Astral Codex Ten

GLP-1 agonists

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GLP-1 agonists

Article

GLP-1 agonists is a recurring concept in the Astral Codex Ten archive, appearing 4 times across 4 issues between November 30, 2022 and July 01, 2025. The archive places it in contexts such as “this post focuses on GLP-1 agonists”; “several other pharma’s with GLP-1 agonists in development”; “pharmacology of the GLP-1 agonists”. It most often appears alongside FDA, Novo Nordisk, Ozempic.

Metadata

  • Category: Concepts
  • Mention count: 4
  • Issue count: 4
  • First seen: November 30, 2022
  • Last seen: July 01, 2025

Appears In

Source Context

Recovered passages from the original issue text. When the raw archive preserved outbound links inside the source passage, they are listed directly under the quote.

Highlights From The Comments On Semaglutide
November 30, 2022 · Original source
Sixth, this post focuses on GLP-1 agonists, which makes sense, because those drugs are starting to have an impact today. But the Morgan Stanley report also notes that amylin analogue cagrilintide may be approved for weight loss as soon as 2025. This drug has a completely different mechanism than semaglutide, but likely offers similar weight loss benefits. The crazy thing is that the weight loss benefits stack. So Novo Nordisk hopes to sell Cagrisema, which combines amylin analogue cagrilintide with semaglutide, and hopes to offer a ~30% average weight loss. This is roughly double what semaglutide offers, and is getting closer to bariatric surgery efficacy.
I think those numbers might be "over one year", and they could stay on it longer than a year. I was kind of lazy just asserting “drugs might get better”, but I think the upcoming CagriSema combination and AMG-133 are good examples of how this might play out. Max Görlitz has done the proper thing and made Manifold markets for each of my predictions - see here, here, here, here, and here. Despite the problems with prediction markets for decades in the future, the “will obesity be cut in half by 2050” one seems popular: 5. Do You Have To Stay On Semaglutide Forever Or Else Gain The Weight Back? Biff_Ditt writes: I saw on the 1 year follow-up to the STEP-1 trial that most of the participants gained all of their lost weight back. Biff is probably thinking of Weight Regain And Cardiometabolic Effects After Withdrawal Of Semaglutide, which finds people gained back 2/3 of the lost weight after a year. The graph looks like it’s in the process of plateauing but not quite there, so I don’t know if we should expect them to regain the other third later. This matches what I would expect from my understanding of other diets and weight loss drugs. Still, some people disagree. Maximum Liberty writes: Anecdote is not the singular of data, but my better half lost 25 pounds on it, then had to get off it for reasons unrelated to the drug. She has not regained the weight yet -- and consistently eats less now that she had for years. So in at least one case, the drug helped with a successful change in eating habits. Lauren Thomas writes: So there's been a lot of research on dieting and losing weight, etc., and one of the things that has been found is that your body has a "set" point weight wise that it will try REALLY hard to return you to. If you lose weight, your body will slow its metabolism until you return to that weight. If you gain weight, your body will rev up metabolism. That's why you might gain 10 lbs over Christmas and then lose it in January without purposefully trying to lose weight. (this is all in the short term, ofc, as people do tend to naturally gain weight as they age). This seems to imply that semaglutide would need to be taken forever. However, there seems to be an important caveat: you *can* reset your set point, it just takes a long time at the new weight. When most people go on diets and lose weight, they end up regaining the new weight quite quickly after they "end" their diet, so they don't have a chance to reset their set point. Speaking from personal experience, I had kind of an accidental natural experiment with this: I once lost 40 lbs over the course of a year and a half, where I began with a very strict low carb diet that very very slowly trailed off to a normal diet, mostly because I got progressively more tired of being on the low carb diet. So by the time I had gotten back to my normal diet, I had been losing weight for a long time. I ended up regaining 10 lbs of the weight, but no more, and am still ~30 lbs below my peak even today (5 years later). Something like this has been my experience with dieting too so far. And something like set point reset has to exist in order to explain things like why so many obese people fail to lose weight after they start eating healthy, and maybe other things like anorexia. And maybe it works for some people. Still, the evidence suggests that most people who stop semaglutide will regain the weight, at least for the protocol used in the study. Maybe some other protocol that had them on it for more than a year would have done better? 6. Personal Anecdotes Edgehopper writes: I couldn’t get Wegovy at a reasonable price when it was approved, and then Novo Nordisk started having huge supply chain problems with their injectors. Fortunately, Eli Lilly’s coupon for Mounjaro was less restrictive at first, though they’ve had to crack down as they have trouble meeting demand for both off-label weight loss use and for the approved T2D use. I am what the doctors call “morbidly obese,” and it’s been more effective than anything else I’ve ever tried. Down about 35 lbs in the first three months, and unlike with other diets I’ve tried, I’m not feeling miserable or hungry all the time. Assuming there aren’t scary side-effects in the future, these really are miracle drugs. I do expect the price to come down relatively quickly due to competition, which is a good thing. Education Realist (blog) writes: I am on Mounjaro, and have been for four months. Lost 20 pounds so far, and I'm not yet on full dosage. Occasional mild nausea but real issue for me is....tiredness. Not fatigue or exhaustion. I'm a former insomniac who can now hit the sack at 9:00 and sleep happily to 6 am, which is insanely weird. I have been trying to lose weight for 6 years, and for most of that time been in a 20 pound range that is 100 pounds over what someone of my height should weigh. I've eaten 1500 calories a day and not lost a pound, have to drop to 1100 to lose weight verrry slowly (that's with intermittent fasting and low carbs, around 50 grams). Last year before Mounjaro I started intermittent fasting and lost 20 pounds very quickly and then stopped cold. I do not have eating issues. I don't binge. I cut out the "four white foods" six years ago because I learned that I do better on meat and cheese and vegetables than I do on pasta or bread or potatoes and vegetables. I put on weight despite walking two and in some cases four miles a day, which I can do easily. I am ridiculously healthy and do not have an obesity diagnosis. Stone cold normal readings in A1c, glucose, cholestrol. My doctor sent me to an endocrinologist after I lost 20 pounds and then stopped cold despite the same behavior (which I still do today) because she agreed I might be insulin resistant. Endocrinologist shrugged, said it's multifactorial, but agreed that anyone with my numbers, appearance, and obvious good health was clearly doing everything right and put me on Mounjaro with no further questions. Diagnosis: insulin resistance. My insurance pays around $500 but I'm on the $25 coupon. I didn't change a single thing about my eating habits and lost ten pounds in 2 months on the low dosage. Higher dosages have finally reduced my appetite somewhat, but my endocrinologist and I have decided to stop the increases at 12.5 (15 is the top) and then maybe even reduce, since my appetite is decreasing but the weight loss rate is constant. Because I lost weight doing the same behavior and no drop, I'm quite convinced that something far different than appetite suppressing is also going on (fwiw, I was on phentarmine back in the day and liked it fine). Mounjaro is supposed to increase insulin production and reduce the liver's sugar production, although what that means I dunno. I have no idea what's up with obesity but the idea that it's all about cutting intake and exercise is just stupid. I should have been losing weight for all of the past six years and haven't. Plenty of people eat healthily and are still obese. We're probably the descendants of famine survivors. Anyway, I wrote about it here: https://educationrealist.wordpress.com/2022/10/09/weight-loss-and-mounjaro Eliezer Yudkowsky writes: I tried semaglutide and it did nothing to slow rate of weight gain, just produced stomach upset, going up to 2.4mg injectable. I know one other person trying semaglutide and they reported something similar. I wonder if they played some clever games with their choice of patients. My expectation of how the news goes here is a whole lot of people who try semaglutide, maybe after fighting really hard to get on it, and find that it does nothing. That said, I know at least one friend of a friend, if not a friend per se, who claims that semaglutide was their miracle drug. So maybe still worth that hard fight, even if I'm guessing that the real proportion who get nothing out of it will prove to be over 50% in real populations. Further fun fact: Semaglutide comes heavily recommended with diet and exercise and many stern injunctions about that! The actual insert sheet includes a graph for how much weight people lose with and without "lifestyle interventions" added. The two graphs are roughly the same. Lan writes: I wonder about the adoption of the medication, though. I took victoza (=saxenda, but approved for diabetes) and the absence of the desire to eat lead to some unforeseen lifestyle side effects. Given that 5 almonds made me full for the day, I was not interested in having dinner with the family or going out with friends. There is the reality that some restaurants would probably not be happy if you only ordered the smallest appetizer. In addition, alcohol was also very difficult, because the drug slows down gastric emptying and your stomach ends up absorbing alcohol for hours. I got really, really drunk for an entire night from a single glass of wine once. Before taking this drug I had not fully appreciated how much of one's (social) life revolves around food; lunch break with colleagues, dinner with family or friends, drinks on the weekend, a sweet treat, snacks and a movie etc. But once I was not interested in food anymore, combined with the tiredness that comes with eating little, a lot of those activities also lost their appeal. (On the upside, I slept like a log.) Walter Sobchak, Esq writes: I have been taking Wegovy for 14 months. When I began I weighed 275 lbs and my BMI was 39.9. I have hypertension, albeit well controlled by medicines. Diet and exercise phaaahhh. I could eat faster than I could exercise. And no, I eat very little fast food and little candy and soda. I worked with my doctor to be prescribed Wegovy. It was only approved by the FDA in June 2021. My doctor was reluctant because he was unfamiliar with the class of compounds. He does not like to prescribe off label so he was not willing to to start me on Ozempic. But, the FDA solved that problem. I knew to ask for the drug because my daughter was pre-diabetic and had been put on Metformin and Ozempic. She lost 100 lbs. in 2019 and 2020. I started on Wegovy in September 2021. I now weigh 220 and my BMI is 31.5. That represents a 20% reduction in my original weight. 220 was my original goal. To get a BMI under 30 I would have to be under 209. I doubt that I will get there. I am back in 40 in. trousers which I had not been able to wear in 30 years. 220 was my original goal. I have had no major side effects other than constipation. Even that is a little hard to tease out. I am on 7 Rx drugs and at least 5 of them are constipating. I have been pounding Metamucil and Colace for years. I have been able to fill my prescriptions using a GoodRx coupon at $1328 for a box with 4 injectors. A year requires 13 boxes. The total cost for 15 boxes has been about $20,000. I can afford it and it has been worth while. I call it a bargain, the best I've ever had. I understand that it still way too expensive for the American health care system to afford. But given the bonanza size of the market. There will be lots of competition starting with the Lilly's tirzepatide. There are several other pharma's with GLP-1 agonists in development. I am sure that the cost will come down. My doctor tells me that I can expect to stay on semaglutide for the long term. He is proposing that I switch to Ozempic 2 mg for maintenance as I can buy that for less than $1,000 for a four dose pen. My only sadness is that semaglutide wasn't invented 40 years ago when i would have saved me from a lot of damage. But, I am grateful that it exists now and that it has helped my daughter so much. Also from Walter, and I was wondering about this: I was very concerned with the injections before I started Wegovy. My experience is that the injector is fast and almost painless. My pharmacist was important because he showed me how to do it correctly before I started. 7. Tangents That I Find Tedious, But Other People Apparently Really Want To Debate Why can’t people just diet and exercise? (142 comments)
Inline links: here, here, here, here, here, writes, Weight Regain And Cardiometabolic Effects After Withdrawal Of Semaglutide, writes, writes, anorexia, writes, Education Realist, blog, https://educationrealist.wordpress.com/2022/10/09/weight-loss-and-mounjaro, writes, writes, from Walter, Why can’t people just diet and exercise?
The Compounding Loophole
August 22, 2024 · Original source
Now that we’ve gone over the pharmacology of the GLP-1 agonists, let’s get back to the economics.
Inline links: the pharmacology of the GLP-1 agonists
I’m pretty encouraged by it. Not only does it provide GLP-1 drugs for a quarter of the price, but also people were really worried that diabetics wouldn’t be able to get their diabetes drugs because dieters would grab them off the shelf first. But now there’s more than enough GLP-1 agonists for everybody. This dramatically demonstrates how drug shortages are mostly regulatory problems (Adderall users, take note!)
…and they’re now the most valuable company in Europe. So they can probably eat the loss. What happens when the shortage ends? Compounding pharmacies are only allowed to do this because of a law that suspends some drug regulations during a “shortage”, ie when the drug is on the FDA’s drug shortage list. At some point, Novo Nordisk will build enough factories to meet capacity and there won’t be a shortage anymore. What then? Will the fun be over? Will GLP-1 agonists go back to costing $1,200/month again? Will most of the current users have to stop the drug and regain the lost weight? This would make tens of thousands of people really mad. I don’t know if the FDA has the guts to offend that many people. Their style is more to crush drugs before they ever come out, before anyone knows what they’re missing. During COVID, the DEA said that telemedicine was allowed to be cheap and convenient so patients could get care during lockdown. After the pandemic died down, they tried making it hard and expensive again, but so many patients protested that they backed off. The uproar we’ll get if the FDA tries to make GLP-1 drugs expensive again will make that one look like a tempest in a teapot. But Big Pharma will be even angrier if they don’t. And besides, they can’t keep the drug on their shortage list if everyone knows there’s no shortage. I really don’t know what will happen, and I don’t envy whichever FDA official is in charge of setting a policy on this. I did see one proposed solution somewhere or other (sorry if it’s yours and I’m not crediting you). Compound pharmacies are always allowed to make compounded medications for specific patients who have a “medical necessity” for a non-FDA-approved product. So in theory, you could try something like: Tell the patient to say that Ozempic causes them nausea.
Inline links: the most valuable company in Europe, they tried making it hard and expensive again
Links For September 2024
September 12, 2024 · Original source
30: CerebralLab argues for restraint around GLP-1 agonists - he is optimistic about them for people with serious disease, but reminds everyone that drugs have side effects and it might be worth pausing and thinking before basically healthy people take them to lose a few extra pounds.
Inline links: argues for restraint around GLP-1 agonists
Links For July 2025
July 01, 2025 · Original source
27: Works In Progress on whether SLGT-2 drugs could be the next GLP-1 agonists - a diabetes drug which magically cures everything else too - in this case, heart disease, kidney disease, liver disease, maybe even increased life expectancy. Shame about the genital gangrene, though.
Inline links: SLGT-2 drugs