptide-1 receptor agonists, also known as gLP-one's, also more commonly known as Ozempic, or Wigovie, or Mungaro, or Zepbound. If you have not listened to that show, I think you'll still feel safe and entertained within the bounds of this episode, but if you want to know more about how these drugs work, their effect on insulin and glucose in the brain's reward center, or the questions they raise about obesity and the nature of willpower. I strongly encourage you to queue up that show.

Today, in part two, we have two guests. First, Zach Ratano is the CEO and co-founder of the telehealth platform Roe. He's here for a few reasons. First, he has a bird's eye view of the GLP1 marketplace, the rise in demand, the supply chain, the economics of pricing and insurance. He's also written several relevatory essays, pulling in research from think tanks and medical experts and investment banks that have done a lot to shape my understanding of these drugs and the effect they could have on the population and the economy.

Our second guest is Robert Lustig. Dr. Lustig is an endocrinologist who spent years as a pediatrician and researcher at the University of California, San Francisco. And as you'll hear, he's going to offer a kind of counterpoint to my optimism. He is much less certain that these drugs will revolutionize obesity medication in America. And it's my view that even as optimistic as I am, that they will, the only way to be optimistic is to be an educated optimist. Otherwise, I'm just being willfully ignorant. So we're going to hear out Dr. Lustig's case against the biggest possible impact of the GLP-1 drugs, even as he reserves some faith that they will play a major role for people

who are obese. So first, in this episode, to level-set our understanding of the GLP-1 market, I want to say a few words about the market size for these drugs. It is estimated by Morgan Stanley that about 5 million people in the U.S. are taking GLP-1 drugs, these weight-loss drugs. Four million are taking them for type 2 diabetes, and about 1 million are taking them for weight Now, that's not huge, you could say. But here is one way to think about how big this market could get. If patients decide, if, I want to be clear, if patients decide that these drugs are

worth sticking with, in the 1980s, 40 years ago, roughly 10% of people diagnosed with high blood pressure took medication for high blood pressure. But then, over the last half century, with advancements and ace inhibitors and other medications, that figure has soared. Today, tens of millions of Americans are on blood pressure medication, and it has dramatically contributed to a decline in cardiovascular deaths. If GLP-1s follow a similar trajectory, the number of Americans on these drugs

could easily triple in the next decade. And the implications for health are one thing, right? lower obesity would clearly reduce a host of chronic diseases and pains. But what about other industries? What about the effect on food? Morgan Stanley Research and survey data suggests that patients on GLP1 drugs reduce calorie intake by 20 to 30 percent. And that's not an even 20% cut across all food categories. Candy, sugary drinks, and cookie consumption for patients on GLP-1s declines by 60%. Alcohol consumption plunges. Meanwhile, fruits and vegetables soar by 40% in terms of consumption share. Chicken and fish go up by 20%. So if you work in packaged food and beverage

or in restaurants or in grocery stores, and you believe that a high share of your clientele is likely to go on and stay on these drugs in the next decade, these drugs which are likely, essentially, an anti-snacking drug, how does that change your menu, your supply chain, your acquisition strategy? We can't answer every single GLP1 implication today. The ripples are too wide, but these are the sort of questions that I'm interested in. And then, because I like having my optimism checked from time to time, these are the sort of predictions, I'm excited to have interrogated by Dr. Lustig. I'm Derek Thompson. This is plain English.

Zach Ratano, welcome to the show. Thanks for having me. All right, let's start with Roe, where you are the CEO and co-founder. How did your life and experience lead you to start this company? I have, I can tell this story with a big smile on my face, which might be hard to see on a podcast, but it does have a happy ending. So everyone in my family, myself included, has had some, some life-threatening illness at some point in time. So my sister, who's the biggest warrior of all of us, is a two-time cancer survivor and has an autoimmune disease. My mom has neurological disease.

I have a congeneral heart condition and had a heart procedure when I was about 18. And my dad's had four heart attacks and a stroke. But I was very, very lucky in the sense that in addition to that, happening to my dad, he was also a doctor. And he took care of each one of us and saved our lives. grown up multiple times. And that really shaped both my experience as a patient and why I started a row. I'm sure a therapist would have a lot to say about this, but in many ways, I think I'm trying to recreate my dad with software. And I think the biggest difference when your dad's your doctor

is that, yes, they care about your health, but they do it through the lens of trying to make sure that you live a happy and fulfilled life. And so when I was 18 and again, when I was 25, the main side effect of my heart medication was erectile dysfunction. And that's originally where Rose started is overall in sexual health. So patients come to us. They tell us what they want to achieve. We work backwards to help them achieve that goal. And we do it by seamlessly integrating doctor's office, pharmacy, and labs.

So you guys are the digital platform. People can come to you for drugs, for hair loss, erectile dysfunction, weight loss, which we're going to talk about today. before the GLP1 revolution, what were the most popular medications that people were ordering from your platform? Yeah, so we've actually been in the obesity category for about three years. So the biggest sort of four areas for us, four categories, obesity or metabolic health was one of our most popular prior to the launch of GLP1s. That's why I think that's one of the reasons why I think we were quote unquote early here is that we had been helping patients. We've helped hundreds of thousands of patients start their weight loss and obesity journey. sexual health, dermatology, and fertility are the biggest four categories for us.

So you've been this advocate for the GLP revolution for a while, an advocate for doing everything that we can to reduce the cost and increase the availability of GLP1 drugs because you say you think their widespread use is inevitable and that as a second order, their widespread use could have major implications for health, lifestyle, consumption patterns, economics. Of course, some people listening are going to say, well, also the increased use of GLP-1s are going to be really beneficial for your business as well.

And we'll talk about that, the degree to which the mainstreaming of these drugs could drive more people to Roe as well. I want to start with the initial claim, the claim that these drugs are, to use your word, inevitable. Today, a few million people are on GLP1 drugs like OZempec and Wigovi. You think that number could go to the moon in the next few years, the next decades. What does inevitable mean to you and why are GLP-1s in your view inevitable? That's a great question. Because again, I think to your point, like the assumption of there being inevitable then forces us to think about, well, how to accelerate access to them,

because right now there is a massive disparity in who has access to these treatments and who doesn't. The main reason that I think they're inevitable is that there has never before been a treatment that has satisfied five criteria, which is it treats the most common chronic condition in the U.S. So the majority of the U.S. population has overweight or has obesity and is eligible for treatment. So that's number one, the majority of U.S. population. Number two is it's extremely effective, right? And we could talk about what that means, but on average, people are losing, depending on the drug, 15 to 20 percent of their body weight, which is unlike any other pharmaceutical treatment.

there are surgical treatments, but I would argue that this is the third criteria, which is that it is scalable. So, bariatric surgery, highly effective. There's only about 250,000 a year, and so it would take about 100 years right now to get everyone who needs one, access to one. Number four is, and this isn't the case with always with effective, scalable treatments that would benefit people's lives. Patients desperately want it, right? So there are many things in health care, many, many, things that patients need, but there are. that patients don't want. This is one that they want. And then the fifth is that providers want patients to have it. And so, and then I would, I would bucket providers and then also attach the

rest of the health care system to it. So like the health care system in, which as you talked about, like, you know, show the incentives and show behavior. The health care system wants these things to be as widespread as possible for a wide variety of reasons. Different stakeholders have different incentives. But when you take something that is the majority of the population is eligible for, it's highly effective, it's scalable, they want it, and the health care system wants it, that's never happened before. And so I think when you put those five things together, it is their adoption and their widespread adoption, I think, is inevitable. So I wanted to talk to you because we had Dr. Beverly Chang on the show to talk about her scientific advocacy for these drugs

earlier in the week. But I wanted to understand from a telehealth platform perspective, what you're seeing in terms of uptake and patient experience, and then furthermore, how you think these drugs could shape the future of several industries like food and beauty. So let's start with some nitty-gritty details. How does Roe make sure in a scarce marketplace that the people who are getting OZempic and other GLP-1 drugs from your platform are qualified? Like, we're What qualifications do they have to meet? Yeah, absolutely. So patients come on and they start with what we refer to as a dynamic online business.

And that means they answer questions related to their health history, their metabolic health, their dietary preferences, their history with their weight, height calculated. We use that to calculate their BMI. But they basically go through a comprehensive overview and history of their metabolic health to understand whether they would be... initially eligible for lab testing. They then would, if they are eligible for lab testing, then they would choose to either go to Quest

or we send them an at-home diagnostic kit. And from there, that panel is what we refer to as a metabolic panel, gets an underlying picture of their overall metabolic health. So measuring their A1C, their lipids, thyroid, kidney function, and a few other things. Based on that lab test, their comprehensive history, as well as an interaction with a health care provider. The health care provider will determine, based on the patient's preference and the

healthcare provider's evaluation, whether that person might be safe and appropriate for treatment. Rowe then will also, depending on the patient's preference here, will grab the patient's insurance and then go through what we refer to as sort of our insurance concierge. And we will work with the patient and their insurance company to maximize their ability to get coverage assistance, whether that's. requires a prior off, whether that requires appealing the response to a prior authorization, whether that allows them to use savings cards, which are prevalent initially when drugs come out. So we then will help patients sort of maximize and maximize the ability to reduce the cost of

that treatment. And then that's the start of the program. And there's a lot of controversy over the side effects of these drugs. Do you have a clear way of seeing what side effects your patients are experiencing? One of the things actually that we do on our platform is we allow people to report side effects in a very structured way. So they don't just message their doctor in free text. They'll actually say, here's the side effect I'm experiencing, here's the severity, here's the duration, here are any associated side effects. And that creates a structured interaction that's immediately reviewed by a healthcare provider. There are different side effects for different medication.

Typically, some of them are gastralintestinal challenges or nausea are the ones that people experience most frequently. I would say that the side effects is not the primary reason that people don't adhere to the medication or that they, let's say, dropped out of the trials. That was not the primary. What we see at least in our data is that cost and access, so the two things that deter people the most. But every drug has side effects, and they need to be closely monitored and tracked. But these drugs are not meant to be taken lightly. And I don't think. think that the way that they're not meant to be taken lightly. And I don't think they are panaceous. I think they're really, really valuable tools in a provider's toolkit and in a patient's toolkit

to improve their overall health and to live a higher quality of life. And I think that the data bears that out. And Wigali right now is priced technically at $1,400 a month. I know most people pay much less than that. What do the drugs cost on your platform and on similar platforms? And then what would it take to make them cheaper? Yeah. So about there's the only people who are paying $1,400 a month, because this is a really sort of interesting and I think a fascinating part of our health care system. But the only people who pay the list price of the drug are really people who are either uninsured or underinsured. Like people, people who are paying cash for a drug. Insurance companies aren't paying that much. And so there's a big gap between like the list price and the net price and how much provide. how much pharmaceutical companies actually receive. When there is coverage, and there's different research about this, so about 80% of people who are covered,

which means that their insurance company will cover Wagovi, 80% of people are paying $25 or less. So when it is covered, it's not very expensive for them, for the vast majority of people. It's $25 per week? Per month, okay. Yeah, or less, depending on their coverage. Then that's about 80% of people.

And then 20% of people will have different forms of coverage where their copay might range. It could range to $50 to a couple hundred dollars, really depending on what their insurance company is willing to cover. Zepbound actually was recently released, and it's in pharmacies right now, actually. So Zepbound is, for people who have heard of Mungaro, that is FDA approved for diabetes. Zepbound is the same active ingredient, but it is FDA approved for obesity instead. And there is a savings card for that drug where the list price is just over $1,000. And I think this is very, very interesting because it's coming in about 20% cheaper than Wagovi. It's about 20% cheaper and it's a more effective drug, which you talked about sort of statins earlier and how they can serve as a really

interesting analog for the obesity market. So it's very, very interesting that a more effective drug comes in after the fact 20% cheaper. Their savings card is additionally even more sort of aggressive from a pricing perspective. So if someone is not covered, they will actually pay just around $500. So cutting it in half or a third of Wagobe. So there's some interesting price competition that's happening now in the marketplace. Help me understand the degree to which there's any kind of price crisis here. If 80% of patients are getting this drug for $25 a month, I mean, for a drug that's this important, that's obviously a very affordable price. It's talking about $6 a week. It seems like there's not a price crisis then. It's more just how do we get as many people as possible

the kind of insurance coverage that leads the drug to cost $25 a month. Yeah, so there's a coverage challenge, right? So there's both a coverage challenge and then there's the higher level sort of philosophical question around like who pays for health care, which is all of us individually at some point in time, whether it's through suppressed wages or our taxes or our premiums. We are paying for our health care. So I do think that there is underneath it all a price issue. But if we were just to say, like, is there an immediate price issue, like how much someone

pays when they receive it? The majority of people are not covered for this drug, right? So commercial plans, the majority of commercial plans don't cover it. Medicare is actually regulatory prevented from covering it. So in 2006, there was a law that prevents the coverage of anti-obesity medications. So that is for patients who are on Medicare, the only GLP ones that they'll be able to access, at least injectable GLV ones, will be OZEMPIC or the ones or Moonjar are the ones that are FDA-approved for diabetes. So, and then Medicaid, there's only about 10 states that cover anti-obicity medications.

So when you look across, you do see the majority of commercial plans not covering it. Obviously, people who are underinsured have to pay an extreme amount. Medicare doesn't cover it, and the majority of states for Medicaid don't cover it. There are really, I think, forward-looking pockets where they're either self-insured employers that have long-tenured employees that sort of see the tremendous benefit that happens to the quality and quantity of patient's lives. you also see all federal employees, their health plans cover it, which I think is an amazing act by the government seeing the benefits of these medications.

I want to think about what the forces are that could drive down the cost of these medications even further. You've mentioned some of them. You could have pressure on insurance companies to cover it, pressure on the federal government to have Medicare make an exception for this new class of anti-obesity medications to cover it. You also have some innovations, obviously, the fact that there's so much demand for GLP1s means you have more companies that are trying to develop new injectables but also new orals. Help me think through all the various categories of the forces that could in the next few years or decade drive down the cost of this category of medication. Yeah, there's probably three big ones, if I had to think about them. There's

government intervention, right, which has happened in other categories, right? It's happened in insulin as an example. But government intervention, both by having Medicare covered, Medicaid cover it, and that's at both the state and federal level. There's also allowing Medicare to negotiate more hardly, right? So there's that component. Competition is a big one, right? So we are seeing Eli Lilly, which I think is a very, very interesting strategic choice. They're coming in with a more effective drug at 20% at a 20% lower price. It's still too expensive for the majority of Americans, right? Even $1,000 a month, even with the savings card 500, is still too expensive for the majority of people.

But competition, I think, is a big one. I think there's also, when you think about, like, how to drive that down from competition, there's really three large, quote-unquote, like, payers of health care. I think it's the government, its employers, and it's individuals. It's not really insurance companies. And there's a whole bunch of nitty-gritty details. So it depends how wonky you want to get in terms of, like, the flow of money in the health care system. But largely speaking, I think one of the fastest ways to dramatically reduce the price would be to put more and more money.

in the hands of individuals and let competition sort of do its thing. And I think that what's fascinating about GLP-1s and the market is that I really do think it is going to serve as sort of this microscope on PBM rebates because there hasn't ever been a large enough group of people that have all wanted access to the same thing, where you've seen the gross to net, or the list price to net be so pay. painful and so magnified, right, where some people are paying a thousand. And then they're realizing that the pharma company is only making 300. And where did the $700 go? And why are they the ones funding that? And then they see their health care costs go up. They see their wages be suppressed

because of the role that employers pay. You see employers being, quote unquote, like disincentivized, certain employers being disincentivized to cover it because people change health plans and they change their employer so frequently, that what's the benefit of someone covering GLP-1s when the benefits might take years to take hold? So there's a lot of conflicting incentives when you think about preventative health, when you think about the drive of an individual to both improve their present and future that their employer might not have, but that the government definitely has. So I do think that you're seeing it. I mean, they're making that decision with their own employees, right? So those are the big sort of three would be government intervention through a variety

of forces, trying to facilitate more and more competition. So you do see a massive pipeline there. And the third, I think, is advocacy at the individual patient level. Let's talk about some of the ripple effects that we could see the GLP ones have throughout society. You've written really interestingly about this. And we can break it down into three categories. That is health care, consumption, and lifestyle. Let's talk about health care first. I wonder how you think the increased uptake of GLP1 drugs could change the demand for certain kinds of health care products and services. So, for example, lots of knee surgeries or hip surgeries are downstream of the reality

that roughly 40% of Americans are obese, roughly 70% of Americans who are obese are or overweight. So there's an example of a health care service. that could really be impacted if you have tens of millions of Americans taking a drug that has caused them to lose 20% of their weight. What are some other categories in the bucket of healthcare services and products that you think could most be impacted

by a really strong uptake for GLP ones? Yeah, I think it's interesting because the combination of the five things that we talked about before, sort of the majority of the U.S. having overweight or having obesity, the efficacy of the medication, the scalability, patients wanting it, and the healthcare system wanting it.

That combination does, I think, presents an opportunity for rapid adoption unlike anything we've ever seen. On the healthcare side, what's fascinating is we often blame the healthcare system, and obviously it can improve in many ways. But it is playing whack-a-mole with chronic disease for the most part, right? We've done an amazing job at solving the leading causes of death that existed 100 years ago. Like, we don't die at 30. We don't die from infectious diseases a lot of times.

We're now dying from these chronic diseases. And a lot of it could be, a lot of it is driven by the society that we have created. We have such a drive to consume and our society has, and there are a lot of benefits to that. But it's created an entire economy based on like delicious cheap and ultra-prone. processed food. And so what's fascinating about gLP ones, the reason why I sort of give that background is because very few treatments do both help the underlying health of that individual and reduce the, let's say in this instance, reduce the obesity-inducing behavior. Right. So hypertension medication does not reduce the likelihood that you go and take actions that increase,

the likelihood that you experience hypertension. But this medication actually does work upstream. It prevents you. It radically shifts calorie consumption, right? So not only does it improve your A1C and lower your LDL and increase your ACL and do a lot of the things that, well, we'll start as a drug for diabetes, but do all those things. But because of its impact on upstream, right, in addition to helping the, in addition to sort of the downstream, I do think that that's where we'll see a massive shift in the healthcare products and services that people need. So you mentioned knee surgeries. There's hip surgeries.

So like what surgeries do people need more or less of? Do people qualify for more or less bariatric surgeries? Do we see, because you do in certain instances, have to lose weight prior to getting bariatric surgery. Do we see more or less uses of certain devices, right, from continuous glucose monitors? that people use, right? So do we see more or less usage of those?

What products are purchased more or less, from auto injectors to syringes to people getting more and more prescriptions and going in CVS and walking along the aisle, right? And normally at a small scale, a couple million people, you might not see that massive shift, but you have 110 million plus people

and that number is getting larger and larger that are eligible for this. And you have already probably about 5% of the US population who's taking it now. So what happens when you have tens of millions of people take that, I think the health care implications are really, really fascinating. This is such an important point that I want to make sure we hammer home for listeners.

In your view, these drugs are behavioral modifiers. They take on the mismatch between our gene-influenced appetites and our modernity-influenced environment, and they change the way we interact with this environment, right? I think the really interesting thing that you called out is this massive mismatch between our environment and our current environment, right, and how we are and how we were designed, right? Because for not even the vast majority, like 99.95% of our human existence, we've been hunter-gatherers. For 0.4% were farmers. And then, you know, for 0.1% were startup founders and authors and podcasters. And so we have never lived in a calorie-rich environment. So it makes sense that our body, like, our drive to consume and our drive to sort of survive and reproduce naturally protects against weight loss.

Like it does not, our bodies do not want you to lose weight. It stimulates a starvation response. But we've never had to protect against waking. There's this assumption that people who take GLP-1s eat donuts all day, just less of them. and that they use it to eat the exact same things, but just operate at a calorie deficit. And that just, like, could not be further from the truth. And this is where it becomes really interesting

from a societal perspective. Because what we see in our data is that not only is there, and this is both in our data and sort of outside sources, is that there's a natural decrease in calorie consumption by about 20 to 30 percent. But what the people on GLP-1s eat radically shifts, and so they start to eat more vegetables, more fish, more poultry, far less processed food, far less confectionaries, far less of all of the sort of negative foods that are commonly associated.

And the fascinating thing is like the Pareto ratios of sort of those behaviors, when you think about, let's say smoking cessation, I think is a good example. About 10% of smokers account for like 90% of the consumption. And so that parade of ratios is very similar for other what people would consider like negative habits or bad habits. So eating ice cream and cereal and gambling and doing all of these different things, the things that traditionally act on the rewards center of your brain. And so when you not only have a decrease in calorie consumption of 30%, but in a population that might have been extremely highly concentrated consuming specific categories, there's a much, I think, a disproportionate shift in what people are going to consume. So that to me is when people talk about when you hear it in Walmart earnings calls or Nestle

earnings calls or all these different things, I think people are sort of overestimating what's happening like right now. There's a national shortage of the drug. Like 50 million people don't have this. But our world has been shaped by our desire to consume these things. And what happens when you take a massive haircut on it for 50, 100 million people? That to me will have a like a fascinating ripple effect. because these GLP-1s are like a jetpack

for positive behavior change. Yeah, these drugs re-engineer our taste for food in a way that is really astonishing to look at when you look at the Morgan Stanley research surveys. I mean, you called this out in your last response, but when Morgan Stanley AlphaWise asked people who were on GLP-1s about changes to food category consumption, fruits and vegetables consumption went up 46%,

poultry and fish, up 23%, Candy down almost 70%. Alcohol, salty snacks, cookies, carbonated and sugary drinks, all down more than 60%. They re-engineered taste for food. I mean, if you take this seriously, if you take these results seriously, and you project forward that these drugs are going to have an uptake that could increase by an order of magnitude in the next five to ten years, it would be irresponsible not to start thinking big thoughts

about how does the food system change? How do restaurant menus change? How does PepsiCo change its entire business strategy, understanding that it is a snack company for a country that is medicating itself to eat 60% fewer snacks forever? I mean, that is an enormous, enormous thing. diet and exercise is is something that you you do see people do twice as frequently or twice as much

once they start gLP once and diet and exercise is phenomenal for your overall health but it has historically based on all the data available not been linked to significant and sustainable weight loss right and so the way that people talk about treatment versus prevention is um really really important and thinking about like missing the right techniques let's say is i think The analogy that Dr. Lurone is an expert in obesity that he uses that I find fascinating is it's, because people are very critical of people taking these drugs or of my advocating that people who are eligible for this drug deserves this drug, right? People usually use the argument, well, let's fix the food supply. And the answer is like, yeah, I would like to do that too.

Like they're, and, and, like, let's do that and. But ignoring sort of these incredibly effective treatments, it's akin to, and this is what Dr. Luteroni uses, he says it would be akin to someone using a smoking cessation program to treat lung cancer, right? So there's like a whole group of people who are experiencing this problem and have experience it for decades. We have designed, so to talk about like the Pepsi's of the world, all of those different things, but like we've created this obstacle course of incredibly delicious food. So yes, our brains are engineered to love these things, but also what doesn't exist in nature is like maple wrap bacon. Like, that doesn't exist, right? And it certainly didn't exist at the press of a button. And so,

like, we have engineered this world based on our drive to consume, and we are fixing this problem ourselves. I think, like, obesity is a product of progress, and it's highly correlated with GDP, right? So, like, it's a good thing overall that we've solved famine for, in large, largely speaking. With most chronic diseases, there's a role of like genetics, environment, and behavior. And it's the mismatch between those things that sort of can take us off course, right? Because we didn't have such extreme forms of obesity like a hundred years ago. And, you know, in early 1900s, like 2009, we consumed the same amount of calories that we did in 1969, right? But there wasn't a massive challenge with obesity in the early 1900s.

And that's because generally, like, life was exercise. But over the last, let's say, 40 or 50 years, we've dramatically reduced the requirement to expand energy. Right. Life is no longer exercise. And so we've reduced sort of the friction in our lives. And we've dramatically reduced the friction to consuming. It's, you know, obesity is a product of our own progress, and we're sort of going to solve it with technology as well. So I think it's fascinating that we sort of have these unintended consequences from our drive to survive and thrive.

And then we have to solve the negative externalities on top of it that we create for ourselves, right? But I think it's, yeah, it's a really, there's a really interesting thought experiments. That's a very interesting frame that, yeah, that technology and progress made us misaligned with our, made our biochemistry misaligned with. our environment and then we invented another technology that aligned our biochemistry with our environment. That's an interesting thing about it. I think that's right. I think the pendulum is just going to, it has to keep swinging, right? Because people talk about our food supply and the safety of it. Like, it's probably, I mean, I don't even have to say probably. It's, it is the safest food supply that has ever existed ever, right? So now that it's the safest food supply that's

ever existed ever, we still have problems with it. Like, let's, we don't, we want to stop here. We have to make improvements to it. But yeah, I think that there are, there are negative externalities star drives, and we'll fix them, as we do with any new technology. It makes me think, you know, maybe someday Nestle, Kirchie is going to invent a chocolate that's actually so delicious, it overrides the effect of these drugs. Just a game of ping pong between the food supply system and pharma? Yes, the 100-year war, food versus pharma. So, okay, I want to bracket the conversation about food this way. You know, we are dis-evolved to use your language. We're disavile.

for this world of caloric density and tasty abundance. And the fault lies not at the level of individual morality, but rather at the level of population-wide genetics and environment. And what's so fascinating is that if we take the survey evidence seriously, long-term GLP-1 use should change tastes in ways that actually do shape the food supply, reshape the food supply, reshape the food that is being offered to us through the demand channel. That is a really powerful thought. So, okay, let's move on from talking about OZMPIC, GLP-1s, and food, and start talking about beauty.

We're seeing all sorts of celebrities taking these drugs, clearly changing their bodies in dramatic ways. But one of the more notorious side effects of OZempic is what some people call Ozempic face. Ozempic face. People's faces, when they're on the drug, lose weight, they get excess skin. Is this a problem? Well, if this is a problem, do you see it as an opportunity for new cosmetics, plastic surgeons, the beauty industry? I mean, I do. I think that there's a lot also to talk about OZempic face in general, because I think this is one of those things that it's a little bit of like, not entirely, but it is a little bit of like media fear mongering.

I think when I hear the word OZEPIC face because it's not specific to the use of OZemPEC or GLP1s or medication. It is typically what happens if someone experiences rapid weight loss regardless of the mechanism. So I think that's like sort of number one. And number two, it does actually remind me,

and I wrote about this, and I think it's like pretty funny, so I'll bring it up, and you can cut it later if you don't like it. But there is something in 1895, actually, and I remember writing that this. In 1895, literary digest warned about this thing called bicycle face. And it specifically referred to like what happens when people look like wearied and exhausted on a bicycle.

They said like usually they were flushed, pale. And it was right at the moment where in the late 1890s, it was a very powerful tool, bicycles were a very powerful tool and an instrument that empowered feminism because it was agency and mobility. and this was a mechanism to use bicycle face to like criticize that level of mobility and agency. And so like I do, I personally, when I see things like this get frustrated because I think it's a tool,

like there is enough stigma attached to, there's enough like body shaming in the world and there's enough stigma attached to people either having shame about their current weight, having shame about taking action towards trying to lose weight. People who have challenges sort of with, and there's different terms that people refer to it, but like their own self-image of their body composition,

whether people use the term body positivity, which has pros and cons or body neutrality. There's a bunch of, like, it's hard to talk about to use the right words. But those ones to me are always a little bit frustrating because I do think that they are, I think it is the media, using certain language that adds additional weight to people seeking action for their health.

And I don't think you would see the same thing. Whenever I ask myself whether I think there's stigma or bias attached to something, I say, like, would the same words be used if the treatment were only for diabetes or only for heart disease? And I don't think so. And by the way, I think people wouldn't be arguing about the price either. In fact, I mean, you talked about sort of all-L-SQL holding things constant. Like, there's a beautiful Ceteris paribus in terms of how, society reacted to a once a week shot when it was exclusively for diabetes. No one had a problem

with it. No employers had trouble covering it. No one complained about the sort of the overall benefit on someone's health. And the second that it is used to treat obesity, you see employers looking for services that off-board people or that make it harder to get. Or you talk about insurance companies. So to me, like anyway, I know that's not like, the rant you bargained for when you asked about sort of a beauty and mentioned the word as epic face, but I couldn't help myself

because I think it's just like rings, it sort of echoes. No, I think it is the rant that I bargained for. I do think that the way that we talk about weight sometimes, I mean, you know, one word that comes to mind is struggle. They're struggling with their weight. We think of getting healthy, staying healthy,

as being a kind of rightly Sisyphian struggle. It should hurt to be at the gym. It should hurt to run half a marathon, that health should be downstream of some kind of intense, sweaty, effortfulness. And it is a novel idea that health could be purchased at the tip of an injectable or through an oral pill. So, you know, I remember I saw another interview where you were asked, do you think that these drugs are cheating? which is not a word that I would ever use to describe these drugs, but is a word that I can imagine other people sort of holding at the back of their head. Like, you know, getting healthy is something you should struggle to do,

and these drugs are easy. How do you think about the cheating word? I think it's pure bias. Honestly, I think that we should want to live in a society where it is easy as possible to live a happy and fulfilled life and to be healthy. And health is obviously a means to an end to do that. And I think it's incredibly unfair to put people in an environment where it is an obstacle course to be healthy. And I think that when it comes to, when it comes to the GLP1 medications, the other thing that I think people should really, really understand is like they're helpful, but they're not a panacea.

Someone still, and we see this, like, they still, someone still would greatly benefit from diet and exercise, right? there are concerns for certain people and considerations related to muscle loss, right? You do, regardless of calorie consumption, there are qualities of calories that are either that are more beneficial for someone versus less. And exercise is probably one of the few things. I mean, some people can have too much of it, but it's really, really hard to have too much exercise. You basically can do as much as you humanly can for as long as you can, and it's generally

beneficial. So these things are still really useful for people, and they should still continue to do them. But I think the idea of us requiring hardship for health is so utterly twisted. It's hard to adequately explain on a podcast. Now, with this drug in particular, do I think that there are, like, do I think, again, that is sort of at 30,000 feet? Do I think everyone should be on this drug? No. Do I think that this drug is going to solve all our society's problems? No. Will it be a miracle for some people, absolutely. And so the goal should just be like, how can we get this in as many hands as possible for whom it is ideal and appropriate? And this is what I wrote about it. When we create

this gap where rich people or people with means are sort of like unperturbed by the conversation that is happening and they're going to just say, wait, there's this drug that I get once a week that I'm guided by with my doctor and I go back and forth. And what it allows me to do is lower my A1C, I experience weight loss. I improve my LDL, HDL, blood pressure, quality of life. I lose weight so I can't exercise more and I sleep better. And I can get that, right? And then there's another group of people who need other people's permission to get access to it.

They need their insurance company or their employer or the government. And each day we make that harder, we risk, in my mind, dramatically accelerating health and equity to the point where it's going to be really hard to unwind. Like the gap right now between a county that has the highest life expectancy and the lowest is about 25 years. It's like 60 to 85, which by the way is incredibly sad and embarrassing for being the richest country in the world. But that gap exists. Then, and there are many other factors related to social determinants of health, and there's many other things we can do. But there isn't, to my knowledge, a more scalable and effective intervention that could bridge that gap.

And I worry that if you let five, 10 years go by where that's not what we're trying to do, we're going to regret it. That's my biggest worry with the rapid adoption of these drugs is that the adoption is so unequal that it's difficult for us to unwind because the benefits compound on themselves. Zach, thank you so much. This is really fun. Appreciate the time. That was my interview with Zach Gritano, the CEO and co-founder of Rowe.

Next up is my conversation. with the endocrinologist Robert Lustig about the benefits, yes, but also some of the risks and the informed skepticism about these GLP1 drugs. Here is Robert Lustig. Dr. Robert Lustig, welcome to the show. Thanks for having me, Mr. Thompson. My pleasure. So I'm very excited to talk to you because I have recorded a few interviews about GLP1s with people that are really optimistic about the future of these drugs. And you are more of a skeptic. And it is my feeling that if I, as a podcaster, as a journalist,

am going to be educatedly optimistic about any kind of scientific or technological revolution, I might as well listen to skeptics because without hearing the skeptics, it's not educated optimism. It's just willful ignorance. So I'm very, very grateful to have you on this show. Before I ask you to play the role of intelligent skeptic, I want to make sure that we retrace a few places of agreement with Dr. Beverly Chang and the other people that I've spoken to about these drugs, the GLP-1s, and this weight-loss revolution. First off, I just want to make sure

that on a ground level, you would agree that these drugs are different, that there is a there-there, there. These are different from previous generations of weight loss drugs in that they really do seem to be having a large and sustained effect on weight loss for people that are obese that we didn't see in previous generations of medications. Do you agree with that overall thesis statement? Well, there were some medications that did promote significant and durable weight loss. The problem was that their side effect profile was enormous. And ultimately, those drugs did not capture the imagination of physicians and also of patients and ultimately went by the wayside or got pulled by the FDA. We've had drugs that actually promoted weight loss since the

1940s. The fact that it's dinitrophenol DMP worked very well for weight loss and also made people very sick. Thyroid hormone worked for weight loss. My mother took thyroid. My mother took thyroid hormone for weight loss. And to be honest with you, you didn't want to be in the same room with her. So I do understand this. And the fact is that GLP1 analogs do have a significant, clinically relevant weight loss effect that is durable. And in that respect, they certainly can join the party.

And I am not against these drugs. I want to make that very clear. In fact, I'm actually for them, despite my skepticism. And I want to make that clear as well. My issue is, who is it good for, why, and does the benefit outweigh the side effects and the cost? And for that, we have to be a little bit more granular and a little bit more nuanced with the data. Another place I want to retrace relative agreement is the mystery of these drugs. Like, in many cases, we're not exactly sure why they work the way they work.

What would you say are the one or two most interesting scientific mysteries that these drugs mechanisms really propose to us? These GLP-1 analogs are extraordinarily interesting from a physiological standpoint. They bind to their receptors. and the receptors are in three places. Number one, the beta cell to increase insulin. But increasing insulin usually causes weight gain, not weight loss. They also bind to receptors in the brain and contribute to satiety.

Lastly, they bind to receptors throughout the small intestine to delay gastric emptying. And it is probably a combination of the satiety and delayed gastric emptying that ultimately leads to reduction in food intake and weight loss. Now, that sounds like a good thing, but there are nuanced downsides to that, which I'm sure we'll discuss. We'll discuss them, and I just want to make sure sure it's what I find so interesting about these drugs, almost from a philosophical standpoint, and I think you sort of share this philosophical curiosity, is that they do, because they bind to receptors in the brain, they do seem to almost, at a blood chemistry level, like, act on what we might call willpower. Like, I know that's a very, you know, that's a big term. But you would

agree that there is a really active, almost philosophical mystery about how these drugs seem to change behavior in a way. Yes. So the question is, does the behavior drive the biochemistry, or does the biochemistry drive the behavior? Now, I will tell you, this is, this is a very important. This This has been my research for the past 25 years. Two decades ago, I took care of children at St. Jude Children's Research Hospital who became massively obese following their brain tumor treatment. These children were normal weight, and then they developed a brain tumor. They started gaining weight at the rate of 30 pounds per year, ad nauseum, ad infinitum,

to levels of 300, 400 pounds. And it was up to me to try to treat them. We knew that these children released large amounts of the hormone insulin, and it was the insulin that was driving their weight game. So I gave them a different drug, almost the anti-GLP one. It's a drug called octreotide, which suppresses insulin release. And by suppressing insulin release, we were able to show that these children lost weight. because we suppress their insome release.

And even more to the point, these children started exercising spontaneously. One kid became a competitive swimmer. Two kids started lifting weights at home. One kid became the manager of his high school basketball team, running around, collecting all the basketballs. These were kids who sat like lumps on a log, and the parents would say, this is double jeopardy.

The kid survived the tumor only to succumb to the therapy. And now they were acting normal because we suppressed their insulin. So getting your insulin down can cause you to lose weight. Well, GLP-1 analogs are almost the opposite because they increase insulin but still get you to lose weight. So this is a, shall we say, a conundrum in terms of understanding mechanism of these drugs. It's so interesting. I didn't know that detail, but that's utterly fascinating. All right, let's move beyond the philosophy, which I could do for an hour with you.

And let's talk about your skepticism. So I think the best way to set up the first skepticism, which is about muscle, is to confess that I'm a big fan of Peter Atia. I think you might be a fan of Peter Atia as well. He wrote this book, Peter I had good friends. Okay, great. He wrote this excellent book, Outlive. Yes.

Peter believes and is very persuasive on the point that being able to build muscle and sustain muscle, especially into older age, is absolutely essential. for health and longevity. Tell me what these drugs do to muscle mass. I know that they make people lose weight by losing fat. Do they also cause people to lose muscle? How do we know if they do, and what does it mean that they might?

So it's a very good question and very appropriate. There is a disease called sarcopenia, loss of muscle. and Peter in his book spends a lot of time talking about sarcopenia and that sarcopenia predicts early demise. And you can ask any little old lady if she wishes she had a little bit more muscle before she breaks her hip. The fact of the matter is that muscle mass predicts longevity. So anything that increases muscle mass is thought to be good. Now, unfortunately, increasing muscle mass usually means increasing insulin, and increasing insulin also means increasing mitogenesis, that is, cell division, and also increases the risk for cancer.

So this is the problem of increasing muscle. Otherwise, everybody would just be on a high protein diet, and we could call it a day. There is a downside to increasing muscle, and that is the increase in insulin. Nonetheless, sarcopenia is a major risk factor for early demise. And so you do want to keep your muscle up. It has been shown now in multiple studies that the weight loss achieved with these GLP1 analogs is a combination of fat and muscle. You lose equal amounts of fat and muscle. Ostensibly, you should only want to lose fat.

You shouldn't want to lose muscle. But in fact, you are losing both. Well, you know what else causes an equal amount of loss of fat and muscle? Starvation. In fact, the effects of GLP1 analogs look exactly like the effects of starvation in terms of how starvation induces weight loss. Now, the question is, is weight loss with starvation a good idea? Yes or no? And the answer is, it depends.

Because, yes, if you lose weight and that contributes to improving metabolic health, that's good. If you lose weight and that puts you at risk for osteoporosis, breaking a bone or hip or something else, maybe not so much. So we're always balancing these two issues. Optimally, a weight loss drug should cause you to lose fat. and specifically fat from metabolically active areas like visceral fat and liver fat, even more than subcutaneous fat. It's only the subcutaneous fat, though, that drives people to the doctor. Help me get into this bathing suit. That's actually not the fat that we want to lose. The fat we want to lose is the fat that's surrounding our organs that's causing chronic

metabolic disease like diabetes and heart disease. So people get on these GOP1 drugs. if they're overweight or obese, you put them in these scanners, these dexas scanners, and it turns out that they are often losing relatively equal amounts of muscle and fat. Losing fat, pretty good overall,

losing muscle, not so good overall. My question for you is, is this a problem that we could solve with the muscle loss problem, with either behavioral change, or with some other medication? So I, for example, I've been reading all sorts of,

investment reports about Novo Nordisk and Eli Lilly. There's some evidence that I saw that various companies, various biotech firms, are working on drugs whose purpose is to build muscle. There's a monoclonal antibody called bimagromab, which is currently in phase two trials, which seems to potentially stimulate skeletal muscle growth. We don't know yet. It's phase two trials. But the point is those drugs are being worked on. So the question I'm proposing back to you is, yes, I stipulated that the loss of muscle mass is a big deal. How fatal is this flaw? Could it be assisted with behavioral activation? People on GLP-1 is also going to a trainer or the future of biotech firms developing something that taken alongside GL-1s might be

able to preserve muscle mass? Your guess is as good as mine. We don't know yet. Okay. 25 years ago, scientists developed the mighty mouse. Okay? It had a defect in a protein called myostatin. Myostatin means muscle stop growing. And when they had a defect, these animals became massively overmuscular. That sounds great. And these animals were also very lean. They were like the ultimate bodybuilders without bodybuilding. Yeah, but they died early. Okay, so we don't know the answer to this yet, and it's going to require an enormous amount of clinical research before we're going to be able to say, yeah, we can team a GLP1 analog with a muscle building compound and basically negate the negative side effects of the one with the other. I'm not ready to say that. And to be honest with you, if anyone is ready to say that, they're a fool or a liar. Let's look at what's already happening now, rather than me sort of predict hyper-optimistic visions of the future. There is some evidence, some survey evidence and some clinical evidence, I think, that people on OZepbic, or Wigovie, or Majaro Zepbound are eating less sugar, are drinking less alcohol.

There's even some evidence that they're snacking less, and snacks tend to be, you know, dense caloric Cheetos and tend to be eating even a little bit more poultry and chicken. and even vegetables and fruit. In a vacuum, wouldn't you agree that any medicine that gets people to eat less sugar, drink less alcohol, eat more vegetables, eat more fish, like Cedars Paribus, shouldn't that be good for metabolic health? And in a vacuum, that would be correct. And we don't live in a vacuum.

In fact, what we know about this is that patients who take these GLP-1 analogs, reduce their alcohol, reduce their sugar, absolutely, reduce their smoking. All things that are driven by the reward center of the brain, the nucleus accumbens. Very clearly, GLP1 has an effect on the nucleus accumbens. There is a pathway directly from the midbrain to the nucleus accumbens, the reward center of the brain. Well, that sounds great. However, in the extreme, if you turn off the reward center of the brain, you get severely depressed.

In fact, major depressive disorder has now been seen in multiple patients on GLP1 analogs and even suicidal ideation. To that point, let's harken back to 2006 when a different obesity drug, hit the European market. Now, this drug was called Accomplia. Okay, the generic name was Romanovance. This was an endocannabinoid antagonist. Okay. So anti-cannabis. It's the anti-Munchy's drug. It bound to the CD1 receptor in the brain and caused people to reduce their food intake. And it was very successful in terms of weight loss. And it got approved in the European Union. The European Food Safety Authority approved it for use.

Within two months of its release, there were 21 suicides in Europe on people who had used it, all with major depressive disorder. Because if you shut down the reward system completely, as these drugs did, there's no reason to live. In fact, reward is the thing that gets you up in the morning. Rewards what gets you out of bed. Rewards what makes you go to your job. So if these GLP1 analogs are having a negative effect on the reward center, that's not necessarily a feature.

That's a bug. That's something we actually have to be worried about. Do you know if the FDA or European Medicines Agency has confirmed in any review of GLP1 drugs for type 2 diabetes patients, they've been taking these longer, or people for weight loss, have any of these reviews found a signal of suicidality across populations? Like, I'm willing to acknowledge that there are anecdotes, and anecdotes might eventually amount to data,

but is there a broad population-wide signal of increased suicidality? yet. Not, so not of suicidality, but of depressive disorder, yes. So, you know, there's a difference between depression and suicidal ideation. You know, that's like one more step. I have not seen, I've only heard the anecdotes about suicidality. However, there is data on increased major depressive disorder being seen with these drugs being used. So this is something where, when you, you know, release it to the, to the market, you know, you're done with your phase three, and now you're doing your post-marketing trials and thousands to millions of people start taking it,

then you have enough data to be able to see the effect. And of course, Novo Nordisk and Lili, Eli Lili, are monitoring for this and appropriately so. Is it something to worry about? Yeah, it's something to worry about. Well, let's go deeper into this category, because I have really three categories that I wanted to talk to you about,

categories of skepticism. Number one, we already talked about the muscle question, and number two is the side effect question. You've talked about the behavioral side effects, depression, maybe anxiety, maybe the social anxiety of your life is changing, right? I, for example, I really like going out and drinking whiskey and wine with my friends. If I was on a drug that made drinking whiskey and wine make me nauseous, that would change my life.

So I am willing to admit that people's lives are changing here. Let's talk a little bit more about the side effect profile. The most common side effects in the phase three clinical trials and also, I think, for clinicians are things like nausea or gastric distress, relatively moderate amounts of gastric distress. Talk about the more serious side effect profile that you're monitoring that makes you skeptical of the larger uptake of these drugs. So as I mentioned earlier, these drugs bind to the GLP1 receptor. Well, there are GLP1 receptors throughout the front of the intestine. I'll ensure why, since the hormones in the back of the intestine.

But nonetheless, they delay gastric emptying. And that's possibly one of the ways that the drug works to reduce total food intake. Because if your stomach isn't moving the food along, there's no reason to be throwing more food down your gullet. The problem is that some patients, and we don't know who yet, there's no marker for this, but some patients will get nausea, and that's a relatively common finding.

They will get vomiting, or less common, but nonetheless still significant finding and can certainly be behaviorally challenging. If you all of a sudden vomit in the middle of a cocktail party, they increase the risk of pancreatitis also within the same symptom complex. But the one that I am most concerned about is gastroparicis, gastro-stomachis. gastro stomach paracus paralyzed in fact stomach turning to stone there are numerous patients now who have taken these glp1 analogs who have had their stomachs basically stop moving and if you stop moving not only do you vomit not only do not want to eat but in fact that's a great way for weight loss because you can't eat and And that is not a little thing.

Worse yet, when you stop the medication, the gastropyracist does not get better. Now, this is really worrisome. The last thing I want to say about these drugs is that about one third of the patients who go on these medications come off these medications because of the side effects. And we've also learned that virtually every single, patient who goes on these medications, if they lose weight, and most of them will, and that's good, turns out if you stop the medication, they gain all of the weight back. Now, if you are truly

affecting metabolic health, if you are truly alleviating the problem that caused their obesity, you would expect to have a little bit more lag time before an increase in weight gain once you discontinue the medication, but you don't. So what this suggests to me is, in fact, we're not actually dealing with the cause of the obesity. We're actually papering over the effects with these drugs, and that the true reason for the obesity is still there. I want to do two things in my response to that. First, I want to acknowledge that you anticipated my third category of concern, which is the adherence problem. when the last episode came out,

some people forwarded me a study that I had not seen. This was a 2020 study of adherence to GLP1 drugs for people with diabetes or with type 2 diabetes. It found that 70% of patients in this study discontinued therapy before 24 months. So only 30% of people were still in a therapy two years later. That is not a relatively high level of adherence. Now, the study could not pinpoint

whether discontinuation was the result of side effects or cost issues. And we're going to get to cost issues in just a second. But I just want to point to your concern that the adherence question is important. I want to double back and ask about what might be an incredibly stupid question about gastro precess because I don't know, I don't really know anything about it. How serious is it and how reversible and how reversible is it? I mean, when you talk about a stomach being paralyzed, I mean, I hear death when you say that. How serious is gastroporesis and how reversible is it?

Well, so we don't yet know what GLP1 analog-induced gastroporesis means for long-term health. We do know what diabetic gastroporesis means for long-term health. We've had a lot of data over the years about diabetes. leading to gastroporesis because of changes in neural function within the stomach wall itself. It is extremely morbid in terms of problems down the line and earlier mortality. Does that hold for the GLP1 analogs? I don't think we know the answer to that yet. Yeah.

In the reports that I read, there were several endocrinologists that said they saw the potential for these drugs. to cause gastropresis, and you're talking about a handful of examples that you know of, some anecdotes. I should say that in the... I have a family member. Oh, wow. In the Phase 3 clinical trials,

for those who are looking at that data, Eli Lilly and Nova Nordisk did not report gastropriesis out, but they did, to your point, find that between 25 and 30% of patients said they experienced nausea on tersephiope. on samagliteite, it was closer to, it was closer to 14, well, five to 14%. So the other side effect profile is there. Yeah, that's what I'm saying. The profile is very real. The last category of

skepticism that I would love you to talk about is the cost. This is one place where I think it's, it's a little bit like college costs where sometimes the sticker price would be $40,000, But when you look under the hood, it turns out that the average person attending one of these schools is paying like $5,000. The reports that I've read suggest that these costs, that these drugs are listed between $1,500 and $1,500 a month. But there's some estimates that the average patient, or 80% of patients, I should say, are spending no more than $50 a month with the rebates and insurance coverage. What is your concern about cost if, indeed, it is the case that the majority of people are not paying more than $50, $100 a month for these drugs? Now, the last time I did this analysis was before the release of Manjaro and Zepound, the Tersepetide. So we only had semaglutide on the market at that point.

but the average retail cost at that point in time was $1,300 a month. And that's actually one of the reasons the only people who were on that drug at that point were the people in Hollywood because they could afford it. And virtually nobody else was getting it. If we take $1,300 a month as the retail cost, okay? And we're not talking about discounts. We're not talking about rebates. We're not talking about, you know, the manufacturer's sticker retail price, you know,

like a car, okay? But you know, just talking about, you know, what they say it costs. If everyone in America who qualified for a GLP1 analog actually got it, that would be $2.1 trillion dollars to the health care system. Now, currently the health care system is $4.1 trillion. That would be a greater than 50% increase in direct costs to the health care system. We can't afford the $4.1 trillion. We're certainly not going to be able to afford a $6.2 trillion health care system. Okay, Medicare is going to be broke by the year 2026. Social Security is going to be broke by the year 2034.

What do you think is going to happen if we add a $2.1 trillion sticker price on top of that? For, by the way, a 16% mean weight loss. That's what you get. A 16% mean weight loss. Now, 16% is not chicken feed. I mean, that's very real. And it has loads of metabolic benefits to be 16% less weight. So I'm not arguing that.

However, if we just cut the added sugar in our diet down to USDA guidelines of 6 to 9 teaspoons of added sugar per day, we would induce a 29% weight loss mean. So almost double the efficacy. And we would save $3.0 trillion. So that's a $5.1 trillion swing for a drug that has side effects versus fixing our food supply. To me, the first thing to do is fix the problem. and the problem is the food. And that's the one thing we've learned from all of the research,

including the research on GLP-1 analogs. It's the food. My response to that point is that if I were president, or better yet, czar of the world, and there were two levers in front of my left and right hand, and one lever was zep bound for all, terseptide for all who are obese, and the lever in front of my right hand was fix the food supply.

I would pull the lever with my right hand and fix the food supply. But I don't see that that lever exists. The food supply is controlled by a range of agricultural and retail companies. It is also shaped by consumer demand. I don't know what lever I could possibly pull to, say, for example, reduce the consumption of Cheetos or candy or sugary drinks. I mean, we're talking about so many different companies from Pepsi and Gatorade and Coca-Cola,

what is the lowest hanging fruit that you see to, as you say, fix the food supply? So, number one, the food supply currently is an absolute disaster, and we're all in agreement on that. Number two, there are 51, different government agencies that regulate our food supply. 51. And the food industry likes it that way, because one doesn't know what the other one is doing. Now, that may change because the FDA is considering appointing a food czar. So we might be able to align interests all under one roof and be

able to actually do something. So, you know, we'll see how that, you know, plays out over time. Number three, you actually can change ultra-process food. We have done it. We've been doing this now with a offshore company in the Middle East, basically the Nestle of the Middle East, called Kuwaiti Danish Dairy Company. Okay. Now, they make frozen yogurt. They make ice cream. They make flavored milks.

They make confectionery. They make biscuits. They make tomato sauce. Like all bad stuff. All right. And Kuwait has an 18% diabetes rate and an 80% obesity rate. And they came to me three years ago and said, we want to be a metabolically healthy company. We want to contribute to the solution not be part of the problem.

And so we convened the scientific advisory team who's been working for the past three years. And we basically came to a consensus on what has to be done to ultra-processed food to make it metabolically healthy. Three things. Protect the liver, feed the gut, support the brain. And we came up with a set of procedures, a set of principles by which any product that this company made, and there were 180 skews in their portfolio, could be turned around to become metabolically healthy. And to their credit, 10% of their company has already been overhauled and re-engineered to be metabolically healthy. And we, have data that customers are still purchasing at the same rate. And the reason is because we didn't tell them. We just did it. How about that? If you tell them it's healthier, they won't buy it because they'll say, oh, it doesn't taste as good. We didn't tell them, and they haven't noticed. How about that? So the idea that you can't change the food system is a canard. You can't change the food system with players who don't want to change the food system. The point is people have to

vote with their feet and they're starting to. We now know, we have data generated by the food industry that says that people want better food because they recognize that ultra-processed food is the reason for the diabetes and the obesity and the heart disease and the cancer and the dementia and young people in particular are calling for better food. So this is going to happen. it's already in progress. So my goal, to be honest with you, is to put Novo Nordisk and Eli Lilly out of business. It is ironic that your goal is to put Novo Nordisk and Eli Lilly out of business. And yet, you know, we've acknowledged that people on these GLP-1s shift their diet

toward almost exactly the kind of diet that you would propose everyone else have for themselves. They shift away from candy, away from sugary drinks, away. from salty snacks toward vegetables and fruit and poultry and fish. I'm not asking you to suddenly become, you know, a cheerleader in the streets for Novo Nordus, but I am pointing out an irony here that one of the side effects of GLP1s is this behavioral shift toward a better food supply. I want to return to the question of skepticism about these drugs by way of summarizing you're, I think, really, really smart.

I won't say case against, but case for caution. Number one, it can reduce muscle mass, and muscle mass is incredibly important for health and longevity. Number two, these drugs do have a nasty side effect profile, while things like nausea are much more common than something like gastroporesis. The risk of gastropriasis is absolutely something to watch out for. Number three, the fact of these nasty side effects could contribute to a low adherence, which means that all of the optimism that people like me feel about GLP1s won't come to pass because if you start the clock now and check back in nine, 12, 24 months,

most people on these drugs will no longer be on these drugs. And as you said, the benefits accrued by being on these drugs don't last when you stop taking them. And number four, and this one I'm a little bit more ambivalent on, you know, if everyone who needed it was on it, it would break the U.S. government. I'm more optimistic about the fact that the combination of generics coming out in 10 years plus competition plus insurance coverage would make it so that Medicare and Medicaid would not be completely overwhelmed by GLP-1s,

but I absolutely stipulate that the cost issue is important because at some point someone has to pay for these drugs. Big gulp of air, followed by my asking, what's the good news? What would you say these drugs are good for, even if your optimism is more bounded than others? what are GLP-1's doing? What can they do that is good, that needs doing,

given the risk of obesity and weight in America? JLP1 is a hormone. Hormones treat hormone deficiencies. Okay, if you're cortisol deficient, you take cortisol. If you're growth hormone deficient, you take growth hormone. Does anyone have GLP-1 deficiency? The answer is no, nobody does. for it. It doesn't exist. So these GLP1 analogs, they do have this effect of, you know, reducing total

food intake and inducing weight loss, and that's good. But we're not fixing a deficiency here, so we have to then question, who is this good for? This is going to come out in further studies, post-marketing studies, figuring out who the best recipient for these drugs are. I don't know the answer to that yet, we will know the answer probably in about four to five years. What I can say is that people with morbid obesity who are at risk of dying, who have enormous comorbidities that are going to cost an enormous amount of money, who are going to end up either with bariatric surgery or death. GLP1 analogs now exist as a possible alternative to bariatric surgery for these patients. That's a good thing, because bariatric surgery should always be last resort. I'm for that. Like I said,

when we started, I'm not against these drugs. I'm actually for them, for the right patient. We have to figure out who's the right patient, and we haven't done it yet. I think it's a very fair case. I think that one way I might sort of place your perspective along a spectrum of other people that I've spoken to is that the people that are more optimistic about these drugs, see these drugs as the solution to more people. They look at the population of people that are obese or overweight, and they say, we're talking about a population that is 110, 150, 250 million Americans. That's the possible population that could be helped by these drugs. And you're saying, divide that by 10. These drugs could absolutely be game changers,

but they are most significantly game changers for people who are obese or who are type 2 diabetes, who haven't talked a lot about the original population of these drugs, who have type 2 diabetes or are significantly obese, who need a solution now because they're at grave risk of death

or otherwise getting bariatric surgery. That is the appropriate population we should be looking at for these drugs. Look, the people you've talked to who think that this is a game changer across the board, they think obesity is a disease. No. Obesity is a syndrome of multiple diseases.

I just described one to you of these kids with brain tumors. They're different than these other patients, right? The point is, there are multiple ways one increases adiposity. I've actually written this up in biochemical pharmacology last year, 2022. All the different hormones, all the different receptors, all the different mechanisms by which weight increases. okay we have just gotten a paper accepted which will be out shortly that is a unifying hypothesis as to how obesity occurs okay why is it that there are chemicals that cause obesity okay like bpa and phallates and pbdees all right they don't have calories right but they still cause

weight gain all right why is it that we have obese newborns when they're They don't diet and exercise. Okay? Four different studies showing an increase of 200 grams at birth and it's all fat. Something else is going on and obesity is just one manifestation of a whole host of different disorders. Now, if you take them all and throw them into one pot and you say, yeah, we can help a whole bunch of people with these drugs. that's missing the point. The goal is find the problem and fix the problem.

And we're just not smart enough to do that yet, but we're getting smarter every day. I want to end on the final place of agreement that I think you and even other GLP1 optimists, as I'll call them, have, which is that I think that for the last few years and even the last few decades, you'd agree that the news media, my comparison, Patriots and some doctors, yours, have often treated obesity as a moral failing, as if this were simply a matter of trying hard or not trying at all, as if the difference between the thin and the fat and those in between is simply a spectrum of willpower. Let me tee you up here. How do you feel about that view?

I am on record since 2006 that says that this is an absolute. absolute fallacy. It is a canard. Okay. The first law of thermodynamics states that energy can neither be created nor destroyed just moved around. The total energy inside a closed system remains constant. Now, in human terms, the standard mantra from the doctors and the nutritionists and the Institute of Medicine and the NIH and the White House and Congress and the food industry is the following. If you eat it, you better burn it or are you going to store it? Therefore, it's about energy balance. Therefore, it's about calories in, calories out. Therefore, it's about two behaviors, gluttony and sloth. Therefore, if you're fat, it's your fault. Therefore, any calorie can be

part of a balanced diet. Therefore, don't pick on our calories. Go pick on somebody else's calories. All of this comes from this notion that the first law starts with behavior. I just showed you a group of patients where we lowered their insulin with a medicine, and they stopped eating, reduced their weight, and started exercising spontaneously. And we actually showed that their resting energy expenditure went up. And the degree of energy expenditure increase correlated with their degree of insulin decrease. So there's another way to express that first law. If you're going to store it, that is an obligate weight gain set up by biochemical forces out of your control,

such as insulin, such as BPA, such as PBDE, such as thallates, you know, and down the line. Paphas, that's another one. And you expect to burn it, that is normal energy expenditure for normal quality of life, because energy expenditure and quality of life are synonymous. Anything that increases your energy expenditure makes you feel good, like ephedron, caffeine, anything that reduces your energy expenditure makes you feel lousy, like hypothyroidism, starvation. So if you're going to store it and you expect to burn it, then you're going to have to eat it. In which case, the two behaviors associated with obesity are actually secondary to a biolibor.

biochemical process. If these GOP-1 analogs have done anything, it has shown us that obesity is driven by biochemistry, not by behavior. And for that, I am eternally grateful. Dr. Robert Lustig, thank you so much. Really appreciate you talking me through your skepticism, your case. I think it's really powerful in something that I'm going to keep front of mind as I continue to follow the story as it will, no doubt, continue to evolve. Thank you very much. Thank you for having. Thank you for listening. Plain English is produced by Devin Biroldi. We've got new episodes every Tuesday and Friday. If you like what you're hearing, give us five stars and a nice review on Apple Podcast or Spotify or wherever you get your podcast. For feedback

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