What we got wrong about GLP-1s

25:55welcome back to the show so can you tell me literally just like what are glp ones doing inside of your body like what are the mechanics of how these drugs work okay so when we're talking about glp ones as a class we're talking about this class of medications the first one actually came out in 2005. But like this popular conversation is referring to the ones that have come out in the last couple of years. And the sort of first one is semaglutide, which is Ozempic or Wrigobi. Then the second one that's already approved and been on the market for a couple of years is terzepatide, which is Zepbound or Munjaro.

26:37And then there's this one in the pipeline that I literally cannot pronounce, the one with the R. Reditrutide. Reditrutide is like the worst possible name. Yes. Like I can't spell it. I can't say it. So semaglutide is this peptide that is a GLP-1 agonist. An agonist means that it's a peptide that binds to the GLP-1 receptor in the body. And GLP-1 in the body does a couple of different things. It slows gastric emptying. So it makes your stomach stay full longer. Like not the feeling, not just the feeling of being full, but literally like if I eat a salad, it stays there. Exactly. That does absolutely increase your fullness and gets you to fullness faster.

27:17Yeah. It also does increase your sense of fullness by working on like hormone receptors in the brain and it decreases hunger and increases satiety. And then it, and this is why it's really important and works in diabetes, it works on glucose balance. And so it provokes the pancreas to release insulin in response to high glucose levels. So it doesn't cause your pancreas to just like willy-nilly release insulin all the time, but it augments the insulin response to high glucose levels in your body. And what's the relationship between, like glucose enters my body when I eat like sugar or bread or something like that.

27:54What's the relationship between glucose and insulin? So when you eat anything that has carbohydrates in it, it gets broken down to release glucose, which is like sugar, in your blood. In response to glucose in the blood, the pancreas, which is like an organ in the back of your belly, releases insulin, which is a hormone. Insulin helps your muscles take the glucose out of your blood into the muscle and use it for energy. What happens in people of type 2 diabetes or people of prediabetes is they develop insulin resistance, which means that they have decreased response to insulin, which means they are less effective at taking the glucose out of your blood.

28:34And that means that your body needs to release more insulin in order to take that glucose out of your blood. So for diabetics, who often have very high levels of glucose just like circulating in the blood, high levels of glucose is called hyperglycemia. It has all sorts of downstream effects. It hurts your eyes. It hurts your kidneys. Eventually, it contributes to plaque buildup in your arteries, which can cause heart attacks and strokes. So what you want to do in diabetics is get their glucose levels, their average circulating glucose levels down. And GLP-1 agonists help do that by signaling to your pancreas when you have a glucose spike to release insulin so that the glucose spike doesn't spike too high.

29:14Basically, it helps sort of maintain your glucose levels within a range that your body can handle. And GLP-1 agonists, through that sort of combination of effects, the semaglutide like Wugo-Vozempics lead to like 10 to 15 percent body weight loss over the course of a year. the studies. But the thing that I think is really interesting about these drugs, and one of the reasons that they've inspired so much excitement is because they've had effects that we sort of anticipated that were like targeted effects in the initial trials, improved blood sugar control and weight loss. And then they've had a bunch of unexpected downstream effects probably related to weight loss and better blood sugar control, like they prevent heart attacks, they prevent strokes.

30:01They prevent people from progressing to diabetic kidney disease. They seem to improve people's knee arthritis, which like was really unexpected. They seem to improve heart failure. And then they also have this potential effect around addiction. And that's interesting because you really can't attribute that impact to weight loss. So like, There's no reason to think that if I'm 225 pounds or 180 pounds, I should want to drink more or less. Right, exactly. Other than maybe there's some psychological impact, et cetera, et cetera. But what we're sort of interested in is it's revealed that there are GLP-1 receptors in places where I think we didn't totally recognize they were there, didn't fully recognize their potential role in things that we weren't thinking about.

30:52So there are GLP-1 receptors in like the dopamine reward circuitry in your brain. And one sort of hypothesis around the addiction stuff or the sort of strongest hypothesis is that GLP-1 agonist binding there is interrupting reward circuitry pathway stuff in a way that for people who have strong reward pathways built around addictive behaviors, like it interrupts that. And is it like these sort of unexpected positive effects, the ones that are sort of surplus effects that go beyond what you would have modeled as likely benefits of just like losing weight? Does it suggest that maybe being like a certain amount of overweight can be more dangerous to our health than we understood?

31:40Or is it more like these things are just doing things in places that we don't understand? I think it's the first. I think that one of the things that's really interesting about the diverse array of effects that the GLP-1 drugs seem to have is that it suggests the fact that obesity, which people who study obesity have long asserted, is a pathological condition that has consequences way beyond just being overweight and moving around the world in a bigger body. having a lot of excess fat tissue on your body changes all sorts of hormone signaling and homeostasis mechanisms in your body. So losing that adipose tissue, that fat tissue, makes a huge difference in changing how your body self-regulates.

32:26And that seems to improve a whole bunch of things that we maybe didn't totally anticipate. There's this sort of hand-wavy thing that the GLP-1s decrease inflammation, which is true. We sort of do know that, that they decrease inflammatory markers in the body. And just seeing all the different ways in which decreasing inflammation seems to help people is really fascinating. Yeah. You've described the known benefits. You described that there's some, like, sort of, I don't want to say unknown possible benefits, but, like, question-marky things that look good. A million things that are, like, question-marky things that look good.

33:00Like, I should just list some of them because it's so exciting. Cancer prevention. So we know this is another one where, like, on the one hand, we know that there are a bunch of cancers for which obesity is a risk factor. Breast cancer is like that. Colon cancer is like that. GLP-1s seem to help with those. There are a bunch of cancers where we don't think of obesity as being a risk factor, where GLP-1s, because of this anti-inflammatory sort of impact, we're not totally sure, may also play a role. So there are trials to look at cancer prevention. There are trials to look at Alzheimer's prevention.

33:35The first Alzheimer's prevention trial was negative, which means, like, the drug didn't make a difference. But I don't think it's conclusively negative that it doesn't help with Alzheimer's prevention or treatment necessarily. There's sort of more trials to be done there. There are trials happening in Parkinson's disease. Like, these are big, extremely common conditions that either lead to death or that totally derail people's lives. And so the potential benefits that are still under-characterized or unproven are super exciting. And what are the current unknown or questionable possible harms that you're tracking?

34:11I mean, one that's sort of been studied some, but I think not in a way that's super, super conclusive, is for some people it does seem to provoke a depression. There's been this concern about increased suicidality that has not borne out in studies thus far, but like it's on the radar as a thing that people are concerned about. But these psychiatric neurologic complications I'm interested in and paying attention to. The most common side effects with these drugs are the GI side effects, so like bad nausea and vomiting and constipation. And so I'm really interested in both increased clarity around what standard of care looks like for prescribing them to minimize those side effects and whether these future, like, GLP-1, 2.0, 3.0, 4 .0s are going to improve that side effect profile because that would actually make a very big difference.

35:05Right. Because there's people that can't tolerate those side effects. Yeah. I mean, some people are really nauseous and vomit at the beginning because they just haven't figured out how to eat on the drugs. Yeah. They're still eating too much. But some people have, like, constipation that they just can't tolerate. Some people are persistently nauseous in a way that doesn't get better. For most people, it gets better. But that's a real, like, rate-limiting step. So there's a world of discourse and media, which I belong to, which bungled this story for at least a year. In the world of the patient populations who you treat, like, what was actually happening far away from the discourse?

35:42Can you just tell me stories like from early on, like what type of patient was taking these medicines at your clinic and how is it affecting them? Sure. So I work in New York City. New York State has generous Medicaid. New York City's public hospital system has its own pharmacies and they did some amazing job. I don't totally understand, in which they were able to provide access to the GLP-1s even during the period when it was very, very hard to get them at sort of regular community pharmacies. And so between both that sort of generous insurance and that access in our hospital pharmacy, I have had this incredible good fortune of being able to prescribe Ozempic for diabetic patients since like 2023 or 2024.

36:33who are poor and otherwise would not have access to it, right? And this is like a huge issue is that like for most patients like my patient population, they aren't on it yet because their insurance doesn't cover it. Yeah. Or if their insurance covers it, it covers it only for a very narrow set of indications and they have trouble getting it or whatever it is. My patients have been able to get it the whole time. And I do think it's sort of like a miracle breakthrough in primary care for underserved populations that have the morbidity burden that my patients have. So most of my patients have diabetes and high blood pressure and high cholesterol and some degree of kidney disease and maybe some degree of other complications of diabetes like retinal disease in their eyes and fatty liver disease.

37:20Most of my patients also have some addiction history in my homeless clinic, so alcohol or other substances. And it's been my experience that for the patients for whom I've been able to prescribe Ozempic, which is the one that I've been able to get paid for, it really does help with all of those things. Like, their diabetes improves. They lose weight. Their chronic pain improves. Their blood pressure improves. Their cholesterol markers improve. And patients really like it. I mean— What did they say? Like, I had this great paranoid schizophrenic lady who was on it. She was the first patient I ever prescribed it to in primary care.

38:03And she was in my office, and she's sort of, like, a little bit psychotic at baseline, but she takes her medicines. So she's telling me some story, like, I kind of can't follow about, like, some people who have been, like, tapping her phone. And then I said, oh, wow, you lost like 12 pounds or something. Because I'm looking at her chart. And she pauses and she like locks in. And she goes, I haven't weighed this much since 1996. And I died. Like, I was like, you go, girl. Like, amazing. So happy for you. And that's like, that's been true for a bunch of my patients. That they feel better in their bodies, both psychologically and physically.

38:40And they don't work for everybody. There are certainly, you know, 5 % to 10 % of people who don't tolerate them because the side effects are too much. Like some people just get much more nauseous than the average person. And then they're just like, I can't do this. I don't like it. A few people have said more in my personal life than in my practice that they thought that they felt low on them, that made them feel a little bit depressed. I haven't had that happen in my practice. But, you know, that's just to say that there are a bunch of reasons why some people don't tolerate them. But for people who tolerate them and for whom they work, they're an incredible intervention.

39:12Most of my patients are on like eight to ten medicines a day. And for them to be able to take one shot a week, lose weight, improve their diabetes, improve their high blood pressure, improve their high cholesterol, you know, carrying less weight and also have less inflammation in their body so their pain is better, their depression is better. Like that's an extraordinary thing to be able to offer them. It's not everybody's experience, but for people for whom it worked, like it works better than any other single intervention I've ever given someone other than curative ones. And so, like, I'm unbelievably grateful for them and I'm incredibly excited about them.

39:50You know, like I think as there's this arms race in developing better, more effective, more targeted GLP-1s, and as we get more and more studies about how to dose them correctly for different conditions, et cetera, et cetera. Like, you know, I mean, it already has, but it will absolutely revolutionize primary care practice.

40:13Dr. Bedard says that part of this revolution has come because, maybe surprisingly, maybe not, one side effect of the huge demand surge for these drugs in 2023 and 2024 is that the price has been driven down. When the manufacturers of drugs like Ozempic couldn't meet demand, compounding pharmacies entered the marketplace, selling compounded versions at a much lower price. That ended up pushing prices further down, even on the name brand GLP-1s. So now, semiglutide, which not so long ago cost$1 ,200 a month without insurance, can be found online for as low as$150 a month. A healthcare market that, for once, seems to have kind of sort of worked, eventually.

40:53We're going to take one more break, and when we come back, Dr. Bedard gives us her take on people who are taking these shrugs for decidedly off-label use.

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42:15This episode of Search Engine is brought to you in part by Snapple. Hey, before we jump back into the show, let's take a quick break. But not just any break. This is a refreshing break with Snapple. We all know about Snapple's iconic real facts. So let's take a moment to go over some of my faves. Snapple Real Fact 1361, a nun held one of the first PhDs in computer science. Snapple Real Fact 1643, the first search engine's name is Archie. Snapple Real Fact 1517, in New York, it is illegal to sell a haunted house without telling the buyer. Snapple Real Fact 1228, chimps can develop their own fashion trends.

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44:16Welcome back to the show. Do you, just in your social life, do you have like non-patient people, like friends, family members still asking about the drugs? Constantly. Constantly, so. Constantly. Like I take like an unofficial example to consult a day. What do you tell people right now? I mean, I am very GLP-1 supportive. So, you know, it's case to case. Like it's not for everybody. But I will give you sort of examples of like the kinds of things. Like, you know, I have lots of women in my life who are struggling with postpartum weight gain or like pregnancy weight gain and not being postpartum feeling overweight.

44:54Or people who one of their real anxieties about getting pregnant again is that they gained a huge amount of weight and they don't feel like they're back in their own bodies and they don't want to gain more. I'm really supportive of people using a GLP-1 for a period of time to help them lose, you know, weight that they gained really suddenly and are having a hard time losing. There are obviously some people who have long histories of eating disorders in their lives, right? And where you think, I think if you do this, this is not going to be great for you, actually. Like, I think that this is reigniting a series of obsessions that, like, you've done a lot of work to try to get past.

45:27For those folks, I don't think that they should, you know, entertain the idea of a GLP-1. But for lots of people, I think it's a fine thing to do. Do you talk to people who are talking about using it, I guess, off-label, to manage addictions? I have, so, I know one guy who was taking it so that he would post on Twitter less. Really? Yeah. Did it work? He said so. And then he's posting a lot recently, so maybe he's off. I don't know. If I really thought it was a cure for Twitter use, there's people, I would, no, I would stand outside other people's houses with, like, a blow gun and just, like. I mean, you know, I think, yes, I absolutely have people who, I have a close friend whose primary motivation in trying it was that he wanted to drink less.

46:15He also probably wanted to lose 10 or 15 pounds, but like probably wouldn't have taken it just for that alone. Yeah. Asked, and I said, yeah, try it, see how you tolerate. You know, the other thing is that they just are quite safe. That doesn't mean that they're safe for everybody to take for 60 years week after week. You know, like, we don't totally have exactly that data, but we have 20 years of data about this class of medicines. And we have a pretty good sense of there is a very narrow slice of the population who they're totally inappropriate for. If you've had a family history of certain rare cancers for the majority of people, giving them a shot and seeing how you tolerate is totally appropriate and fine.

46:50And so this friend, like, took them. He didn't identify as an alcoholic, but he identified as someone who wanted to drink less and who drank daily. And for this friend, he took them for six months or something or four months, totally changed his relationship to drinking. I think he's been off now for a little while, and he said he's not back to drinking the way that he was. He feels that relationship feels altered for him, even if he's not as suppressed in his desire as he maybe was when he was on the medicine week after week. I had one last question for Dr. Bedard. I wanted to know if she had a perspective on a class of drugs that are adjacent to, but in my view, fairly different from GLP-1s.

47:36Internet peptides, the wilder West of molecules many people are now using. Drugs we've covered elsewhere on the show. I think that I think that it is both GLP-1s and peptides to some degree are part of a larger shift in health wellness medicine, which is this like paradigm shift between thinking of medicines as things that we use to treat illness to thinking of pharmaceutical products as something that we offer people to help them feel the way they want to feel. And is that a bad shift? Is that a neutral shift? It's a complicated shift, I think. So, you know, the better example to me than peptides is, like, the use of hormone supplementation for a million different indications, right?

48:25Like, that's another huge discourse. It's like, you know, women taking estrogen supplementation in their early 40s when they start to feel what they self-diagnose as perimenopausal symptoms. Women on testosterone, there's been a bunch of essays about that. men on tests, you know, like, it's a very different way of conceptualizing the rule of healthcare than it's not why I went into healthcare. And it's also different from the sort of paradigm I trained in. But I'm also a little bit trying to remain neutral about this and thinking about the changing relationship between patients and providers to one that's a more sort of shared goal setting, shared decision making model, which doesn't quite answer your peptides question.

49:08But I kind of see all of like the peptides, the GLP-1s, the cosmetic procedure stuff. It's like all part of a thing of like, I don't feel the way I want to feel in my body. I don't look the way that I want to look in my body, et cetera, et cetera. I'm going to seek medical intervention to help me become the thing that I want to become. I have really complicated reactions to it, but I don't yet have a definitive opinion about it. I'm really trying to think it through. I can't tell if what you're describing is that interventions that we just would have understood as cosmetic before are becoming much more socially acceptable, or if it's more complicated, which is that, like, interventions like we thought of as cosmetic were now in our own minds labeling as medical.

49:49I think it's the second one. So I think that we have, in a weird way, medicalized a lot of the experience of being, like, in the human life cycle, you know? Yeah. And that's complicated. You know, and again, like, these are all sort of questions and discourse topics, et cetera. So they're so far afield from my medical practice and my patients' lives and my patients' bodies. And they're so far afield from sort of what are the things that sick people actually live with, what are the things that actually kill people, et cetera, et cetera. So with the sort of large caveat that all of my initial anxieties about the GLP-1 discourse apply to this other sort of wider discourse around other interventions that are for self-fulfillment but are sort of being medicalized, I'm trying to be like a little bit thoughtful before I just sort of react to them as a knee-jerk moral panic around those.

50:41But it's like you feel uneasy, but you feel uncertain about your uneasiness. Yeah, I'm like really working through it. I think that's an intellectually honest position. Thank you. Thank you for talking about this. My pleasure. Thank you for having me.

51:01Dr. Rachel Bedard, she's a doctor and writer, will have a link to her story about the rise of Ozempic in the show notes. Also, I have to say, there was one more part of this conversation, which it was the part I found myself talking the most about with friends the week afterwards, but it was on a slightly adjacent topic. So we got more into this idea of cosmedicine, like the place where cosmetic interventions and medical interventions kind of meld together, and about how there are middle-aged people who are thinking about interventions like taking testosterone or estrogen, or going to the dermatologist for lasers to try to look more the way they think Anne Hathaway looks, or men going to Turkey to get a new hairline.

51:42I don't know how we're supposed to think about this era where looking older seems to be becoming more optional, where many people on the internet seem forever 35. And talking to Dr. Bedard, who is also working this stuff out, it really helped me. These ideas have already been swirling around my brain. It's settled them a little bit. If you want to hear that conversation, we're going to publish it as an extra small feature on incognito mode. You can sign up for that at searchengine.show. If you're already signed up, it is in your feed now.

52:15Thank you.

52:41Search Engine is a presentation of Odyssey. It was created by me, PJ Vogt, and Shruthi Pinnemanini. Garrett Graham is our senior producer. Emily Moltero is our associate producer. Theme, original composition, and mixing by Armin Bazarian. Our production intern is Piper Dumont. Piper also fact-checked this episode. Our executive producer is Leah Reese Dennis. Thanks to the rest of the team at Odyssey. Rob Mirandi, Craig Cox, Eric Donnelly, Colin Gaynor, Moore, Curran, Josephina Francis, Kirk Courtney, and Hilary Schuff. Also, if you have a business which you would like to advertise on our show, please email us.

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