#226 – How do weight-loss medications affect metabolic health? And will Ozempic and other GLP-1s actually solve the obesity crisis? | Dr. Rob Lustig & Dr. Casey Means

Medications, such as Ozempic, Wegovy, and more, have become increasingly popular for weight loss. These drugs are glucagon-like peptide 1 (GLP-1) receptor agonists, and they mimic a hormone that, among other things, tells the brain a person is full so they eat less. But are they safe, and do they help improve metabolic health? Dr. Rob Lustig and Dr. Casey Means discuss these weight-loss drugs and their effects on the body, and why such medications likely won’t solve the obesity crisis, for which the food industry is culpable.

Helpful links

Robert Lustig, MD: https://robertlustig.com

Robert Lustig, MD, on Instagram: https://www.instagram.com/robertlustigmd/

Robert Lustig, MD, on Twitter: https://twitter.com/RobertLustigMD

Metabolical by Robert Lustig, MD: https://robertlustig.com/metabolical/

Casey Means, MD, on Instagram: https://instagram.com/DrCaseysKitchen

Casey Means, MD, on Twitter: https://twitter.com/DrCaseysKitchen

6:10 — The mechanisms of action for weight-loss medications

Dr. Rob Lustig explains some of the mechanisms of action of glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide (sold under the brand names Ozempic and Wegovy).

They’re both GLP-1 agonists. They look like glucagon, but they’re not, and they bind to a specific receptor. And that receptor exists in several places in the body. One is in the pancreas to increase the amount of insulin, which then controls blood glucose better, and that’s why it’s used for diabetes. But the fun part, if you will, of this molecule is that there are receptors for GLP-1 in the brain, in the brain stem, not in the hypothalamus, but lower in the brain stem, mostly in the nucleus tractus solitarii. And what it does is the GLP-1 analog binds to those receptors and basically tells your brain you’ve eaten. This is actually part of the satiety signal, and what we’re doing is we’re basically hijacking it. And because we have these longer acting medicines than our own GLP-1, it can last longer. So it basically reduces total food intake, and this ultimately results in weight loss.

9:01 — Dr. Casey Means shares her perception of the popularity of GLP-1 medications

Dr. Means recently moved to Los Angeles and has noticed an uptick in conversations surrounding GLP-1 RAs.

Well, I have to say, Rob, the number of times it has come up—I’ve lived in LA for two months—the number of times it has come up… I mean it is the ultimate conversation starter in LA. People are like, “Oh, are you on Ozempic?” It is wild. I can tell you in Bend, Oregon, no one was talking about Ozempic, but in LA it’s literally everywhere. Doctors are talking about it. It’s a tidal wave, which is one of the reasons why I wanted to talk to you about it.

13:12 — GLP-1 RAs lead to fat loss but also muscle loss

Dr. Lustig shares his concerns about GLP-1 RAs, including the loss of muscle mass, which could contribute to sarcopenia. Sarcopenia is an age-related decline in muscle that contributes to frailty.

Well, this drug is not maintaining muscle mass. You are losing equal amounts of muscle and fat. Now, does that improve how you look in a bathing suit? Sure. But does that improve how long you’re going to live? Not a bit. So this is a major issue for this. Now, when you look at people who’ve taken Ozempic, number one, you can actually see it because their muscle just sort of dissolves from their face. They kind of look like they had lipodystrophy, from like the people who were on protease inhibitors for HIV. It’s called “Ozempic face” for that reason because they’re losing muscle out of places that they shouldn’t be losing muscle out of. So this is a big issue and is one of the things that I’m most concerned about. Yes, Ozempic and Wegovy—they basically tell your brain you’ve eaten, and they make your GI tract think that you’ve basically stuffed yourself. And so you have lots of side effects related to nausea, vomiting, and—in rare cases, but nonetheless—well-documented cases of pancreatitis.

18:05 — Do GLP-1 RAs improve metabolic health?

Dr. Lustig breaks down metabolic health concepts and how GLP-1 RAs may affect metabolic health. Ultimately, what a person is putting into their body still matters.

This drug’s job is not to improve metabolic health. Yes. If you lose weight, you are losing fat. And you’re losing fat from places that are metabolically relevant, like for instance, your visceral adipose tissue, your liver. And so there are studies that show reductions in visceral, adipose tissue and reductions in liver fat with Ozempic and Wegovy and Mounjaro, and that’s good. But it’s because of starvation. So the loss of liver fat, the loss of visceral fat, the things that improve metabolic health are also coming along with the loss in muscle mass, which of course is where most of your mitochondria are burning up your energy anyway. And you are losing muscle in a way that is potentially unhealthy and even downright dangerous long term. Now, does it improve mitochondrial function if it reduces the sugar content of your diet because you are eating less and so you’re eating less sugar? Well, then that would be a good thing and that would improve mitochondrial function. But what if you were taking Ozempic and Wegovy to lose weight but you decided to go on a dessert diet and so you were plying yourself with extra sugar. That sugar is still the same mitochondrial toxin.

20: 43 — Dr. Lustig discusses the high cost of GLP-1 RAs

Dr. Lustig compares the greater healthcare costs associated with these medications with an alternative solution.

The fact of the matter is that these medicines are unbelievably expensive. They’re $1,300 a month at the moment. If everyone in America who qualified for Ozempic or Wegovy or Mounjaro got it, that would be a total of $2.1 trillion a year to the healthcare system. Now, the healthcare system currently expends $4.1 trillion a year, so this would be a greater than 50% increase in order to get a 16% weight loss and a mild improvement in metabolic dysfunction. You could get a 16% weight loss with a 70% improvement in metabolic dysfunction if we just got sugar consumption in this country down to USDA guidelines. Instead of spending 2.1 trillion, we would save 1.9 trillion. So to me, this is a Band-Aid. It’s not solving the problem. It’s not fixing the metabolic dysfunction because it’s not targeted to do so; it’s acting in a different place and it’s basically creating a different problem than the one you had. You had obesity, now you’ve got starvation. Now, how good for you is starvation? Not so good with a whole lot of side effects to go with it.

27:47 — Dr. Lustig makes the case for fixing the food problem

Although GLP-1 medications have their place in the healthcare system, Lustig argues that the nation needs to do better on fixing what’s in the food supply to truly reverse the rising rates of obesity.

It only works as long as you’re on it, and as soon as you’re off it, all the weight comes roaring back. Just like if you did a starvation diet and then stopped, all the weight would come roaring back. So this is something you have to be very circumspect about. You have to know your patient. You have to evaluate your patient for whether or not this is the right thing to do, whether there’s any other way to deal with this. Now, I will tell you, until we fix the food, we’re not going fix this problem. We have to fix the food to fix this problem. And by the way, when we do fix the food, we’ll also fix climate change too. So you get two-for-one. So fixing the food is where I’ve spent my entire retirement trying to do that.  Ozempic and Wegovy is not fixing the food. And, yes, it will help some people, but it may actually make more people worse for the reasons I’ve mentioned.

35:46 — How can patients use GLP-1 RAs as a jumpstart?

Dr. Means and Dr. Lustig propose that GLP-1 RAs could be a jumpstart for people to gain momentum in improving their metabolic health. In that case, potentially people wouldn’t need to be on the medications long term for sustained weight loss.

Dr. Means: Given the fact that there are going be millions of Americans on this medication, there are going to be probably a lot of people who have an awakening about the fact that this is not a panacea; it’s not a silver bullet. They might have horrible side effects, and they want to get off it. I think there’s probably going be a huge opportunity for essentially plans for people to—while they’re on the medication—also set themselves up for success for getting off it. Maybe use the medication as a jumpstart to get the motivation and energy to then do the things that actually get to the root cause. So let’s say someone’s listening who’s on Ozempic. This episode’s kind of freaking them out a little bit and they’re thinking they might want to eventually get off it. What do you think are some of the steps that someone could take to really set themselves up for success when weaning? Dr. Lustig: I think that ultimately these medications will be good jumpstarts. In other words, that means that they will be adjuncts to other therapies—ways of getting people to have early success so that they can basically feel some self-efficacy, some agency, that they can actually do something to help themselves and ultimately be able to carry that forward. I’m for that. I’m totally for that. And if that is ultimately how Ozempic and Wegovy are used, I will likely be a proponent for them. That’s not how they’re being used now.

44:20 — Dr. Lustig shares his concerns about the use of GLP-1 RAs in children

Dr. Means notes that in its recent obesity guidelines, the American Academy of Pediatrics recently made the recommendation that these medications and other pharmacological agents be used in kids as young as age 12. Dr. Lustig weighs in on the topic.

Can we ultimately get kids to change their diet so that they don’t need medicine? The answer is no we can’t, because the food environment that they find themselves in is so unbelievably toxic. We have to fix the food environment in the schools. We have to fix the food environment in the grocery store so that the food environment at home can ultimately be fixed. And the parents—we expect them somehow to be the gatekeepers. And the problem is they can’t be. It’s too difficult. We’ve made it too difficult, and of course, that’s the food industry’s goal is to make it too difficult. In addition, most of those parents are sugar addicts themselves, so how are we going to fix the food for the kids if we haven’t fixed the food for the parents? How do you expect the kids to get better when the parent is the sugar addict? … So to me that doesn’t work. It requires a much bigger effort and not expecting that the parent alone is going to be able to solve this problem. Giving drugs to kids is not the right answer, even though I did it, but I did it for the right patient, for the right reason at the right organ. But just throwing Ozempic and Wegovy at kids is not the answer to this problem.

Dr. Rob Lustig (00:07):

This is a bandaid. It’s not fixing the metabolic dysfunction because it’s not targeted to do so. It’s acting in a different place and it’s basically creating a different problem than the one you had. You had obesity, now you got starvation. How good for you is starvation? Not so good with a whole lot of side effects to go with it. One third of the patients who go on these medicines come off them within a very short period of time because of the side effects, not because of the cost. I don’t see this as being the answer to our metabolic health crisis.

Ben Grynol (00:52):

I’m Ben Grynol, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health. And along the way we have conversations with thought leaders about research backed information, so you can take your health into your own hands. This is A Whole New Level.

Casey Means (01:21):

Hello and welcome to A Whole New Level. This is Dr. Casey Means, and I could not be more excited to be sitting here with the incredible Dr. Robert Lustig. If you are a part of the Levels ecosystem, you know this incredible human being as the author of so many incredible books, Hacking of the American Mind, Metabolical, Fat Chance. He’s written over 135 peer-reviewed papers. He’s a professor emeritus of pediatric neuroendocrinology at UCSF. He’s a Levels advisor. He contributes to so many press articles and writes opinion pieces in major outlets. He is absolutely one of the most incredible and smartest humans I know and is absolutely one of the reasons that I’m here today, an absolute inspiration for me and my journey through medicine. And today we are going to talk about one of the hottest topics right now in the press and taking over the world, which is GLP-1 agonists, including Ozempic for weight loss and diabetes, and get Dr. Lustig’s take on the potential of these medications, what they are, what do, and whether they are really going to solve the metabolic health crisis. So welcome to a whole new level, Dr. Lustig.

Dr. Rob Lustig (02:39):

First of all, Casey, thank you for that very kind introduction. None of it’s true. It’s all a lie. But having said that, I do have some opinions on this subject. Unfortunately, they are opinions rather than facts because this is a field that is still in process. We don’t know most of what we think we know.

Casey Means (03:02):

Well, I think that in and of itself is so interesting because so many Americans are taking these medications now and the fact that there isn’t that really hard, clear science is very telling in itself. So let’s jump right in. For people who just are trying to understand the landscape, you are an endocrinologist, so you can really speak to this. What is GLP-1? What is a GLP-1 agonist medication and how are these medications… How have they been used traditionally? And then how are they being used now?

Dr. Rob Lustig (03:35):

Wow, what a complex question. All right, here we go. Endocrinologists have known about a hormone called glucagon for decades. Glucagon is the hormone that we give to diabetics when their blood glucose goes too low. When they’re in hypoglycemia, we give them a glucagon shot to raise their blood glucose because glucagon goes to the liver and basically gets the liver to release all the stored glucose in order to correct the hypoglycemia. So we’ve known about glucagon forever. What we learned back in the early 1980s is that there’s this bigger protein called pre-pro glucagon and that the pancreas, the alpha cells of the pancreas that make it have a different way of chopping it up into making different pieces for different purposes. And so people started looking at, well, what are these pieces? And it turned out that they found pieces that seem to cause the beta cell to release more insulin, not less.

(04:52):

And they called these glucagon-like peptides because they look like glucagon, but they’re a little bit different. And those then got to the pharmaceutical industry and they started making the first GLP-1 agonists. Now, the first successful GLP-1 agonist was actually obtained from the Gila monster from Gila monster spit. And it’s one of the reasons why the Gila monster is poisonous. And that peptide was called exenatide, also marketed under the trade name Bayada. And we started using Bayada in pediatric endocrinology and adult endocrinology for taking care of diabetes because it seemed to kick the beta cell to release more insulin. And so that was a good thing for a while. And Bayada had a reasonable success as an adjunct to diabetes therapy for several years. And over the course of time, as you’d expect, the pharmaceutical industry started making better, longer-lasting, more potent agonists that would do the same thing in terms of being able to treat diabetes.

(06:11):

And they came up with one called Semaglutide or Ozempic. Back in about 2017, 2018, the data started rolling in that Ozempic was a better adjunct for diabetes therapy than Bayada was. And what they saw was that there was a modicum of weight loss as well. So some brilliant guy at Novo Nordisk said, “Well, if this is causing weight loss, maybe we can give a bigger dose and it will cause more weight loss.” So that resulted in this branded version called Wegovy. So both Ozempic and Wegovy are the same medicine. They’re both semaglutides. They’re both GLP-1 agonists. They look like glucagon, but they’re not. And they bind to a specific receptor. And that receptor exists in several places in the body. One is in the pancreas to increase the amount of insulin, which then controls blood glucose better and that’s why it’s used for diabetes. But the fun part, if you will, of this molecule is that there are receptors for GLP-1 in the brain, in the brain stem, not hypothalamus, but lower in the brain stem mostly in the nucleus tractus solitarius.

(07:42):

And what it does is the GLP-1 analog goes to those binds to those receptors and basically tells your brain you’ve eaten. So this is actually part of the satiety signal, and what we’re doing is we’re basically hijacking it. And because we have these longer acting medicines than what our own GLP-1 did, it can last longer, so it basically reduces total food intake and this ultimately results in weight loss. And so Novo Nordisk got approval for both Ozempic and for Wegovy. Eli Lilly is working on their own medicine, which is a GLP-1 analog, but also has secondary effects on a second receptor that’s involved in satiety called GIP, which is gastric inhibitory peptide. So it has double duty, and that one is called Tirzepatide, also known as Mounjaro.

(08:46):

And that’s coming out very shortly and has been approved by the FDA for weight loss as well. So these are now available and they work and people are like, “Whoa, the first medicine that actually works.” And there are good data and lots of double-blind placebo controlled trial data that show that you can lose 16% of body weight with these medicines. And so obviously everybody and his brother wants it. And unfortunately it’s $1,300 a month. So only the people in Hollywood are getting it. And in fact there’s a shortage because everyone in Hollywood’s on it, maybe that’s why you moved to LA, Casey, only kidding. You look fantastic. And I know it’s not because of Ozempic. I promise the audience that is not why. Okay, I love Casey. She is not an Ozempic addict.

Casey Means (09:50):

Well, I have to say Rob. I’ve lived in LA for two months, the number of times it has come up, people saying… I mean, it is the ultimate conversation starter in LA. People are like, “Oh, are you on Ozempic? Are you trying…?” I mean, it is wild. I can tell you in Bend, Oregon, no one was talking about Ozempic, but in LA, it’s literally everywhere. Doctors talking about it. It is a tidal wave, which is one of the reasons why I wanted to talk to you about it. Just to make sure I understand the science, because medical school was a long time ago. So I understand that glucagon naturally in the body, it raises blood sugar, but it also stimulates the beta cells to secrete insulin. So I’m confused about how those two things kind of happen together. I would imagine that if it was stimulating more insulin secretion… Well, three things I’m a little confused about. If it’s stimulating insulin secretion, why wouldn’t that lower blood sugar?

Dr. Rob Lustig (10:45):

Well, it does lower blood sugar,

Casey Means (10:48):

But what is the glucose raising effect that you were mentioning?

Dr. Rob Lustig (10:51):

So the glucagon was raising it, but the GLP-1 is not because it’s actually stimulating insulin to keep the glucose low, which is why it works in diabetes.

Casey Means (11:00):

But it’s acting as an agonist.

Dr. Rob Lustig (11:03):

That’s right. It’s acting at the GLP-1 receptor, not at the glucagon receptor. Those are two different receptors.

Casey Means (11:09):

Got it. Okay. So its main point is to stimulate insulin secretion. So then I guess the second question I have is how is that conducive physiologically to weight loss if it’s… Yes, because I would imagine we know from your work and [inaudible 00:11:26] work and others that excess insulin hyperinsulinemia is going to potentially contribute to insulin resistance and storage of fat. So how’s that working?

Dr. Rob Lustig (11:34):

Totally. So this is the dichotomy of this, and one of the reasons we don’t understand this very well, for just that reason. When you ask the question, why does this work? The answer is we don’t really know. To this day, we still don’t know. And that is exactly right because if you are actually increasing insulin release, which these medicines do, then you should be forcing more energy into fat, but yet people are losing weight. Okay, so how do you square that? How do you rationalize that? And the answer is we don’t really know, except that people who take these medicines eat much less. And so they are losing weight because they are eating less, irrespective of the fact that their increased insulin secretion should be driving more fat gain. Now the question is, are these people losing weight because they’re losing fat? Or are these people losing weight because they’re losing muscle or are they losing something else entirely?

(12:50):

So the data on this is very clear. You put these people in DEXA scanners, so you can look at body composition changes. And what you can see on people who are taking Ozempic and Wegovy and Mounjaro is that they are losing equal amounts of muscle and fat. Now the question is, is that a good thing? And the answer is absolutely not. That is by far and away not a good thing. So when you lose both muscle and fat, that’s what starvation does. So your body composition is changing in a way that is consistent and indicative of starvation. Now, if you’re a 65-year-old or older and you lose muscle, you’re going to die. Sarcopenia, which is loss of muscle mass, is one of the hallmarks of aging and one of the hallmarks of early death. And just read Peter Attia’s book, Outlive, about how important it is to maintain muscle mass.

(14:01):

Well, this drug is not maintaining muscle mass. You are losing equal amounts of muscle and fat. Now, does that improve how you look in a bathing suit? Sure. But does that improve how long you’re going to live? Uh-huh. Not a bit. So this is a major issue for this. Now, when you look at people who’ve taken Ozempic, number one, you can actually see it because their muscle just sort of dissolves from their face. They look like they had lipodystrophy, like the people who were on protease inhibitors for HIV. It’s called Ozempic face for that reason because they’re losing muscle out places that they shouldn’t be losing muscle out of. So this is a big issue. In addition, and one of the things that I’m most concerned about, yes, Ozempic and Wegovy, they basically tell your brain you’ve eaten and okay, that’s good, but they tell your brain you’ve eaten and they make your GI tract think that you’ve basically stuffed yourself.

(15:17):

And so you have lots of side effects related to nausea, vomiting. Rare cases, but nonetheless well-documented cases of pancreatitis. There’s a concern about thyroid cancer. There’s a concern about pancreatic cancer, at least with the old versions of GLP-1 analogs like Bayada, there was a definite relationship to pancreatic cancer. That has not yet shown up with Ozempic and Wegovy, but I don’t think it’s been out on the market long enough for us to be able to see that in post-marketing studies, so that’s a continued concern. I just read this morning about a set of cases of patients who now have gastroparesis. They have paralyzed intestinal tracts, paralyzed stomachs that can’t move food through the intestine at all, even though they’ve been off the medicine for six months to a year. So these are things that happen in post-marketing once it’s available to the entire country or even the entire world that weren’t necessarily obvious in the original studies to get it approved because it was a much smaller population. So I don’t think the final story on Ozempic and Wegovy is written.

(16:42):

There are people who are absolutely excited about it because it’s the first time that a drug has actually worked for weight loss. I mean, every other drug for weight loss has been pulled off the market for side effects. Well, guess what? This one has side effects too. Different kind of side effects than before, but nonetheless, side effects. So this is not something for the squeamish and it is not something just to fit in a bathing suit. Does it make a difference for people who are morbidly obese? Can it improve their lives? Yeah, sure. But you’re bypassing the problem. You’re not fixing the problem. The problem is not that you have GLP-1 deficiency. No one has GLP-1 deficiency. That’s been looked for. There is not one case of GLP-1 deficiency. You are not treating a hormone deficiency with a hormone. If you have diabetes, you’re treating it with insulin. Okay, that makes sense because you’re actually fixing the problem. Here, we’re bypassing the problem. We’re basically telling your brain, “Yeah, you’re fat. So starve.” And an emaciated fat person is not a thin person.

Casey Means (18:06):

If you’ve heard me talk on other podcasts before, you know that I believe that tracking your glucose and optimizing your metabolic health is really the ultimate life hack. We know that cravings, mood instability, and energy levels and weight are all tied to our blood sugar levels. And of course, all the downstream chronic diseases that are related to blood sugar are things that we can really greatly improve our chances of avoiding if we keep our blood sugar in a healthy and stable level throughout our lifetime. So I’ve been using CGM now on and off for the past four years since we started Levels, and I have learned so much about my diet and my health. I’ve learned the simple swaps that keep my blood sugar stable like flax crackers instead of wheat-based crackers.

(18:53):

I’ve learned which fruits work best for my blood sugar. I do really well with pears and apples and oranges and berries, but grapes seem to spike my blood sugar off the chart. I’m also a notorious night owl, and I’ve really learned with using Levels, if I get to bed at a reasonable hour and get good quality sleep, my blood sugar levels are so much better. And that has been so motivating for me on my health journey. It’s also been helpful for me in terms of keeping my weight at a stable level, much more effortlessly than it has been in the past. So you can sign up for Levels at levels.link/podcast. Now, let’s get back to this episode.

(19:37):

The question that’s just been weighing on me and one that I’ve been trying to sort of pick apart research papers to see if I can answer this question, but I don’t think I have a clear answer, which is do GLP-1 agonists actually improve metabolic health in any way that we know? And first of all, maybe you can answer that question by defining or on a biomarker level how you would define metabolic health. And we have an episode that we did on that in the past talking about some of the key biomarkers and whether we know whether these medications actually are improving those critical biomarkers of metabolic health. And basically, does this improve our mitochondrial function, improve our oxidative stress, improve the things in our cells that are actually going to make us fundamentally metabolically healthier? Is there a clear understanding of this?

Dr. Rob Lustig (20:30):

So the answer to that is that’s not this drug’s job, is not to improve metabolic health. Yes, if you lose weight, you are losing fat and you’re losing fat from places that are metabolically relevant, like for instance, your visceral adipose tissue, your liver. And so there are studies that show reductions in visceral adipose tissue and reductions in liver fat with Ozempic, the Wegovy and Mounjaro, and that’s good, but it’s because of starvation. So the loss of liver fat, the loss of visceral fat, the things that improve metabolic health are also coming along with the loss in muscle mass, which of course is where most of your mitochondria are burning up your energy anyway, and you are losing muscle in a way that is potentially unhealthy and even downright dangerous long-term. Now, does it improve mitochondrial function? If it reduces the sugar content of your diet because you are eating less and so you’re eating less sugar, well then that would be a good thing and that would improve mitochondrial function.

(21:55):

But what if you were taking Ozempic and Wegovy to lose weight? Okay, but you decided to go on a dessert diet and so you were applying yourself with extra sugar. That sugar is still the same mitochondrial toxin whether you’re on Ozempic or Wegovy or not, because it still has to get metabolized and it’s still going to interfere with AMP kinase and ACADL and CPT-1 in your mitochondria. And so you are still going to have mitochondrial dysfunction. These drugs do not fix that. What they fix is your overeating. Okay, can you stop your overeating and still be metabolically unhealthy? Absolutely. It’s not going to fix that. But if you eat less, that’s at least less burden on your liver and on your pancreas. So yes, there are improvements in metabolic parameters related to weight loss, but not related to dietary improvement.

(23:10):

That’s what it comes down to. The fact of the matter is that these medicines are unbelievably expensive. They’re $1,300 a month at the moment. If everyone in America who qualified for Ozempic or Wegovy or Mounjaro got it, that would be a total of $2.1 trillion a year to the healthcare system. Now, the current healthcare system currently expends 4.1 trillion a year. So this would be a greater than 50% increase. In order to get a 16% weight loss and a mild improvement in metabolic dysfunction, you can get a 16% weight loss with a 70% improvement in metabolic dysfunction. If we just got sugar consumption in this country down to USDA guidelines and instead of spending 2.1 trillion, we would save 1.9 trillion. So to me, this is a bandaid. It’s not solving the problem.

(24:29):

It’s not fixing the metabolic dysfunction because it’s not targeted to do so. It’s acting in a different place and it’s basically creating a different problem than the one you had. You had obesity, now you got starvation. Now how good for you is starvation? Not so good with a whole lot of side effects to go with it. The nausea and the vomiting, there are a lot of people who go on one of these drugs and they’re on it for a weekend. They come right off it. One third, fully one third of the patients who go on these medicines come off them within a very short period of time, within two months because of the side effects, not because of the cost, but because of the side effects. Now the cost doesn’t help. I don’t see this as being the answer to our metabolic health crisis, both from a physiologic level, from a side effects level, and also from an economic level. I think this is a bandaid. Okay, it’s a good bandaid. It’s a better bandaid than what we had before. But no, this is not going to be the answer. We’re not there.

Casey Means (25:40):

So what I’m hearing you say is that there’s almost essentially a $4 trillion delta between if we go triple down on this, spend $2.1 trillion potentially on giving this to everyone who qualifies for it. And of course that may not really reduce any healthcare costs. So we’re adding basically $2.1 trillion to the system versus if we focused on food and getting the sugar out of the food, getting people access to the real whole unprocessed food that feeds the gut, supports the liver, we could actually cut $1.9 trillion from our 4.1 trillion healthcare costs. We’re really looking at just a monumental kind of misinvestment in resources potentially that could go towards something else, but of course feed the pharmaceutical industry’s bottom line. And it’s been so interesting to see how Nova Nordisk and the incredible amount of payments they’ve made, consulting fees and payments to doctors over the past few years, really trying to, I think really influence the primary care and obesity medicine and endocrinology landscape.

(26:50):

And you can’t help but wonder what’s happening there. And the real push towards classifying obesity as a chronic disease and a real push towards federal funding and insurance coverage for these medications, it really feels like there’s a big force happening here to essentially use taxpayer money to go towards a pharmaceutical intervention rather than a food intervention. And I think a lot of people say, “Well, the food is too hard, it’s too hard to do.” But I step back and think, if we’re talking about trillions of dollars here, is it really that hard? Could we not figure this out with trillions of dollars, how to give people whole food and get rid of the sugar? And so it just feels like a really interesting interplay of sure, like advanced science and technology, which all for innovation, but also just really a distraction from the core issues that we’re facing.

Dr. Rob Lustig (27:51):

That’s how I view this. I view this as a distraction, unfortunately. I wish it were not. I wish there were a better answer. What I see is that there are people who are an extremist because of their obesity and they need help. Okay, I’m a scientist, but I’m also a doctor and I also have compassion. And I recognize that there are people who actually need help and this should be available for them. So I am not against these medicines. Hell, I used Bayada. I mean, I’m retired now, so I haven’t used these newest GLP-1 analogs, but I used to use the other one for the right patient. And I’m not against this for the right patient, but to sort of throw this out willy-nilly is sort of missing the point. This is exactly what we did with bariatric surgery. And what we found was that when we did bariatric surgery on a whole host of people and not in a clinical research study being done, but rather just out in the community, fully one third of patients gained the weight back.

(29:03):

And the reason was because their problem was not one that bariatric surgery could fix. They had food addiction or they had stress eating, and in fact, the bariatric surgery didn’t fix those things. Bariatric surgery will fix hunger. It won’t fix reward or stress. So you have to screen patients for who’s who, who the best patient to use it in is. We’re not doing that. We’re basically treating them all like they’re all the same. Basically that they all have a moral failing, and that’s the whole story, and that’s complete utter garbage. And I’ve spent my entire career debunking that notion. Unfortunately, there are still doctors out there who think that obesity is a moral failing, and so they’re going to say, “Well, you haven’t responded to anything else.” That’s because you haven’t actually dealt with the problem. “Okay, so here’s this medicine. And there you go.” And look, the medicine does work, and as soon as you stop it, all the weight comes right back. So how good is that and is that going to solve any problem?

(30:11):

All you’re going to do is waste all this $2.1 trillion a year, and it only works as long as you’re on it. And as soon as you’re off it, all the weight comes roaring back. Just like if you did a starvation diet and then stopped, all the weight would come roaring back. So this is something you have to be very circumspect about. You have to know your patient, you have to evaluate your patient for whether or not this is the right thing to do, whether there’s any other way to deal with this. Now, I will tell you, until we fix the food, we’re not going to fix this problem. We have to fix the food to fix this problem. And by the way, when we do fix the food, we’ll also fix climate change too. So you get two for one. Fixing the food is where I’ve spent my entire retirement, is trying to do that Ozempic and Wegovy is not fixing the food. Yes, it will help some people, but it may actually make more people worse for the reasons I’ve mentioned.

Casey Means (31:21):

One question I have is about the type 2 diabetes population who have been taking semaglutide for diabetes management. Does the research suggest that taking this does improve metabolic parameters over the long term as well as improve survival and reduction of other comorbid diseases that may cause premature mortality like cardiovascular disease and stroke, cancer, and chronic liver disease. Does it seem to prevent some of those outcomes and extend life, or is it mostly improving the parameters like glucose levels? And I guess more broadly, does it improve insulin sensitivity in a type two diabetic patient or does it just reduce blood sugar levels?

Dr. Rob Lustig (32:13):

These are really, really good questions, Casey, and we don’t have the answer to those. Okay, that’s like a really, really important question. So what you’ve got here is a give and take. You’ve got to trade. So yes, you’re losing fat, but you’re also losing muscle and probably micronutrients that you need because you’re eating less. So there’s going to be some good things out of reducing your weight and there are going to be some bad things out of reducing your weight. And ultimately those events and mortality, we don’t have the answers to those yet. Drugs haven’t been around long enough to be able to look at that. This is very similar to the question that we had with bariatric surgery. Okay, does bariatric surgery improve lifespan? And the answer is in some patients, not in everybody. In fact, bariatric surgery increases the risk of alcoholism by a lot.

(33:20):

And the reason is because those people were sugar addicts before and now you’ve made it so that they can’t get their fix because you’ve put something in there to keep you from being able to consume it. And so instead of eating their fix, they’re going to drink it. All right? Now, I’ve heard about people going on Ozempic and Wegovy, I’ve seen at least anecdotal reports that it’s increasing the risk of depression and it’s increasing the risk of suicidal ideation because it’s interfering with your ability to generate reward. So if you’re a sugar addict, then you’re supposed to be… I mean, the only thing that’s keeping you from the abyss is your next dose and you now are not consuming it. Maybe that’s going to be a problem in terms of reward, think about the medication back in 2006 that was put up for approval at the FDA called Rimonabant.

(34:27):

Do you remember Rimonabant, Casey? So Rimonabant, also known as Acomplia, marketed by Sanofi in Europe and was approved by the European Drug Commission. It was an endocannabinoid antagonist, so it bound to the same receptors that marijuana binds to the endocannabinoid receptor because we have endocannabinoids in our brain, 2-AG and another one I’ve forgotten the name of right now. The bottom line is people who went on Rimonabant lost a lot of weight and the reason was because you suppressed reward by using these medicines. Well, you suppress rewards, so you suppressed food intake and you also increased the number of people who jumped off bridges. Okay? Massive depression. 21% of all patients who took Rimonabant ended up with major depressive disorder and a lot of them committed suicide, and the US never approved the drug.

Casey Means (35:33):

I had sort of been under the impression that some of this mental health, the rumblings about this may be impacting mental health in a negative way, were potentially due to gut and microbiome issues, of course… And who knows? But I hadn’t made the link between the reward. That is so interesting for me. I’m just like, “You don’t mess with the gut and not expect something to happen.” The gut is everything I preach to the choir, but that to me feels like a Pandora’s box that we’d want to understand before mass prescribing to kids as young as 12, which it’s now is approved for. So that’s so interesting about the reward circuitry. One question that I’m sure people will want to double click into that you touched on earlier was this idea that people regain the weight after they get off this medication. Can you speak to two things? What does the data say about weight regain after stopping this? How many people are gaining it back?

Dr. Rob Lustig (36:39):

If you stop it, it comes back. It’s that simple basically going on. This means you’re staying on it forever. The reason is because you’re not solving the problem. You are bypassing the problem. The problem is still there.

Casey Means (36:52):

So would the experience be for patients you’ve had who have maybe gone on in [inaudible 00:36:58] Moffitt that you get off it and are you insatiably hungry or what is that experience like?

Dr. Rob Lustig (37:05):

That is what I hear. What I hear is you basically put the weight back on within a month or two. So this is really just sort of a stopgap measure, and as soon as you stop it, it will roar back. It’s not solving the problem, it’s bandaiding the problem. So now in some cases, do you need a band-aid? Sure. Okay. But you have to be very circumspect about who you’re going to use this in. And right now we’re not doing that because it’s new. So everyone uses it, all these early adopters, and then we find out, “oh, not so much.” And then the whole pendulum swings back the other direction, nobody should be on it. And ultimately it will find someplace in the middle where it will settle in because that’s the nature of how all new therapies get rolled out. It gets used, then it gets overused, then it gets underused and it comes back to the center. Right now we’re in the overused state.

Casey Means (38:14):

So given the fact that there are going to be millions of Americans on this medication, and there are going to be probably a lot of people who have an awakening about the fact that this is not a panacea, it’s not a silver bullet. They might have horrible side effects, they want to get off it. I think there’s probably going to be a huge opportunity for essentially plans for people to, while they’re on the medication, also set themselves up for success for getting off it and maybe use the medication as a jumpstart to get the motivation and energy to then do the things that actually get to the root cause. So let’s say someone’s listening who’s on Ozempic, this episode’s kind of freaking them out a little bit and they’re thinking they might want to eventually get off it. What do you think are some of the steps that someone could take to really set themselves up for success when weaning?

Dr. Rob Lustig (39:00):

Right. I couldn’t agree more. I think that ultimately these medications will be good jump starts. In other words, that means that they will be adjuncts to other therapies, ways of getting people to have early success so that they can basically feel some self-efficacy, some agency that they can actually do something to help themselves and ultimately be able to carry that forward. I’m for that. I’m totally for that. And if that is ultimately how Ozempic and Wegovy are used, I will likely be a proponent for them. That’s not how they’re being used now.

(39:42):

But if you can see that changing your diet will basically be something that you can actually do and follow through on and Ozempic and Wegovy help you get there to that point where you can actually change what’s in your pantry and you’ll be able to sort of subdue the cravings so that you don’t go backwards and fall backwards, I think that would be a fine way to do it. So it could be sort of a short term jumpstart and then come off it and use it in that respect with that in mind. But that means that you need a nutritionist involved. That means that you’re going to need your primary care physician to really sort of take command and help you navigate how to do this and how to navigate the grocery store going forward. So I could see these drugs being an adjunct to a more codified lifestyle program, and then maybe there’ll be a good value to them.

Casey Means (40:56):

Yeah, I mean, I’m just thinking like, okay, let’s say there’s someone who is morbidly obese and they’re really just don’t have the energy or motivation to get started. They get some early success with a medication like this, get more energy, they’re able to move more. I can imagine a situation in which at that moment, if they’re able to get a support team around them, exactly what you said, learn how to cook, shop at the grocery store, prepare whole foods, start a resistance training program so they lose as little of the lean muscle mass as possible, maybe even build some, really dial in on protein and amino acids and prevent the sarcopenic effect work on the mental health piece. And then maybe it helps them then eventually just move from one state to a much better future and get off the medication eventually. But I just don’t see a situation in which, if none of that happens, there’s no resistance training, there’s continuing to eat ultra processed foods, just less of them, that the body getting less of something crappy is not the equivalent of health.

Dr. Rob Lustig (42:09):

If something is toxic, then less of something is less toxic, but that doesn’t make it healthy.

Casey Means (42:15):

Well, okay. So you have some of the most, I think, amazing perspective on actually evidence-based, the actually evidence-based ways for sustained weight loss, especially in children. And I know you’ve done some research in your work on this, so I know the American Academy of Pediatrics recently and their obesity guidelines that were released in January made a recommendation that these medications and other pharmacologic agents for obesity could be used in children as young as 12. I wonder if you could just speak to some of your research about weight loss in children, about what are the factors that actually allow children to lose weight in a sustainable way? And maybe just your commentary generally on the AAP guidelines.

Dr. Rob Lustig (43:02):

Right. So the AAP guidelines that came out earlier this year said two things, and one I agree with and the other one I disagree with. So what did it say? It said that obesity is a problem. I agree. Obesity is a problem. They said that pediatricians have far too long ignored obesity in the children that they see. And that by saying to parents, “Oh, it’s just baby fat, it’ll go away.” You’re actually perpetuating the problem. So they called the pediatricians on the carpet for basically ignoring the problem as the problem festered under their feet. That part of the AAP guidelines I agreed with. Then was the second part, which I disagree with. What it said was “Because obesity is such a problem and because it is a disease and because kids aren’t getting better, you are entitled and rightfully, appropriately commissioned to use medication as young as 12 years old.”

(44:26):

Now look, I used medication when I was head of the OBC program at UCSF. Fully, one quarter of the patients that I took care of were on Metformin. And the reason that they were on Metformin was because Metformin was targeted at the problem. These kids had insulin resistance. They needed their insulin to go down. I knew that as long as their insulin stayed up, they were going to continue to gain weight because insulin is the energy storage hormone. Get the insulin down. And Metformin was the drug that we had at our disposal at that time that kids could take that would get the insulin down. And the reason is because it worked at where the insulin problem was, the liver. It was targeted to the liver to improve insulin sensitivity at the level of the liver by increasing the enzyme AMP kinase.

(45:25):

Now AMP kinase is the fuel gauge on the liver cell. It is the thing that tells your liver to make more mitochondria. So if you increase AMP kinase activity, you’re going to make more mitochondria, which means you’re going to burn energy better and faster, and you’re going to improve insulin sensitivity, and you have then a chance to get your insulin down and have weight loss. That’s why we used it because it was directed to the correct problem. I also knew from my own studies from back in the nineties when Metformin first came out, that if the kids consume soft drinks, Metformin was useless, did not work. And the reason was because they were poisoning that AMP kinase. So you can’t raise your AMP kinase when it’s being poisoned. It doesn’t work. All right, so soft drinks were the antithesis of Metformin activity, and I had to get people off the soft drinks before the Metformin would work.

(46:27):

All right? I had to do both. I had to stop the soft drinks and do the Metformin, but when I did that, then it would work. And I had plenty of good data to show that. And I published this. This was out in the world. How many people did it? How many the pediatricians adopted that? Only the ones who listened to me, which is not enough. All right, now, can we ultimately get kids to change their diet so that they don’t need medicine? And the answer is no, we can’t because the food environment that they find themselves in is so unbelievably toxic. We have to fix the food environment in the schools. We have to fix the food environment in the grocery store so that the food environment at home can ultimately be fixed. And the parents, we expect them somehow to be the gatekeepers. And the problem is they can’t be. It’s too difficult that we’ve made it too difficult.

(47:38):

And of course, that’s the food industry’s goal is to make it too difficult. In addition, most of those parents are sugar addicts themselves. So how are we going to fix the food for the kids if we haven’t fixed the food for the parents? How do you expect the kids to get better when the parent is the sugar addict and is still bringing the Oreos into the house? What’s that about? So to me, that doesn’t work. It requires a much bigger effort and not expecting that the parent alone is going to be able to solve this problem. So giving drugs to kids is not the right answer, even though I did it, but I did it for the right patient for the right reason at the right organ. But just throwing Ozempic and Wegovy at kids is not the answer to this problem.

Casey Means (48:42):

Wow. I feel like we need to end on a more uplifting note because this… I mean, I know we’re working on… Both of us, Eat REAL is an amazing organization that’s trying to change food in schools.

Dr. Rob Lustig (48:54):

We’re fixing K to 12 food in schools because it’s actually cheaper to make real food than it is to make processed food if you know how. And that’s what Eat REAL does. So everybody out there eatreal.org, look it up, support it, get your school cafeteria food services director to call us.

Casey Means (49:18):

Absolutely. Nora LaTorre, the founder, is just an amazing powerhouse. And I think that organization is just… It’s at the nexus of children’s health, family health, school, food and environment because of the way we’re growing food and it’s so powerful.

Dr. Rob Lustig (49:36):

I got two female forces in nature. I got you. You’re a redhead. And I got Nora. She’s a blonde. Okay, I’m looking for a brunette.

Casey Means (49:45):

Yeah. We got to find one. Well, Rob, thank you so much. I mean, I think this has been such an interesting conversation and yeah, no, I’m pretty pissed at the AAP about this guidelines. Honestly, the recommendations are that pharmacologic intervention for kids for weight as well as bariatric surgery. And it’s like we’re going to say that bariatric surgery and drugs are the answer, instead of fixing food, even though it would be cheaper in the long run to fix food and almost call it… In the guidelines, which I read the entire, they’re saying it’s a social justice issue, which is true. And that’s why we have to lean on medications and surgery because it’s almost easier. But it’s like if the AAP, yeah, if they got on a grandstand and said, “You got to fix the food.” So it’s like, why isn’t every doctor on that panel, on every platform possible screaming for better food? We all have voices. Why is that not happening?

Dr. Rob Lustig (50:53):

Why is that not happening?

Casey Means (50:56):

So on that note, Rob, it has been such a pleasure. This episode, I learned so much. I think a lot of people are going to learn so much. I’m so grateful for you and every single thing you’re doing in the world. You are changing the world with every word you say and everything you do. And I’m so grateful for you. Thank you so much for being on the episode.

Dr. Rob Lustig (51:19):

I’m grateful for you.