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 and thousands of ordinary members on r/caloriedeficit subreddit or other fitness subs!
> 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.)
>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.
I do not agree with this. Those studies being used to push the idea that "diet and exercise failed obese people" are flawed, and I posted a comment on this post explaining all the flaws. You can choose to respond to them instead; I won't copy paste it here.
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.
We've already achieved guaranteed results within 2–3 weeks for free (we make no money from this) for all of our users for weight loss or gain, with validation from 17,000+ users for free.
If we are just "scammers," how do we make money by pushing this idea?
You can read reviews and testimonials from people.
A deficit so small that most users won't even know that they are at deficit!
You know that if i remove 150kcal from your diet, your wouldn't notice? that's like 2 slices of bread. So the hunger suppression will never be a question for vast majority of fat people
150kcal deficit over a year = 7.1kg or 15.6 lbs lost! and 300kcal = 31.2lbs or 14.2kg!! all this without any injection or drug without any exercise or severe loss of lean masss
>You're conflating association and causality.
Same is true when you talk about positives of GLP-1s, most of the benefits actually come from "calorie restriction" and it's very hard to seperate which part comes from where.
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.
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
There is another plausible causal mechanism: weight gain flowing from hunger/metabolic dysregulation. This dysregulation being caused by some "factor X" which also causes other problems.
GLP-1 then addresses factor X, and the problems it causes, including weight gain.
Not that obesity doesn't independently cause problems but very plausible causality runs more than one way.
>There is another plausible causal mechanism: weight gain flowing from hunger/metabolic dysregulation. This dysregulation being caused by some "factor X" which also causes other problems.
GLP-1s are being promoted to and used by the general public, who aren't even obese, because GLP boosters push the magical properties of GLP-1s.
Even most obese people do not actually need GLP-1s.
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"
GLP-1 probably reduces systemic inflammation, with far-reaching consequences. That is a much bigger effect than just losing weight, though weight loss contributes to that.
Then there are the mental effects, such as people reporting that they lost various addictive habits (gambling, compulsive shopping etc.)
I get that science has to be thorough, but how is it at all worth writing about that losing weight makes your risk of heart attacks lower? That GLP-1s are involved suddenly makes this news?
Again, not trying to be snide. I'm on the side of science here, but there's gotta be something the scientists are looking at that I'm not.
It is my impression that the topic is being constantly rehashed precisely because the effects of GLP-1s are observed to be significantly more pronounced than what can be attributed to the weight loss alone.
>“GLP-1 receptor agonists are being shown to benefit many chronic diseases over and above their effect on weight,” John Deanfield, FRCP, FESC, professor of cardiology at the Institute of Cardiovascular Sciences at University College London, told Medical News Today. “These include liver diseaseTrusted Source, kidney diseaseTrusted Source, diabetes, and neurological diseasesTrusted Source such as Parkinson’s diseaseTrusted Source. They should therefore not be labeled merely as ‘weight loss’ drugs, but as drugs that can have a direct effect to improve patients’ health.”
>Building off this research, Deanfield is the lead author of a new study recently published in the journal The LancetTrusted Source that provides further evidence of semaglutide and lowered major cardiac event risk, regardless of how much weight a person loses while taking the GLP-1 medication.
>“Semaglutide has previously been shown in the SELECT trial to significantly reduce major adverse cardiovascular events in overweight/obese patients with known heart disease but without diabetes,” Chen explained. “This study analyzed the information from the SELECT study, and found that this benefit to cardiovascular health did not depend on how overweight patients were or how much weight they lost.”
>“This interesting finding suggests that the cardiovascular benefits of semaglutide act through a biochemical mechanism not dependent simply on changing the body weight of an individual,” he continued. “This may open up other avenues of research and therapies that could improve heart health.”
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
>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.
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.
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!
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.
Every gram of body weight needs energy to stay alive. If you are in a caloric deficit, you will lose weight until your energy expenditure matches the caloric intake.
If you stay in "caloric deficit" forever you will actually starve by definition.
Properly defining what you mean (comparatively low caloric intake without defining it via the current weight) is actually quite tricky, as your height, body composition and physical activities are all inputs to what counts as a "normal" caloric intake.
>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.
Not that easy unless you really try: shared IV needles and receptive anal sex without condoms (preferably repeatedly to really prepare the tissue). And you gotta find a willing donor who is not on modern HIV drugs.
Not really, in most cases! I read up on the per-exposure chances of actually picking up HIV a while back[1] and was shocked at how low the risk is, especially for heterosexual men (4 in 10,000 per-exposure; insertive vaginal sex with an infected partner).
Even in the highest-risk scenario (receptive anal sex) the risk is ~138/10,000 per exposure.
pregnancy would seem rare too if you only looked at the averaged per-incident chances (swings from 0% to 33%ish for about 2 days for a perfectly healthy breeding-aged couple); or if you were to compare the amount of heterosexual sexual encounters overall to the amount of pregnancies.
but that's not really how the risk should be considered.
If your risk is 138/10000 per exposure and you have sex with your partner once a week for a year, that's about a 50% chance of infection overall. (Assuming the infection risks are independent, which they might not be.)
If it's 4/10000 per exposure then that's a 2% chance of infection after a year, which for sure isn't huge but I personally would take an annual 2% risk of getting HIV quite seriously.
(Obviously the "once a week" figure is an arbitrary choice for the sake of simplicity, and I am well aware that some people have a lot more sex than that and some have a lot less.)
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.
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.
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?
How is it a conflict of interest for GLP-1 makers and the scientists who work with/for them to look for new medical value in an academic setting with willing collaborators and all the usual peer review?
It's not but there's a lot of historical evidence that those situations are more likely to produce research that looks favorible to the sponsoring company. So it means you have to be a little more careful when looking at those results.
> Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.
And no! It's not unusual, nor does it mean the results are wrong. It just means there's a known bias towards results that favor the sponsor's interests that needs to be taken into account when evaluating the research. Again, that doesn't make it wrong. But it should make you cautious before thinking that a single study (in a very specific sub-population, at that) is necessarily going to generalize. It might. I hope it does! GLP-1's are awesome. But cautiously.
"Competing interests
G.A.M. serves as a research consultant for Merck, GlaxoSmithKline/ViiV,
and Gilead. M.J.C. serves as a scientific advisor for TruDiagnostic. V.D.
and R.S. are employees of TruDiagnostic. All other authors declare no
competing interests."
These are known risk factors. I've never said drug companies are bad. I literally take corporate funding for my own research. But you also don't get to stick your head in the sand and ignore the competing interests that all make the research more likely to show favorable results. Again for those in the back: These results probably _are_ correct! But do they generalize? Will they hold up on replication with a larger population? Do they matter, or is the proxy they're measuring not actually relevant for long term things in humans? Dunno. That's the thing about a _statistical likelihood of bias_ -- you have no idea exactly how to apply it to a single paper other than to say "ok, known possibility of bias, interpret accordingly."
Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources.
This isn’t that. It’s just FUD in this context. Nobody casts aspersions about Google authors on their latest database query optimizer paper with Stanford.
Because Google doesn't have much of a financial interest in that kind of paper. Drug companies have a financial interest in studies that evaluate their drugs.
If you want a CS analogy, the google-co-authored papers about internet policy do get a lot more scrutiny. And rightfully so! That doesn't make them bad -- many of these are written by friends of mine whom I hold in great esteem -- it means we have to be aware of the potential for all of us to be influenced by the money.
Academic research is subject to dozens of potentially corrupting biases, named and otherwise. We still do it and get great benefit from it.
Again, what’s the evidence that this research in particular should be suspect? It looks a lot like all the other research that goes on in this space. Experimenting with biological systems & real humans is expensive, even when you’re mostly doing data collection. It needs funding!
All research from people who financially benefit from the outcome that they have reported should be suspect. Being questioned is not a punishment.
If you ask your child who enjoys video games to stop playing video games and do their homework, and they tell you they don't have any homework, you're silly (trying to use a kind word) if you don't apply far more scrutiny than if they told you that they had an enormous amount of homework that would keep them from playing video games for the next few days.
You don't need evidence to question this. That the reply is convenient is itself evidence. The reply is consistent with someone who is lying in order to play video games. It is not proof.
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.
One thing they are spending them on is tons of new research. Lilly is spinning up massive facilities in Indiana, of all places. I know some absolutely fantastic researchers at Indiana University but I had never thought of it as a biotech hub before.
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.
The problem is these treatments on the bleeding edge of biological understanding are going to start out expensive.
That puts most Western governments with limited budgets in a pickle, having promised their citizens modern medicine equitably at affordable cost, tax or otherwise.
I am EXTREMELY skeptical of epigenetic clocks at the moment, and have been for a few years, but at the same time it's important for these clocks to be investigated and shown to be what they are.
Even though I personally expect them to be readouts of things that don't affect healthspan much, I don't have any more evidence than those trying to work out what they are. I've been wrong before, and also most tech development does not end up living to its promises, but without the investigation we'll never know.
> Big Pharma gold rush where the profits dwarf any eventual regulatory fines
With pharma malfeasance, the penalties are actually big enough, unlike most other fields. Unless you have something particular in mind?
A few examples. Eli Lilly (Zyprexa): $36B sales vs. $1.4B fine, Pfizer (Bextra & others): $16.8B vs. $2.3B, Pfizer (Neurontin): $2.12B vs. $430M, Johnson & Johnson (Risperdal): $10.8B vs. $2.2B, Amgen (Aranesp): $7.4B vs. $762M, GlaxoSmithKline (Paxil & Wellbutrin): $9B vs. $3B
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.
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
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.
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.
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.
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.
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.
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.
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
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.
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?
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.
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.
Unless there are literally fatal side effects, these drugs seem pretty miraculous.
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.
Nonetheless, Dr. Carvalho agrees with avoiding sugary drinks:
"We have a lot of recent evidence, recent studies after [Lustig's] talk. The link between soda and weight gain and obesity and other chronic diseases is quite strong."
Drink fewer sugary beverages, consume fewer calories (eat less), exercise, and drink less alcohol.
If you're getting it compounded it may be time to switch providers.
Seriously, in the first week you should feel a bit of nausea at .25mg. After 2-3 weeks you should see something, either weight loss (most) or gain (some).
Or you could be one of those who have no effect, which sucks. I'd go over your process with your provider, from storage to injection.
Not everyone gets nausia. On .25 I had zero side effects. At .5 minor sulpher burps that lasted a few days and then again down to zero side effects. In the online communities of people on GPL-1 very few people have side effects.
Why on earth would having no side effects suck? As long as its working (weight loss) then thats the ideal scenario.
glp1 doesn't increase your basal metabolic rate, it curbs your appetite. so it's still possible to ingest an excess of energy and to maintain your energy storage volume if you continue the dietary habits that got you fat in the first place -- eating slop and/or eating for the sake of eating.
even one caffeinated corn syrup slurpee that people consume like it's no big deal can be a quarter or more of your daily energy requirement. a few snacks on top of that and that leaves preciously little budget for real food.
It's baffling that so many seemingly intelligent people on Hacker News fall into the GLP-1 booster bandwagon!
The studies being used to claim “dieting is not effective for weight loss” and for boosting GLPs are flawed and demonstrate corruption and intellectual dishonesty!
GLP-1s are tool like a screwdriver but you do not use one to brush your teeth!
They are being over prescribed and abused, resulting in hair loss, bile/gallbladder stone risks, severe loss of lean mass, etc. Studies are already out on this! So why cherry pick satudies only positives of GLP-1s?
Many boosters have suffered 1 or many of these and now want others to suffer as well to further GLP-1 research at expense of general public!
There is a strong GLP booster group. Most people do not need GLP-1s; all they need is a calorie deficit!
The market is filled with "Eat X for weight loss, eat Y for weight gain."
The average person actually does not choose the right strategy for weight loss, which is a "calorie deficit."
But implementing it is not "EASY" until you understand how expenditure, calorie intake, and weight movement work, which is too much work to understand for an average Joe.
But once you understand the "core idea" it becomes very EASY AND SIMPLE!
Let's take something as simple as "calorie deficit."
Being at a calorie deficit itself requires knowing two things:
1. How much you burn in a day (total daily energy expenditure or TDEE)
2. How much your intake is for the day
Deficit = TDEE - Intake
You can do calorie counting for #2. But what can you do for #1?
The average guy does not know how to calculate these properly, let alone judge weight movement, which can move a lot in the opposite direction due to water weight fluctuations that can exceed 1 kg+ of movement a day.
We use neural network to solve #1 problem (solution is given away for free, we make no money!), you can also do it manually using calculation listed here but it won't be as accurate as our neural network!
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.
Comparisons like this, while seeming to make sense using “common sense” rarely impart any value or scientific meaning. Maybe it works like that, maybe it doesn’t.
If as a result of less caloric consumption you’re starving your cells of needed nutrients, maybe that’s the one that degrades earlier.
People just hold onto their beliefs. GLP-1 believers aren't going to forego their beliefs, even when a large body of evidence is supplied that GLP-1s aren't really necessary for the majority of people.
People believe what they want to believe; evidence has little to do with it.
They simply assign less weight to evidence that does not meet their "narrative or belief."
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)
https://journals.viamedica.pl/medical_research_journal/artic...
Pleio-, many; -tropic, having effects; pleitropic effects, many effects effects.
Fat is inflammatory, especially visceral fat, so reducing that fat naturally reduces inflammation.
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.
Yeah entirely possible that GLP-1s are the closest thing to exercise in a pill.
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.
GLP-1s don't.
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 and thousands of ordinary members on r/caloriedeficit subreddit or other fitness subs!
> 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.)
>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.
I do not agree with this. Those studies being used to push the idea that "diet and exercise failed obese people" are flawed, and I posted a comment on this post explaining all the flaws. You can choose to respond to them instead; I won't copy paste it here.
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.
We've already achieved guaranteed results within 2–3 weeks for free (we make no money from this) for all of our users for weight loss or gain, with validation from 17,000+ users for free.
If we are just "scammers," how do we make money by pushing this idea?
You can read reviews and testimonials from people.
The method we use is "slight deficit", see this: https://macrocodex.app/knowledge/rethink/adaptive-tdee/ (you can find all citation/research being used to achieve this)
Our solution is available for free to use!
A deficit so small that most users won't even know that they are at deficit!
You know that if i remove 150kcal from your diet, your wouldn't notice? that's like 2 slices of bread. So the hunger suppression will never be a question for vast majority of fat people
150kcal deficit over a year = 7.1kg or 15.6 lbs lost! and 300kcal = 31.2lbs or 14.2kg!! all this without any injection or drug without any exercise or severe loss of lean masss
>You're conflating association and causality.
Same is true when you talk about positives of GLP-1s, most of the benefits actually come from "calorie restriction" and it's very hard to seperate which part comes from where.
> Citation needed! it's not actually difficult
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.
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
There is another plausible causal mechanism: weight gain flowing from hunger/metabolic dysregulation. This dysregulation being caused by some "factor X" which also causes other problems.
GLP-1 then addresses factor X, and the problems it causes, including weight gain.
Not that obesity doesn't independently cause problems but very plausible causality runs more than one way.
>There is another plausible causal mechanism: weight gain flowing from hunger/metabolic dysregulation. This dysregulation being caused by some "factor X" which also causes other problems.
GLP-1s are being promoted to and used by the general public, who aren't even obese, because GLP boosters push the magical properties of GLP-1s.
Even most obese people do not actually need GLP-1s.
I would use the word "possible", not "plausible". GP's scenario is plausible since it doesn't need positing an as of yet unknown factor X.
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."
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.
I've been around research enough to be allowed to comment: "oh you sweet summer child".
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"
GLP-1 probably reduces systemic inflammation, with far-reaching consequences. That is a much bigger effect than just losing weight, though weight loss contributes to that.
Then there are the mental effects, such as people reporting that they lost various addictive habits (gambling, compulsive shopping etc.)
People have been claiming similar effects for astrology, alchemy, and other things as well.
I mean sure sure, I get that, but take this article I found from a simple Google search.
https://www.health.harvard.edu/heart-health/weight-loss-drug...
I get that science has to be thorough, but how is it at all worth writing about that losing weight makes your risk of heart attacks lower? That GLP-1s are involved suddenly makes this news?
Again, not trying to be snide. I'm on the side of science here, but there's gotta be something the scientists are looking at that I'm not.
It is my impression that the topic is being constantly rehashed precisely because the effects of GLP-1s are observed to be significantly more pronounced than what can be attributed to the weight loss alone.
I see. So, instead of
"GLP-1s cause an improvement in cardiovascular health"
if you said
"GLP-1s cause an improvement in cardiovascular health more than as would be expected by equivalent weight loss"
would that be more specific? Is this right?
>“GLP-1 receptor agonists are being shown to benefit many chronic diseases over and above their effect on weight,” John Deanfield, FRCP, FESC, professor of cardiology at the Institute of Cardiovascular Sciences at University College London, told Medical News Today. “These include liver diseaseTrusted Source, kidney diseaseTrusted Source, diabetes, and neurological diseasesTrusted Source such as Parkinson’s diseaseTrusted Source. They should therefore not be labeled merely as ‘weight loss’ drugs, but as drugs that can have a direct effect to improve patients’ health.”
>Building off this research, Deanfield is the lead author of a new study recently published in the journal The LancetTrusted Source that provides further evidence of semaglutide and lowered major cardiac event risk, regardless of how much weight a person loses while taking the GLP-1 medication.
>“Semaglutide has previously been shown in the SELECT trial to significantly reduce major adverse cardiovascular events in overweight/obese patients with known heart disease but without diabetes,” Chen explained. “This study analyzed the information from the SELECT study, and found that this benefit to cardiovascular health did not depend on how overweight patients were or how much weight they lost.”
>“This interesting finding suggests that the cardiovascular benefits of semaglutide act through a biochemical mechanism not dependent simply on changing the body weight of an individual,” he continued. “This may open up other avenues of research and therapies that could improve heart health.”
https://www.medicalnewstoday.com/articles/weight-loss-drug-h...
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
> the one on [GLP1s] will lose more weight
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.)
>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.
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.
The two explicitly identical people have the same TDEE.
No, they don't. It's very difficult to have the SAME TDEE even in identical twins, eating the same food and having same activity level.
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.
Yeah!
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 was abundantly clear about this exact thing in my comment.
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!
Many people don't do their jobs properly. Why should scientists get the benefit of the doubt?
If something is true it will survive the scrutiny, requires no appeal to authority.
Do you admire science for its explanations? Do you like explanations generally?
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.
Just sharing to spread the good word: with my ex-wife also having EDS and rheumatoid arthritis, she saw a large benefit from low dose naltrexone.
https://www.ehlers-danlos.com/effective-doses-of-low-dose-na...
With RA it’s better to reduce systemic inflammation than mask the pain. Though I get the desire to reduce that chronic pain.
What kind of benefits? For arthritis it’d presumably be joint pain. For EDS did it reduce subluxations?
Did she try TNF-α inhibitors?
Have u maybe tried SPM from fish oil?
Isn't being "underweight" generally shown to reduce the speed of aging
Yes, people have been trying this the "old fashioned way" since the 90s https://en.wikipedia.org/wiki/CRON-diet
At the expense of weakened immunity, bone health, muscle wasting, and fertility issues!
Came here to say this. Also caloric deficits.
Probably you both really mean the same thing.
Every gram of body weight needs energy to stay alive. If you are in a caloric deficit, you will lose weight until your energy expenditure matches the caloric intake. If you stay in "caloric deficit" forever you will actually starve by definition.
Properly defining what you mean (comparatively low caloric intake without defining it via the current weight) is actually quite tricky, as your height, body composition and physical activities are all inputs to what counts as a "normal" caloric intake.
I saw reports on that before the GLP1 craze. Calorie reduced diets for lab animals generally increased their life span.
I thought caloric deficits lead to starvation.
>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.
> slows down the accumulation of biological aging markers in the DNA of adults with HIV
And if you don’t have HIV?
Easy to pick it up
I thought I was on Reddit for a split second
Not that easy unless you really try: shared IV needles and receptive anal sex without condoms (preferably repeatedly to really prepare the tissue). And you gotta find a willing donor who is not on modern HIV drugs.
Not really, in most cases! I read up on the per-exposure chances of actually picking up HIV a while back[1] and was shocked at how low the risk is, especially for heterosexual men (4 in 10,000 per-exposure; insertive vaginal sex with an infected partner).
Even in the highest-risk scenario (receptive anal sex) the risk is ~138/10,000 per exposure.
[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC6195215/
pregnancy would seem rare too if you only looked at the averaged per-incident chances (swings from 0% to 33%ish for about 2 days for a perfectly healthy breeding-aged couple); or if you were to compare the amount of heterosexual sexual encounters overall to the amount of pregnancies.
but that's not really how the risk should be considered.
Most people have sex more than once.
If your risk is 138/10000 per exposure and you have sex with your partner once a week for a year, that's about a 50% chance of infection overall. (Assuming the infection risks are independent, which they might not be.)
If it's 4/10000 per exposure then that's a 2% chance of infection after a year, which for sure isn't huge but I personally would take an annual 2% risk of getting HIV quite seriously.
(Obviously the "once a week" figure is an arbitrary choice for the sake of simplicity, and I am well aware that some people have a lot more sex than that and some have a lot less.)
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.
No matter what drugmakers spend money on, you hear complaints:
- 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?
What’s the concern here? Too much justice? Holding powerful institutes to account frequently seems like a good thing to me.
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.
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?
How is it a conflict of interest for GLP-1 makers and the scientists who work with/for them to look for new medical value in an academic setting with willing collaborators and all the usual peer review?
It's not but there's a lot of historical evidence that those situations are more likely to produce research that looks favorible to the sponsoring company. So it means you have to be a little more careful when looking at those results.
What evidence are you talking about? Do you think industrial scientists collaborating with academics and vice-versa is unusual?
In addition to the funding bias wikipedia article someone else already cited:
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.MR...
> Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.
And no! It's not unusual, nor does it mean the results are wrong. It just means there's a known bias towards results that favor the sponsor's interests that needs to be taken into account when evaluating the research. Again, that doesn't make it wrong. But it should make you cautious before thinking that a single study (in a very specific sub-population, at that) is necessarily going to generalize. It might. I hope it does! GLP-1's are awesome. But cautiously.
This is a federally funded study. Says so in the bright yellow “Key takeaways” box at the top of TFA.
But ok, sure, drug companies bad. Man hn is really turning into Reddit these days.
Dude. From the paper itself:
"Competing interests G.A.M. serves as a research consultant for Merck, GlaxoSmithKline/ViiV, and Gilead. M.J.C. serves as a scientific advisor for TruDiagnostic. V.D. and R.S. are employees of TruDiagnostic. All other authors declare no competing interests."
These are known risk factors. I've never said drug companies are bad. I literally take corporate funding for my own research. But you also don't get to stick your head in the sand and ignore the competing interests that all make the research more likely to show favorable results. Again for those in the back: These results probably _are_ correct! But do they generalize? Will they hold up on replication with a larger population? Do they matter, or is the proxy they're measuring not actually relevant for long term things in humans? Dunno. That's the thing about a _statistical likelihood of bias_ -- you have no idea exactly how to apply it to a single paper other than to say "ok, known possibility of bias, interpret accordingly."
From your cite, as you quote:
Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources.
This isn’t that. It’s just FUD in this context. Nobody casts aspersions about Google authors on their latest database query optimizer paper with Stanford.
Because Google doesn't have much of a financial interest in that kind of paper. Drug companies have a financial interest in studies that evaluate their drugs.
If you want a CS analogy, the google-co-authored papers about internet policy do get a lot more scrutiny. And rightfully so! That doesn't make them bad -- many of these are written by friends of mine whom I hold in great esteem -- it means we have to be aware of the potential for all of us to be influenced by the money.
https://en.wikipedia.org/wiki/Funding_bias
Academic research is subject to dozens of potentially corrupting biases, named and otherwise. We still do it and get great benefit from it.
Again, what’s the evidence that this research in particular should be suspect? It looks a lot like all the other research that goes on in this space. Experimenting with biological systems & real humans is expensive, even when you’re mostly doing data collection. It needs funding!
All research from people who financially benefit from the outcome that they have reported should be suspect. Being questioned is not a punishment.
If you ask your child who enjoys video games to stop playing video games and do their homework, and they tell you they don't have any homework, you're silly (trying to use a kind word) if you don't apply far more scrutiny than if they told you that they had an enormous amount of homework that would keep them from playing video games for the next few days.
You don't need evidence to question this. That the reply is convenient is itself evidence. The reply is consistent with someone who is lying in order to play video games. It is not proof.
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.
Investing in potential future blockbusters and encouraging investors to value the equity by returning some fraction of profits is the business model.
One thing they are spending them on is tons of new research. Lilly is spinning up massive facilities in Indiana, of all places. I know some absolutely fantastic researchers at Indiana University but I had never thought of it as a biotech hub before.
Lilly is headquartered in Indiana so it isn’t some huge surprise..
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.
The problem is these treatments on the bleeding edge of biological understanding are going to start out expensive.
That puts most Western governments with limited budgets in a pickle, having promised their citizens modern medicine equitably at affordable cost, tax or otherwise.
I am EXTREMELY skeptical of epigenetic clocks at the moment, and have been for a few years, but at the same time it's important for these clocks to be investigated and shown to be what they are.
Even though I personally expect them to be readouts of things that don't affect healthspan much, I don't have any more evidence than those trying to work out what they are. I've been wrong before, and also most tech development does not end up living to its promises, but without the investigation we'll never know.
> Big Pharma gold rush where the profits dwarf any eventual regulatory fines
With pharma malfeasance, the penalties are actually big enough, unlike most other fields. Unless you have something particular in mind?
A few examples. Eli Lilly (Zyprexa): $36B sales vs. $1.4B fine, Pfizer (Bextra & others): $16.8B vs. $2.3B, Pfizer (Neurontin): $2.12B vs. $430M, Johnson & Johnson (Risperdal): $10.8B vs. $2.2B, Amgen (Aranesp): $7.4B vs. $762M, GlaxoSmithKline (Paxil & Wellbutrin): $9B vs. $3B
Wonder where GLP-1s will end up
> I am EXTREMELY skeptical of epigenetic clocks
I hear that word and I immediately think of "that" guy that runs the cocktails of additive interventions to "improve" it.
Yes, I hear what you’re saying… Let me tell you about peptides!
Valid questions.
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.
https://en.wikipedia.org/wiki/Bayh%E2%80%93Dole_Act
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.
I don't understand this fixation. If you literally had a cure for X for X in all ailments known to man, you would in fact have a Pharma gold rush.
Interesting hypothetical. Let me know when you've got one, can't wait
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
It says 42% of treatment group showed slower aging, and reduction in telomere length... is there an effect size published anywhere?
> randomized, placebo-controlled clinical evidence
:)
> data from a...clinical trial of 108 adults with HIV associated lipohypertrophy
:(
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.
Why the sad face?
Title of the post hints to a generalization. Study otherwise is pretty specific in the group of people being studied.
I guess I've become so used to the Science News Cycle that I'm not even surprised when I see it behave like this:
https://phdcomics.com/comics/archive.php?comicid=1174
This, and also it's a pitifully small sample size regardless.
It's fine if the effect is big enough. Somewhere around 10-20% puts that sample size in the range of statistical significance, IIRC.
> howunfortunate
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.
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.
They absolutely do, of course.
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.
Everyone I know that is using these looks just fine. Better than before, as they’ve lost weight.
This is why anecdotal evidence is pretty bad.
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.
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.
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
A take you knew was so dumb that you had to create a new account to post it.
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.
I've lost 6kg of fat (I've maintained muscle mass) in 2 months with only the 0,25mg monthly dose using Wegovy.
This is one of the most interesting ideas in medicine right now
People have been achieving far greater rate of weight loss using crash dieting, it's nothing new.
You probably lost a major chunk of lean mass if GLP-1 is the only thing you used without much diet changes or exercise.
Nah. I had body comp measurements and it’s fat.
This is new because I actually don’t feel hungry.
Unless you got DEXA or MRI those smart scales are not accurate.
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.
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?
why wouldn't you need a double blind?
If you’re testing eating sugar a then taking blood sugar test, do you need to give people fake sugar? Only you don’t think the test works…
If you're testing even 6 hours later then yes. Otherwise the people who didn't eat sugar might have eaten sugar at home.
You see this is why analogies are bad. People can be taking GLP ones at home guys.
Presumably mediated by caloric intake reduction, which is already known to slow aging?
I'd be more suspicious of what side effects this thing has.
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.
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.
Unless there are literally fatal side effects, these drugs seem pretty miraculous.
>I suppose we all could wind up with cancer in 10 years or something hypothetically
Extremely unlikely, GLP-1 receptor agonists have been on the market for more than 20 years now, exenatide being first used in 2005.
Its been decades since it was invented so perhaps we'll find out soon.
I don't know, let's restrict it's use just to be safe. Unproven, unresearched peptides though, we should have the FDA bless them for sell.
It would be pretty funny if it turns out it doesn't have any side effects and it really is just a silver bullet.
you already feel it. we live in a chaotic world which is a consequence of people, especially those with power, live longer than their predecessors.
I, for one, do not welcome our basically-inmortal AI overlords-to-be.-
a cruel destiny for humanity.
Controlled by increasingly unfeeling, sociopathic masters, who grow more and more in power. And now also do not age or get sick.
The power those at the top hold far exceeds any king or emperor throughout humanities history.
Ok, can you list which diseases and conditions we should not be trying to treat because evil rich people would benefit?
a very good question for JEV
They used to poison themselves with mercury, in search of something the disembodied few will have. Black Mirror as a PSA fell short.-
I wonder if people were waiting for horrible side effects to be found after antibiotics were invented.
scy hub link? anyone?
You know what else slows aging? Eating properly and exercise.
but what about the people with a BMI already under 20?
not like we can take GLP-1 even if it was affordable
btw soluble fiber helps people naturally secrete more GLP-1 but of course not on the same level as a dedicated drug
What's preventing you from taking a GLP-1 with a BMI under 20? I started semaglutide with my BMI at 19.
How did you get your prescription?
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.
If you don't have diabetes, it would be off label use in that case, which is not illegal.
that's fascinating to me as I've not heard any similar feedback and it seemed counter-intuitive
may I ask for how long now? are you athletic? have you experienced any muscle loss?
Once at optimal bodyfat/weight afaik CRON diet is the long term solution?
Jesus Christ is there anything this thing can’t do?
I have been injecting this stuff for months now with no weight loss
I think you still have to eat less.
Robert Lustig's Sugar: The Bitter Truth hammers on fructose being a major culprit to weight gain:
https://www.youtube.com/watch?v=dBnniua6-oM
Dr. Gil Carvalho (medical doctor, research scientist, science communicator) debunks parts of Lustig's 30-year-old claims:
https://www.youtube.com/watch?v=vdoDx9dIuNE
Nonetheless, Dr. Carvalho agrees with avoiding sugary drinks:
"We have a lot of recent evidence, recent studies after [Lustig's] talk. The link between soda and weight gain and obesity and other chronic diseases is quite strong."
Drink fewer sugary beverages, consume fewer calories (eat less), exercise, and drink less alcohol.
If you're getting it compounded it may be time to switch providers.
Seriously, in the first week you should feel a bit of nausea at .25mg. After 2-3 weeks you should see something, either weight loss (most) or gain (some).
Or you could be one of those who have no effect, which sucks. I'd go over your process with your provider, from storage to injection.
Not everyone gets nausia. On .25 I had zero side effects. At .5 minor sulpher burps that lasted a few days and then again down to zero side effects. In the online communities of people on GPL-1 very few people have side effects.
Why on earth would having no side effects suck? As long as its working (weight loss) then thats the ideal scenario.
One of my reports at work started out with heavy diabetes and 300 pounds. Now he’s down to under 200 and has no diabetes less than 5 months later.
Can t2 diabetes go to remission?
Yes, if you improve your insulin sensitivity. It's effectively how bariatic surgery "cures" T2 diabetes. T1 is different though.
Why are you continuing then
glp1 doesn't increase your basal metabolic rate, it curbs your appetite. so it's still possible to ingest an excess of energy and to maintain your energy storage volume if you continue the dietary habits that got you fat in the first place -- eating slop and/or eating for the sake of eating.
even one caffeinated corn syrup slurpee that people consume like it's no big deal can be a quarter or more of your daily energy requirement. a few snacks on top of that and that leaves preciously little budget for real food.
Luckily, like exercise, there are cardiovascular benefits even without weight loss.
https://www.medicalnewstoday.com/articles/weight-loss-drug-h...
I'd assume most of what it does is a due to losing weight and reduced metabolism due to lower caloric intake.
Of course it does. /s
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.
It's baffling that so many seemingly intelligent people on Hacker News fall into the GLP-1 booster bandwagon!
The studies being used to claim “dieting is not effective for weight loss” and for boosting GLPs are flawed and demonstrate corruption and intellectual dishonesty!
GLP-1s are tool like a screwdriver but you do not use one to brush your teeth!
They are being over prescribed and abused, resulting in hair loss, bile/gallbladder stone risks, severe loss of lean mass, etc. Studies are already out on this! So why cherry pick satudies only positives of GLP-1s?
Many boosters have suffered 1 or many of these and now want others to suffer as well to further GLP-1 research at expense of general public!
There is a strong GLP booster group. Most people do not need GLP-1s; all they need is a calorie deficit!
The market is filled with "Eat X for weight loss, eat Y for weight gain."
The average person actually does not choose the right strategy for weight loss, which is a "calorie deficit."
But implementing it is not "EASY" until you understand how expenditure, calorie intake, and weight movement work, which is too much work to understand for an average Joe.
But once you understand the "core idea" it becomes very EASY AND SIMPLE!
Let's take something as simple as "calorie deficit."
Being at a calorie deficit itself requires knowing two things:
1. How much you burn in a day (total daily energy expenditure or TDEE)
2. How much your intake is for the day
Deficit = TDEE - Intake
You can do calorie counting for #2. But what can you do for #1?
The average guy does not know how to calculate these properly, let alone judge weight movement, which can move a lot in the opposite direction due to water weight fluctuations that can exceed 1 kg+ of movement a day.
Even GLP-1 users on Triz subreddit agree with this! https://www.reddit.com/r/tirzepatidecompound/comments/1omfgx...
We use neural network to solve #1 problem (solution is given away for free, we make no money!), you can also do it manually using calculation listed here but it won't be as accurate as our neural network!
They also cause sexual dysfunction while you're taking them. Not a problem I guess when you're overweight, but on weight...it's a huge problem.
Or put another way, "Let me pluck one of the rare side effects and make it seem like its a common one because I know nothing about this"
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.
Comparisons like this, while seeming to make sense using “common sense” rarely impart any value or scientific meaning. Maybe it works like that, maybe it doesn’t.
If as a result of less caloric consumption you’re starving your cells of needed nutrients, maybe that’s the one that degrades earlier.
People just hold onto their beliefs. GLP-1 believers aren't going to forego their beliefs, even when a large body of evidence is supplied that GLP-1s aren't really necessary for the majority of people.
People believe what they want to believe; evidence has little to do with it.
They simply assign less weight to evidence that does not meet their "narrative or belief."
This is such an oversimplification of complex biological processes that it borders on medieval superstition.
Should we similarly expect those who use their muscles more to be in worse condition than someone who doesn’t exercise?
Oxygen is a reactive species, that's how we do what we do. How we swim the thermodynamic eddies and flows across quadrillions of chemical reactions.
But burning that fuel is damaging.
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I did CS, bio, and chem as an undergrad. I'd like to think I have an artistic appreciation.