CHAPTER ONE: The fears around weight loss drugs
Hi I’m Wendy Zukerman and you’re listening to Science Vs. <<doo doo doo>> Today on the show we are looking into the latest fears around drugs like Ozempic <<doo doo dunnn>>
And before we jump in - in this episode .. we are talking a little bit about suicidal thoughts. So please take care when listening to the show. And we'll put some mental health resources in our show notes. Ok, let's get started…
Last year, just as drugs like Ozempic were gaining steam, we did our first episode about them. But since then, a lot has happened … Prince Charles became King Charles… Twitter rebranded to X…and Taylor Swift joined the NFL! Yeaaa!! But one thing that hasn’t changed? These weight loss drugs are still big news.
One hot topic everyone in Hollywood still seems to be talking about is Ozempic
And it's not just Ozempic … there's a bunch of similar drugs out there – like Wegovy, Mounjaro, and Zepbound – and something we keep hearing about them – is that they’re causing these weird and very scary side effects …
The Ozempic hype is starting to wither, replaced with the reality that it and similar drugs are very risky. Even deadly.
Last year there were all these stories of people becoming suicidal soon after taking these weight loss drugs
<NEWS CLIPS>
Regulators looking into reports of suicidal thoughts
I remember thinking to myself my family would be so much better off without me, because I was so, just so depressed
There are now fears that these drugs are sapping our bodies of muscle - which we’re told can be incredibly dangerous
Lustig: You are losing equal amounts of muscle and fat. Does that improve how you look in a bathing suit? Sure. But does that improve how long you’re gonna live? Uh uh not a bit.
And some claim that drugs like Ozempic have paralyzed their stomachs – leading to awful side effects…
Debilitating gastric issues. Vomiting daily, hospitalized repeatedly
A year ago when we first looked at these kinds of drugs – they looked pretty safe … But did science miss something here? As millions and millions of people are being put on these kinds of drugs – how worried do we need to be? Today on the show we’re looking at the cutting edge research on these new weight loss meds to find out – are they scarier than we first thought?
When it comes to Ozempic there's a lot of …
The Ozempic hype is starting to wither
But then there's science…
AHHHH
That’s all coming up after the break
PREROLL BREAK
WZ Welcome back to the show. Today we’re finding out if weight loss drugs like Ozempic are scarier than we once thought. ... Ok so last year when we talked about Ozempic, we looked at how these kinds of drugs work, which is to mimic this hormone that makes you feel full. So it’s basically like an appetite suppressant. And when it comes to losing weight -- these drugs really really do work. They help a lot of people lose a lot of weight. But the question we’re asking today, is are they safe? What do we know now? And to tell us all about this - is senior producer at Science Vs - Rose Rimler. Hey Rose!
RR: Hi Wendy
WZ: So, Rose, as you’ve been seeing these headlines of like, muscle wastage, suicide risk, stomach paralysis, what has been going through your head every time these headlines pop up?
RR Uhhh, I’m a little– I’m very curious but I’m a little skeptical. Because I know people just love to talk shit about these drugs. And the last time we covered this, they actually seemed pretty safe. There was some concerns about pancreatitis, and gallstones, and thyroid cancer. But a lot of it was kinda theoretical, seen in rats, or very rare. So it seemed pretty safe. Actually the biggest problem was that a lot of people get GI issues. Like stomach upset, nausea, on these drugs. And that’s kinda where we landed last time.
WZ And I hear you that you can definitely feel in the air that people want to talk shit about these drugs. It doesn’t feel like you can lose this much weight and not have some consequence. But at the same time, a lot more people are taking these drugs, and it does sort of feel like maybe science missed something here in the early clinical trials, which CAN happen.
RR It could totally happen.
CHAPTER TWO: Do these drugs melt your muscles?
WZ Right so Rose let’s start with this thing that we’ve both been hearing a lot about, which is this idea that Ozempic can mess with your muscles, and basically that you’re not just losing fat, which is the goal for many people, but you’re also losing a ton of muscle on these drugs. So here–let me read you some headlines that I have read recently. "The Race Is On to Stop Ozempic Muscle Loss" another one: "Ozempic May Cause Dangerous Muscle Loss" and perhaps my favorite: "Are fat-loss shots a ticking timebomb? Doctors warn Ozempic & Wegovy are shrinking patients' muscles!"
RR Yeah I’ve heard about this too and I’ve heard a lot of people talk about it on podcasts, y’know, those bastions of misinformation.
WZ Oh yeah you gotta watch out for those.
RR And I’ve specifically have heard this claim that this muscle wastage that happens when people are on these medications can also melt muscle off your face and make you look gaunt and weird and they call that Ozempic face[1].
WZ Oh god it has its own name. Ozempic face?
RR Yeah Ozempic face
WZ OK so… like how freaked out do we need to be about this?
RR Well — if it's true that the Ozempics are melting your muscles away - that would be a big deal[2]. Because y’know our muscles aren’t just there to yank our bones around … which is kinda how I had previously thought about it. It’s actually a very important organ, and it’s a very active organ. So one thing they do is they pull sugar from our blood and then store the sugar[3]..
WZ Oh that's cool, I didn't know muscles did that!
RR Yeah and I talked about this with Vibha Singhal, she’s a doctor and scientist at Harvard[4].
VS Even when we are sitting, muscle is sort of sucking up all the glucose. Like almost like, you know, a vacuum machine, it can just suck away all the glucose so muscle is sort of a storehouse of energy and to maintain healthy blood sugars, healthy metabolic state — healthy muscle is very very important
RR So the less muscle you have, the less efficient this whole thing is[5].
WZ: mhhmm
RR This is all part of what’s called “insulin sensitivity.” And so just to really land this point– one study took healthy people and had them stay in bed for a week. Because they were inactive for a week, they lost about 3 pounds of muscle, and their insulin sensitivity plummeted. It went down by 30%[6]
WZ Oh whoa!
RR And that’s bad, like that could lead to a whole bunch of problems. Type 2 diabetes but also high blood pressure, heart disease, yadda yadda yadda[7]. So hearing all this you want to keep your muscle, right?
WZ Yes! Love my muscles. So does Ozempic melt them away?
RR OK - straightaway, you need to know that every time someone loses weight, they lose muscle. In fact, studies that have looked at weight loss generally find that on average, 20 to 50% of the weight that people lose comes from their lean tissue – which is mostly muscle[8][9][10][11][12].
VS so if somebody loses 10 kilos, Two kilos of that could be muscle to up to five kilos, which is a lot
RR That is substantial!
VS That is substantial.
RR: And one reason for this is when you’re losing weight, because you’re taking in less energy — by eating less — your body is gonna look for energy in other places, it’s gonna try to get sugar. One place it can get that sugar? From your muscles[13]!
WZ: OK - so every time we lose weight some of that weight is muscle because your body, searching for energy, eating away at things including your muscle. And on average, about 20% to 50% of the weight that you lose is muscle. Is that right?
RR Yeah
WZ So then the question becomes, when you’re on these meds, are you losing more muscle than you normally would?
RR: Right – that is the question. So to find that out ... Researchers have pulled people into these scanners that can measure how much of your body is fat, how much is bone, and how much is lean tissue, muscle.
WZ: Ok
RR And so they scan people before they start these medications and then again after they’ve been on them a while and lost a bunch of weight. And here’s what they have found. So in one trial for tirzepatide, the stuff in Mounjaro and Zepbound, out of all the weight people lost - on average, about 25% of that was muscle[14] . And then in another trial for semaglutide, that’s the stuff in Ozempic and Wegovy, almost 40% was muscle[15].
WZ: Oh. Almost 40% and then 25%? So that is exactly what you would expect. Is that right?
RR: It’s exactly what you would expect[16]
WZ So there’s nothing special happening here
RR Not as far as we can tell, no
WZ But there’s so much vitriol around Ozempic and the muscle wastage problem, I haven’t read any headlines that were worried about muscle wastage when people were losing weight through other means. Why all the focus on these drugs?
RR Yeah that’s weird right?? Vibha thinks there’s just a spotlight on these meds. Any little thing they do it’s gonna be breathlessly reported on. So this is how we wind up with these discussions around quote unquote Ozempic face.
VS When you lose weight, you lose weight from everywhere
RR Including your face
VS Including your face! So I don't believe in Ozempic Face, it's the weight loss face
WZ So there’s no– so when it comes to muscle wastage, whatever, I dunno is there anything to particularly worry about with these drugs?
RR Yeah as far as I know - I haven’t seen any evidence that the way people’s weight comes off on these meds is different than from any other means of weight loss. But that being said, I mean it is a fair point that people should be aware of this whole muscle loss thing, but people do lose weight, on these medications or otherwise, they should be trying to preserve muscle, build muscle, so yknow that looks like getting plenty of exercise and eating enough protein[17][18][19].
WZ right right
RR And the best exercise for this is resistance exercise, stuff like lifting weights. But Vibha says any exercise you do consistently will help some. She gave me this very cute example of a family she works with.
VS I have one family that likes to dance as a family for 30 minutes every evening. Great! Whatever gets you moving works[20]
WZ That’s really sweet. Really sweet.
RR It’s cute I like that
WZ All right so dance for 30 minutes if you’re on Ozempic. Love that.
RR That’s the takeaway, yes
WZ So Rose what’s next?
CHAPTER THREE: Do these drugs increase the risk of suicidal thoughts?
RR So the next thing I want to dive into is pretty scary sounding, actually
WZ Ok
RR So there have been hundreds of people who have reported that after they started one of these weight loss meds – they got really depressed … and some people have even reported feeling suicidal[21].
WZ That's so scary, the idea of you take a drug and your whole attitude in life switches over. Cause that’s the claim right?
RR Yeah… the claim is that the meds were causing depression, causing suicidal thoughts. And there were enough reports of people saying this was happening to them that the FDA[22]. decided to look into it. And that made the news. Other countries decided to look into it too.[23][24] . So all the media around that, that’s actually where our next guest heard about this.
NV That’s really when it captured my attention.
RR This is Nora Volkow. She’s a neuroscientist and is the director of the National Institute on Drug Abuse[25].
RR Why did it capture your attention?
NV Because so many people are taking these medications, I mean, so many people are being exposed to them.
WZ This could be bad.
RR Yeah and it’s not wild to think that this could happen, that a weight loss medication could cause depression and suicidal thinking. In fact, there actually is a warning on these drugs that says people should watch out for depression or suicidal thoughts[26][27].
WZ Are you serious?
RR Yeah. Wegovy and Zepbound both have this warning. I asked the FDA about that. They told me the reason it’s there is that weight loss drugs in the past have been linked to feeling suicidal[28]. In fact, there was one drug that was pulled off the market because of this[29].
WZ So what do we know here? Do these new drugs actually increase your risk of suicidal thoughts?
RR So Nora and her team decided to dig into that question. So they pulled medical records from people across the United States, and they combed through them to see who had been prescribed semaglutide - that's the stuff in Ozempic and Wegovy – and they were looking over a period of about a year and half.
WZ OK
RR And they also pulled medical records from people who had been prescribed a different kind of weight loss medication over that same period.
WZ Great
RR This was the control group.
WZ Loving this study. This is exactly what we need. Thank you Nora.
RR In the end they had more than 100,000 people in this part of the analysis. And when they crunched the numbers - to see – were people on semaglutide more likely to feel suicidal… they found… NO.
WZ Mmmhmm no OK
RR In fact - Nora told me they found something really unexpected — which was that the people on semaglutide had LOWER rates of suicidal thoughts - than the other group.
WZ OH!
NV Actually, we were very surprised because we, based on what the accounts were saying, we were expecting them to be higher. But, so, we were surprised when we saw that they were significantly lower[30].
WZ Oh wow
RR And in fact scientists are digging into this whole other question– of whether it’s possible that this class of drugs can have ANTIdepressant effects.
WZ WHAT!
RR And that evidence is very preliminary– it’s mostly from rat studies – but some suggestion this could be happening, so it’s pretty interesting.[31][32][33]….
WZ Well this is quite a switcheroo from science
RR It is a switcheroo. Yeah. And no one’s saying that those reports of people feeling suicidal - aren’t real.
WZ The ones that triggered this whole thing?
RR Yeah so like what’s going on there. It’s possible these were coincidences, it’s also possible it’s happening as a result of these meds but it’s very very rare. But overall in January, the FDA said, they concluded that there’s no clear relationship between these meds and feeling suicidal based on current evidence[34].. Here’s how Nora put it …
NV The evidence right now does not support that these medications will increase by themselves the risk of suicidal thinking or behaviors[35][36],
WZ Mmmhmm OK! Well this is great news for the many people on these drugs
RR Yeah
WZ But the episode isn’t over yet!
RR No… So everything might not be quite this rosy from here on out. I’m gonna tell you why after the break.
BREAK
CHAPTER FOUR: Can they really paralyze your stomach?
WZ Welcome back. Today on the show we are looking into fears around Ozempic. Rose, this choo choo train, Ozempic train … has hit which station? Is that? That's not even a pun. It's not even a pun
RR It's not really anything.
WZ Laugh
RR We can go with it
WZ Wegovying where next?
RR That's good.
WZ Thanks.
RR That's good.
WZ: Thank you. Where? All right. Where are we going? Where are we going? Next?
RR To the Guts!
WZ Next stop. The guts.
RR Choo choo! So last time. We heard that it was pretty common for people to get stomach aches.
WZ Hahhahah Sorry. All right,
RR Choo choo
WZ Last time.
RR So last time we heard, it was pretty common for people to get stomach issues on these drugs. So, like nausea, especially when they first started taking them.
WZ Yes. Yes. I remember that person you interviewed who ate some fried chicken and then vomited it all up. I mean, yes.
RR Yes, that kind of thing.
WZ Okay.
RR Very common.
WZ Right.
RR But she got over it, and it wasn't too bad for her. So now what's in the news is people who are having something way more serious happen to them. And in fact, there are a bunch of lawsuits right now on behalf of people who say that these medications really messed up their stomach, including claims from some people saying that their stomachs were paralyzed after taking these drugs.[37][38]
WZ What does that mean exactly?
RR That they weren't moving your stomach has to move to get food crunched up and like on its way out the door[39]. But, the what these claims are is that the stomach has stopped moving or is moving so slowly that people have these, like, terrible symptoms. One woman says it was so bad it sent her to the emergency room several times. She says she vomited so much that she lost teeth[40][41] .
WZ Oh god oh god
RR Alright that’s the claim, so let’s dig into this, I called up Michael Camilleri, a gastroenterologist and researcher at the Mayo Clinic[42].
MC So we actually have done some studies here and with one of these weight loss medications and we examined the patients’ stomach emptying at baseline and after treatment
RR Michael is not grossed out about this stuff. But I am. So for the life of me I can’t figure out why I’m always sitting in this chair talking to you about disgusting semi-digested foodstuff.
WZ It is not, laugh
RR How does this keep happening? Why do I do this to myself?
WZ There is nothing disgusting about a good shit. So what is going on here?
RR So Michael and his team did this study to better understand what happens in the stomachs of people on these kinds of medications.
WZ Mmm
RR So they got 124 people into the lab, About half of them were on a drug like Ozempic– actually an earlier version, but it works in a similar way. For everybody, they cooked them up a very nice breakfast…
MC At Mayo, we use real scrambled eggs. So we. Use two eggs, a glass of skim milk, a slice of brown bread
But then Michael adds a special ingredient
MC … and then a small amount of isotope[43] which is a very small amount of radioactivity
WZ Excellent and why is he spiking their breakfast with a small amount of isotope?
RR Because adding an isotope lets Michael follow the food as it’s moving through the digestive tract.
WZ Oh
RR Because if you point a special kind of camera, called a nuclear camera, at people and take pictures of them, you can see the food glowing through the gut. So Michael’s team took pictures of people with this glowing breakfast as it moved along and timed how long it took food to get squeezed out of the stomach. And I’ve seen pictures…it’s funny bc you can’t see the person, you can just see the chewed up food in their stomach, kinda glowing, in the pics it’s white, black and white pics
WZ And you can see it going down down the gut?
RR At 1 hr, 2 hr, 3 hrs, less and less is in the stomach and it’s moving into the small intestine[44].
WZ So is that that process of moving food through the gut… getting scrambled by these weight loss meds?
RR Um
WZ Did you get that pun? Scrambled
RR Yes, got it, registered.
WZ Excellent. No need to laugh
RR I know we’re beyond that. We’re more sophisticated than laughing to show appreciation for a pun
WZ 100%
RR Quiet appreciation is kinda where I’m at these days.
WZ Beautiful haha
RR So when Michael carefully watched what happened to that radioactive meal when the people on the medication were digesting it, here’s what he saw...
MC It was significantly slower. So it was a good, almost an hour longer to get half the meal out of the stomach[45]..
And what Michael thinks might be happening here is that on the medication, the stomach isn’t contracting the way it typically does[46][47]
MC So instead of contracting, let's say two or three times a minute after the meal, it might only contract once a minute or once every two minutes.
RR the whole stomach as a, as like a muscular bag is not squeezing the way it's supposed to.
MC That's exactly right.
WZ OH interesting
RR And this happened to around 30% of the people in Michael’s study who are on these drugs. Meaning that their digestion slowed down and stayed slowed down[48]. And for some people, not everyone, but for some people this can be bad. It can lead to something called gastroparesis, which is another way of saying paralyzed stomach. So your stomach isn't moving properly. And the symptoms for that are people feel really bloated or they're unable to eat, or it might make you vomit[49].
WZ Right, the woman who vomited so much she lost teeth. Oh god.
RR Really terrible. Wendy we reached out to the drug companies to ask about this gut stuff and the lawsuits that are going on. We talked to Eli Lilly, they make Zepbound, and Novo Nordisk they make Wegovy. They both say they’re always monitoring, evaluating and reporting safety stuff. And Eli Lilly also told us yes - there can be bad GI reactions to these meds. But they said healthcare providers know about those risks. And both companies told us they’re vigorously defending against the claims in the lawsuits[50][51].
WZ Ok … So then I guess how common is it to have really really nasty GI symptoms from these drugs? Like from Michael’s study it looks like quite a lot of people might experience slowing stomachs but what about really nasty stuff like stomach paralysis?
RR Yeah Michael says we don’t have a fantastic study yet to ask that question. But I looked around and I think we do have some clues. So for example there’s one paper that looked at bad gut reactions from people taking semaglutide. And researchers of that study looked specifically for reports of gastroparesis. They looked at more than 600 people who were taking semaglutide
WZ Ok
RR and found that only FOUR of them got gastroparesis[52].
WZ Ok
RR So 4 out of 600ish.
WZ Ok so if you have 1000s of people on this drug, you’re gonna get some with this
RR It’s gonna pop up. But it’s not all that common as far as we can tell…
RR And actually what Michael and other experts think is the more common problem from this whole stomach slowdown thing is actually about what can happen if you have to have surgery. So normally, before you have surgery you’re asked to fast –
WZ mmhmm
RR The reason is they don’t want you to throw up under anesthesia and choke[53]. Well researchers are finding more and more often that people on this class of medication still have food in their bellies.
WZ Oh right right
RR Even after they’ve fasted. Like they’ve actually poked cameras down into people’s stomachs and seen — whoops — there’s food in there[54][55][56]. And sometimes, Wendy!! They even find this thing called a bezoar.
WZ What is a bezoar?
RR That’s what I asked Michael….
RR First of all, bezoar, I mean, that sounds medieval. That's a real thing?
MC Laugh … A bezoar basically is a collection of nondigestible food that remains in the stomach.
RR So Wendy, do you ever put veggies in a food processor or a blender or have you ever made like a kale smoothie and there’s a chunk of the kale that won’t break up? Not getting caught in the blades?
WZ Obviously I have never made a kale smoothie but I get the concept. Yes yes still a chunk of stuff in the food processor. That is what a bezoar is?
RR It’s a chunk of stuff.
RR What does a bezoar look like? Have you ever seen one?
MC Yuck. Yes. haha
RR Did I finally, did I finally find something that grosses you out?
MC you know, nothing really grosses you out if you're a gastroenterologist
WZ I wanna see. I wanna see it.
RR Yeah I have a picture for you and I’m sending you the link . Fig 1
WZ Ok I’m opening the link. Ooooooooh gasp. Oh wow it’s like a marble … small brown piece of shit. It what it looks like, piece of crap
RR It’s like a black slimy stone. I can imagine it in a tide pool, I don’t want to imagine it in my stomach.
WZ And it’s just stuck there?
RR Yeah it has to get broken up.
WZ And does it get broken up?
RR Well a doctor might have to do it, they might have to go in and chunk it up and pull it out[57]. Or you know what Wendy? Another way they heal bezoars is with Coca Cola[58].
WZ Really?
RR They have a tube, a tube of Coca-Cola and you get admitted to the hospital and they run Coke through your nasal passages and into your stomach and round and round and round and it like breaks it up[59].
WZ Haha wow because Coke is so acidic and gross that it can break up a bezoar? Wow. WOW!
RR I don’t know how they figured this out. But I know your next question. Yes – Diet Coke works too[60].
WZ Laugh Woah … And so wait so why do they have to like flush it through your nose over and over again — like can you just drink it?
RR I mean you can – Ok you can also just drink it[61]. But my favorite way is the stomach pumping with Coke. I mean that’s way better right?
WZ OK so and people on Ozempic and similar drugs are probably at a higher risk of getting bezoars than other people?
RR Yeah you can get bezoars for other reasons, a lot of people get them from eating persimmons[62] – fun fact. But for people specifically getting them from these medications, we don’t really know how common it is. But there is a paper where surgeons specifically looked in people’s stomachs before they had surgery for bezoars and found that of 23 people who took this kind of medication, 4 had a bezoar[63].
WZ Right. And that’s higher than you’d expect from the general population?
RR Well when they looked in the stomachs of a bunch of people who weren’t on these meds, none of them had bezoars.
WZ : Riight …
RR: So it seems like there could be a higher risk here…
WZ: So are we about to have a bezoar epidemic?
RR I don't know. We need to have. I hate to say this. We need more studies. Of course we do. But we really don't have more information on the bezoar thing. This this is kind of a new concern, but I thought it was worth bringing up because we know that bezoars can do things like they can obstruct your stomach, they can cause stomach bleeding, and they can and need to be removed with Coke or surgery. So, you know, it could be a real issue if that happens to people. WZ Okay. All right. So so jokes aside, bezoar headlines may await us. This is this could be a serious this could this. What are we to make of this?
RR I don't know, we'll see. I'm going to keep looking. I'm going to keep following it. Yeah. Don't worry, everyone, I'm on the case.
WZ Good, good to hear.
RR Yeah. I think the jury's out on how serious this is, but one thing that has come up within the last year is that experts are now a little bit more aware of this stomach slowdown thing and how it could be a problem for surgery, like I mentioned. And so now the official recommendation is that if you're on one of these medications and you have to have a surgery, you skip a dose before you go under the knife[64]. That's one implication here. Another one is that like if you have a really bad gut reaction, gastroparesis, and maybe you get a bezoar, you might have to go off these medications. And so that means that there's a chunk of people out there that the supposed game changing weight loss drug is not going to work for them.
CHAPTER FIVE: Some good news!
WZ: Mmhh interesting, and now, I guess we've spent a lot of the episode talking about the fears and side effects about Ozempic and drugs like it - but what about the good stuff? Obviously it's helping a lot of people who want to lose weight, lose weight, but are we hearing about anything else?
RR Yeah. I mean, the big one was, clinical trial of people who are on semaglutide for weight loss, who had heart disease. This paper made a big splash. And the reason is because it didn't just measure, like, how much weight did you lose or how much how did your cholesterol change? Your blood pressure change? This one actually measured how many heart attacks people had and how likely they were to die. And it found that people on these medications have fewer heart attacks and were less likely to die[65]. So I mean, death, that's a pretty lack of death is a pretty spectacular outcome, right?
WZ Yeah exactly, so all over social media you see a lot of scare mongering about these drugs … but then there's studies like this! I mean, that's that's huge - less heart attacks!
RR Yeah, the whole thing is a it's all about the pluses and the minuses, right? Like all medications. And so,Vibha - who's the doctor that we talked to earlier in the episode about muscle loss. This is one thing that she and I talked about. And she said that at the end of the day, we know that for a lot of people and a lot of her patients specifically, the pluses here outweigh the minuses.
RR My pet theory is that people are overstating some of these downsides because they're morally opposed to the medications because it looks like an easy way out, what do you think, do you agree with that?
VS I agree, yknow there are definitely– even amongst my colleagues, physician colleagues, it’s a new concept. These are tools. They’re no magic wand but they’re a beautiful tool and should be used appropriately
WZ Yeah right, cause um just to summarize what we’ve learned today. When you look at muscle loss, yes it does happen on these drugs, but it’s nothing special. It’s just part of losing weight. The fears around having suicidal thoughts doesn’t seem to be panning out. And then these stomach issues, I mean we’re gonna have to wait and see what’s going on with those bezoars, and yes stomachs do seem to be slowing, but really really nasty symptoms, they seem to be quite rare. And so if we as a society could separate out our emotions about these drugs and facts around these drugs, that would probably be a good thing.
RR if we could separate– if we as a society could separate our emotions from what the facts are, then you and I would be out of a job, Wendy.
WZ That’s true, laugh, well lucky for us then I guess! Thanks Rose
RR Thanks Wendy
CHAPTER SIX: How Did You Find the Bezoar?
WZ: Hey Rose, so we're gonna try out a new segment on this show. Called how did you find the bezoar? Bing!
RR Wow, is that going to be a recurring segment? How did you find the bezoar
WZ: Who knows? Who can say at this point
RR: in every episode?
WZ: I just have to ask you, how did you find the bezoar?
RR: I saw the paper where 4 out of 23 people when they stuck an endoscope down their throat they found bezoars.
WZ: was like the headline of that paper, like, Bezoars, or was it Hidden Deep?
RR: oh, it was in the headline. That was it. That was an easy click for me.
WZ: And did you know what a bezoar was at that point?
RR: Okay, well that delighted me because there's like a scene in Harry Potter where a bezoar is used as an antidote to a potion, and it's, it's like something about like a medieval remedy when there's a stone of a goat stomach or something, and so I thought of it as like, A, extremely old fashioned, B, kind of magical, and C, something that happens to goats. So, I had a lot to learn about bezoars
WZ: And then that brought you to the Coca Cola how? Ha
RR: Some paper I was reading about bezoars, every paragraph is more absurd than the preceding paragraph. It was like, bezoars, goats, poison, they're real, they can be cured with Coca Cola. And I was like, excuse me? And then the next paper was like, other researchers tried this with Diet Coke. And I was like, Diet Coke?
And, uh, it was just too good to, it was too good to leave behind.
WZ: Well that caps off our inaugural segment of How did you find a bezoar?
RR: Can’t wait to see what people talk about on the second segment. I think we've pretty much covered it
CITATIONS
CREDITS
This episode was produced by Rose Rimler, with help from Wendy Zukerman, Meryl Horn, Michelle Dang, and Joel Werner. We’re edited by Blythe Terrell. Fact checking by Erica Akiko Howard. Recording assistance from Selena Seay-Reynolds. Mix and sound design by Bobby Lord and Peter Leonard. Music written by Bumi Hidaka, Emma Munger, Peter Leonard, So Wylie and Bobby Lord. Thanks to all of the researchers we spoke to for this episode, including Dr. Kristen Beavers, Dr. Ellen Fallows, Dr. Joseph Henson, Dr. Dimitrios Papamargaritis, Prof. Roger McIntyre, Prof. Russ Waitman, Dr. Sahib Khalsa, Dr. Travis Masterson, and Dr. Etienne Wang. Thanks also to Bryant Smith and Lori Segal. And special thanks to the listeners on these medications who checked back in with us.
A special thanks to the Zukerman Family and Joseph Lavelle Wilson.
Science Vs is a Spotify Studios Original. Listen for free on Spotify or wherever you get your podcasts. Follow us and tap the bell for episode notifications.
I’m Wendy Zukerman. I’ll fact you next time.
[1] 13:40-14:08 https://youtu.be/AKNnxKAaONc?t=818
[2] “Muscle tissue is essential for a healthy metabolism, bone (re)modeling, thermoregulation, and preservation of functional capacity and can also function as a storage for glycogen, fat, and protein.4 A substantial loss of muscle tissue can, therefore, result in a decreased basal metabolism, functional impairment, and poorer quality of life.5-7”
[3] “Skeletal muscle is the major site of glucose uptake in the postprandial state in humans.
[4] https://nutrition.hms.harvard.edu/people/vibha-singhal; https://researchers.mgh.harvard.edu/profile/7421072/Vibha-Singhal
[5] Supporting the role of SM in cardiometabolic health, multiple observational have repetitively demonstrated an association between low relative FFM and cardiometabolic complications (Srikanthan and Karlamangla, 2011; Lee et al., 2018; Zhang et al., 2018). In older individuals, sarcopenia as defined by musculoskeletal decline (Cooper et al., 2012) has shown itself to be associated with altered glucose homeostasis (Yang et al., 2017; Shou et al., 2020) as well as autonomy and overall quality of life (Tsekoura et al., 2017).
[6]https://diabetesjournals.org/diabetes/article/65/10/2862/35009/One-Week-of-Bed-Rest-Leads-to-Substantial-Muscle “Bed rest resulted in 1.4 ± 0.2 kg lean tissue loss … Bed rest induced a 29 ± 5% decrease in whole-body insulin sensitivity (P < 0.01).” “We performed hyperinsulinemic-euglycemic clamps prior to and after 1 week of bed rest to assess whole-body insulin sensitivity and observed a substantial ∼30% decline in glucose disposal (Fig. 2A).”
[7] “Insulin resistance plays a major pathophysiological role in type 2 diabetes and is tightly associated with major public health problems including obesity, hypertension, coronary artery disease, dyslipidemias, and a cluster of metabolic and cardiovascular abnormalities that define the metabolic syndrome (1, 2, 3).”
[8] “Examination of intervention related changes in body composition reveal that two-thirds of lost weight is from fat mass and one-third is from lean mass, which is in general agreement with findings reported in other studies (15).” (physical activity + dietary intervention, not medication)
[9] “the physiology indicates that about 75% of the weight loss consists of a loss of fat mass, whereas the remaining 25% consists of a loss in fat-free mass” (low-calorie diet)
[11] “In medical practice, most diets and current pharmacotherapies will lead to some degree of lean mass loss (Figure 2) ((6-8)).... Even if lifestyle modifications and currently available therapies for weight loss can deliver substantial decreases in fat mass, 15% to 40% of the weight loss represents reductions in lean mass ((6-8)) (Figure 2).”
[12] After bariatric surgery: “Our meta-analysis demonstrated over 8-kg FFM and LBM loss within 1-year postbariatric surgery, which reflected 21% and 22% of total body weight loss, respectively. In comparison, weight loss by a 12-week low-caloric diet of 800–1000 kcal/day resulted in 1.5-kg FFM loss (16% loss/WL), whereas another 12-week isocaloric diet with 25% restriction of habitual diet resulted in 2.1-kg LBM loss (23% loss/WL).71, 72 Although bariatric surgery induced greater amounts of FFM and LBM loss, proportional loss is quite similar to dietary interventions on the long term. This suggests a strong relation between weight loss and FFM or LBM loss, in which higher weight loss automatically results in greater FFM or LBM loss. However, higher proportional FFM losses of 30–33%loss/WL are observed within 3-month postbariatric surgery, which suggests that excessive FFM loss predominantly occurs shortly after surgery.” [FFM = fat-free mass; LBM = lean body mass]
[13] Once the glycogen stores are used up, the body shifts to metabolising fat to get the energy it needs to function.
But not all tissues can use fat for energy – such as the brain. This is why the body needs to metabolise your muscles when you’re in a calorie deficit.
Protein (from the food you eat) is stored in your muscles. The body can convert this stored protein into glucose for energy. But this means you subsequently lose the muscle tissue itself when that happens.
[14] “Participants treated with tirzepatide had a percent reduction in fat mass approximately three times greater than the reduction in lean mass, resulting in an overall improvement in body composition. The ratio of fat-mass loss to lean-mass loss was similar to that reported with lifestyle-based and surgical treatments for obesity.21” At baseline, total mass = 104.8 kg = LM + FM
At baseline, FM:LM = 0.93 --> FM = 0.93 x LM
104.8 kg = LM + 0.93LM = 1.93LM
LM@baseline = 104.8/1.93 = 54.30 kg
FM@baseline = 104.8 – LM = 104.8 – 54.30 = 50.499 kg
At 72 weeks, FM loss = 33.9% of baseline FM
FM loss = 0.339 x 50.499 = 17.119 kg
FM@72 wks = FM@baseline – FM loss = 50.499 – 17.119 = 33.380 kg
At 72 wks, FM:LM = 0.70
LM@72 wks = FM/0.70 = 33.380/0.70 = 47.685 kg
LM loss = LM@baseline – LM@72wks = 54.30 – 47.685 = 6.615 kg
Total mass loss = LM loss + FM loss = 6.615 + 17.119 = 23.734 kg
LM loss / Total mass loss = 6.615/23.734 = 0.279 = 27.9% = ~28%
[15] In STEP 1 trial, testing semaglutide. See Table S5 in Supplement. Fat mass kg change was -8.36 kg. Total lean body mass change was -5.26 kg. Total body weight lost was 13.62 kg. 5.26/13.62= 38.6%
[16] GLP-1RAs generally found: “In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery.”
[17] “Regular physical activity, especially resistance-type exercise training, and high protein intake (1.25–1.5 times the RDA for sedentary persons and >1.5 times the RDA for those who exercise) are recommended for persons with obesity who undergo weight-loss therapy to limit the loss of muscle mass (80–82), because dietary amino acids, insulin, and contractile activity are the major regulators of muscle protein synthesis and breakdown (83).”
[18] “A high whey protein-, leucine-, and vitamin D-enriched supplement compared with isocaloric control preserves appendicular muscle mass in obese older adults during a hypocaloric diet and resistance exercise program and might therefore reduce the risk of sarcopenia.”
[19] Comparing people with “normal” or “high” protein intake: “Qualitatively, about one-half (48%–50%) of the normal protein groups lost ≥30% of body mass as lean mass, compared with 21% to 22% of the higher protein groups; furthermore, only 9% to 14% of the normal protein groups lost <20% of body mass as lean mass, compared with 39% to 42% of the higher protein groups.”
[21] From RR FAERS search: Semaglutide: Depression: 301. Suicidal ideation: 208. Tirzepatide: Depression: 70. Suicidal ideation: 31.
[22] For glucagon-like peptide-1 (GLP-1) receptor agonists: “Potential Signal of a Serious Risk / New Safety Information ... Suicidal ideation ... FDA is evaluating the need for regulatory action.” https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/july-september-2023-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
[24] https://www.lyfjastofnun.is/frettir/vegna-tilkynninga-um-alvarlegar-aukaverkanir-sykursykis-og-thyngdarstjornunarlyfja/
[26]“WARNINGS AND PRECAUTIONS: … Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue ZEPBOUND if symptoms develop...Suicidal behavior and ideation have been reported in clinical trials with other chronic weight management products. Monitor patients treated with ZEPBOUND for the emergence or worsening of depression, suicidal thoughts or behaviors, and/or any unusual changes in mood or behavior. Discontinue ZEPBOUND in patients who experience suicidal thoughts or behaviors. Avoid ZEPBOUND in patients with a history of suicidal attempts or active suicidal ideation.”
[27] "Wegovy® may cause serious side effects, including: depression or thoughts of suicide. You should pay attention to any mental changes, especially sudden changes in your mood, behaviors, thoughts, or feelings. Call your healthcare provider right away if you have any mental changes that are new, worse, or worry you”
[28] Pers. comm with FDA rep: “This information is also included
in the labeling for other prescription weight loss products and is based on a potential increased risk of suicidal thoughts and actions observed with a variety of other older drugs used or tested for weight loss. One GLP-1 RA approved for chronic weight management,
Saxenda, had an imbalance in suicidal ideation and behavior in its adult clinical trial and one participant in a Saxenda pediatric trial died by suicide. This information is included in the Saxenda label; however, there was insufficient information to establish
a causal relationship between suicidal ideation and Saxenda based on these data. There was no imbalance in events of suicidal thoughts or actions in clinical trials of Victoza, which contains the same active ingredient (liraglutide) as Saxenda. There were
no imbalances in events of suicidal thoughts or actions in clinical trials of Wegovy or Zepbound, the other two products approved for chronic weight management. “
[29] “In The US Food and Drug Administration analysis of the four major trials as well as unpublished trials, psychiatric adverse events were found to be more common with Rimonabant (20 mg/day) than placebo [16]. Furthermore, two deaths from suicide were reported in patients taking Rimonabant. The drug was never approved in the United States for the treatment of obesity. The marketing approval for Rimonabant has since been removed by the European Regulatory Authorities.”
[30] “In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32–0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32–0.60) suicidal ideation, consistent across sex, age and ethnicity stratification.”
[31] https://pubmed.ncbi.nlm.nih.gov/25023888/ “Acute liraglutide (50 μg/kg; i.p.) and imipramine (10 mg/kg, i. p.) treatment per se significantly decreased duration of immobility in FST compared to vehicle treated rats. Additionally, 3-week liraglutide treatment (50 μg/kg; i.p., daily) partially reversed metabolic abnormalities and depression-like behavior with long-term olanzapine-treatment in rats.” FST = forced swim test
[32] https://pubmed.ncbi.nlm.nih.gov/29705602/ “However, whether liraglutide is an effective antidepressant remains unknown. Therefore, we tested this hypothesis in the depression model of chronic administration of corticosterone (CORT) in mice and treated the animals daily with liraglutide (5 or 20 nmol/kg ip.) to assess its therapeutic potential as an antidepressant. Behavioral studies showed that liraglutide administration attenuated depressive- and anxiety- like behaviors in this depression mouse model, and attenuated the hyperactivity induced by the stress hormone.”
[33] https://pubmed.ncbi.nlm.nih.gov/35133924/ “Our results demonstrated that liraglutide attenuated ouabain-induced hyperlocomotion and depressive state.” ( in rats)
[34] https://www.fda.gov/drugs/drug-safety-and-availability/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type
[36]https://www.cambridge.org/core/services/aop-cambridge-core/content/view/CF59CBBAE25474754AC4382A8E72BD7F/S0924933823024744a.pdf/postmarket-safety-profile-of-suicideself-injury-for-glp-1-receptor-agonist-a-real-world-pharmacovigilance-analysis.pdf
[37] https://www.reuters.com/legal/litigation/ozempic-side-effects-lawsuits-centralized-pennsylvania-court-2024-02-02/
[38] https://www.businessinsider.com/mounjaro-lawsuit-alleges-stomach-is-paralyzed-from-glp-1-use-2023-12
[39] The term gastroparesis literally means “stomach paralysis.” Gastroparesis could be defined as a condition of collective symptoms of nausea and vomiting associated with bloating and early satiety plus or minus upper abdominal pain, caused by delayed gastric emptying in the absence of mechanical obstruction.[1] In the absence of mechanical obstruction, gastric stasis can occur due to abnormalities in the process of normal gastrointestinal motor function. It is a series of complex events that require coordination of the parasympathetic and sympathetic nervous systems, neurons, and pacemaker cells within the stomach and intestine, along with the smooth muscle cells of the gut.
[41]https://www.nbcnews.com/health/health-news/makers-ozempic-mounjaro-sued-stomach-paralysis-claims-rcna97819 “Bjorklund is claiming that she was “severely injured” by the medications and had to go to the emergency room multiple times due to stomach problems, according to the lawsuit. She vomited so violently that she lost teeth, the suit claims.”
[43]Michael’s study: “Gastric emptying of solids was assessed by scintigraphy using a 320kcal 99mTc-radiolabeled egg, solid-liquid meal.17 ” Citation 17 says: “after an overnight fast, subjects ingested a 99mTc-labeled meal consisting of 2 scrambled eggs, one slice of whole wheat bread and one glass of skim milk.” (The isotope mentioned here is technetium-99m.)
[44] Primary endpoint was GE T1/2, which was measured by linear interpolation of the imaging data acquired during the 4-hour postprandial period. In addition, we quantitated GE at 1, 2, 3, and 4 hours after ingestion of the radiolabeled meal,
[45] Re-assessment letter: https://pubmed.ncbi.nlm.nih.gov/37927173/. At 5 weeks, the average rate of half emptying was 74 min longer than baseline (191.6-117.2 min). At 16 weeks, it was only 37 min longer than baseline (154.4-117.2 min).
[46] Failure of the enteric nervous system fails the peristaltic contractions leading to stagnation of chyme propagation within and through the stomach.
[47] “GLP-1 suppresses gastric emptying by inhibiting peristalsis of the stomach while increasing tonic contraction of the pyloric region [4,5].” [GLP-1 = glucagon-like peptide]
[48] Described in follow-up analysis: “In conclusion, liraglutide is associated with significant GE delay in 57% (39/67) of patients with obesity, but tachyphylaxis restores normal GE in 19/39, so that GE delay is persistent in 30% at 16 weeks.” [GE = gastric emptying]
[49] Gastroparesis could be defined as a condition of collective symptoms of nausea and vomiting associated with bloating and early satiety plus or minus upper abdominal pain,
[50] Pers. comm Novo Nordisk believes that the allegations in these lawsuits are without merit, and we intend to vigorously defend against these claims. However, we are pleased with the Judicial Panel on Multidistrict Litigation’s decision to coordinate federal lawsuits related to GLP-1RA medicines in a multidistrict litigation proceeding before Judge E.K. Pratter in the Eastern District of Pennsylvania.
Patient safety is our top priority at Novo Nordisk, and we work closely with the U.S. Food and Drug Administration to continuously monitor the safety profile of our medicines. GLP-1 medicines have been used to treat type 2 diabetes (T2D) for more than 18 years, and for the treatment of obesity for 8 years. This includes Novo Nordisk GLP-1 products such as semaglutide and liraglutide that have been on the market for more than 13 years. Semaglutide has been extensively examined in robust clinical development programs, large real world evidence studies and has cumulatively over 9.5 million patient years of exposure. The known risks and benefits of semaglutide and liraglutide medicines are described in their FDA-approved product labeling. Novo Nordisk stands behind the safety and efficacy of all of our GLP-1 medicines when they are used as indicated and when they are taken under the care of a licensed healthcare professional.
[51] Pers. comm Patient safety is Lilly’s top priority, and we actively engage in monitoring, evaluating, and reporting safety information for all our medicines. Our FDA-approved labels clearly warn that Mounjaro and Trulicity may be associated with gastrointestinal adverse reactions, sometimes severe. These risks were communicated to and widely known by healthcare providers. We are vigorously defending against these claims.
[52] See gastroparesis in Table 1 https://jamanetwork.com/journals/jama/article-abstract/2810542
[53] The combination of food in your stomach and going to sleep under anesthesia could cause you to aspirate. That means your stomach contents come up, then go back down into your lungs. This can be dangerous and make you very sick.
[56] After adjustment for confounding, GLP-1 RA use was associated with a 30.5% (95% CI, 9.9%-51.2%) higher prevalence of increased RGC [Residual gastric content] (adjusted prevalence ratio, 2.48; 95% CI, 1.23-4.97).
[57] “Endoscopic therapy has focused on mechanical disruption via a variety of instruments, including polypectomy snares, tripod forceps, water piks, neodymium yttrium aluminum garnet lasers, and bezotriptors (modified lithotripters that break up bezoars with shock waves).2”
[58] “...a wider range of therapeutic options have been used, including acetylcysteine, papain, metoclopramide, cellulase, and instillation of Coca-Cola (The Coca-Cola Company), the latter of which was first reported in 2002.15-19 However, some of these agents are associated with adverse reactions; for example, case reports have found gastric ulceration, esophageal perforation, and hypernatremia with the use of papain, which is a proteolytic enzyme.20 Both cellulase and Coca-Cola have been better tolerated, without any adverse effects reported to date.19-24 A recent paper reviewing the medical management of bezoars reported on the administration of 3–5 g of cellulase enzyme that was dissolved in 300–500 mL of water and administered orally each day for 2–5 days.6 Coca-Cola administration has been performed by nasogastric lavage (NG) of 3 L of Coca-Cola over 12 hours, oral ingestion, as well as endoscopic injection and irrigation.”
[59] “A double-lumen nasogastric tube (12 F) was inserted into the stomach of the patient, and continuous gastric lavage was performed using 3 l of Coca-Cola over a 12-h period. During lavage, the patient remained in the recumbent position to prevent aspiration. Drainage of the Coca-Cola was done by gravity. No procedure-related complications occurred.” and “…gastric suctioning or gastric lavage, which means washing. Both things happen during the procedure. A healthcare professional will alternately rinse your stomach with water or saline and then draw the contents out. They do this through a tube passed from either your nose or your mouth, into your stomach.”
[60] “We report 3 patients with gastric phytobezoars who were successfully treated with a combination of Diet Coke (The Coca-Cola Company) and cellulase.”
[61] After diagnosis of the phytobezoar, each patient was instructed to drink one 12-oz can of Diet Coke twice daily.
[62] “Trichobezoars and phytobezoars are more common, compared to the other types. Most phytobezoars are formed after the frequent consumption of persimmons…Persimmons are a rich source of tannins. Tannins exist in numerous other organic materials, including plants, woods, and seeds. When large amounts of persimmons are achieved, tannins may interact with gastric acid and polymerize fibers to form a hard phytobezoar [5].” (PDF download)
[63] “Four of 23 (17.4 per cent) patients who were being treated with GLP-1RA medications were found to have moderately large gastric bezoars at gastroscopy (diameter 4 cm or more), whereas 0 of the 77 patients who were not receiving these medications had bezoars.” “We consider it most likely that these bezoars occurred due to delayed gastric emptying caused by GLP-1RA therapy, as the bezoars were not present after the therapy was ceased and because delayed gastric emptying in some patients is a reported side effect of GLP-1RA drugs2,4,5. Larger studies are required for a more accurate assessment of bezoar incidence.”
[64] For patients on daily dosing consider holding GLP-1 agonists on the day of the procedure/surgery. For patients on weekly dosing consider holding GLP-1 agonists a week prior to the procedure/surgery.
[65] https://pubmed.ncbi.nlm.nih.gov/37952131/ “In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months”