Thank you for the info. One common cause of overweight these days is antidepressant use. Weight gain's a common side effect. Dunno whether anyone's figured out whether people on the drugs eat more, or whether there's a metabolic change. Any info on whether these weight loss drugs work just as well when zoloft et al. are the culprit?
GLP-1 users were found in the latter study to have:
9.09 times greater risk of pancreatitis
4.22 times greater risk of bowel obstruction
3.67 times greater risk of gastroparesis (which means you can barely eat because the stomach is constantly full—and in many cases after Ozempic, ends up being permanent)
1.48 times greater risk of biliary disease (e.g., painful gallstones).
Your first source is ignorant schizopoasting. The person's post shows they're a conspiracy theorists who doesn't even have a grasp on what discontinuation means and makes The Worst Argument Against Ozempic: https://www.cremieux.xyz/p/the-worst-argument-against-ozempic.
She’s a she and she’s correct to be leery of modern medicine. Modern medicine has created the least healthy humans in the history of the planet. There’s a basic conflict of interest with medicine much like with therapy. If you’re healthy they don’t make any money.
Are you aware that published studies can be real pieces of shit? Here's one, findable via pubmed, arguing that schizophrenics suffer from demonic possession: https://pubmed.ncbi.nlm.nih.gov/23269538/
These are not good studies that don't take into account other issues. I hope you're not one of those who go around trying to stoke fear about this with obscure studies that don't actually represent the reality: these are some of the safest drugs you can possibly take
Apart from you drawing conclusions from one retrospective study, you need to actually read the papers you cite:
“This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but NOT biliary disease.”
Pancreatitis seems the most prevalent of these conditions, at 33 cases per 100,000 globally. So these drugs may raise it to almost 3 per 1000. 3 per 1000 is still a low-ish number, and most people would take that risk to get rid of obesity, which causes higher risks of several other conditions. Diseases with a prevalence of 3 per 1000 tend to be those that we laypeople haven't heard of much, as they're so rare.
You should do a post on the future. Will GLP-1s become like vision correction (eyeglasses and contact lenses), with many/most people on them for life? With obesity/diabetes, there might have been genetic selection against fat genes (more precisely, genes that lead to fat with modern diets). Not sure how that will happen now.
I understand that the "no excuses" in the title is an artistic exaggeration. Still, unfortunately, even though these drugs usually lead to weight loss, it doesn't mean weight loss until you're perfectly lean. Fat people who lose 6 lbs are still fat people, and may feel like they need an excuse for that. Of course, it's better than nothing, and the good effects of these drugs seem to outweigh any bad ones heavily.
GLPs won’t eliminate obesity. They lead to typically 5-25% of body weight lost. That’s GREAT, it’s more effective than almost anything else we know, it’ll improve health…but if you start out at 400 lb and go to 300 lb, you’re still gonna be pretty fat. Even 50% loss isn’t enough to take some people from morbid obesity to normal weight.
They appear able to *practically* eliminate obesity (https://x.com/cremieuxrecueil/status/1955109071725449272). Reducing the rate by two-thirds or more with existing GLP-1RAs alone is an enormous effect even if it's not total. The "or more" is ~75-85% for retatrutide, so I'll just call that practical elimination of obesity and note that, if we increase early life usage, we can prevent future generations from ever ballooning up to the size that we have to worry about how 400-pound people will ever recover.
Thank you for sharing this. I’m on semaglutide for Type II diabetes, and this clarifies things for me. One point, though: why is it an “excuse”? Is weight a moral or legal, rather than a medical, issue? That seems to me (philosophy doctorate) to conflate value systems.
It's an excuse because it's technically possible to choose to not be obese. GLP-1RAs have eliminated excuses because they've reduced the extent to which excuses actually count for something.
"It's hard" is the real explanation for people with things like M4CR deficiency, and that no longer works for most of them, and it's harder for them than for non-carriers.
Interesting article. However, I thought there were around 20-25% of people who simply don't respond to GLP-1s at all. This is just more depressing news for them, but also scientifically intriguing. If all of these mechanisms that you walked through don't prevent GLP-1s from working, I wonder what is going on with that population.
Over a meaningful timeframe, there are incredibly few people who do not respond to modern GLP-1RAs. I've looked in EHR data and found <1% of those prescribed fail to lose weight if you have measurements of them after six or more months. The belief that there are so many failures is based on studies like this (https://pmc.ncbi.nlm.nih.gov/articles/PMC11751938/), which involve subsetting away large shares of the population and failing to note things like that *by far* their most powerful moderator of treatment success was maximum drug dosage used.
In that study, relative to a dosage of ≤0.5 mg, the chance of being a <5% responder was about 66% lower at 1 mg (RR ≈ 0.34), 84% lower at 2mg (RR ≈ 0.16), and 77% lower at 2.4mg (RR ≈ 0.23). The fraction of nonresponse attributable to low maximum dosage (≤ 1mg) in this sample comes out to ~40-43% of all nonresponders if you compare the people taking those doses with those taking 2 or 2.4mg. If you look at the raw composition, the 'nonresponders' (who still might be responders if we follow up for longer) were 71.3% users of such low dosages. Noticing the nonlinearity when we know the dosage effect is linear in trials, we can also see there's confounding to consider, which these authors practically did not.
I lost a ton of weight on Monjaro, but gained it all back after stopping. I'm trying again now with retrariride.
It certainly easier to lose weight with these drugs than without, but some of the side effects are really hard to deal with.
At higher doses I'm pretty much knocked out for the first two days after the shot. I work from bed due to the nausea, weakness and general bad mood that it puts me in. (I think it must be the low blood sugar, responsible for the bad mood)
I can mitigate some of these things by forcing myself to drink a shake or do vigorous exercise early in the morning this kind of snap out of it, but it's hard.
Anyway I hope to lose the weight again and this time stay on a maintenance though instead of stopping cold turkey.
The reason I stopped the first time was cost and availability. (Your first article solved that problem, am now an amateur chemist)
Despite the accessibility of fitness centers, my only workout is approx. 5k steps a day. I think we all have our vices—even if there's no 'excuse' for them. Not sure it's productive to say things like that there are 'no excuses'—it probably doesn't feel the best to be on the receiving end of that, and, if anything, such rhetoric might turn people off of changing for the better just out of like spite and stuff.
"Excuse" is a moral term. Do you mean to say that we make moral choices (or fail to make them) if we are overweight, and that we are to be execrated for those choices?
I’ve had this debate a lot of times in a very personal way.
1) until glp-1s, every weight loss claim was snake oil at best and absolutely harmful at worst
2) conscientious people noticed this and reject glp-1s based on this experience
3) I’m personally convinced “this time it different” by the evidence, but it’s going to take at least a generation to get different results.
4) don’t judge people who have good instincts based on all human experience up until five minutes ago. Try to educate them as best you can
Thank you for the info. One common cause of overweight these days is antidepressant use. Weight gain's a common side effect. Dunno whether anyone's figured out whether people on the drugs eat more, or whether there's a metabolic change. Any info on whether these weight loss drugs work just as well when zoloft et al. are the culprit?
Antidepressants don't lead to weight gain through metabolic changes, but through increasing caloric intake.
These drugs still work for antidepressant users, with the possibility of reduced efficacy (e.g., https://journals.sagepub.com/doi/10.1177/87551225221110850). Notably, GLP-1RAs work in people with different mental illnesses (https://www.sciencedirect.com/science/article/pii/S0306453025001386), and they appear to help with depression itself (https://www.ajgponline.org/article/%20S1064-7481(23)00394-9/fulltext).
Nothing about serious adverse side effects?
Please read: https://www.midwesterndoctor.com/p/the-great-ozempic-scam-and-safer and https://jamanetwork.com/journals/jama/fullarticle/2810542.
GLP-1 users were found in the latter study to have:
9.09 times greater risk of pancreatitis
4.22 times greater risk of bowel obstruction
3.67 times greater risk of gastroparesis (which means you can barely eat because the stomach is constantly full—and in many cases after Ozempic, ends up being permanent)
1.48 times greater risk of biliary disease (e.g., painful gallstones).
"Please read:"
Your first source is ignorant schizopoasting. The person's post shows they're a conspiracy theorists who doesn't even have a grasp on what discontinuation means and makes The Worst Argument Against Ozempic: https://www.cremieux.xyz/p/the-worst-argument-against-ozempic.
Your second source shows you missed the memo on residual confounding: https://www.cremieux.xyz/i/168430028/matching-is-usually-insufficient. You can see the error by looking at some of their findings like their absurd result for pancreatitis. Compare their result to condition-matched samples (https://x.com/cremieuxrecueil/status/1948127978195386629) or trials (https://x.com/cremieuxrecueil/status/1948127991352983754).
Think more about methods before getting overly concerned.
You seem to have a personal stake in ozempic being a miracle drug. It obviously has side effects.
I am very leery of the 'A Midwestern Doctor'; he seems to be against all modern medicine, a kind of medical Luddite, a home remedy advocate.
She’s a she and she’s correct to be leery of modern medicine. Modern medicine has created the least healthy humans in the history of the planet. There’s a basic conflict of interest with medicine much like with therapy. If you’re healthy they don’t make any money.
"Modern medicine has created the least healthy humans in the history of the planet."
That is a demonstrably stupid and inaccurate statement.
No it’s not. It’s actually quite accurate for the most part.
Are you aware that published studies can be real pieces of shit? Here's one, findable via pubmed, arguing that schizophrenics suffer from demonic possession: https://pubmed.ncbi.nlm.nih.gov/23269538/
These are not good studies that don't take into account other issues. I hope you're not one of those who go around trying to stoke fear about this with obscure studies that don't actually represent the reality: these are some of the safest drugs you can possibly take
You probably said the same thing about the Covid shots. The JAMA study covered 16 million patients. It doesn't get much better.
Having a large sample size doesn't obviate methodological concerns, like with insufficient matching.
Try reading something like https://www.nature.com/articles/s41586-021-04198-4
I did not, which is why you're showing you don't read studies and instead are anti medications as a personal identity trait.
Can you comprehend that? Anti vaxxxx (for better reasons than you, I can tell), and pro GLP-1?
Agreed, see my comment.
Apart from you drawing conclusions from one retrospective study, you need to actually read the papers you cite:
“This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but NOT biliary disease.”
(Emphasis mine)
Pancreatitis seems the most prevalent of these conditions, at 33 cases per 100,000 globally. So these drugs may raise it to almost 3 per 1000. 3 per 1000 is still a low-ish number, and most people would take that risk to get rid of obesity, which causes higher risks of several other conditions. Diseases with a prevalence of 3 per 1000 tend to be those that we laypeople haven't heard of much, as they're so rare.
You should do a post on the future. Will GLP-1s become like vision correction (eyeglasses and contact lenses), with many/most people on them for life? With obesity/diabetes, there might have been genetic selection against fat genes (more precisely, genes that lead to fat with modern diets). Not sure how that will happen now.
Great article.
I understand that the "no excuses" in the title is an artistic exaggeration. Still, unfortunately, even though these drugs usually lead to weight loss, it doesn't mean weight loss until you're perfectly lean. Fat people who lose 6 lbs are still fat people, and may feel like they need an excuse for that. Of course, it's better than nothing, and the good effects of these drugs seem to outweigh any bad ones heavily.
GLPs won’t eliminate obesity. They lead to typically 5-25% of body weight lost. That’s GREAT, it’s more effective than almost anything else we know, it’ll improve health…but if you start out at 400 lb and go to 300 lb, you’re still gonna be pretty fat. Even 50% loss isn’t enough to take some people from morbid obesity to normal weight.
They appear able to *practically* eliminate obesity (https://x.com/cremieuxrecueil/status/1955109071725449272). Reducing the rate by two-thirds or more with existing GLP-1RAs alone is an enormous effect even if it's not total. The "or more" is ~75-85% for retatrutide, so I'll just call that practical elimination of obesity and note that, if we increase early life usage, we can prevent future generations from ever ballooning up to the size that we have to worry about how 400-pound people will ever recover.
Thank you for sharing this. I’m on semaglutide for Type II diabetes, and this clarifies things for me. One point, though: why is it an “excuse”? Is weight a moral or legal, rather than a medical, issue? That seems to me (philosophy doctorate) to conflate value systems.
It's an excuse because it's technically possible to choose to not be obese. GLP-1RAs have eliminated excuses because they've reduced the extent to which excuses actually count for something.
"It's hard" is the real explanation for people with things like M4CR deficiency, and that no longer works for most of them, and it's harder for them than for non-carriers.
Interesting article. However, I thought there were around 20-25% of people who simply don't respond to GLP-1s at all. This is just more depressing news for them, but also scientifically intriguing. If all of these mechanisms that you walked through don't prevent GLP-1s from working, I wonder what is going on with that population.
Over a meaningful timeframe, there are incredibly few people who do not respond to modern GLP-1RAs. I've looked in EHR data and found <1% of those prescribed fail to lose weight if you have measurements of them after six or more months. The belief that there are so many failures is based on studies like this (https://pmc.ncbi.nlm.nih.gov/articles/PMC11751938/), which involve subsetting away large shares of the population and failing to note things like that *by far* their most powerful moderator of treatment success was maximum drug dosage used.
In that study, relative to a dosage of ≤0.5 mg, the chance of being a <5% responder was about 66% lower at 1 mg (RR ≈ 0.34), 84% lower at 2mg (RR ≈ 0.16), and 77% lower at 2.4mg (RR ≈ 0.23). The fraction of nonresponse attributable to low maximum dosage (≤ 1mg) in this sample comes out to ~40-43% of all nonresponders if you compare the people taking those doses with those taking 2 or 2.4mg. If you look at the raw composition, the 'nonresponders' (who still might be responders if we follow up for longer) were 71.3% users of such low dosages. Noticing the nonlinearity when we know the dosage effect is linear in trials, we can also see there's confounding to consider, which these authors practically did not.
Thank you - this is very informative.
If it eats like a hippo it should look like a hippo.
Exactly. Imagina writing about something like ozempic without mentioning side effects at all.
talk to me when these drugs come in a pill and don’t require sticking yourself with a needle every day for the rest of your life
https://x.com/cremieuxrecueil/status/1968096846548812105
Wow
https://open.substack.com/pub/thetimetravellers/p/the-great-balloon-race-how-to-eat-inflate-and-shrink-all-at-once-11b0f474e215?r=69wi1d&utm_campaign=post&utm_medium=web&showWelcomeOnShare=false
Crem you better be at your target weight if you're gonna put a headline like this on the article, lol.
I want to be heavier.
I lost a ton of weight on Monjaro, but gained it all back after stopping. I'm trying again now with retrariride.
It certainly easier to lose weight with these drugs than without, but some of the side effects are really hard to deal with.
At higher doses I'm pretty much knocked out for the first two days after the shot. I work from bed due to the nausea, weakness and general bad mood that it puts me in. (I think it must be the low blood sugar, responsible for the bad mood)
I can mitigate some of these things by forcing myself to drink a shake or do vigorous exercise early in the morning this kind of snap out of it, but it's hard.
Anyway I hope to lose the weight again and this time stay on a maintenance though instead of stopping cold turkey.
The reason I stopped the first time was cost and availability. (Your first article solved that problem, am now an amateur chemist)
Despite the accessibility of fitness centers, my only workout is approx. 5k steps a day. I think we all have our vices—even if there's no 'excuse' for them. Not sure it's productive to say things like that there are 'no excuses'—it probably doesn't feel the best to be on the receiving end of that, and, if anything, such rhetoric might turn people off of changing for the better just out of like spite and stuff.
I was pretty obese. About 32 bmi. Covid changed it and through long walks every morning I got down to 23.5 or so.
But i gained 10 lbs.
3 weeks on glp lost the 10 lbs.
These things really work. You just don't want to eat a lot - which off them I do.
"Excuse" is a moral term. Do you mean to say that we make moral choices (or fail to make them) if we are overweight, and that we are to be execrated for those choices?
Incidentally I have lost 20kg on Ozempic...