What is a GLP1-RA?

You’ve heard about Ozempic and Zepbound, but what are these GLP-1 receptor agonists designed for? We go beyond the celebrity weight loss hype to explain the discovery of the GLP-1 hormone, the development of these medications for diabetes, the role of BMI, side effects, and much more.

We take a moment to remind you that while this is a medical discussion, it is not providing a diagnosis or treatment or any medical advice. The only way to get a diagnosis, treatment or medical advice for your particular condition is through a discussion with your doctor.

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This episode was produced and edited by Erin Stein. Music: “All We Live For (instrumental)” by Wolfclub licensed through Audiio.com. Intro and outro edited, and video created, by Ian Mayer. The Savvy Patient logo by Amanda Spielman.

TRANSCRIPT

00:00 Introduction 

00:33 GLP1 Definition and Discovery

06:01 Creating GLP1 Receptor Agonists

11:52 From Diabetes Treatment to Weight Loss

15:29 Why Body Mass Index is Problematic

25:37 How to Look at Body Weight

28:43 GLP1-RAs for Weight Loss

32:11 Different Formulations and Side Effects

39:36 Rapid Weight Loss and Celebs

43:13 Cost and Insurance Coverage

46:47 Do I Need a GLP1-RA Forever?

49:04 Future Potential of GLP-1 Medications

Erin Stein: Hello everyone. Welcome to this episode of the Savvy Patient in which we will dive into the fancy GLP-1 conversation. You've heard of Ozempic, I think. There's been a lot of media articles. You've heard of Wegovy And if you haven't, I don't know, you're apparently not watching television because there's about eight million commercials every two seconds now. This is how all the celebrities are losing weight and starting to look too skinny. So, what are these things? What's happening? Gillian is going to tell us and even though she's talked about this so many times, I don't retain too much of this information. It begins with a lizard.

Gillian Goddard: It so does. It's my favorite thing actually about this. So...

Erin Stein: Go ahead and tell us about the lizard, Gillian.

Gillian Goddard: Well, I think we need a little bit of backstory before we get to the lizard. Sorry.

Erin Stein: Fine. You always want to add backstory.

Gillian Goddard: Sorry. So GLP-1 is a hormone that we all make. We make it in the cells in our gut, actually. And it tells our pancreas to make and release insulin. it wasn't actually discovered until the 1980s that we even had this hormone. We actually discover that we have new hormones, not infrequently. And people were immediately interested in how it might be useful for treating type 2 diabetes. But here's the catch. The GLP-1 that we make in our gut lasts in our circulation for a grand total of about six minutes. Before our body metabolizes it, it gets broken down by enzymes. And so that is not the recipe for a fantastic medication. One that only lasts for six minutes.

Erin Stein: Should we spell out GLP just once? Glucose? Blah blah blah.

Gillian Goddard: Glucagon-like peptide one.

Erin Stein: Thanks. So that's why we say GLP-1 because who other than Gillian is going to remember that? But okay, it also is insane that we did not even know we had this until the eighties. Like that is our lifetime. That's our childhood.

Gillian Goddard: Yeah, so we at the moment think that we have roughly 50-ish hormones, but we don't know. And we have some of those 50, we don't really understand what they do. When we talk about estrogen and thyroid hormone, we're barely scratching the surface.

Erin Stein: Fun, fun. but it's true. It's one of the points we're trying to make on this podcast. It's not just estrogen and testosterone. There is a lot of other stuff happening in your body. How did we discover this hormone? Do you know?

Gillian Goddard: It was part of a process of the way we usually discover hormones. Someone's like, ‘huh, something's triggering that.’ And they find the receptor first. So, they find the receptor on the cells in the pancreas that make insulin. And then they kind of reverse engineer from there.

Erin Stein: It's just science, science-ing. That's all.

Gillian Goddard: Ha ha!

Erin Stein: Okay, so they basically know what it does. And it doesn't last long.

Gillian Goddard: They knew what it did at its most fundamental. They certainly didn't understand all the things that it did.

Erin Stein: All right, probably, think we still don't totally understand all the things that it does. Okay. All right, continue.

Gillian Goddard: That is correct. So, so for a long time, they were sort of stymied by this, by the fact that this hormone doesn't last very long until they found out that the venom from a lizard from my home state of Arizona contains a GLP-1 like substance called Exendin. Except the Gila monster venom lasts for several hours in the prey's circulation.

Erin Stein: Now here's my other question which you may or may not know. Were they looking for this or some lizard guy was just like, hey, I have something like that if you're interested.

Gillian Goddard: I suspect it was a little bit of they were looking for it and a little bit of some zoologist lizard guy said, well, this is how Gila monsters kill their prey, they make them hypoglycemic.

Erin Stein: Well, yeah, when you put it that way.

Gillian Goddard: And actually, interestingly, exendin was found in the in the venom of Gila monsters, which are from Arizona, but it was discovered by scientists working at the Bronx VA, which is like right over there. And where I did a fair amount of my medical training.

Erin Stein: For listeners [and readers!], Gillian just pointed in a direction from where she's sitting.

Gillian Goddard: Hahahaha.

Erin Stein: I don't know if you can hear this vague noise in the background, but my cat is making muffins nearby. So, if you're hearing some weird little squishing, that's for the cat lovers out there. Okay, so they figured out there's this thing these lizards make. Then what?

Gillian Goddard: Yep. So then they started being able to look at the molecular structure of that. And it was actually not long after that that they were able to create and patent the very first GLP-1 receptor agonist. And that was exenatide. Exenatide was approved for the treatment of type 2 diabetes in 2004. And the reason you don't hear a lot about exenatide is because it was pretty short acting. you had to take it twice a day by injection and it didn't result in a lot of weight loss. It was kind of revolutionary for treating diabetes, but it was still a tough sell.

Erin Stein: Well, was it trying to encourage weight loss or what was the treatment for diabetes? What was it actually supposed to be doing for?

Gillian Goddard: What it was really supposed to be doing is lowering blood sugar. But people thought that it might result in some weight loss. And it did result in some weight loss. And endocrinologists were pretty interested in the potential for these medicines to be helpful with weight loss, not necessarily in the general population, actually, but among patients with type 2 diabetes. Because at the time, most of the medicines that we had for people with type 2 diabetes actually caused them to gain weight. And that makes your diabetes worse. And so, there was this real push-pull there.

Erin Stein: So, seems like a good idea to have something that doesn't make you gain weight to help train your blood sugar levels. So that first form wasn't amazing, but they kept working on it.

Gillian Goddard: Right. Exactly. They did. The next form was liraglutide.  It was instead of a twice-a-day injection, it was a once-a-day injection. And interestingly, it is the GLP-1 receptor agonist that most closely resembles human GLP-1. There's only one little amino acid in there that's different from human GLP-1. But that one little amino acid is important for helping it stay circulating in the blood for roughly 24 hours. And so that going from a twice-a-day injection to a once-a-day injection, that was big. The other thing, is liraglutide was also the first GLP-1 that showed significant weight loss both in people with type 2 diabetes, but also in people without diabetes. And it was actually approved in 2014 as the drug Saxenda. And so, it was the first GLP-1 receptor agonist to be approved for weight loss.

Erin Stein: Again, not that long ago. Really not that long ago.

Gillian Goddard: No, it's been, you know, 12 years. I remember where I was when Saxenda got approved for weight loss. I was in the office where I work now.

Erin Stein: I wouldn't think of that as a momentous event for a lot of people, but for an endocrinologist…

Gillian Goddard: Interestingly, it was the approval of semaglutide that I really remember being anxious that it would happen quickly. Because I had all these patients on liraglutide and they were often on the highest dose that we could prescribe. And it wasn't as effective as I would have liked it to be. And the clinical trials of semaglutide for treating type two diabetes suggested that it was much more effective both for type two diabetes, but also much more effective for weight loss. In fact, there were a bunch of GLP one receptor agonists that came out in between liraglutide and semaglutide that were once a week. And so, we had already made that leap from once a day to once a week. But they weren't always very powerful. They didn't result in a lot of weight loss. And one of them was only on the market for a very brief period of time, maybe only a year or two. Its big claim to fame was that it didn't cause nausea. But probably that means it wasn't slowing gut transit very much. And so, it didn't result in any weight loss at all.

Erin Stein: I'm afraid to ask what that means, because I have a guess.

Gillian Goddard: I was going to say it means pretty much what I just said. It means that food that you put in your mouth makes its way from your mouth through your gastrointestinal tract and out more slowly than without the medication. And that is one of the mechanisms by which these medicines work both to lower blood sugar and to help with weight loss.

Erin Stein: By affecting your gut transit.

Gillian Goddard: Yeah, so if food stays in your stomach longer, you stay feeling full longer so you don't want to eat as much. And then when the food gets into your small intestine where carbohydrates are absorbed, if it's getting to your gut sort of more gradually, you're not getting a big spike and drop in your blood sugar, which is good if you have diabetes. But that spike and drop in blood sugar also stimulates hunger and carb craving. And so, it's also probably good for weight loss as well.

Erin Stein: Huh, that is very interesting. That is new information that I have not heard. The gut transit part. Okay, so we approved this medication for diabetes. Then we kept developing new forms of it to improve it. But then it gets approved for weight loss.

Gillian Goddard: Yeah, so it got, like I said, the first approval for weight loss was liraglutide in 2014. Semaglutide got approved as Ozempic for type 2 diabetes in December of 2017 and it was approved for weight loss in June of 2021. I will tell you, I and other endocrinologists were using Ozempic off-label before it was approved for weight loss, for weight loss, especially in people who maybe didn't meet the criteria for type 2 diabetes, but were headed in that direction. They had pre-diabetes or PCOS. so, this is something that people don't realize. Once a drug is approved by the FDA, doctors can prescribe it under any circumstances, we aren't restricted in how we prescribe it. But if the FDA hasn't approved it for a particular indication, your insurance company is unlikely to cover it. Although back in those days, you if you said someone was pre-diabetic or had insulin resistance, a lot of insurance companies would cover it, even if they didn't have type 2 diabetes. That has changed.

Erin Stein: Let's pause on it got approved for weight loss, but that doesn't mean anyone can walk in the door and say, I want to lose weight, so give me this drug. Like what is the type of weight loss it is meant to help? What kinds of patients is this really meant for?

Gillian Goddard: Yeah, I mean, I think that is the most important question and the thing that people are happiest to ignore or forget. So, the technical indication is that it is approved for the treatment of obesity in people with a body mass index of 30 or above, or it is also approved for the treatment of overweight in someone with a body mass index of 27 or above if they have a quote unquote weight related comorbidity. Examples of weight related comorbidities include pre diabetes, high cholesterol, high blood pressure, fatty liver, sort of metabolic issues and actually sleep apnea is also considered a weight related comorbidity.

Erin Stein: I guess that makes sense. So, this is something that working on the newsletter I was surprised that “overweight” on its own is considered a condition because we use it as a regular word all the time like that person is overweight or whatever but overweight on its own is it's a technical term also.

Gillian Goddard: Right. It is, it's a technical term. Technically, overweight is someone with a body mass index of 25 to 30. But when they did these studies, they weren't looking at people with body mass indexes between 25 and 27. They really limited it to 27 and above. And I think that probably part of the reason they did that is because there's less evidence around the benefits of weight loss from a health perspective in people who have lower body mass indexes. And we can delve in.

Erin Stein: Are you ready for your BMI rant? All right, let's do it.

Gillian Goddard: I'm ready for my BMI rant. Okay. Body mass index was never intended to be applied to a specific individual human being. It is a calculation that simply normalizes your weight for your height. And it was developed for research studies. It was developed to study populations, to understand how people with different body sizes, how their bodies behaved from a disease development point of view and a mortality point of view. And so, we talk about body mass index a lot and I talk about body mass index a lot, but I would argue body mass index is probably not the metric we should be using when we're talking to individuals about both the possible benefits of weight loss, the possible benefits of weight loss medications and it is not the metric we should be using to set goals for people's weight loss.

Erin Stein: Okay, so let's unpack it a little bit more. So, it was created for research purposes when you're looking at data from tons of people, right?

Gillian Goddard: Right, because a six-foot-tall man who weighs 200 pounds and a five-foot-tall woman who weighs 200 pounds, those are two very different people with different body sizes relative to their height. So, you needed some way of comparing those people.

Erin Stein: Right, okay, so the calculation was sort of to be able to compare apples to apples, oranges to oranges, but people of similar body mass. That should have been an obvious end that sentence. It took me a second to get there. so how did it go from being a research tool calculation to being part of diagnostics and the way we talk to people about their diet and weight. Like how did it get there? Yeah, how did we get here?

Gillian Goddard: Basically, the first research that people did using Body Mass Index was research about the development of chronic disease. So, the big thing that happened in the 20th century, right, is we went from dying from infections and accidents and those types of things to dying from chronic diseases like heart disease, strokes, cancer. And so, we wanted a way to figure out which people were at risk for these chronic diseases. And to be clear, when they first started using the metric, they suspected that people with larger bodies may be at higher risk for these chronic diseases, but nobody had proven it yet. The problem is when you lump people into different categories by body mass index that is by definition not a randomized study, right? So, I can't take 10 study participants and randomize them to have a body mass index in the overweight range or a body mass index in the obese range or a body mass index in the quote unquote healthy range.

Erin Stein: Mm-hmm.

Gillian Goddard: I can only take those 10 people and slot them into those categories as they come. But determinants of body size and body composition, and BMI does not take body composition into account at all, which is one of its early criticisms. But the participants who have a higher body mass index have many other things about them that are different from the people who have a quote unquote healthy body mass index, many of which are almost certainly as we sort of disentangle all of this genetic. The way we used to view this and the way some people still view this is that people who have large bodies made lifestyle choices that created those large bodies and then the large body then puts them at risk for heart disease, stroke, diabetes, etc.

Erin Stein: Mm-hmm.

Gillian Goddard: It's becoming increasingly clear that the determinants of body size are incredibly complicated, that they're an interplay of our genetics and our environment, including, by the way, our environment in utero, what happens to us before we are born, when we are developing, how our genes get turned on and off, and that many of those factors are beyond the control of an individual. And it may be that those same genetics that set someone up to have a larger body also put them at risk for diabetes, heart disease, stroke. And so, it's not necessarily clear anymore that just having a larger body alone is what confers the risk. And it's certainly not clear anymore. And I would say it's been pretty well debunked at this point that people have total control over their body size.

Erin Stein: Yeah, so people I know, people I've seen write in our comments, have gone to the doctor and been told your fat, go lose weight. That's your problem. 

Gillian Goddard: They blame everything on body size.

Erin Stein: And it's really offensive, you know, because that may be part of what's happening, but that's not something they can go home and just do most of the time.

Gillian Goddard: I remember this patient who came into my office. She had seen a number of different doctors. She had obesity. She had struggled with weight her entire life. And one of the doctors she had seen before me had told her that there was absolutely no way that she was consuming fewer than 3,600 calories a day. And she said, I'm absolutely, I'm counting calories, I'm working with a dietician, I am tracking my food, and I am not eating anything close to 3,600 calories a day. And I said, I believe you. And she burst into tears because it was the first time anyone had ever acknowledged the fact that perhaps her body size was not something totally and completely within her control.

Erin Stein: Yeah, well, and also just believed her. You've just summarized something pretty big in that they did this study, they used BMI, they made these assumptions, and we've had to unravel that and unpack that a bit. Or a lot.

Gillian Goddard: Yeah. Yeah, I mean, they really, we talk about this all the time when we talk about observational studies. And I think this is such a good example of why we cannot say a lot of correlational data equals a good randomized study. There are some things that are impossible to study in a randomized study like body mass index and how it affects health. But this situation is illustrative of why we cannot confuse correlation and causation.

Erin Stein: You're going to hear it a lot, folks.

Gillian Goddard: Think about this. You probably, as an adult, don't get your height measured every time you go into the doctor's office. But you probably get weighed most of the time when you go into the doctor's office. 

Erin Stein: Yeah. At least for a physical.

Gillian Goddard: Height is relatively static. And so, there's lots of data. it's super easy to build an algorithm to calculate BMI. As soon as you put in the patient's height and weight, it automatically calculates the BMI. So, it's very easy from a study perspective and even from a clinical perspective, it's right there, always.

Erin Stein: So, you want to use it, right?

Gillian Goddard: Well, we were taught to use it.

Erin Stein: How did we get from, it's a thing that exists and now it's automatically calculated for everybody and you're being taught in medical school to use it.

Gillian Goddard: Because we confused correlation with causation, we took those correlative studies that said that people with higher BMIs have more chronic disease and we said, then the way to fix that is to lower people's BMIs and that the way to optimize your risk for long-term disease is to optimize your BMI. That data is not super amazing either. There is some data that if you lose something in the neighborhood of five to ten percent of your starting body weight, whatever that is and whatever your body mass index is, that you can reduce your blood pressure. Blood pressure actually responds quite nicely to weight loss. You can reduce your risk for diabetes or pre-diabetes if you were at risk to begin with. You can improve sleep apnea, but there's actually no evidence that if you take someone from a BMI in the obese range to a BMI in the healthy range, that you do more from a health perspective than if they lose a more modest amount of weight. And we're making the assumption that everyone with a BMI above 30 is automatically ill.

Erin Stein: That's a big statement. Yeah, that's a big deal. Okay, so BMI, kind of bullshit. so how do we know what we should weigh, right? Like how do we know what's healthy? What's a healthy weight for us? How do we know that if we're not using BMI to calculate that?

Gillian Goddard: I think that that's a really good question. And part of the reason BMI has become shorthand for this is because it's a lot easier than the answer I'm about to give. Which is, we should be looking at individual humans holistically. We should be looking at their individual risk for things like heart disease and diabetes and sleep apnea. And then we should be looking at what signs they have already that they are developing metabolic disease and we should be looking to help them bring the overall picture into a better place. That was more complicated. I know, I know. I know.

Erin Stein: Boring. No, but that is how health care really should work. You are an individual. You should go to the doctor and have a conversation about you and your body and what's happening there.

Gillian Goddard: Yeah. And P.S. we now know, and I think diabetes is a great example of this. So, we used to say, and people still say this to me all the time, my grandpa has diabetes, but he's got a terrible lifestyle. Well, I've got news. Type 2 diabetes is among the most heritable diseases there is. If you have a family member on one side, like a first-degree family member, with type 2 diabetes, you've got a huge chance of developing type 2 diabetes yourself. And if it comes from both sides of the family, you have upwards of 70 % chance of developing type 2 diabetes. So it isn't that grandpa has a terrible lifestyle. That may not be helping matters. But grandpa also inherited genes that made his body respond to his lifestyle in this specific way.

Erin Stein: The other takeaway really is that weight is not necessarily the thing we should be focusing on, not that that's never something someone is dealing with, but we spend so much time talking about how much we weigh and the goal weight and how to get there and huge fitness industry and diet industry and supplement industry all based around how much you weigh.

Gillian Goddard: Yeah, about a number on the scale.

Erin Stein: It’s about a number on the scale and that's not what we should be worrying about.

Gillian Goddard: It shouldn't be our main focus and it shouldn't necessarily be our main metric. It's just easy.

Erin Stein: Yeah. It is easy and so we'll circle back now. These drugs have now taken off because so many people are still looking for an easy answer to the easy problem, weight loss. How do we talk about that?

Gillian Goddard: By again, looking at the bigger picture. So, if someone comes to me and says that they are interested in potentially starting a GLP-1, that they would like to lose some weight, the first thing I do is go through all their other health problems. Do they have high cholesterol? Do they have pre-diabetes or impaired fasting glucose? Do they have high blood pressure, do they have sleep apnea, do they have fatty liver, do they have heart disease or signs that they could get heart disease. All these other things, do they have a history of gestational diabetes in pregnancy? I want to get at all those other metabolic things to understand sort of where you are and what your risk is. It's also true that now after many years of doing more study of these medications, we also understand that they both indirectly and directly affect many of the diseases that I just mentioned. And so, if I can say, well, not only is it going to help this person lose weight, it's going to reduce the risk of progressing from pre-diabetes to diabetes. It's going to reduce the risk of developing heart disease or having a heart attack. It's going to fix their fatty liver. It's going to get the fat out of their liver and prevent them from progressing from fatty liver to cirrhosis or even liver cancer. Then I think we have a medication that is doing something worthwhile. My concern is that when we focus on the number on the scale and we go back to that, what we are going to go back to is people who are frail and too thin. And when you look at those survival curves from way back when with body mass index, the people at the low end also had increased risk of mortality. So being underweight was also unhealthy. I'm seeing an epidemic of osteoporosis in our future.

Erin Stein: Some of us have those genes that just make us skinny and underweight.

Gillian Goddard: Right. Much as there are genes that make people have larger bodies, there are definitely also genes that make people have smaller bodies.

Erin Stein: Yes, I have a lot of empathy for people who get crap from their doctors because I don't get it from the doctors, but everyone else is like, you need to eat more. You just eat, eat more food. And I'm like, I eat plenty of food. Nothing's going to change it. Just is the way it is. So, the drugs are still developing. They're still innovating. There are different ways to take them. They just introduced the pill over the shots. Is that better? Is it not better? Let's talk about that. Let's talk about side effects. If you have PCOS, you have diabetes or pre-diabetes, it can be extremely helpful. We've known people who've had amazing turnarounds on them but actually taking them what does that entail it's not easy is my understanding.

Gillian Goddard: Sure. Yeah, so I think the first thing is let's talk about how we take them. So, GLP-1 is a peptide hormone and these receptor agonists are very similar to real GLP-1. That means they get broken down very quickly in the stomach and they don't get absorbed in the gut. So, that's why they were injectable for so long. That's why it took decades to come up with a pill version. The pills that have come out, there's two now. There's a semaglutide pill, is marketed as Rybelsus for diabetes and Wegovy pill for weight loss. And then there's orforglipron, try saying that five times fast. The brand name of which is Foundayo, which was just approved for weight loss and will be getting approval for diabetes presumably in the future. Orforglipron is a completely different molecule, but it is most similar to tirzepatide, which is Mounjaro and Zepbound in that it actually is a dual agonist. It acts on both the GLP-1 receptor and on another receptor called GIP. The biggest misconception out there and it is because at least one online weight loss telehealth company is marketing them this way. The pills people think are if you only want to lose a little weight and the injectables are if you want to lose a lot of weight. That is categorically false. The pills were tested in the same types of people that the injectables were tested in. They were tested in people with overweight and obesity in the same way that the injectables were. And both pills result in roughly equivalent amounts of weight loss as the Wegovy injection. So, the idea that the pills are if you only want to lose 10 or 15 pounds and that the injectables are for someone who needs to lose 50 or more pounds is actually categorically false. The pills are very similar in their efficacy. In both cases, they had to do something to get the pill to get into you through your gastrointestinal tract. And I won't bore you with the biochemistry of each of them, but they're different in that way. And that means that one of them is very finicky. You have to take it on an empty stomach. You have to wait 30 minutes to eat. You can't take it with more than four ounces of water. The other pill, the new pill, Foundayo, that one you can take any time. All of these medicines, whether they're given by injection or orally, especially at first, will cause nausea. And then either constipation or diarrhea depending on the person and the drug. That's correct. That is correct. I love for a while there was this idea out there that these medicines caused stomach paralysis, which is not actually a diagnosis. That's not a medical term.

Erin Stein: There's that gut transit again.

Gillian Goddard: I mean, not paralysis, but slowed gut transit is one of the mechanisms by which these medicines work. So, yes.

Erin Stein: I think it's just that nobody talks about that. Like, I've never heard anyone talk about that element of what they do, being part of how they do what they do. The pills, it makes sense to me that they would try to have something that's easier because not everyone wants to do an injection. Myself would be included in that. And the injection now, it's not daily anymore right. Some of them are weekly. So, the most popular ones Wegovy and Ozempic and Mounjaro and Zepbound are once weekly. How do you know which one of these, there's a question of whether you want a shot or a pill, but aside from that, there's several different formulations. Like how do you know which one is the right one for a patient?

Gillian Goddard: Yeah, so here we I get a little like in the weeds with the data and with the actual biochemistry of the molecule. Semaglutide, which is Ozempic and Wegovy is about 80 percent similar to the GLP one that we make in our body. Tirzepatide, which is Mounjaro and Zepbound. At this point, we're really choosing between those two when we're talking about injectables. Tirzepatide is much less similar, it's less than 50% similar to our own GLP-1. There are many studies looking at the different benefits of semaglutide beyond weight loss. And there are fewer studies looking at the benefits of tirzepatide beyond weight loss. So, they both reduce your risk of developing prediabetes. They both reduce your cardiovascular risk, although semaglutide reduces your cardiovascular risk more than tirzepatide does. Semaglutide reduces fatty liver, protects the kidneys from kidney disease. They've done a lot of studies looking at all the other effects. And so, if that is something that I am looking for, if somebody's had a heart attack before, if someone has a very high risk of cardiovascular disease, I might lean more toward that medication. Tirzepatide head-to-head has been shown to result in more weight loss. So, if someone is very obese. Their obesity is really limiting their mobility. I will go with tirzepatide because they are more likely to lose the degree of weight loss that they would need to lose to allow them to do the kind of activities that they would like to do physically in their daily lives, which is something we haven't even talked about yet, but which I think is an important benefit of weight loss for many people who are obese. And so, and then the side effect profile is a little different. Some people do better with semaglutide, some people do better with tirzepatide, and so there's a little trial and error there.

Erin Stein: We talked about some digestive changes and nausea, but are there other kinds of side effects that people have.

Gillian Goddard: Those are the main ones. Sometimes people feel fatigue. It's probably multiple factors. GLP-1 does cross the blood brain barrier and there are GLP-1 receptors in the brain, which is why people are interested in it for addiction and dementia. But it also probably has to do with the fact that people significantly reduce their caloric intake and hunger and thirst are very similar stimuli in our brain and our brain can't always distinguish between hunger and thirst and so when we suppress hunger, we also suppress thirst and so I think a lot of times people are not being mindful of staying hydrated when they're taking these medicines. 

Erin Stein: Well, that's interesting.

Gillian Goddard: There is one type of very specific type of thyroid cancer that it has been shown that these drugs cause to grow, but it is a very rare type of thyroid cancer that occurs in familial syndromes. So, you would have like a big family history if you were at risk for this type of cancer. You're not supposed to take it if you have that genetic mutation.

Erin Stein: I've also seen some people complain about other things like there's a thing about gallbladders.

Gillian Goddard: Many of the other problems or side effects that people talk about are actually not related to the drugs themselves. They are related to significant weight loss. So, it is true that if you lose weight at a rate above three-ish or four-ish pounds per week, you are at increased risk of precipitating gallstones. And that is true whether you do it with weight loss surgery or with these medications. I manage for that by slowing how I titrate the medication so that people aren't losing weight quite so quickly.

Erin Stein: Yeah, I think that's really important with these drugs and any conversation about them. It's unhealthy to lose weight too fast. It's bad for your body.

Gillian Goddard: That is correct.

Erin Stein: I don't think that's talked about nearly enough because everyone's like, I gotta lose weight, I gotta fit into this dress for this wedding and that's part of why these drugs get talked about so much is that they can help you lose weight fast, but that's actually really dangerous.

Gillian Goddard: My target is not more than two pounds a week, actually. Because of the gallstones, but because of other things as well. There's a lot of misconception about these drugs because when they did the studies, they had set titration of the medicine. So, you started on the lowest dose then after a month, you moved up a dose then you moved, and it was very prescribed. And if you didn't, if you weren't able to tolerate that dose escalation, you had to leave the study. The reason they had such a strict titration is that they were trying to show that the drug was effective for weight loss in a limited period of time. You do not want to pay for a clinical study to go on for years and years and years. But in clinical practice, there is no race to the end and there's no reason to be jacking up the doses of these medicines. And I think actually a lot of the really significant problems that we see with them come from prescribers who don't have a lot of experience prescribing them just following what they did in the studies and not using their clinical judgment.

Erin Stein: Not good, not good. So, you do need to have some awareness before you go in and ask your doctor about these things. They seem like a magic pill and in some ways, they are, but they are not in the way that sometimes they get talked about would be my assessment.

Gillian Goddard: I would say that's pretty accurate.

Erin Stein: And look at me, I'm not even a doctor. I think that's being fed by the celebrity conversation as well, right? I don't even know if celebrities have admitted to taking them or people are just assuming that they're taking them.

Gillian Goddard: Some celebrities have been open about it and some have not. Oprah was very open about having tried it. after the Oscars and the awards season there was all this chat about Demi Moore being too thin.

Erin Stein: Right, she's the one, yes. Yes, which also Demi Moore has always been thin, so I don't--

Gillian Goddard: I think a lot of this is speculation. 

Erin Stein: There's something about just being thin and then you get older, you look a little thinner because you're losing some youthful fat and collagen and I know that's my future. I already know that. It's always been a conversation with Hollywood because it's always tortured women and told them they need to lose weight.

Gillian Goddard: It's like a whole industry set up just for that.

Erin Stein: It's nice that we would prefer they don't, but yeah, we're still just judging women for how they look, so neither way is great. What about cost of these medications, getting insurance to cover it? 

Gillian Goddard: Sure, it's getting better. When these medicines first came on the scene, they were quite expensive and coverage of obesity medicines has historically been spotty in part because until these medicines came along, we didn't have a lot that was all that effective. Obesity medicines do not get covered like medicines for everything else by your prescription drug plan. The class is called anti-obesity medicines and they get covered under a separate rider that the benefits manager has to opt in to offering. If you have this coverage for anti-obesity medicines, then your doctor has to do a prior authorization. They have to prove with a chart note from a visit that you meet the criteria, and that is based on body mass index and we can talk till the cows come home about the pluses and minuses of body mass index, it's based on body mass index. If you do not have this rider under your coverage, your insurance will not cover these medicines unless you have type two diabetes.

Erin Stein: I was just going to say I bet it's body mass.

Gillian Goddard: Right now, they are only covered for two things, type two diabetes and anti-obesity. There is a little bit of wiggle room with Zepbound specifically for sleep apnea. But you have to have a sleep study within the last year and it has to show very specific metrics around sleep apnea. You have to have moderate to severe sleep apnea and that's based on the number of apnic episodes over the course of the study, over the course of the night.

Erin Stein: So, if you're taking it for PCOS, is that not covered?

Gillian Goddard: Only if you get it covered as an anti-obesity medicine. Because the FDA has not approved these medicines specifically for the treatment of PCOS, even though there is a growing literature showing that they are beneficial for many people, many women with PCOS.

Erin Stein: If you are not getting it covered, you're paying for it.

Gillian Goddard: Eli Lilly makes tirzepatides, Mounjaro and Zepbound and orforglipron. Novo Nordisk makes semaglutides, so Ozempic, Wegovy, Wegovy Pill and Rybelsus. Both Eli Lilly and Novo Nordisk offer cash pay programs where they basically have their pharmacy set up and they offer the medications at discounted prices when you buy it directly from them. Those prices range based on dose and how many fills you filled anywhere from $149 for a month supply to $449 for a month supply. And if you're listening to this in six months, it's probably lower already. They are lowering the prices pretty actively every six to nine months or so as new things come on the market.

Erin Stein: Yeah. I find it interesting that they're now advertising to the menfolk. They're like, hey guys, join the club.

Gillian Goddard: Yes. Your wife looks great. So, my practice is like 90 % women and the 10 % men I see mostly were dragged there by their wives because they thought they needed to lose weight.

Erin Stein: If you're taking it for weight loss, are you on it forever? Do you take it just until you lose the weight and then you go off do we know anything about taking it for a long time, a short time?

Gillian Goddard: The common thinking in the zeitgeist and what people say often is that you need to take it forever. That is based on a study that Novo Nordisk did at the end of their weight loss trial. They randomized the people who were on the highest dose of Wegovy to either continue on the highest dose or to just stop it cold turkey and they found that the people who were randomized to stop it started to regain weight. The pharmaceutical companies are not incentivized to do the trials that look at weaning people off of this. Doesn't take a mastermind to figure that out. But there is a study that came out recently that was a medical record study that looked at thousands of patients who had received prescriptions for GLP-1s and then stopped them and looked at the trajectory of their weight afterwards and found that about half of people regained the weight that they lost and the other half of people either maintained their weight loss or even continued to lose weight. So, we don't know yet, who's who. I can't look at you and tell you you're going to be one of those people who can come off, you're going to be one of those people who has to stay on for forever, with the exception of the fact that I find that the people who have struggled with weight from childhood ever since they can remember often need to stay on them. It's probably because so much of their struggle with weight is genetic and not lifestyle. But I definitely have had patients come off of these medications successfully. The key is to wean off and not to stop them from a high dose and just stop taking them.

Erin Stein: Yeah, I think that's generally true with a lot of medication that you need to wean yourself off of it if your body's gotten used to it.

Gillian Goddard: Yes.

Erin Stein: These medications seem, again, like miracle wondrous medications and as we've talked about only recently really discovered and come on the market. They are still being studied for what we're using them for now, but they're also being studied for all kinds of other uses and potential miraculous things they might be able to do. Tell us a little bit about some of those things and do you think that there's something there, there?

Gillian Goddard: Yeah, yeah, yeah, yeah. the things that people are really interested in, where we've seen other than the things I've already mentioned, dementia, Parkinson's disease, addiction and cancer prevention. And yeah, and kind of seems like it's all over the place. But if you drill down on many of these diseases, there is a component of glucose metabolism happening in many of them.

Erin Stein: That's a lot.

Gillian Goddard: Addiction is the one where it's less clear, but it's increasingly clearer that degenerative brain diseases like dementia are metabolic, meaning that they're related to how the cells are individually metabolizing sugar. And cancer too, cancer cells love sugar, love, love, love sugar. Some cancer cells more than others. And so, it makes sense mechanistically that a medication that lowered blood sugar and helped your body process blood sugar better would be beneficial in those situations. The benefit for Parkinson's and for addiction may be similar. They're thinking is that maybe it's affecting dopamine and so, both addiction and Parkinson's disease, you know, dopamine plays a role in the path of physiology of both and there's some mental illness too, so that dopamine idea makes sense. And in fact, many people are interested also in, how these medicines affect executive function and whether they might play a role in ADHD and that would be probably also dopamine from a mechanistic point of view. But you know that I firmly believe that a lot of chronic illness is metabolic and that how we process sugar is the problem. I've threatened to title my next book, It's All Metabolic and have been told no way. I promise I'll come up with a better title.

Erin Stein: It's not the sexiest title, we'll brainstorm maybe some better ones. Cause who knows what metabolic means? Like we say metabolism all the time, but ask someone to define it. can't, you know?

Gillian Goddard: Hahahahah. Alright, fair enough, fair enough.

Erin Stein: So yeah, we gotta relearn a lot first. But I mean, all of that makes sense and it's, again, this brings me back to science is great, people. Be pro-science because science is never ending. We're still discovering new things about our bodies and how they work. We don't know everything yet. And then people are like, well, why should I believe anything anybody says? It's like, we have the best knowledge we have now, but we change it as we get new knowledge. We literally did not have these drugs 25 years ago. That's a lot about GLP-1 and their RAs so we'll certainly talk about them again. Please read the Savvy Patient's newsletter for lots of detail about these drugs. Gillian writes about all the latest news as it comes out. And we have a helpful primer if you could not follow all the millions of names of these things. I told Gillian we need a chart and she made a chart. So, check it out and until next time.