Ozempic

Ozempic is being hailed as “the end of the Obesity Epidemic.” This week, Mike and Aubrey dig through the sensational claims. But will they make it past the caveats?

Links: 

• How a Canadian scientist and a venomous lizard helped pave the way for Ozempic 
• The Discovery and Development of Liraglutide and Semaglutide 
• Ozempic and Wegovy maker courts prominent Black leaders to get Medicare's favor 
• Insurers clamping down on doctors who prescribe Ozempic for weight loss
• Ozempic prescriptions can be easy to get online. Its popularity for weight loss is hurting those who need it most    
• Glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: real-world evidence from a Mediterranean area
• Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity
• Real-world weight change, adherence, and discontinuation among patients with type 2 diabetes initiating glucagon-like peptide-1 receptor agonists in the UK
• Safety of Semaglutide
• Semaglutide for the treatment of overweight and obesity: A review
• Once-Weekly Semaglutide in Adolescents with Obesity
• Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5
• Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases
• Real-World Adherence and Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists Therapy in Type 2 Diabetes Mellitus Patients in the United States
• Medications and conditions associated with weight loss in patients prescribed semaglutide based on real-world data

Thanks to Doctor Dreamchip for our lovely theme song!

Transcript

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Aubrey: Wait, have I ever told you about steakhouse or gay bar? Hang on, I want to look it up just because it's-- yep. 

Michael: Is it?

Aubrey: Here we go.

Michael: What does it have? 

Aubrey: Magic Castle. 

Michael: Oh, it's got to be steakhouse. 

Aubrey: Yeah, correct. Stockyards. 

Michael: Oh, that's a gay bar. 

Aubrey: Incorrect, steakhouse.

Michael: What? 

Aubrey: Excelsior. 

Michael: That's either a bad steakhouse or a bad gay bar. 

Aubrey: Oh, gay bar. 

Michael: Fuck yes. 

Aubrey: Oh, Juicy Lucy's, that's a steakhouse.

Michael: Thick cock in my asshole. [laughs] Steakhouse, wow. 

Aubrey: Charlie Brown's. 

Michael: Not touching that. I'm not touching that, let's move on. 

[laughs]

Aubrey: It was a steakhouse. 

Michael: Aubrey, why can't we do a fun episode? Why can't we just do this for an hour instead of talking about Ozempic?

[music]

Michael: Welcome to Maintenance Phase, the podcast that works in the short term, but has never been tested for more than two years. [laughs] That's kind of true. Actually, accidentally. 

Aubrey: That is a pretty accurate thing to say about our podcast. It hasn't been tested in long term. 

Michael: People go back to where they were. I'm Michael Hobbes.

Aubrey: I’m Aubrey Gordon. If you would like to support the show, you can do that at patreon.com/maintenancephase or you can subscribe on Apple Podcast. It is the same audio content. Michael.

Michael: Aubrey, let's start with your nervousness, my nervousness.

Aubrey: [makes retching noises] We're going to talk about it. 

Michael: Your complicated feelings. 

Aubrey: So, today we are talking about Ozempic, Wegovy, and their active ingredients, semaa-glutide.

Michael: Wait, I thought it was sema-glutide.

Aubrey: I thought it was too. And then, I heard a million doctors say semaa-glutide.

Michael: Semaa-glutide?

Aubrey: Doesn't that seem wrong? 

Michael: Yeah, but sure, I mean, they're made-up words anyway, and then on some level, every word is made up, so whatever. 

Aubrey: Well, listen, Mr. Denouement, [laughs] it's a safe space for creative pronunciation. 

Michael: The thing is, so much of the fucking feedback to this show is about my pronunciations of words. No one ever wants to give me feedback on the content of the show. 

Aubrey: Michael.

Michael: Aubrey.

Aubrey: This episode is actually a little different than how we usually do things.

Michael: Yes.

Aubrey: I'm going to walk us through the drug and its origins. You're going to walk us through the clinical trials into this sort of class of drugs. And then, we're going to talk about what I think is the thorniest part of all of this, the discourse around those drugs. 

Michael: The discourse. 

Aubrey: This is a big one. It feels like a really high stakes conversation. So, I'm curious about for you, what are some of the things that you're sort of like bringing to that?

Michael: I think my weirdness with this episode is the culmination of my weirdness with every episode of the show where both of us are interested in public health, in the kinds of things that are prescribed, how drugs get approved, what they mean societally. Whereas because Americans have been trained by health media for our entire lives to see everything through an individualistic lens, we are going to be spending, basically, this entire episode talking about the narratives around Ozempic and Wegovy. We have this new generation of weight loss drugs that as of now, appear to deliver much more weight loss than any previous generation of weight loss drugs. And we've had this immediate huge wave of media being like, "Is this the end of obesity? Does this invalidate body positivity? And being a dietitian in the age of Ozempic," and all this just insufferable kind of endpoint prediction stuff based on very little information.

And what we are interested in and what we have been talking about behind the scenes nonstop for the last couple of months is how poisonous these narratives are. But what people tend to hear is individual health advice. "Mike and Aubrey think you shouldn't take Ozempic," or, "Mike and Aubrey think you should take Ozempic." And that is just not something that we are interested in. We've said on the show before that if you want to lose weight and you want to do keto or a cleanse, you can do that. We don't have opinions on that. 

Aubrey: Yeah, totally. 

Michael: And if people don't want to do that, they also shouldn't be pressured to do so.

Aubrey: Yes. And I just know that this is like a big topic for a lot of people, for me included. Both because I'm engaging with all of this media and fat people writ large or engaging with all this media that is like, "Could we finally be rid of fat people?", is the framing of a lot of this conversation. But on top of that, I mean, we've talked about this before on the show that one of my very best friends was diabetic and passed away because she couldn't access treatment. 

Michael: Yeah. 

Aubrey: That was facilitated by a lot of things. It was facilitated by capitalism and anti-blackness and transphobia and lots of things, but it was also facilitated by our sort of cultural disregard and disdain for people who have diabetes or any health conditions that we deem as "doing it to yourself." For many folks, this is like a matter of body image, which is really tender and personal. For other folks, for people who are on this medication for their diabetes, this can very literally be a matter of life and death. 

We're talking about a wide range of big feelings and it's understandable. This is one of the most intense and sort of widespread moments of body-related discourse we've had in quite some time. People who are taking this for weight loss are told that they're sort of taking the easy way out, which they absolutely are not, and which also presumes that people are fat because they don't try hard enough, right?

Michael: Right. 

Aubrey: And when those people are fat, they're often being forced into this kind of weight loss in order to access health care treatments, surgeries, other super basic needs. This just feels huge that way. 

Michael: I think a fun bit for the show would be to just do a bunch of table setting and caveats and then just never get to the topic. [laughter]. "Another thing we want to say right off the bat--"

Aubrey: We have gotten dangerously close to an entire episode of caveats. 

Michael: We're working toward it. 

Aubrey: So, for part one, we're just going to talk about the drug itself. We're going to talk about semaglutide, which is the active ingredient in Ozempic and Wegovy.  Ozempic and Wegovy are injections that are produced by Novo Nordisk, which is a big pharmaceutical company. They're part of a group of medications that are called GLP-1 agonists. GLP-1 helps regulate our hunger and satiety signals and production of other hormones like insulin. There are other GLP-1 agonists sort of on the market, most of them approved for diabetes treatment. Those are Rybelsus, Mounjaro, and there are about another dozen that are sort of coming down the pipeline. Semaglutide has been on the market as a treatment for type-2 diabetes in the US since 2018 under the name Ozempic. When it's prescribed for weight loss, it's prescribed under the name Wegovy. It's the same thing, they're just different doses. Interestingly, the weight loss one requires a slightly higher dosage of semaglutide.

So, this drug started to be sort of studied, its glimmers begin in 1984 with an endocrinologist at the University of Toronto. His name is Dr. Daniel Drucker, and he discovers a new hormone in humans, which is GLP-1. It's called glucagon-like peptide 1.

Michael: Girl glucagon.

Aubrey: As he and other researchers tried to figure out how GLP-1 functioned in the human body, it starts to show real promise as a treatment for type 2 diabetes, but they have this problem. GLP-1 sort of disappears from your system very quickly, so it makes it really hard to study, much less sort of reproduce it. So, they start looking for alternate sources of GLP-1 that might last a little longer than the human version. And that's when the Gila monster comes in. 

Michael: Oh.

Aubrey: Mike, have you ever heard of the Gila monster? 

Michael: Yeah, they're like a cute little lizard. They're like kind of like a thick, robust lizard. 

Aubrey: I did not know about them before this episode. I didn't know a thing about them. They're the largest lizard in North America. They're almost 2ft. 

Michael: Oh, I've never seen one in real life, but I've seen them in zoo books, and they're really cute. 

Aubrey: Well, listen, Dr. Drucker had one shipped to him in Toronto. Because it goes through long periods without food, and it has the ability to slow down its appetite and metabolism, and Drucker wanted to know how they were able to do that. And he discovers that those Gila monsters have genes for something called exendin-4, which, when sort of synthesized in a lab eventually became Ozempic. 

Michael: How ironic that a thick lizard gave us thin women. Interesting. 

Aubrey: [laughs] Researchers don't totally know the mechanism for what makes GLP-1 agonists work the way that they do. But we do know that semaglutide sort of mimics that GLP-1 hormone that is again released after you eat. It's part of what makes you feel full and it's part of what signals your brain that it's time to stop eating.

Michael: And so, it works by you end up eating less because you just basically feel full after each meal. So, it triggers your satiety hormone. So, ordinarily you'd be hungry again 2 hours after breakfast, but now it's like 3 or 4 hours after breakfast. And so, over the course of a day, you just end up eating like, I don't know, 20%, 30% less. 

Aubrey: Yes. And on top of that, it's holding that food longer in your stomach, so you are physically full for a longer period of time. And it's triggering a release of insulin and also it may help grow pancreatic beta cells, which are the cells that produce and release insulin. So, it's not just that it helps you release insulin in the short term, it's also sort of like building up your ability to release insulin in the-- 

[crosstalk]

Michael: Oh interesting, so it's like flexing a muscle. It's actually like building the muscle that secretes insulin.

Aubrey: It seems like it. It seems like it might be. The results for people with diabetes in clinical trials are really incredible. So, for diabetic people, the most important measure of your blood glucose is your A1c. That's a measure of the amount of hemoglobin in your blood that reflects your blood glucose levels over the last few months. Most guidance for people with type 2 diabetes suggests that they should keep their A1c below 7 to minimize complications. But people whose blood sugar isn't well managed can have A1c's that are like 10, 11, 12, 13, like really high. It can lead to damage to that person's eyes including possible blindness, their kidneys including kidney failure, to their nerves, and to their heart. With the introduction of these GLP-1 agonists, the results are kind of miraculous. There are stories that are told about the initial presenting of the research on these at the American Diabetes Association Conference and people were weeping and gave it a standing ovation.

Michael: No way.

Aubrey: Because what they're talking about is people whose A1c’s went from like 11 to 7. From really heightened urgent risk down to a pretty safe range just with this one drug. 

Michael: I do think one of the fundamental difficult things to process about any of these kinds of health conditions is that we all kind of hate pharmaceutical companies under a system of capitalism. It's like these are big global, profit-maximizing entities. But then, on the other hand, they deliver a product that is genuinely lifesaving. 

Aubrey: Yeah.

Micheal: I always just get kind of weird whenever people praise pharmaceutical companies. I'm like, "I don't know about that." But then whenever people overly criticize pharmaceutical companies, I'm also like, "I don't know either."

Aubrey: So, in the trials for Ozempic, they start noticing pretty significant weight loss, and researchers start going, "Oh what if we could just use this as a weight loss drug?" So, they created Wegovy, it's the same drug at a higher dose. It uses more of the active ingredients, semaglutide, and because of that, it costs more. Diabetic version hovers at around $900 a month. And it costs more for weight loss, it costs like one $1300 a month out of pocket, and most insurers do not cover it. 

Michael: Not that my main purpose with this show is to widen the availability of weight loss drugs, but there is something fascinating about how we've gotten all this stuff about, "The obesity epidemic is so bad, and it's killing our kids." And then, it's like we get a drug that ostensibly treats it, and that's too expensive. 

Aubrey: Yeah, it is really wild that this is an issue where we talk out of both sides of our mouths constantly as a culture. In a lot of ways, the experiences of people who are taking Wegovy for weight loss or Mounjaro or Rybelsus, or whatever the other ones are that are getting prescribed off label, a lot of folks are being told that they're taking the easy way out.

Michael: Yeah, that's really bizarre.

Aubrey: That's the kind of rhetoric that reveals itself to be not about concern, not about your health, just about "I want you to suffer for looking the way that you look."

Michael: We're doing discourse, Aubrey. We're adding to the discourse.

Aubrey: We're doing discourse, and we're not even into the discourse section, Michael. 

Michael: [laughs] I know, I know. I’m keeping my discourse powder dry, but here we are, we're discoursing. 

Aubrey: So, Wegovy was approved for weight loss by the FDA in June 2021. Almost as soon as Wegovy was approved for weight loss, both Wegovy and Ozempic went into shortage.

Michael: Okay.

Aubrey: That impacts both people seeking the drug for weight loss and the people using it to manage their blood glucose for diabetes. Because what happens is that Wegovy goes into shortage first. That's the weight loss one. And then, doctors start prescribing Ozempic, the diabetes medication off label [crosstalk] to people who want to start to lose weight. Then, that goes into shortage too. So, as we record this, Wegovy and Ozempic are both in shortage according to the FDA's sort of drug shortage database. When a drug goes on the FDA's shortage list, the FDA then allows what are called compounding pharmacies to mix up what is basically their own version of that drug without prior FDA approval or screening. When Ozempic and Wegovy went into shortage, compounding pharmacies across the country started compounding their own versions of semaglutide. Here's the problem.

Michael: Oh.

Aubrey: Novo Nordisk has patented the semaglutide molecule, and only they can produce it until 2032, so the active ingredient simply isn't available to those compounding pharmacies. 

Michael: Wow. 

Aubrey: These compounding pharmacies are prescribing something, they're calling it semaglutide. 

Michael: Okay.

Aubrey: it's not Ozempic and it's not Wegovy. It might be a watered-down dose of those things. It could be something called semaglutide sodium.

Michael: Okay.

Aubrey: It's called semaglutide, but it's used in lab animal experiments and is not cleared for use in humans.

Michael: Oh, that's like when people were taking like horse antibiotics that you could buy on Amazon because they couldn't get human antibiotics because they're like roughly the same thing. 

Aubrey: Well, except this is not roughly the same thing and is hazardous to human health. Semaglutide sodium is not cleared for use in humans because it is bad for humans.

Michael: Oh, fuck.

Aubrey: And the third option is that it's something else entirely. Because this is in shortage and because there is less FDA oversight, these compounding pharmacies are not required to tell anyone what's in the drugs that they are giving people. This may sound niche. These compounding pharmacies may sound niche. This is every web advertisement you see that says, "Ozempic for $99 a month," or $499 a month or whatever. All of these-- all of the little startups that are like, "Just call and talk to a doctor and you'll have it the next day," all of that stuff is powered by compounding pharmacies. 

Michael: No way. 

Aubrey: So, this got so bad, the compounding pharmacy stuff has gotten so bad that the FDA has issued a number of official warnings about this and specifically has warned against buying from these startups.

Michael: This is such a bizarre system. 

Aubrey: It's so weird. 

Michael: It's like there's a shortage of this drug, so we're just going to let people buy it from weird, fly-by-night, carnival barker ass companies selling whatever the fuck on the internet, we're not going to regulate it at all?

Aubrey: There's not an enforcement mechanism beyond these letters so far. Like, they're not doing more than that yet, at least not in reporting. 

Michael: Do you have any sense of when this could resolve itself? Like, has Novo Nordisk said that they're massively ramping up production? 

Aubrey: Basically, the goalposts just keep getting moved for when the shortage will end. You know, I checked a couple months ago, it said it would be over by the fall. I checked again, it said it would be over by the end of the year. 

Michael: Oh, it's like self-driving cars. It’s always five years away. 

Aubrey: Right on the horizon. As we're talking about these compounding pharmacies, big weight loss companies are buying up these startups. WeightWatchers bought one of these and their stock price jumped almost 60% in a day.

Michael: Oh, from like 12 cents to like 16 cents or something?

Aubrey: I mean, listen, WeightWatchers stock was not doing great, but a 60% increase is a 60% increase. 

Michael: They've gone from a limp to a gait.

Aubrey: And I would say because the discourse around this is all focused on, "The Real Housewives are taking it and frivolous rich people and celebrities are taking it," it makes the issue seem like it isn't incredibly pressing and important, particularly for people with type 2 diabetes, particularly for people who can't access health care and other basic needs at their current weight. This is the other thing about this discourse that drives me utterly fucking bananas, is that there's not meaningful acknowledgment of the straight up income barriers to getting this medication. That this is a shortage that is largely, presumably, created by people with the disposable income to pay out of pocket for a weight loss medication that almost no insurers are covering.

Aubrey: You and I have discussed this until we're blue in the face, neither one of us wants to litigate individual behaviors, but that is one that really doesn't sit right with me. 

Michael: My views on this are also very contingent. Honestly, once we get to a point where these are super-duper available, if you want to take one to lose ten pounds, genuinely, I don't give a shit. In the same way I don't give a shit if you want to get a nose job. But in time of a shortage--

Aubrey: Same thing. There's an Adderall shortage. If you're not prescribed Adderall, don't take Adderall right now.

Michael: if you don't need sriracha, I've been doing my part in buying slightly less sriracha than usual.

Aubrey: Dude, the sriracha shortage has been a big topic of conversation in our household. 

Michael: Are you still doing it? Can I cancel you for eating sriracha in a time of need? 

Aubrey: We had a bottle. It was about halfway done. I got another one. 

Michael: Hypocrite.

Aubrey: Totally.

Michael: You're hoarding sriracha.

Aubrey: One and a half bottles. Come, take them from my cold, dead heads. I'm just kidding. So, Michael.

Michael: Aubrey.

Aubrey: This is unusual for us, but this topic was so big and expansive that you and I both actually researched this one and I dug in on sort of the discourse side and the reporting side and you really dug in on the research side. So, can you walk us through just what do we know from the research? 

Michael: This is a weird format break for us because ordinarily, one of us researches and one of us listens, but it would be odd to pretend that we haven't both been following this obsessively for the last couple of months.

Aubrey: Yes.

Michael: I have deliberately avoided the discourse because I find the discourse annoying. But I have been following the research and I have a literal spreadsheet of the various studies that have been done. And for these drugs, there's actually a quite finite amount of information. And I, for the love of God, just want to walk through what we know and what we can expect from these drugs. 

Aubrey: Yeah, sounds great. 

Michael: Basically, the trials of semaglutide for weight loss are all grouped under this heading of the STEP trials, which is the Semaglutide Treatment Effect in People with obesity, which should be STEPO, but is actually STEP.

Aubrey: STEPO, what, the fifth Marx brother? 

[laughs]

Michael: And these are sort of classic pharmaceutical company randomized control trials. They are global. They comprise 5000 people, all of them are 68 weeks long. One of them is a little bit longer, we'll get to it. They are funded by Novo Nordisk, of course. And the way that they structure these, they sort of do it like moon missions. You know there’s like Apollo 1 and Apollo 2. These large pharmaceutical trials are like, there's step one, step two, step three, and they break them down into specific things that they want to know. 

Aubrey: And step one, step two, step three are not different phases in the same study, right? They are separate studies. 

Michael: So, step one is like the overall, just like, "We're going to give fat people semaglutide for weight loss." Step two is the same thing, but on people with type 2 diabetes. Step three is semaglutide with intensive behavioral therapy.

Aubrey: BLTs.

Michael: And then, the rest are kind of like smaller shading. So, step four is they put people on semaglutide for a while and then they switch half of them to a placebo. Step five is a two-year trial. Step six and seven are the same thing, but they're done on Japanese, South Korean, and Chinese people. And step eight is testing semaglutide versus one of the other GLP-1s. So, it's semaglutide versus liraglutide.

Aubrey: So, when you say-

Michael: I hate these fucking names.

Aubrey: -step six and step seven are focusing on East Asian folks. It's worth mentioning that most of these trials, for Wegovy in particular, are just overwhelmingly white, as many diet studies are. One of the sort of leading meta-analyses of studies involving over 11,000 participants was 80% white, 10% black, and 5% AAPI. 

Michael: Although for diet studies, I mean, we both see diet studies that are like 97% white fairly frequently. So, it's funny, like 80% white, I'm like "Ooh, not bad." 

[laughs] 

Aubrey: Oh, the bar is in hell. 

Michael: Yeah. Like, by the standards of fucking diet research, it's like a very diverse sample. The results of these semaglutide trials are quite consistent, like remarkably consistent. So, roughly 80% of people who take semaglutide lose some amount of weight, roughly 5% of their body weight. And roughly half of people who take semaglutide lose 10 to 15% of their body weight. So, like a one in two chance of losing like a moderate amount of weight. And then, the biggest number-- And the thing that is like sent the entire weight loss industry into overdrive on this is that roughly one-third of people who take semaglutide lose more than 20% of their body weight, which is roughly on par with bariatric surgery.

And then, another thing that is a pretty big deal about these drugs is that the results seem to hold up. So, there's one trial where people took semaglutide for two years and by the end of it, 36% of people had lost more than 20% of their body weight.

Aubrey: So, for about a third of patients, they're losing maybe three times as much weight as previous interventions.

Michael: We should also note that there are pretty significant health effects of these drugs. Even in the shorter-term trials, people have better blood pressure. They have better cholesterol. They have improved A1c levels. Also with the longer-term trials, we've seen modest, but also like kind of big deal reduction in heart attacks and strokes.

Aubrey: So, that's really exciting. 

Michael: Yeah. 

Aubrey: If there is a drug that people can take and they are less likely to die--

Michael: Yeah. 

Aubrey: --I pro that drug.

[laughs] 

Michael: I actually looked this up and it's roughly in line with the effect of statins. So, this is genuinely like a big deal. Like, even if you take the weight loss stuff off the table, we should also talk about the side effects. The side effects of the drugs seem to be almost universal. Some studies find-- I think the lowest one I found was like 60% of people have gastrointestinal symptoms, but then some of them are finding like 93% of people. So, it's like nausea, constipation, diarrhea, vomiting, the sort of tummy stuff that you would associate with pretty significantly fucking with your hunger and satiety hormones.

Aubrey: In addition to all of those side effects, there is sort of this whole class of side effects that get covered mostly in beauty media and gossip blogs like Ozempic face. Have you heard about Ozempic face?

Michael: From you like ten minutes ago right when we started recording. 

Aubrey: Oops. Some of us were trying to keep the illusion alive, Michael. It's basically just the appearance of aging when taking Ozempic and it's just the result of rapid weight loss. However you did it, it's not unique to Ozempic. It's just when you lose a lot of weight really quickly, you end up with loose skin and some of that loose skin will be on your face. And that is also the same kind of thing that happens when people age, so you look older.

Michael: So, Ozempic face is just like "you lost weight" face. 

Aubrey: Yeah, totally. These ones just strike me as were talking about beforehand, these ones just strike me as so fucking mean. 

Michael: It's also so fucked up because it's like our culture is telling you to lose weight all the fucking time and it's like you finally do lose weight and it's like, "What's happened to your face?" 

Aubrey: Yeah, totally. Well, and people treat it as like some kind of comeuppance for taking a drug or daring to lose weight or being too vain. Whatever, it's just steeped in so much judgment, that I'm like, "Could we just set that one down?"

Michael: There's also a bunch of very rare side effects. There's been some worry about pancreatitis. Some trials find that it increases, but then there's a trial of liraglutide that finds that it actually decreases. There's concern about thyroid cancer, but that's based on rodent studies and there haven't been any signs of that in the data, but we don't know kind of any longer than one and a half to two years. There's slightly elevated rates of gallbladder disease, acute kidney injury. There's two cases in Iceland of suicidal ideation and the European Medicines Agency is now looking into that.

And just this week, the FDA updated the label on semaglutide to include this thing, ileus, which is basically when digested food builds up in your intestine and backs up, and the only way to deal with it is surgery, and it's fatal. So, we have 33 cases of this that have been reported to the Adverse Events Database and two deaths. But we don't sort of know what to make of those things because the Adverse Events database, as we've discussed on the show before, it's like anyone can submit cases, so it's basically just like a hotline.

And so, it's something that is like people are looking into more. And there's a study out of China last year that shows that this mechanism exists in mice where it basically stops bowel function. And there was some kind of warning in that study like, "Uh, this might show up in humans," and it might show up around the sort of 18-month mark, meaning like after these studies would have concluded. But that's also like animal studies, super preliminary, we don't know. It's sort of like people don't really know what to make of this yet. 

Aubrey: Yeah. And you know two people dying is nothing to--

Michael: That's a huge deal. 

Aubrey: That's a big deal. That's a big deal. And I think especially in the context of previous diet drugs having sort of gone this way, right? 

Michael: But then, one thing that really stood out to me was we have these near universal side effects. We have these much more rare, much more severe side effects. But the dropout rates in these studies are really low. What you find in most of the studies is almost everybody is getting some side effect or another, and they typically happen in the first couple of weeks of the study when you're upping your dose. It actually takes four months to get up to the 2.4 mg, like weight loss dose, but it typically goes away as people kind of get used to the drugs. And so, in the two-year study, there were 150 people who completed the two-year trial, and only 10 of them dropped out due to adverse effects, which is only 6%. So, what this indicates is that people are getting side effects, but most, like the vast majority of people are willing to push through the side effects and complete these trials. 

Aubrey: Yeah. So, what you're saying is folks are more likely to stay in these studies than other studies into sort of like how folks can lose weight.

Michael: Yes. So far, I've kind of been presenting the case for semaglutide, the way that you read about it in these clinical trials, I've been reading a lot of things from people in the weight loss world, and this is how they talk about the drug, is that it’s delivering very significant weight loss, the dropout rates are relatively low. And before we get to complicating that picture a little bit, I think it's important to first of all just acknowledge that like that is the data that we have and I think this new-generation weight loss drugs is genuinely just a big deal.

At the same time, to me, the most bizarre thing about the discourse, especially recently, but since the results of these trials started coming out, is the weird victory lap that people have been doing. It's like, "Okay, we know we have something now that works for weight loss, we finally have an effective weight loss drug," And then, there's this weird sort of second order thing where they're like, "What are the fat activists going to do now? This ruins body positivity," and there's all this weird shit of like, "Well, now we have a cure for obesity" 

And I feel like just to sort of take these results as we've been presented with them, like the "best possible version" of these events, all of the weight loss, all of the benefits, everything, it's like we're talking about a drug that 50% of people who take it will lose 15% of their body weight. And that is not a world without fat people. This is like the aspect of the drug that drives me absolutely fucking nuts. It's not going to end the "obesity epidemic." It just isn't. We still, as a society, need to work on stigma against fat people, improving medical care for fat people. All of the things we say on this show are still fucking true if every single person in America loses 15% of their body weight.

Aubrey: And that is a dramatic overestimation of what's even about to happen. As you say, even if they work exactly as they are projected to, even if the data doesn't change one bit with future trials, someone my size goes from being 330 pounds to being 280 pounds. That would take me from being a person with an obese BMI to being a person with an obese BMI.

Michael: Yeah.

Aubrey: This whole thing about, "Is this the end of the obesity epidemic?", A, no, it's not, as you've pointed out, but, B, that is the meanest fucking thing to say.

Michael: We currently have this fucking nightmare bullshit, which is like the whole fucking show is dedicated to this, where it's like, a fat person goes into the doctor for a migraine, and they're like, "I have a migraine." And the doctor is like, "You should go on a diet." And then, it's like, "You haven't asked me what I do. You haven't asked me if I eat fast food. You haven't asked me fucking anything. You're giving me this bullshit ass advice when all I want is fucking advice for my migraine." 

Aubrey: Yeah. 

Michael: We're now going into a scenario where you go into the doctor with a migraine and they're like "You should go on Ozempic." 

Aubrey: Yeah. 

Michael: And they're like, "Well, I've already been on Ozempic three times, and I was one of the half of people who lost less than 10% of my body weight. It was costing me more than my fucking rent. I was having weird side effects." People report not enjoying food anymore which is really sad to think about. And then, the minute I went off of it, I gained all the fucking weight back. And I've done that four times. And when I'm going in and you're giving me this generic bullshit fucking advice to go on Ozempic, you haven't asked me whether I've been on it before? You haven't asked me about weight cycling. You haven't asked me whether I tolerate the drug or if it intersects with some antidepressant that I'm taking. We're just redoing the same fucking thing, except instead of go on a diet, it's go on Ozempic. 

Aubrey: Yeah. 

Michael: In the same way that it's not possible for everyone to go on a fucking diet or they've been on a million already, it's not possible for everyone to go on fucking Ozempic and it's not going to work for everybody. 

Aubrey: I mean, listen, I told you this off mic, but I think this is the darkest episode that I have researched for us.

Michael: Yeah, it's really bad.

Aubrey: It is really upsetting. And I will say not just on an individual level, but also systemically. I've stopped seeing doctors for like eight years. I've written about this a bunch of times, and that was at the height of the bariatric surgery craze.

Michael: Yeah.

Aubrey: And that really fucking fueled how doctors would talk to me and what treatments they would offer me. And it was like a very frequent conversation of me being like, "Hey, I'm 24 and I have an entry-level position at a nonprofit where I feel fortunate to have health coverage at all. No, I don't have 25 grand for a weight loss surgery." 

Michael: Yeah.

Aubrey: But that still became a thing amongst healthcare providers who we already know are more likely to think of fat patients as noncompliant, as slovenly, as unattractive, as weak willed, as all of these things. This becomes another reason for that group of people also to stop listening to fat people. It's going to get harder for me to get healthcare. That's part of what's about to happen. 

Michael: This is why I wanted to go out of my way to insufferably present the results of these trials as if they will hold up. Because even in a world in which that happens, that doesn't call anything into question about the need for equal treatment. And at the same time, the results of these trials are extremely unlikely to pan out in the real world.

Aubrey: Yeah, totally.

Michael: So, I have three reasons why these drugs are very unlikely to pan out and deliver, like the end of obesity or all the stuff that the insufferable discourse has been telling us.

Aubrey: Oooh, we're tucking into the debunk bed. 

Michael: Yeah. This is a much more comfortable space for us. The first is that the populations that are being studied in these trials are actually relatively narrow. So, step one, which is the trial that's kind of the overall just normal weight loss drugs being given to people, I'm going to read you the exclusion criteria.

People were not able to participate in step one if they have a history of major depressive disorder, they have a diagnosis of a severe psychiatric disorder, they fill out the patient health questionnaire with a score of over 15. This is one of those questionnaires that has like "I have feelings of hopelessness. Rank from every day to never." 

Aubrey: Yeah. 

Michael: It's basically a measure of how depressed you are. It's like, "Are you feeling tired?" One of them is, "Do you have poor appetite or overeating?" It’s like a funny exclusion criteria to include in this. They're also excluding people with a lifetime history of a suicide attempt, any history of myocardial infarction, stroke, hospitalization, any kind of existing cardiovascular stuff, known or suspected abuse of alcohol or recreational drugs, and female who is pregnant, breastfeeding, intends to become pregnant or is of childbearing age, and not using a highly effective contraceptive method.

Aubrey: Holy shit, that cuts out so many people, Michael.

Michael: Well, the thing is, I mean, with these studies, I sort of get why people who design studies do this stuff because they want to start with a kind of baseline of "normal people" without a bunch of preexisting conditions, which I get for the purpose of a trial. I get why you want to have a clean "sample." However, once these drugs get out into the real world, they're going to be taken by people with depression.

[laughs]

Aubrey: Yeah. When you're designing a trial like this, I imagine you're walking a real line. You want the trial itself to be safe for the people who participate in it, so you want to eliminate things like existing heart conditions, like anything-- existing pancreatic conditions, anything sort of related to the mechanisms involved in this drug, I totally get that.

And you don't want it to make anything worse for anybody. Just on a human level, that totally makes sense to me. The trick is all of that gets translated into an assumption that this is how it will play out for all people who are not being monitored in a study and provided the drug for free, and all people who have all of these other conditions that are extremely prevalent in the US.

Michael: Yes. And also, I mean we-- I probably should have started with this but the second reason why it's unlikely that these are going to deliver on the results that we're seeing in the trials is because there are real-world studies of semaglutide, and they don't find the same results. So, there's a study in the US that followed people who went to weight loss clinics and got these drugs for one year. If you remember, in the trials of these drugs, the average weight loss was around 15%.

Aubrey: Yeah.

Michael: In the real-world trial, people are losing 7.5% of their body weight. And there are other real-world trials, it's quite remarkable actually, that find almost the same thing that the weight loss, 80% of people lose 5% of their body weight or more, in the real world, that tends to be around 40%. So, almost all of the numbers that we're seeing in these randomized control trials are half once we get to the real world. They're not zero. So, this still is going to be again a big deal, but we're not seeing, in the real world, those results continue to show up. It's not totally clear why this is happening. One of them appears to be that in the randomized control trials, people aren't just taking the drug, they're also getting dietary counseling.

So, one of the trials is like super intensive behavioral therapy where they're like meeting with dietitians once a week, but in all of the other trials, they're doing monthly check-ins with counselors and they're having all of these biomarkers taken. And I think there's something about people just being in a study, like you really want to finish because you're like, "Oh, I'm part of this like project, and it's like experimental and super cool." And the adherence rates for these randomized controlled trials are significantly higher than we have in the real world. When you look at the real-world trials, even among people who have type 2 diabetes and who really need these drugs, a lot of them are finding like 50% dropout rates after two years. And some of them-- one of them finds 70% dropout rate.

Aubrey: You can already see, as we're sort of like walking through this research, the gap between the popular claims that are being made about these drugs and what the research actually says. That's where we got to with Fen Phen, that's where we got to with Ally, that's where we got to with-- This is sort of a pattern with weight loss drugs, is that we get out over our skis culturally with this kind of magical thinking, excitement stuff. We then make a bunch of policy decisions based on the excitement and not the data. And then, we're kind of stuck with these sort of adjusted systems that were again changed based on what we thought was possible, not what were actually seeing.

Michael: Exactly. And the other thing that again we have very good data on is that people tend to regain all of the weight the second they stop taking these drugs. So, one of the STEP studies switched people from semaglutide to a placebo at 20 weeks. There's also a trial of another GLP-1, tirzepatide, these fucking tides, that did the same thing. After 36 weeks, they switched people to a placebo. And basically, it's like people start regaining the weight very quickly. And within a year, they've regained almost all of the weight. These drugs seem to put people in the same cycle as fad diets, but just with more dramatic and longer results.

Aubrey: Well, and the people that I have heard talk about taking these drugs are like, "I'm just going to take it until I get down to X weight and then I'm going to stop."

Michael: Yeah. 

Aubrey: Right? And that is people's plan for how this is going to happen, and that's not how these drugs work.

Michael: I'm seeing this discourse among weight loss clinicians too, where they're like, "Well ultimately it comes down to diet and exercise and so we need to get people on these drugs and then teach them the diet and exercise stuff. And then once they know that, we can take them off the drugs." But this trial of tirzepatide, the other drug, had people on an intensive behavioral therapy program when they went off the drug. So, people took it for a while then they switched to a placebo while still doing exercise and cooking classes and all this stuff that everybody says is so fucking effective and they gained all the weight back.

Aubrey: This is another case of pump the brakes and ask a fat person.

Michael: Yeah. 

Aubrey: "Has anybody tried to teach you how to cook? Has anybody offered you a gym membership? Has anybody told you that your form was wrong while you were working out?"  This is every day. The reason that people think that, in part, is that it reinforces our existing beliefs about fat people. Which is just that they're too lazy or they're too unintelligent or they're too uninformed to just do it for themselves, so they need a thin person to teach them how.

Michael: This is going on my Aubrey Gordon soundboard. 

Aubrey: Yeah.

Michael: Step back, ask a fat person.

[laughter]

Aubrey: I mean genuinely that's going to be my advice. Like, 80% of the time, it's like, "Have you even talked to a fat person about this?"

Michael: This is another super fucking familiar pattern where it's like, "Okay, everyone should go on Atkins because low fat diets work or low carb diets work." And then, of course, after six months everyone gains the weight and then it's like, "Well, if you stayed on it, you would have kept the weight off." Which is true, fine, if you can stay on it, but no one can fucking stay on it. We know in the real world, no one can stay on these extreme low carb diets for very long. So, let's move forward on that basis that no one can fucking stay on them.

And with this, it's going to be the same thing of like, "Well, Ozempic does work if you can stay on it." Okay, but people aren't staying on it. We know from real world data that even when it's fucking free, people are not staying on it. 

Aubrey: Well, and if you do stay on it, people characterize it as the easy way out.

Michael: Yeah. And then, you have this bullshit. 

Aubrey: Like, Oprah was just saying the other day, like, "It's the easy way out, so I'm not going to do it." And I'm like, "Oprah, you are in your 60s. How hard do you think you need to have appeared to have tried?" And listen, the discourse makes it worse, because in the discourse is like-- a bunch of the reporting is like, "We really need to tamp down on the stigma facing people who take Ozempic." And I'm like, "Is that the stigma that we need to clamp down on?"

Michael: What's so fucking annoying to me about this discourse, you have successfully radicalized me on this in the last 72 hours. 

Aubrey: Oh, hey. [laughs]

Michael: Because as I've been reading this, it's like this shows up everywhere, like, What about the stigma of taking the drugs?" But the stigma of taking Ozempic is fat phobia. It's the same fucking stigma-

Aubrey: Yes, yes, yes, yes.

Michael: -that fat people are facing, but just like, "Oh, you're taking the easy way out by using a weight loss drug." That's the connection between fatness and virtue. You should lose weight in the virtuous way.

Aubrey: Take the stairs. 

Michael: Yeah, take the fucking stairs. It's like, well, you might look thin, but you're really a fat person. You cannot muster any fucking gumption from anybody to give a shit about stigma against fat people, but they're super chill to invoke fat phobia against people who stop being fat. 

Aubrey: And they still do the fucking stigma against fat people.

Michael: And they still do it. 

Aubrey: It's also been fascinating, I'll say, on the discourse end, that there have been all of these bizarre, hand-wringing pieces from thin people being like, "Was body positivity for nothing?"

Michael: I know it was all a lie.

Aubrey: The vast majority of fat people were under no illusions about broader social acceptance. At best, people said fewer unwanted things about our bodies. It never stopped. We were never lifted up. We were never centered. We got one Lizzo out of it.

[laughter]

Michael: And we don't even have that anymore. 

Aubrey: And we don't even have that anymore. The degree to which this discourse is thin people telling themselves stories that they want to hear. 

Michael: It's funny to me that we meticulously outlined this and planned it out, but neither one of us can resist talking about the discourse.

Aubrey: I hate it so much.

Michael: Who likes fast forwarding to that section. 

[laughs]

Aubrey: Okay, Michael. We've talked about the drug. Let's talk about the manufacturer of the drug. Ozempic and Wegovy are both made by Novo Nordisk. It's a big pharmaceutical company from Denmark.

Michael: From Denmark. 

Aubrey: And their marketing practices have really set the template for all the discourse we've been seeing since.

Michael: Okay, wait, are there ads for Wagovy and Ozempic? 

Aubrey: You haven't seen the "Oh-Oh-Oh-Ozempic!"

Michael: That's like the cover songs that are in all the fucking trailers now. 

Aubrey: The very slow, brooding cover of like I whip my hair back and forth. 

[laughs]

Michael: I’m blue, ba-do-dee-da-di-da, but it's like super dark, yeah.

[laughs] 

Michael: No, as we've discussed many times, we're on very different Instagram experiences and algorithms, and I've never seen an ad for weight loss anything. 

Aubrey: I'll tell you what, Mike, I might give you homework at one point and be like, go watch a half an hour of TV and tell me what you notice about the ads. 

Michael: Dude, no. 

[laughter] 

Michael: Absolutely not. I watch terrestrial TV like once a fucking year when I'm visiting my grandma, and I'm like, "This is actively making me stupider." It's like shocking how bad it is. 

Aubrey: So, we're going to talk a little bit about the marketing practices at Novo Nordisk. 

Michael: Okay. 

Aubrey: There is a lot here that leaves me feeling icky. A very good example of this is a campaign called It's Bigger Than Me. Have you seen this campaign at all? 

Michael: Is it like billboards?

Aubrey: There are ads, there are billboards, there are branded segments on TV shows, there are so many things. The slogan is "Obesity, It's Bigger Than Me."

Michael: Okay. 

Aubrey: The idea behind the campaign is, "It's not your fault you're fat," followed immediately by, "It's because you have a disease, and that disease requires medical treatment, and that medical treatment can only be provided by one company."

Michael: It's bigger than me, it's $15,000 per year.

Aubrey: Yeah, that's right. As part of this campaign, Novo Nordisk has specifically courted black public figures and particularly black women as spokespeople. Their first spokesperson was Queen Latifah. Their next was Yvette Nicole Brown, who was on Community. Their third was Roland Martin from CNN, who ran an hourlong segment on fatness in black communities that was listed as "Powered by Novo Nordisk."

Michael: That's like when influencers say like, "I've partnered with Nike," or whatever. It's like it's just them paying you to say words. 

Aubrey: Well, and on top of that, the reporting around the "It's Bigger Than Me" campaign is just rife with the most garbage messages about fatness and body positivity and all kinds of stuff. I read an interview with Yvette Nicole Brown with TheGrio. In that interview, she said, "Being focused on your health does not mean that you're not body positive. I think it's actually the most exemplary way that you can be body positive because you need your body to continue to live." 

Michael: Aubrey, were you just losing your mind? You hate this body positivity stuff already. This is reifying everything you've said about the whole body positivity thing. That it's all just like they're repackaging the same shit and selling it back to you. 

Aubrey: The article goes on to say that "Brown said, 'somewhere down the line, society at large developed the idea that if you're body positive, you can't care about physical health.'" In my notes, I wrote in all caps, "WHO IS SAYING THIS?"

Michael: Who fucking said this?

Aubrey: Who is saying this? And it's like trolls. It's seeding a bad faith argument to be like, "We don't think that's true. Look at what all those nutty people are saying. They're wrong."

Michael: This is like when conservatives are like, "Feminists don't even want you to get married and have kids."

Aubrey: It's the phenomenon that has built Michael Hobbes' twitter feed. 

[chuckles and laughs]

Michael: Hey, you're familiar with my work. 

Aubrey: Our third section, Michael-

Michael: [whispers] Discourse.

Aubrey: -is the part that I have realized is most troubling to me and that is the discourse. 

Michael: There's been a lot of garbage media about this in the last year. 

Aubrey: Here are three actual fucking headlines from coverage of this. One, "Will Ozempic change how we think of being fat and thin?" "Life after food?" And, "Ozempic settles the obesity debate."

Michael: Oh, that one's annoying.

Aubrey: It is just bad faith proclamations and bullshit question mark headlines like as far as the eye can see. What I am worried about is that when we see a wave of media like we have seen around Ozempic, we also tend to see a wave of increased anti-fat bias, right?

Michael: Right. 

Aubrey: And the reporting that I have seen so far, the think pieces that I have seen so far, none of them are grappling with that. Very few people are asking fat people what they need in this moment. And nobody is asking diabetic people what they need in this moment. Like a thing that I experientially know in every bone in my body is that when people I know start to lose weight, the vast majority of them start to see themselves as more virtuous. Whether they want to or not, whether they mean to or not, whether or not they would say it out loud, it's very common for people to expect social reinforcement for weight loss. And I would say now, as I have said for years now, which is you have got to get people's consent to do that.

The best-case scenario is that you're sending a message that you're not a very good friend to a fat person. And the worst-case scenario is that you're increasing the stigma that they face and potentially also triggering people's eating disorders. This shit is not unthorny. And the fact that you're hearing it everywhere doesn't make it less urgent. I would argue it makes it more urgent to double up on those boundaries. You have got to give fat people an out for this conversation and you’ve got to stop presuming that this is like a good and exciting conversation for everybody.

Michael: I'm not all that invested in the drugs themselves. The drugs are the drugs.

Aubrey: Yeah, same, same.

Michael: I don’t know. I mean, maybe they'll be effective weight loss drugs, maybe they won't, I don't know. But given what we know now, the most likely scenario is that they're going to be prescribed to millions, potentially tens of millions of people. And what you said to me the other day is that you can see the number of people who'd lost like 15 fucking pounds and then all of a sudden are really mean to fat people just like exponentially increasing.

Aubrey: The other thing that I will say about the discourse around this is that every celebratory story about Ozempic that comes out now, that's all going to be mirrored by future panicky think pieces on the rising costs of obesity and how fat people are bankrupting us once again. This is an unbelievably expensive medication. And all of that is going to come back to scapegoating fat people once again. Right now, we're saying it's frivolous housewives and whatever. When we get into the insurance conversations, we're not going to be scapegoating rich people. We generally don't do that. We scapegoat poor people, BIPOC, fat people, queer people. You know what I mean? We've got a list of people we scapegoat. 

Michael: We're also setting ourselves up for another round of excruciating discourse in another couple of years when people look around and they're like, "Wait a minute, there's still fat people, All the magazines told me a couple of years ago that this was the end of obesity. And yet, people are still fat."

Aubrey: We should also say, like, "Listen, you will face serious, serious fucking stigma as a person who stays fat. Trust me, a person who has stayed fat totally through all the interventions." I've already sort of started shifting socially. You know I'm already a very homebody, indoorsy kind of lady, and I'm already restricting who I socialize with pretty dramatically because of this kind of talk and because I'm unwilling to be in spaces where this shit will come up. And for me, that means functionally like a vast majority of people I know who are not fat and some people I know who are. I just want people to understand the stakes of this as a fat person are, "I feel like I don't belong in the world" When people talk about how great it's going to be when I'm not around, that's not me being too sensitive, that's not fat people taking it too hard, that's you saying plainly, "Everything will better when you're gone." And then, fat people like taking that message, that's horrible. 

Michael: The fact that you have been through so many rounds of this, it's like, "Why aren't you on Fen Phen? Why aren't you on bariatric surgery? Why aren't you clean eating?" All this is just new packaging for like "Why aren't you thin?" And that is worth listening to. This isn't like a paranoid fantasy on the part of fat people. This is something that they've been through numerous times over the course of their lifetimes now. We're just doing the same thing again even when the data does not remotely indicate that we're not going to have fat people anymore. It never has. We're always going to have fat people and there's always going to be people, whatever the medical intervention is, that can't use it or it doesn't work for them or they've tried it already, that's always going to be the case. The fact that people are so obsessed with asking the question, "Is this the end of obesity?", like really early, "Is this going to be the reason we don't have fat people around anymore?", it's like it's so fucking telling. 

Aubrey: So, moving forward, we're going to continue to get these drugs. We're going to continue to get this sort of "gold rush." And in that time, I think it is worth being extra skeptical and returning to the voices of fat people and diabetic people when media isn't doing that for us. To actually return to the people who are most impacted by this debate and to spend way the fuck less time speculating about Elon Musk and Kourtney Kardashian and making celebrities defend themselves and trying to think through, "How do we get these drugs to people who need them? How do we design a better discourse that isn't so wildly dehumanizing to fat people and again to diabetic people." And how do we just show up for people a little bit more around this stuff and interrupt some of this dancing in the street kind of energy that is really upsetting to see as a fat person.

Michael: Okay, we've done enough table setting. Let's start the episode [Aubrey laughing] You ready? It’s been 2 hours 45 minutes.

[Maintenance Phase theme] 

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