Been on one for a few years now, it tempered my persistent auto-immune issues. Short term side effects are barely present for me. This stuff has made it so I don't have to be on steroids and antibiotics every other month. I did not start the medication for weight loss purposes, though have lost 10-15lbs, but I attribute that to being off steroids.
Long term? Who knows for sure. Semaglutide has been approved for 9 years. Liraglutide was 2009 and hasn't shown thyroid issues still. Exenatide has been available since 2005.
GLP-1s aren't new and haven't shown widespread negative issues beyond gastrointestinal upset, and that is typically fixed by... drinking more water. The trials in rats have pointed towards potential thyroid cancer risks but those haven't been seen in people.
There is reason to have some healthy skepticism for pharma. But I am sometimes astounded by how unshakably cynical people can be.
I suppose we all could wind up with cancer in 10 years or something hypothetically, due to some unforeseen mechanism. But here's my story.
I went from 200lb to 140lbs at 5' 9" over 3 years. I feel great. I don't need to eat 1000 calories before bed just to sleep through the night. I focus better at work. Blood pressure is back to normal. HDL is back to normal. I can run without joint pain. I feel good about myself. I feel comfortable going on dates. I'm not a near-obese shut-in loner that can't be in a caloric deficit without wrecking my sleep.
Outside of literally fatal side effects, these drugs seem pretty miraculous.
FDA approval of the first GLP-1 agonist was in 2005 and many diabetics have been taking these drugs for close to 20 years, so we have a pretty good picture of what long term side effects are: mostly GI symptoms, and you can have problems with muscle loss and bone weakening if you lose a ton of wieght. otherwise they are well tolerated.
>They also reduce visceral and ectopic fat that accumulates around the abdomen and organs, which may help curb the inflammatory and metabolic signals that promote aging.
Interesting, I wonder if someone will do a study where they pair a GLP-1 with tesamorelin to see if there's any synergy there in terms of fat reduction and reduced aging.
If the DunedinPACE test is so accurate and cheap now, there must be hundreds of people that have a baseline and also measurements after taking GLP’s… also why do you need a double blind if you have this amazing biological ageing test?
I have never seen a user name better fit a hacker news comment.
This also perfectly sums up the whole emotional roller coaster of modern science communication.Oh that could be cool (title)... Hey this might be good work... Fuck thats depressing I will never get this time back.
They work on that group because (as the article says) they show increased aging relative to a normal group, making it easier to detect effects in a relatively short running study.
In the UK you just fill in an online form. I don't think anyone is going to come and weigh you to double check what you put in the form is true. Almost zero oversight which is a bit shocking really.
Since we're selling them the disease and the cure, and society has to pay for both
What about all the other way to solve the problems and improve their lives? It's like people who think you cure depression by lifelong antidepressant treatment...
I'm excited to see more studies done in this context, but without the HIV association. My wife has Ehlers-Danlos Syndrome and Rheumatoid Arthritis. She saw more benefits in inflammation reduction than weight reduction, especially those first two weeks she started taking it. She says her pain levels are night and day difference when on GLP-1 vs off. To me it would then make logical sense that reduced inflammation can have a measurably positive effect on aging.
Let's play spot the conflict of interest. Three of seven authors tied to a company selling biological aging tests. One consults for Merck, GSK, etc.
There seems some promise at times but I also struggle to see the recent slew of "GLP-1s cure X", where X is seemingly any ailment known to man, as much more than the next Big Pharma gold rush where the profits dwarf any eventual regulatory fines, and taxpayers and real patients are left with the costs.
You may be right that they are in a bind wrt public opinion. But that is not a defence against any specific criticism. What is your opinion on the conflict of interest mentioned above?
The concern is the aversive mind that tries to find fault in everything which then leads to politicians creating policies which prevent or hinder medical discoveries and treatments.
This isn’t what justice is. It’s also not holding people (or orgs) to account. It’s complaints against an entity that people often don’t understand or like.
Much like the conspiracy that pharma companies are uninterested in curing diseases, the complaints aren't based on data or facts.
I'll offer cystic fibrosis as an example. Trikafta may as well be a miracle drug. And CRISPR-based gene editing and replacements are being researched that could be an outright cure, as opposed to a 90% cure.
Both opinions can be true, drugmakers should still spend money on R&D, and consumers should hold academic research with significant financial ties to interested sponsors to a higher standard of scrutiny.
Criticism does not have to mean preventing work, we can be critical especially of work that we find important.
I'm inclined to agree with your point, but it seems like there's an obvious thing they could do that I think people wouldn't complain about: Reduce their prices. Of course that would just look like not getting so many billions from GLP-1 drugs, rather than like any specific action one could complain about.
(If anyone reading this feels inclined to say something like "But how would that benefit them?" -- well, if you restrict consideration to things they could do that benefit them, then it no longer seems so unreasonable if all their options look bad to the critically-minded. Maybe they should be doing things that benefit the rest of the world more and themselves less.)
Outside of the occasional spike from a real blockbuster, pharmaceutical companies are not particularly profitable. Without those temporary (patent-protected) “windfall” profits, the business model doesn’t work.
To whatever extent they couldn't afford to reduce prices while staying in business, they also couldn't afford to spend those alleged billions of dollars on basic R&D or stock buybacks.
it's low quality research. you don't need to point to perceived conflicts of interest. the drug is semaglutide, not a merck or gsk product. and semaglutide is coming of patent anyway
What would you propose instead? Who will do this research, with what funding, and why will they want to do it? And why would we trust that research more than this? Wouldn’t we scrutinize research carefully regardless of the source?
There are multiple alternative systems, as we see in other countries. But they all have tradeoffs and some really only make sense if some international entity is doing research somewhere else under a different set of rules.
No. This is what we have government for. The self-interested are the least qualified. They are simultaneously paying to market the drug (which involves exaggerating or lying about its capabilities and minimizing or hiding its drawbacks.)
This certainly seems like something a national health service (or even insurance company) should be doing in its own interest (in order to direct spending), and wouldn't have any intrinsic bias towards any particular outcome other than an accurate one. The problem is that you need a government that is not also owned by the drug company.
In the US we have an enormous amount of government health care spending that would benefit from more knowledge about the effects of these drugs. There's no reason why we should ever take the drug company's word for anything. The research was likely originally done in an academic setting, and likely largely government-funded. The only reason the drug companies get these drugs from that environment is through corruption.
> The Bayh-Dole Act made a key change in federal contracting procedures that allowed contractors the right to retain ownership of inventions made with federal funding.
Agree, in principle, but in the US we are very far from that system, so essentially unrealistic.
And the countries that do have such systems are doing so with US pharma companies cranking out drugs. Presumably if they were fully self-contained that system would be much slower but also generate a higher proportion of medically useful drugs, vs patent-preserving lobbying or other shenanigans.
That's not a common side effect, and I've been watching GLPs for years. In fact, it's more likely to cause divorces due to, you know, becoming more attractive.
If two cars are each three years old, but one has had twice as much gas consumption as the other, which would you expect to show more wear on its comppnents?
Caloric churn is putting the body's systems through their paces - at the very least for everything related to digestion. But really most of life is well described as pieces of a metabolic process.
This feels like the early days of medical marijuana where everything was sunshine and rainbows, and then 10 years later we realize yes, there are still drawbacks.
There is a gold rush happening where every health influencer, telehealth prescriber, and even aging services provider (as is the case with some of these study authors) is trying to push this medication for a wider audience.
Medical marijuana was different, though. The negatives were known medically before and after. The push was almost entirely political and on social media. The few places medical marijuana were medically pushed were either for highly specific applications or as a harm reduction measure: Either as an alternative for patients who demanded opioids (medical marijuana isn’t actually a viable substitute for opioids in severe high level pain, but it’s common for patients to demand to be prescribed something “stronger” for lesser conditions and there was a real problem with opioid over prescription at the time) or from the sector of medicine that sees that patients are seeking out drugs anyway and thought this was a better way to control and monitor it. The way it worked out in practice became a laughable loophole where anyone who wants a card can pay $100 for a meeting with a prescriber who will give leading questions until you say the right things to get the card, which wasn’t even what the original medical marijuana proposals were about.
In the medical and research world, there was never an illusion that marijuana was actually entirely harmless and without drawbacks, except for fringe papers and a few politically motivated researchers.
yes a weight loss drug for a country that is over 70% overweight is absolutely the same as a psychoactive drug with well-understood cognitive side effects and abuse risk, a perfect analogy
I'm always confused with these type of posts because I feel the scientists must know something I don't. Why is it always does GLP-1 help with [general health thing]?
If I understand it correctly, GLP-1 drugs help people with weight loss. People are more healthy when they're not overweight, and GLP-1s help people get down to a healthier weight. So when we ask questions about do GLP-1s help this or that, isn't there a giant confounding variable here? That being overweight causes a litany of health issues has been common knowledge forever now. Thus, my (uninformed, intuitive) guess would just be that GLP-1s, which cause weight loss, also include the subsequent effects of healthy weight loss.
So why are we surprised then that people going from overweight to a healthy weight slows aging, or betters cardiovascular health as I've seen elsewhere? Aren't these already well-studied effects of healthy weight loss? Shouldn't these positive effects obviously just be attributed to weight loss, rather than the thing that causes the weight loss? And why are there articles about this stuff acting like this is unexpected?
I admit I'm a laymen and I hope don't sound too snide or critical here. I'm just kind of puzzled by this out of genuine curiosity.
As another person commented, we currently believe the primary mechanism behind the pleitropic effects of GLP-1's to be a reduction in systemic inflammation and direct improvements in vascular/endothelial function.
The best paper I've seen on this was the recently published and very aptly named:
"Pleiotropic effects of GLP-1 receptor agonists — a narrative review of extra-metabolic outcomes in adults" (2026)
There’s a feedback loop with inflammation and fat. We’ve been telling people for decades to break the cycle by losing weight, but we also have studies that say you can only sustain about 7.5% weight loss per year. Anything more tends to rebound.
Then GLP-1 comes along and we stop fat negativity/positivity overnight.
Exercise does not result in loss of lean mass unless done at a severe deficit. If someone has a low baseline of lean mass, exercise usually boosts it even when a person is in a deficit, but if they are in a surplus, the lean mass boost is more significant.
1. Yes, for many of the benefits of GLP-1s, it's plausible the mechanism is weight loss. But actually achieving significant weight loss with other therapies is incredibly hard, so I think GLP-1s get some credit here.
2. Hunger signalling isn't the only thing GLP-1s do, so no, we should not just assume every effect stems from weight loss alone. E.g. the blood sugar regulation that makes them very effective for diabetes is not purely about weight management.
Stress eating is also a thing, so if we’ve misunderstood a chemical pathway that we created an agonist for it can be a little of column A and a lot of column B.
We have failed blood pressure drugs that turned into boner pills. We have failed blood pressure drugs that reduce social anxiety. In the field of medicine we have a lot of people acting like we understand the body but we don’t know shit. It’s a bit like how physics was “nearly done” before relativistic and quantum physics were discovered. We still don’t know shit. And we are going to kill or fail a lot of people between now and when we can find our asses with both hands.
>But actually achieving significant weight loss with other therapies is incredibly hard, so I think GLP-1s get some credit here.
Citation needed! it's not actually difficult, all you need is calorie deficit and it has been routinely done by bodybuilders, athletes, MMA fighters and movie stars/models
> Hunger signalling isn't the only thing GLP-1s do, so no, we should not just assume every effect stems from weight loss alone
Ofc, they also result in an increased risk of gallbladder stones, bile issues, hair loss, and severe loss of lean mass, and we've got actual studies on this.
> Citation needed! it's not actually difficult, all you need is calorie deficit and it has been routinely done by bodybuilders, athletes, MMA fighters and movie stars/models and thousands of ordinary members on r/caloriedeficit subreddit or other fitness subs!
Bruh, we're not doing this anymore. If weight loss was easy, we wouldn't have an adult obesity rate of 40%. Yes, yes, a handful of extraordinarily motivated individuals can successfully restrict calories to lose weight. But very clearly most people can't.
> Ofc, they also result in an increased risk of gallbladder stones, bile issues, hair loss, and severe loss of lean mass, and we've got actual studies on this.
You're conflating association and causality. They're used by the obese and diabetics, so they're associated with all kinds of things associated with obesity and diabetes. (But the plausible cause is that the 3rd variable is obesity/diabetes.) Loss of lean mass is basically identical to any other similar level of caloric restriction without corresponding resistance training -- if you don't eat enough to maintain muscle mass, and particularly if you aren't resistance training, no shit, you'll lose muscle. (And guess what? It's still better not to be obese.)
It's simple, and people think simple = easy. It's simple, yet very difficult. Walking up 1,000 stairs is also simple, you just put one foot in front of the other until you're up. But it's hard. We know weight loss is hard because of how many people are obese. Most obese people have tried to lose weight many, many times and have failed. If it was easy, they wouldn't fail. Evidently it is difficult, and no other perspective is reasonable.
>But it's hard. We know weight loss is hard because of how many people are obese. Most obese people have tried to lose weight many, many times and have failed
Weight loss requires a calorie deficit, and the average person has no training or education for this. Why would you expect them to be good at something they've had no education or training in? 40% obesity rate is not surprising when no education/training exists for average person.
>Evidently it is difficult, and no other perspective is reasonable.
We already have group of 2000+ people, app with 17,000+ users losing weight on demand! All for free and anyone can verify this.
These studies control for such variables, confounding effects are easy to think of, but 9/10 times here on HN, the authors DID control and adjust for that confounder, the commenters just didn't read the methods.
Eh, no, the vast majority of splashy headline studies that make it to HN show some associative result where causality is not established. They can not control for all possible confounding. The money sentence from the study is "semaglutide was associated with significantly reduced epigenetic aging relative to placebo across multiple generations of epigenetic clocks."
It kinda seems like a bunch of markers moved randomly and some of them happened to move together: "In contrast, causality-enriched epigenetic clocks28 AdaptAge, CausAge, and DamAge exhibited directionally heterogeneous and statistically non-significant changes." That gets you a publication but I don't know that I'd bet money on follow-up study results.
When you see reporting like this it means there was some study that had some evidence of some effect that somewhat matches the description in the headline, but nothing more than that. How good of a study it was, how large the effect, how in alignment or not it is with a body of evidence, how reproduceable it is, how exaggerated the press release is. Are all left out and are all critical to how much anyone should care about the statement. What it definitely does not mean is "all scientists are asserting this truth in the headline"
These scientists, whose job it is to think about this really hard, why didn't they just think of the most obviously obviously thing? I'm sure they didn't!
Glp1s aren't just appetite suppressants. Two identical people doing and eating identical things -one on glp1 and one not - the one on willose more weight and have better biomarkers like insulin sensitivity
True, GLP-1 user will have higher loss of lean mass than one who is dieting on calorie deficit and exercise so they'll look more "shrunken raisin" than other.
>This isn't true. Identical people on identical diets will lose the same weight, GLP1 or not.
No, this isn't true.
Even when two people are identical twins eating the same amount of food and doing the same amount of exercise and activities, weight loss will differ because:
Rate of loss of BodyWeight rate is directly proportional to amount of deficit applied!
Deficit = TDEE (total calorie burn of the day) - Intake
If TDEE is not the same, weight loss will differ, regardless of whether the underlying activity level, genetics, or amount of food or everything else is the same.
Improved insulin sensitivity is associated with lower excess body fat THE MOST and better skeletal muscle metabolic function. Greater lean mass may contribute.
Therefore, if a person on GLP-1 loses more lean mass than one without, they may not actually have better insulin sensitivity.
GLP-1 receptors are G-protein coupled receptors (GPCR). There have been multiple nobel prizes given for work done to understand their function and we still barely understand them. It's a highly nonlinear interconnected signaling pathway. Imagine the worst spaghetti code you've ever seen times 10 - nothing is idempotent, high hysteresis, position state and time dependencies everywhere, every function works exclusively through side effects that mutate global variables, the same molecule can both drive and suppress signalling and that signalling can both cause some effect and stop that same effect.
Basically with glp 1 it seems to be broadly related to the mess of nonsense that has to do with inflammation/immune/cardio stuff - maybe a set of adaptations that made more sense in a world with more infectious disease/food scarcity but less so now, maybe just a grab bag because evolution is stochastic and is not actually survival of the fittest (it's just survival of the things that survive - there could be 10 organisms that are highly adapted to a particular environment and 2 that are not and would be outcompeted and then a rock falls on the 10 and now the gene pool is what it is - evolution doesn't care). So not really surprising that a thing that works via a mechanism we don't super understand against a condition we done super understand has a bunch of impact on other stuff we don't super understand
Everyone I know that are using these looks gaunt and sickly. They also complain of constant nausea and eat like a bird because eating makes them sick O_o. We’ve all seen the “glow” of people that lost weight with diet and exercise — it is not that. I’m glad they exist but worry about the side effects of long term use and medical professionals not using it as a brief intervention then steering towards lifestyle changes.
> Everyone I know that are using these looks gaunt and sickly.
This is a statistical fallacy where you're only identifying the extreme cases. The average obese person loses 14-20% of body weight. (Remember that the "obese" category is already defined as 20%+ above the high end of the "normal" range.) So the vast majority of people on these drugs just look normal, not skinny or gaunt.
> They also complain of constant nausea and eat like a bird because eating makes them sick
This is a high dose phenomenon. They can and should reduce their dose if it is preventing them from eating enough or being comfortable.
> I worry about ... medical professionals not using it as a brief intervention then steering towards lifestyle changes.
Most professionals DO steer towards lifestyle changes. They probably look gaunt and sickly because their excess skin sags and they may temporarily look older due to stretchy skin.
I think a lot of this is that being overweight makes you look fluffy and younger - being just a little "overweight" even makes you look healthier.
So people who were fat and get to a normal weight, if you've always known them as fat then they look like they've aged a decade or two in a year. People who were totally normal weight (i.e. "overweight" according to BMI, which is associated with a longer lifespan than "healthy weight") end up looking like tuberculosis Romantics because they wanted to look like movie stars (who are often on severe, unhealthy diets that they stop when they're not working.)
Losing weight quickly often loses it badly - think meth addicts. Women lose fat from their breasts and both sexes lose the fat pad around the eyes; I think these are generally stable fat stores that don't really replenish after being used, even if you gain the weight back. It's not specific to GLPs, just quick weight loss. If you'd lost more slowly your body wouldn't have resorted to taking from those places. Now, you have super-deep nasolabial folds and marionette lines.
> lost weight with diet and exercise
You lose weight through diet. You gain fitness through exercise.
Virtually all medical professionals steer heavily towards lifestyle changes. If you are obese, you can go to the doctor for a headache and the first words out of their mouth is "you need to lose weight".
I truly, truly do not understand where this mentality that the medical professionals don't encourage lifestyle changes comes from. If you smoke, they will hound you to stop smoking at every single appointment, regardless of what the appointment is for. They will tell you what to eat. They will tell you to eat less red meat, eat less processed food. They will tell you that you need to exercise 30 minutes a day. They tell you all of this, constantly.
That doesn't mean it works, though. You can tell someone to eat less over and over and that doesn't just magically make them eat less.
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[ 0.29 ms ] story [ 51.1 ms ] threadAnd if you don’t have HIV?
Long term? Who knows for sure. Semaglutide has been approved for 9 years. Liraglutide was 2009 and hasn't shown thyroid issues still. Exenatide has been available since 2005.
GLP-1s aren't new and haven't shown widespread negative issues beyond gastrointestinal upset, and that is typically fixed by... drinking more water. The trials in rats have pointed towards potential thyroid cancer risks but those haven't been seen in people.
I suppose we all could wind up with cancer in 10 years or something hypothetically, due to some unforeseen mechanism. But here's my story.
I went from 200lb to 140lbs at 5' 9" over 3 years. I feel great. I don't need to eat 1000 calories before bed just to sleep through the night. I focus better at work. Blood pressure is back to normal. HDL is back to normal. I can run without joint pain. I feel good about myself. I feel comfortable going on dates. I'm not a near-obese shut-in loner that can't be in a caloric deficit without wrecking my sleep.
Outside of literally fatal side effects, these drugs seem pretty miraculous.
Extremely unlikely, GLP-1 receptor agonists have been on the market for more than 20 years now, exenatide being first used in 2005.
Interesting, I wonder if someone will do a study where they pair a GLP-1 with tesamorelin to see if there's any synergy there in terms of fat reduction and reduced aging.
:)
> data from a...clinical trial of 108 adults with HIV associated lipohypertrophy
:(
I have never seen a user name better fit a hacker news comment.
This also perfectly sums up the whole emotional roller coaster of modern science communication.Oh that could be cool (title)... Hey this might be good work... Fuck thats depressing I will never get this time back.
not like we can take GLP-1 even if it was affordable
btw soluable fiber helps people naturally secretion more GLP-1 but of course not on the same level as a dedicated drug
may I ask for how long now? are you athletic? have you experienced any muscle loss?
Our society is fixated on reducing friction or increasing convenience. We trade away a lot of our capabilities for this.
Making things easier for everyone often has negative associations.
What about all the other way to solve the problems and improve their lives? It's like people who think you cure depression by lifelong antidepressant treatment...
Guess what we all here are doing. Using the magic keyboard.
https://www.ehlers-danlos.com/effective-doses-of-low-dose-na...
There seems some promise at times but I also struggle to see the recent slew of "GLP-1s cure X", where X is seemingly any ailment known to man, as much more than the next Big Pharma gold rush where the profits dwarf any eventual regulatory fines, and taxpayers and real patients are left with the costs.
- Marketing, to learn what / whom / how to sell: “They spend more on TV ads than R&D!”
- Basic R&D: “Look at all the conflicts of interest in this academic research!”
- Commercial R&D: “They’re just looking for ways to extend the patent lifetime of drugs that only exist because of government-funded basic R&D!”
- Back to the shareholders (mostly pensions and retirement accounts): “Billions of stock buybacks for Wall Street!”
What should the pharmaceutical companies with billions coming in from GLP-1’s be spending their money on?
I'll offer cystic fibrosis as an example. Trikafta may as well be a miracle drug. And CRISPR-based gene editing and replacements are being researched that could be an outright cure, as opposed to a 90% cure.
Criticism does not have to mean preventing work, we can be critical especially of work that we find important.
(If anyone reading this feels inclined to say something like "But how would that benefit them?" -- well, if you restrict consideration to things they could do that benefit them, then it no longer seems so unreasonable if all their options look bad to the critically-minded. Maybe they should be doing things that benefit the rest of the world more and themselves less.)
What would you propose instead? Who will do this research, with what funding, and why will they want to do it? And why would we trust that research more than this? Wouldn’t we scrutinize research carefully regardless of the source?
There are multiple alternative systems, as we see in other countries. But they all have tradeoffs and some really only make sense if some international entity is doing research somewhere else under a different set of rules.
This certainly seems like something a national health service (or even insurance company) should be doing in its own interest (in order to direct spending), and wouldn't have any intrinsic bias towards any particular outcome other than an accurate one. The problem is that you need a government that is not also owned by the drug company.
In the US we have an enormous amount of government health care spending that would benefit from more knowledge about the effects of these drugs. There's no reason why we should ever take the drug company's word for anything. The research was likely originally done in an academic setting, and likely largely government-funded. The only reason the drug companies get these drugs from that environment is through corruption.
> The Bayh-Dole Act made a key change in federal contracting procedures that allowed contractors the right to retain ownership of inventions made with federal funding.
https://en.wikipedia.org/wiki/Bayh%E2%80%93Dole_Act
And the countries that do have such systems are doing so with US pharma companies cranking out drugs. Presumably if they were fully self-contained that system would be much slower but also generate a higher proportion of medically useful drugs, vs patent-preserving lobbying or other shenanigans.
Caloric churn is putting the body's systems through their paces - at the very least for everything related to digestion. But really most of life is well described as pieces of a metabolic process.
Medical marijuana was different, though. The negatives were known medically before and after. The push was almost entirely political and on social media. The few places medical marijuana were medically pushed were either for highly specific applications or as a harm reduction measure: Either as an alternative for patients who demanded opioids (medical marijuana isn’t actually a viable substitute for opioids in severe high level pain, but it’s common for patients to demand to be prescribed something “stronger” for lesser conditions and there was a real problem with opioid over prescription at the time) or from the sector of medicine that sees that patients are seeking out drugs anyway and thought this was a better way to control and monitor it. The way it worked out in practice became a laughable loophole where anyone who wants a card can pay $100 for a meeting with a prescriber who will give leading questions until you say the right things to get the card, which wasn’t even what the original medical marijuana proposals were about.
In the medical and research world, there was never an illusion that marijuana was actually entirely harmless and without drawbacks, except for fringe papers and a few politically motivated researchers.
How much are the pharma companies paying people to project this nonsense to trick people to take these drugs to make money out of it?
This is the new grift.
If I understand it correctly, GLP-1 drugs help people with weight loss. People are more healthy when they're not overweight, and GLP-1s help people get down to a healthier weight. So when we ask questions about do GLP-1s help this or that, isn't there a giant confounding variable here? That being overweight causes a litany of health issues has been common knowledge forever now. Thus, my (uninformed, intuitive) guess would just be that GLP-1s, which cause weight loss, also include the subsequent effects of healthy weight loss.
So why are we surprised then that people going from overweight to a healthy weight slows aging, or betters cardiovascular health as I've seen elsewhere? Aren't these already well-studied effects of healthy weight loss? Shouldn't these positive effects obviously just be attributed to weight loss, rather than the thing that causes the weight loss? And why are there articles about this stuff acting like this is unexpected?
I admit I'm a laymen and I hope don't sound too snide or critical here. I'm just kind of puzzled by this out of genuine curiosity.
The best paper I've seen on this was the recently published and very aptly named:
"Pleiotropic effects of GLP-1 receptor agonists — a narrative review of extra-metabolic outcomes in adults" (2026)
https://journals.viamedica.pl/medical_research_journal/artic...
Then GLP-1 comes along and we stop fat negativity/positivity overnight.
GLP-1s don't.
2. Hunger signalling isn't the only thing GLP-1s do, so no, we should not just assume every effect stems from weight loss alone. E.g. the blood sugar regulation that makes them very effective for diabetes is not purely about weight management.
We have failed blood pressure drugs that turned into boner pills. We have failed blood pressure drugs that reduce social anxiety. In the field of medicine we have a lot of people acting like we understand the body but we don’t know shit. It’s a bit like how physics was “nearly done” before relativistic and quantum physics were discovered. We still don’t know shit. And we are going to kill or fail a lot of people between now and when we can find our asses with both hands.
We are good at making people live longer, not at making them live better.
Citation needed! it's not actually difficult, all you need is calorie deficit and it has been routinely done by bodybuilders, athletes, MMA fighters and movie stars/models
> Hunger signalling isn't the only thing GLP-1s do, so no, we should not just assume every effect stems from weight loss alone
Ofc, they also result in an increased risk of gallbladder stones, bile issues, hair loss, and severe loss of lean mass, and we've got actual studies on this.
Bruh, we're not doing this anymore. If weight loss was easy, we wouldn't have an adult obesity rate of 40%. Yes, yes, a handful of extraordinarily motivated individuals can successfully restrict calories to lose weight. But very clearly most people can't.
> Ofc, they also result in an increased risk of gallbladder stones, bile issues, hair loss, and severe loss of lean mass, and we've got actual studies on this.
You're conflating association and causality. They're used by the obese and diabetics, so they're associated with all kinds of things associated with obesity and diabetes. (But the plausible cause is that the 3rd variable is obesity/diabetes.) Loss of lean mass is basically identical to any other similar level of caloric restriction without corresponding resistance training -- if you don't eat enough to maintain muscle mass, and particularly if you aren't resistance training, no shit, you'll lose muscle. (And guess what? It's still better not to be obese.)
It's simple, and people think simple = easy. It's simple, yet very difficult. Walking up 1,000 stairs is also simple, you just put one foot in front of the other until you're up. But it's hard. We know weight loss is hard because of how many people are obese. Most obese people have tried to lose weight many, many times and have failed. If it was easy, they wouldn't fail. Evidently it is difficult, and no other perspective is reasonable.
Weight loss requires a calorie deficit, and the average person has no training or education for this. Why would you expect them to be good at something they've had no education or training in? 40% obesity rate is not surprising when no education/training exists for average person.
>Evidently it is difficult, and no other perspective is reasonable.
We already have group of 2000+ people, app with 17,000+ users losing weight on demand! All for free and anyone can verify this.
https://www.nature.com/articles/s41467-026-72861-3
It kinda seems like a bunch of markers moved randomly and some of them happened to move together: "In contrast, causality-enriched epigenetic clocks28 AdaptAge, CausAge, and DamAge exhibited directionally heterogeneous and statistically non-significant changes." That gets you a publication but I don't know that I'd bet money on follow-up study results.
These scientists, whose job it is to think about this really hard, why didn't they just think of the most obviously obviously thing? I'm sure they didn't!
...
Dude. Come on.
I even asked, explicitly, “what do the scientists know that I don’t?”
I asked despite the question sounding dumb, because that’s what you do when you genuinely want to know more!
If something is true it will survive the scrutiny, requires no appeal to authority.
This isn't true. Identical people on identical diets will lose the same weight, GLP1 or not.
> and have better biomarkers like insulin sensitivity
(That part is true.)
No, this isn't true.
Even when two people are identical twins eating the same amount of food and doing the same amount of exercise and activities, weight loss will differ because:
Rate of loss of BodyWeight rate is directly proportional to amount of deficit applied!
Deficit = TDEE (total calorie burn of the day) - Intake
If TDEE is not the same, weight loss will differ, regardless of whether the underlying activity level, genetics, or amount of food or everything else is the same.
For more details u can check my post on this: https://macrocodex.app/knowledge/macrocodex/smart-calorie-bu...
>(That part is true.)
Improved insulin sensitivity is associated with lower excess body fat THE MOST and better skeletal muscle metabolic function. Greater lean mass may contribute.
Therefore, if a person on GLP-1 loses more lean mass than one without, they may not actually have better insulin sensitivity.
Basically with glp 1 it seems to be broadly related to the mess of nonsense that has to do with inflammation/immune/cardio stuff - maybe a set of adaptations that made more sense in a world with more infectious disease/food scarcity but less so now, maybe just a grab bag because evolution is stochastic and is not actually survival of the fittest (it's just survival of the things that survive - there could be 10 organisms that are highly adapted to a particular environment and 2 that are not and would be outcompeted and then a rock falls on the 10 and now the gene pool is what it is - evolution doesn't care). So not really surprising that a thing that works via a mechanism we don't super understand against a condition we done super understand has a bunch of impact on other stuff we don't super understand
This is a statistical fallacy where you're only identifying the extreme cases. The average obese person loses 14-20% of body weight. (Remember that the "obese" category is already defined as 20%+ above the high end of the "normal" range.) So the vast majority of people on these drugs just look normal, not skinny or gaunt.
> They also complain of constant nausea and eat like a bird because eating makes them sick
This is a high dose phenomenon. They can and should reduce their dose if it is preventing them from eating enough or being comfortable.
> I worry about ... medical professionals not using it as a brief intervention then steering towards lifestyle changes.
They absolutely do, of course.
This is why anecdotal evidence is pretty bad.
So people who were fat and get to a normal weight, if you've always known them as fat then they look like they've aged a decade or two in a year. People who were totally normal weight (i.e. "overweight" according to BMI, which is associated with a longer lifespan than "healthy weight") end up looking like tuberculosis Romantics because they wanted to look like movie stars (who are often on severe, unhealthy diets that they stop when they're not working.)
Losing weight quickly often loses it badly - think meth addicts. Women lose fat from their breasts and both sexes lose the fat pad around the eyes; I think these are generally stable fat stores that don't really replenish after being used, even if you gain the weight back. It's not specific to GLPs, just quick weight loss. If you'd lost more slowly your body wouldn't have resorted to taking from those places. Now, you have super-deep nasolabial folds and marionette lines.
> lost weight with diet and exercise
You lose weight through diet. You gain fitness through exercise.
I truly, truly do not understand where this mentality that the medical professionals don't encourage lifestyle changes comes from. If you smoke, they will hound you to stop smoking at every single appointment, regardless of what the appointment is for. They will tell you what to eat. They will tell you to eat less red meat, eat less processed food. They will tell you that you need to exercise 30 minutes a day. They tell you all of this, constantly.
That doesn't mean it works, though. You can tell someone to eat less over and over and that doesn't just magically make them eat less.
This is one of the most interesting ideas in medicine right now
You probably lost a major chunk of lean mass if GLP-1 is the only thing you used without much diet changes or exercise.
This is new because I actually don’t feel hungry.
Also, dieting without feeling hungry isn't new, people have been doing it but only those who truly understand how dieting works. Most people don't.