The best way that I can describe what Semaglutide has done for me is that I feel like almost nothing in my life has changed (other than being down 45lbs, suddenly having normalized liver enzyme levels and blood pressure.) Before starting it, I generally ate until I was satiated, almost never over full. From time to time I'd maintain a caloric deficit, but it meant a large part of my attention was consumed, day and night, by a nagging distraction of food.
Today, I still just eat a normal diet until I'm satiated - but 1/3 of the food is left on the plate. I have a little less of an interest in alcohol and coffee, but other than that it's like nothing has changed.
My point is that there's still a common sentiment that these drugs are some sort of a shortcut for people who want the ability to over-indulge, when in reality that couldn't be further from the truth.
I think what I feel like on a GLP-1 is what most people feel like without one. If you want to know what I feel like without a GLP-1, try not eating until your mind is constantly nagging you to do so - then try staying like that forever. That's what a lot of people propose to anyone who has a problem with their weight.
This is my issue. I have lost 40-60lb many times in the past 15 years, but I always gain it back because the root cause is not fixable. I always have a lingering hunger, and I don't want to spend my entire life hungry.
It seems like there's growing medical acceptance of the idea that everyone has a natural weight that they seem to plateau at (which in some cases is overweight.) 1mg of semaglutide reset my natural plateau from 225 to 180. You are exactly right though - being overweight is either a daily physical battle or an hour by hour mental battle if you are trying to restrict calories.
I'm on 1mg of compounded semaglutide, where I've been for the past 4 months. I have a similar arc in terms of days 2-5 being the strongest effect, but I haven't experienced any nausea (except the smallest bit during the first couple of weeks at 0.5mg.) I was briefly at 1.5mg but was brought down because I started losing weight faster than needed. My weight has been rock steady since coming back to 1mg.
I feel like I have an almost optimal reaction to the drug, which I kind of feel bad about, given all the side effects other people seem to have. My experience mostly matches yours, except without bloating or nausea. I do have a slight urge to drink on day 6 and 7 -- well not an urge, more like an acceptance of it -- kind of hard to explain. I don't even think about alcohol on the other days.
I am injecting the Hims formulation of semaglutide. I had no side effects on my first two injections, so my next two (which were supposed to be the same as the first two) I increased the dosage slightly. I am pretty happy with how I feel so I'm not sure how aggressively I'll ramp up to the full dose.
I’m on Zepbound and I had no side effects for my 2.5mg and 5mg doses. It’s starting to be more prevalent with 7.5mg - and I haven’t moved to higher dose yet.
Are you eating "healthier"? What I've found is I prefer "simpler" meals to more complex/layered/richer dishes. I forgo pasta dishes or sandwiches for simple meals like eggs + a vegetable + fruit. I've actually had to throw out a bunch of ingredients that went bad that I never would have had to before. I've had to adjust my grocery shopping quite a bit, including frequency.
That's usually how it works for me too. I find that days 2-5 I start feeling not very good. I wouldn't say bloated, but almost weird blood sugar levels.
Usually about 6pm in the evening is when I start feeling terrible. Kinda makes me want to eat less.
It works much better, in my experience, to cut the dose in half and take it twice a week. I do Sunday and Thursday, 2.5mg of tirzepatide per injection.
>If you want to know what I feel like without a GLP-1, try not eating until your mind is constantly nagging you to do so - then try staying like that forever. That's what a lot of people propose to anyone who has a problem with their weight.
Ironically- not eating- is what solved this issue for me. I imagine it is what people on GLP-1 feel like all the time.
I spent a long time food fixated, frequently nagged by hunger, until I started practicing going without. Now I can go 2-3 days without eating and have to force myself to eat something.
I encourage most people to try going 2-3 days without food and seeing how it changes their relationship to it.
I'm sure it is in some cases, but overall I think having self control over when and how much one eats is a good thing.
I would be more concerned about unrestrained compulsive eating disorders.
It is interesting that compulsive eating to the point of exhaustion, obesity, loss of mobility, and organ failure is normal, but skipping a few meals is considered strange.
The former is a leading cause of death, while the later is perfectly safe and may even have a number of benefits.
Indicator, not proof. If you're an illegal spy (no diplomatic cover), paranoia isn't a maladaptive behavior. If you're overweight, going days without eating isn't necessarily a sign that you have swapped one bad relationship with food for another - it could just be a way to lose weight. Effective weight loss methods absolutely depend on reining in hunger. Fasting happens do that for some people.
If you weigh 40 kg as an adult and you don't eat for days, you probably have an eating disorder. If you weigh 140 kg as an adult and you don't eat for days, meh?
bingo. As I understand it, disorder is characterized by harm and lack of control. spending time lifting weights for health is usually OK, staying up all night throwing things at invisible monsters is not.
That is because the advice around eating less is focused on old paradigms that have clearly failed.
Those drugs let people experience intermittent fasting and fasting by reducing hunger and snacking.
The danger of suppressing hunger signals is that hunger could've been a important que for nutritional needs.
Muscle loss is severe danger of gpl-1, And muscle size is tied to longevity.
So although promising it's not without danger. And there are other paradigms but those are not yet explored yet the underlying mechanisms work the same.
Edit:
Let's keep HN a place where discussion can be held without just kneejerk down voting.
If people are obese, they’re not getting the right hunger signals anyways. Obesity is heavily tied to longevity. GLP1s cause muscle loss because when you lose weight, some of your caloric deficit will be supplemented by your muscles.
The article suggests that non-weight loss side effects of GLP1s are also worth considering taking the medication for. If you’re maintaining a healthy weight, while taking the drug, you shouldn’t experience the muscle atrophy.
Also, muscle size isn’t tied to longevity, usable muscle and a certain strength and physical ability is tied to longevity. Muscle size is a convenient proxy. Also cardiovascular ability in a related way. You basically just need to be able to move and carry things and act in your environment in a responsible way at an old age so you don’t fall or hurt yourself.
Your points are just reforcing my initial point.
Old paradigms of nutrition have clearly failed. If we could acknowledge that we could move forward and be open to very promosing alternative paradigms.
Which currently are not studied enough, to create clear nutritional guidelines for the public.
Gpl1 and those paradigms work through the same mechanisms action (autophagy, ketones, reducing food intake).
If there is acute problem with health such as (morbidly)obesity then gpl-1 could be a great intervention.
But its not long term solution, nutrition and a healthy relationship with food and lifestyle is.
Muscles are very important for health, but let's not go into that. For muscle size I linked to meta study about muscle size and all cause mortality (longevity)
> Conclusions: Low SMI(skeletal muscle mass Index) was significantly associated with the increased risk of all-cause mortality.
> Old paradigms of nutrition have clearly failed. If we could acknowledge that we could move forward and be open to very promosing alternative paradigms.
> Which currently are not studied enough, to create clear nutritional guidelines for the public.
We have very clear, very obvious nutritional guidelines for the public, and we have lots of research on the healthy food to eat. The TLDR guidelines that would have a positive impact on most people is "eat less". Doesn't seem to work, and it's not an informational problem.
(1) its not long term solution, nutrition and a healthy relationship with food and lifestyle is.
The reality is that plenty of people will just never have this. Some people are "weak" or "genetically predisposed" or "addicted" or "impoverished" or any other number of things that people use to explain poor diet. No amount of nutritional guidelines will fix this. That's just the (unfortunate) reality. Now what do we do?
(2) GLP-1 medication (according to the article) have other benefits beyond nutrition, eg addiction, Alzheimer's, kidney health, etc. These benefits could be very real (some are still being studied). If they turn out real, how does our relationship with the drug change, how that its not just a replacement for a "healthy relationship with food and lifestyle"?
You've mentioned muscle being a proxy for health. Do you consider going to the gym and working out to be a "long term solution"? Why is spending an hour a day performing an artificial activity (lifting weights) generally considered a healthy lifestyle, but taking safe preventative medication not considered part of a healthy lifestyle?
(Generally) society considers vaccines to be safe and healthy, and we recommend them for everyone from a young age. They're obviously quite artificial, and they trick our body by stimulating certain biological pathways artificially.
What is different about certain medication like GLP1 meds that keep us from considering it part of a safe, healthy lifestyle?
The health benefits of eating less and fasting such as autophagy, ketones occurs with or without gpl1. That is how gpl1 is healthy, because eating less and fasting is healthy.
You don't have to go to the gym to activate and stimulate muscles. But our bodies are made for daily usage of muscles.
We always had downtrodden, poor, weak people, in any society. But in the 1970's they were not obese.
We dont take daily vaccins they are a intervention. Gpl1 could be intervention for obesity patients.
The danger of long term usage of gpl1 is that our bodies emerged ecosystems that we don't understand yet. By reducing hunger signals that their motivate a person to get nutrition such as protein, vitamins and minerals, etc
Leads to malnutrition, muscle loss and other diseases.
Your point is that there is no problem with current paradigm of nutrition while at the same time promoting a agent that stops the addictive nature of our current nutritional paradigm.
If you use gpl-1, And it works for you that is great and we should be grateful that gpl-1 is available. My only advice would be, to lift weights or callisthenics to keep your muscle size and strength. And to explore other nutritional paradigms that can help you maintain the weight loss without gpl-1.
> That is how gpl1 is healthy, because eating less and fasting is healthy.
These medications do so much more than this. First, they have all sorts of direct metabolic benefits beyond just eating less, and secondly, studies are linking them to non-metabolic benefits too.
You don’t have to go to the gym to stimulate your bodies, but most people require it because they won’t do it naturally in their life. You don’t need GLP1s to regulate your metabolism, but it seems most people aren’t doing it naturally in their life.
In 1970s, people died of hunger. We’re also not in the 70s and won’t be going back. Our society has a surplus of unhealthy food and an uneven distribution of healthy food. The food is engineered in labs to be addictive. Our society doesn’t make room for regular physical exercise. So many things wrong, and until we start regulating the food industry, the best we can do is correct mistakes.
I’m also not sure there is any real evidence that the GLP1s are causing malnutrition because of “hunger signals”. But ensuring proper nutrition of vitamins and micronutrients is not that hard to monitor.
I’ve never used a GLP1 antagonist. I’m not one to brag to strangers on the internet, but I view myself as rather healthy and athletic. It’s a lot of work, it’s not that fun, it takes a lot of time. I just don’t believe that the only right way to be healthy is waste an hour in the gym every morning and do “hard work”. If there was a CrossFit pill, I’d be here supporting that too.
Some things (working out, vaccines) are basically just a net-good on the health of society. Why isn’t it possible that this is included in that list?
People who tout the dangers of glp1 - and there ARE risks! - are also ignoring the "what did you do instead of a glp1" and the answer is.... remain overweight, which has many risks!
Yes glp1 might increase the risk of a certain kind of cancer. But guess what, it also reduces the risks of many other cancers tied to obesity!
It's hard for me to take hand-wringing over glp1s seriously. Appeals to "JUST do x" are lost in the "just" - hello if people could just do intermittent fasting, or eat less calories, well then there would be less obesity. The obesity epidemic is literally a rebuttal to any of these arguments.
First of all congratulations with your succes, and not take away from that. But IF nor fasting is a silver bullet.
Reducing food intake, and insuline while keeping hunger down is.
Important aspect is keeping hunger down. And if your fasting/excersicsing you can experience the same.
The discussion on weight unfortunately almost always focused on total weight.
But we would like to retain our muscles, and reduce adipose tissue(fat).
With gpl1 people are able to fast, stop snacking and reduce food intake because hunger signals are blocked.
But a fasting lifestyle, which goes further then just IF. And a focus on nutrition(vitamins, minerals, quality sources) could the same.
Furthermore the effects of lowering inflammation of gpl1 is only logical reduction in food intake/fasting will lead to autophagy.
IF/Fasting and other new nutritional paradigms are still new and uncharted. It's not clear yet what the full effects are, and how to implement them correctly.
Yeah, but at the end of the day, it either works, or it doesn't. You can say "you're holding it wrong" all you want, but if it's easy to hold the thing wrong, it's the thing's fault.
GLP-1s work for many more people than any other diet advice we've ever had.
I dont think this is an either or situation. People still need tools in their toolbox if they dont want to be be on a biologic for the rest of their lives.
So in that aspect we agree completely. A few years ago people would call you mad for fasting, and now we have drug that allows people to life the fasting lifestyle.
And if there is a medical reason I'm not making the argument against. I'm making the argument that it's a intervention and that healyhy nutrition, healthy relationship with food will is the long-term solution.
And order todo that we would need to explore other nutritional paradigms than the current one.
Edit:
- Fasting lifestyle, like omad(eat once a day) removes the feeling of hunger and thoughts about food, until it's the moment to eat.
> So in that aspect we agree completely. A few years ago people would call you mad for fasting, and now we have drug that allows people to life the fasting lifestyle.
It's nothing like the fasting lifestyle, it just quiets the food noise.
> I'm making the argument that it's a intervention and that healyhy nutrition, healthy relationship with food will is the long-term solution.
That's like saying "I'm making the argument that diabetes medication is an intervention, and that producing healthy amounts of insulin is the long-term solution". Yeah, it's all well and good, except it doesn't work.
You can yell at people for not <insert favorite reason here>, but, at the end of the day, people have tried diet, they've struggled with it, and it's failed. No matter how much yelling you do, they won't stop. It's like trying to talk a meth addict out of their addiction.
Doctors have long said, "Diet and Exercise", but they couldn't really address the pain aspect of hunger until the last few years.
And hunger is painful.
Hunger is something that is left to the patient to cope with -- usually badly. Sure there could be support groups and exercise groups, but nobody is going to be there in your bed when you're trying to fall asleep with hunger pains.
This thread is kind of painful because it's full of people who have no problem with their weight telling others to "just don't have a problem too!".
I don't eat because I'm hungry. I eat because food is there, or because I remembered that food exists, or because I have nothing better to do, or because stuff tastes good. I can't remember the last time I was hungry.
The weird thing is I can go a really long time without food. I can go 36 hours easily without eating something, hunger doesn't bother me at all. After 36 hours, I think "huh, I should probably eat something".
Such situations where I forget to eat are really, really, really rare. I have to basically be on my own and working on something fun, because that's when I both don't have food in the house and don't want to spend the two minutes it takes to order something.
Kids who went hungry at school had behavioral problems, and couldn't focus on schoolwork. The solution was to give the kids breakfast, not to tell them to cope with hunger until they got home.
On one side, sure GPL-1 may have side effects, maybe bad ones. On the other hand, overweight in the sense of excessive adipose tissue, correlates with a huge number of very bad health problems (both mental and physiological), with an abundance of proof around causality for many of these.
I’m thinking, whatever negative side effects we find for GPL-1 in the future, they will have to be pretty massive to offset all these benefits.
"Compared with those prescribed lifestyle intervention for obesity, adolescents prescribed either liraglutide (Saxenda; Novo Nordisk) or semaglutide (Wegovy; Novo Nordisk) had a 33% lower risk of suicidality over 12 months of follow-up after controlling for potential baseline confounders."[1]
I'm fine with GPL-1 agonists, they seem great, not trying to argue against them.
This is an age old problem in the obesity treatment and research community. It never seems to go away. It's come up with bariatric surgery, with other methods, and now GPL1- agonists.
The issue for me is that "telling people to eat less" is sort of a strawman in some ways. It doesn't work.
What does work, however, at least according to evidence I've seen, is giving people strategies for losing weight, therapy, support, and so forth. It doesn't work for everyone but it does for some.
I would rather people try that first as it can be self-sustaining and doesn't require medication.
I'm not opposed to the medication or people using it, in fact I think it's a good thing, but it seems a little dangerous to me to create a culture where people are just told "take this pill, pay lots of money for it, because nothing else will work" which is not actually true. I don't think we're at that point but it's easy for me to imagine.
It's tricky because losing weight can take a mental load off, it's just getting there that's hard. Once you get there you gain confidence, people treat you differently, doctors take you more seriously, exercise becomes easier (less weight to throw around and less strain on joints), etc.
The problem is the human existing in a modern environment that is hostile to it. GLP-1s enable the human to more effectively operate in said environment. It patches malfunctioning reward centers (addiction and food compulsion), it reduces overall inflammation, it provide cardiovascular protective properties.
As kubectl_h mentions [1], the future is better understanding and fine tuning the mechanisms responsible. I think gene therapy is the end goal (permanent fix vs chronic maintenance with GLP-1s), but others have indicated in previous threads that might not be possible. We need more information and research. This is only the beginning of the "Aha!" moment (The most exciting phrase to hear in science, the one that heralds new discoveries, is not “Eureka” but “That's funny...” —Isaac Asimov).
You're free to your opinion (legit, no snark intended), the market will deliver to the demand. The cost benefit ratio is obvious, even accounting for potential side effects at scale.
Obesity rates aren't consistent because access to cheap calories is not consistent across the globe. I don't mean to be glib, there are certainly other factors, but as a first order approximation obesity rates of a region or country are going to be proportional to how easy calories are to access, followed by how satiating those calories are
Japan and Colorado have just as much access to cheap calories as Louisiana, but notably less obesity. Also, obesity rates have increased faster than access to calories has; it's a surprisingly recent problem.
Even in the eighties, household spending on food was nearly 50% higher relative to overall consumption than today.[0] Japanese households today actually spend 16%(!) of their household income on food, compared to only 7% in the US.[1]
Obviously there are multiple factors, as I said I think the relative satiety of food also plays a role. US food spending has been more or less static over the last two decades while obesity rates have continued to climb so cost can't explain everything (though as an aside, I do think lower costs probably take some time to have an effect). But even if there are multiple factors at play, cost really should not be discounted as a huge driver, especially if we're taking a public health approach to addressing the problem. If we just attribute obesity to individual moral failings, as some are wont to do, I think we're really doing a disservice to ourselves
'problem' is a loaded word. The data is coming in saying that this class of drugs provides potentially massive benefits. If I get a lot of benefit but didn't fully address the root 'problem', I still get a lot of benefit.
Yes, obviously. As long as the drug is available and the earth exists, etc etc
Therapies are contingent on being available. That’s uniform. What’s unique about glp-1s is that they are very effective in weight loss and many other things. As compared to alternatives that aren’t.
One, going off GLP-1 for all I know doesn't have bad side effects, other than going back to your bad diet.
If we are back at the point of supply chain issues that interrupt GLP-1 for any significant amount of time you're starting to look at issues like we had during covid that are going to have all kinds of other effects.
From my understanding getting the pre-compounded components isn't that difficult, and that India and China are making versions of it now.
Yes, but that’s an incomplete view on the obesity epidemic in the West, imo. It’s not just that there’s “more access to calories,” it’s that access to healthy foods is getting more difficult for a large portion of the population. People working multiple jobs don’t have time to cook a complete, nutritious meal. Also, due to our ever-increasing wealth inequality, it’s harder for people to afford healthy food. A whole chicken, a vegetable, and a starch will always cost more than getting something at Wendy’s. Similarly, a jar of jelly is cheaper and lasts longer than a box of strawberries.
I'm Brazilian, but whether you consider Latin America western or western-adjacent, here healthy food is definitely not cheaper than processed food at all. Yet, you can see populations and regions dropping from food insecurity directly into obesity as soon as people do have access to more food.
The time argument might be relevant, but even then, most Brazilians do have cheap and easy access to a very healthy lunch in restaurants or to-go meals, purchased or prepared, with rice, beans, meat, salad... The breakfast is probably bread, but I'd say most people don't eat a lot of that in the morning. Getting proper nutrition at night will probably be problematic, but it's also a smaller window...
But, like I said, processed food is quite expensive here. For instance, a 1 kg of chicken breast goes by less than a third the price of a McDonald's combo. A pack of cookies or snacks will be like double the price of a 1 kg of bananas...
I can only speak for my culture so thank you for the perspective and insights on yours. Just checked and it seems like bananas are 27.5% cheaper in Brazil than America. Chicken fillets are a shocking 71% cheaper! I'm sure I'm not taking a lot of things into account here like the average income levels, but still, that's crazy.
This is like saying that driving doesn't work because people still walk and the real problem is transportation. It simply doesn't matter. It's not an argument.
I'm pointing out the problems of considering this a valid on term "solution." It's simply not. You need a plan to eventually be rid of this compromise.
That GLP-1 has benefits is good. That we could possibly rearrange our food system so we don't need it anymore is better.
You can acknowledge both without hurting _anyone_. You entirely lack an argument.
>That we could possibly rearrange our food system so we don't need it anymore is better.
Ya so you want to change a system that involves millions of selfish actors and corporations looking to profit and that have entrenched themselves, and are protected by freedom of association versus a choice between a doctor and a patient.
This is a textbook case of letting better stand in the way of good.
I'd love to re-imagine our food of food production and consumption, but it sounds like you're arguing that because food production and consumption is a better solution, we shouldn't be promoting GLP-1 agonists.
Sorry, but one is exists in reality and the other exists in our imaginations. When we let our imaginations take precedence over reality, we live in a fantasy and the consequence is that we get neither. Effectively this argues for neither, and that's a bad deal for everyone.
I don't understand your point. Many common medications - ibuprofen, albuterol, insulin injections - function entirely by hiding symptoms of an underlying problem. If the symptoms being hidden are worse than the side effects of the medication, what's the concern?
Solving symptoms and not root causes is how you get band-aid fixes that wind up being inadequate to the task in the end. I would've thought everyone here would be aware of the danger of treating symptoms rather than the underlying issues, given it's such a common pitfall in the computer field.
Again, I genuinely don't understand the point. There's a large and well-funded segment of the nutrition industry dedicated to solving the root causes - Weight Watchers alone has over a billion dollars in annual revenue. We just haven't invented a diet-based solution which works as well as GLP-1 agonists without requiring you to compromise on palatability and feel hungry all day.
It'll be great if we do, although I don't know of any promising research avenues and I lean towards the hypothesis that the average human metabolism is simply tuned to mild obesity under conditions of widespread food availability.
The point, which seems to be routinely massively downvoted on here, is that both things can be true at once:
- these drugs are good and a paradigm shift in the treatment of obesity (and have other benefits)
- we must not lose sight of the need to address a thoroughly sick food industry that necessitate so many people needing to use these. Junk food advertising, lack of subsidies for fresh vegetables, HFCS, food deserts, etc.
Chile is experimenting with banning junk food ads to children and is seeing some early behaviour changes.
The point which people seem to be wilfully missing is that we can have both these drugs and advocate for cracking down on a food system that deliberately poisons everyone in society. Having everyone be on this drug because we shrug and say "free market innit" while big corps continue to feed us crap is not a solution, obviously.
"Fixing" the food industry isn't possible for as long as they have billions to sink into influencing politics. Trying to find a market or political solution has failed. Full stop. The fact that you're still trying to find some way to make it work is embarrassing and depressing. It's time to attack the problem from another direction, one that will also ensure these companies either go bankrupt, lose relevance and power and/or evolve into a form that's less parasitic and more beneficial to us as a species. GLP-1 can be one tool to help us do that.
We can only crack down on a "food system that deliberately poisons everyone in society" if such a system actually exists.
* Food deserts are a problem, but the vast majority of Americans don't live in one. We just don't typically want to eat a pile of fresh veggies when there's other options available.
* Criticisms of HFCS are, as far as I can tell, entirely viral misinformation - not once have I seen someone point to concrete evidence that HCFS is worse than table sugar.
It seems to me that this entire idea of a poisonous food system is an epicycle to avoid the obvious conclusion, that our bodies are calibrated on average to eat ourselves into obesity when we have the means to do so. If you don't start from the premise that there must be an external reason we're getting heavier, it's very hard to explain why potato chips should be any more unhealthy than a traditional breakfast of potatoes and bacon.
IIRC food deserts are a demand issue, not supply. The reason healthy food doesn't exist in those neighborhoods is because it closed because people didn't go there.
I haven't seen any comments on the topic of chronic inflammation. I am not knowledgeable on this topic, but we do know that chronic inflammation is linked to a huge number of disease end points. GLP-1 may be reducing (or preventing) systemic inflammation.
What about people who, with their current habits, are on the bottom range of what is considered "normal" weight (in the BMI sense) or already underweight?
Wouldn't taking GLP-1 agonists (for potential non-weight-loss benefits) be potentially harmful as it may reduce eating even further and lead to being significantly underweight?
> Wouldn't taking GLP-1 (for potential non-weight-loss benefits) be potentially harmful as it may reduce eating even further and lead to being significantly underweight?
Almost certainly at the weight loss dosages people are taking now, but semaglutide (at least) can be tuned up and down for effect. Time will tell what kind of dosage is required for these non-weight-loss benefits.
That said, I think it's more important to focus on how this drug works -- it works in the brain and in specific areas of the brain that we now know are important for weight loss/addiction/inflammation(?) (because of these emergent miracle drug effect). It doesn't seem outside the realm of possibility that drug companies will be able to target these systems with more finesse in the future as opposed to superdosing engineered stable GLP-1 molecules that flood the system.
It is the future understanding of what this drug does that is the real promise for all people -- we are just in the early stages of understanding what we've found.
Sure, it would probably not be helpful to give these people medical anorexia unless there was some huge, huge, more-than-offsetting other benefit. (Less than 2% of the US population is considered underweight by BMI: https://www.kff.org/other/state-indicator/distribution-of-bo... . )
If it really is inflammation, exercise targets that just as well, and also acts as a miracle drug that seems to reduce the risk of just about everything, somewhat paradoxically even orthopedic injuries over a long enough timescale (because you stave off age-related muscle and bone mineral loss).
But that puts us back in the "telling people to exercise doesn't cause them to actually do it" at the public health level. For you yourself, you can simply live a less risky, healthier life. For all yous, probably we need something like a once-weekly pill or injection that doesn't require drastic habit changes. For all of society on a forever timescale, of course, we can ignore the fact that adults won't change their ways and focus on instilling lifelong athlete habits in kids. Doesn't seem to be the direction we're going in, though.
Things like GLP-1 can give a near immediate bodily response that can lead to people starting to work out. When you have inflammation issues I can promise the last thing you want to do is put stress on your body from working out. Especially when most people don't know how to do it properly.
So it looks like GLP-1 may have positive side-effects beyond what can be explained as consequences of weight loss. Surprising linkages between biochemistry/hormones and temperament.
I am slowly (1 kilogram per month) losing weight by eating nothing but meat 2-3 days per week. My understanding is that the extra GLP-1 secreted by the gut when digesting lots of protein leads to appetite suppression. It works, and is surprisingly easy to do (no feelings of hunger).
So will I also be getting the beneficial side effects of GLP-1? If so, high-protein dieting becomes the smart way to lose weight.
> FTA: So we're not only going to be treating (or outright preventing) a number of diseases, we're going to be learning more about the cause of these diseases than we ever did before.
Ultra processed foods (UPF) needs a hard look IMO. It's the leading cause of many diseases stated in the article and several others including cancer and dementia.
Color me a bit skeptical on the "GLP-1 is the cure for everything" hype. These drugs are clearly a game-changer for obesity and T2D, and possibly a few other conditions, but it strikes me as unlikely that a chemical exists that is more or less an across-the-board improvement to health, with no downsides. If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists? Or modify GLP-1 itself?
The best argument against is "starvation was a human universal" and that survival through famines totally dominated the evolutionary trend in GLP-1 related things in the body. But even something as simple as lactose tolerance responded quite quickly to changes in human dietary structure in different areas of the world.
My suspicion is that at least some of these medical record review studies are just driven by confounding - people who find out about GLP-1 agonists are better educated, wealthier, or have behavioral/lifestyle traits that explain many of the apparent benefits.
(still, part of me is still holding out for the "miracle drug" explanation)
> If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists? Or modify GLP-1 itself?
Because evolutionary fitness doesn't care about what we care about, and even if it did it operates so slowly it hasn't yet finished adapting to us having invented cooking.
True, but (a) maybe it would evolve "naturally" given enough time, and (b) the things that humans create are a product of evolution too, no? Albeit not directly through the mechanism of natural selection.
The obesity epidemic is only 50 years old.
GLP-1 seems to be a “thing that fixes your satiety balance”, that is applying to more than just food, but maybe also help you regulate yourself when you have way too much access to alcohol, drugs, etc.
In short: the reason that the human body wouldn’t have evolved to make more GLP-1 automatically yet is because evolution causes populations of organisms (not individuals) to change, over generations, to be better suited to their environment.
And 50-100 years is nothing in terms of evolution. We spent 500k years evolving to optimize gathering every calorie we can. And then yesterday it turned out that maybe it is in fact possible to have too much.
Also, the human body does make some GLP-1 itself. Maybe it was just getting started.
> If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists?
Because we haven't had the infinite years required to "just evolve" every possible bodily improvement?
I don't know if it's an ideal wonder drug or also has downsides we haven't found yet or some of the positives are misinterpreted but if "why didn't we just evolve it" was meaningful it could be an argument against ANYTHING being good in the way presented.
To be fair, we don’t need infinite years/generations to select for favorable traits.
Such a selection process might already be underway - obesity lowers fertility, so there is pressure towards not being obese. IMO the next generation will already be either slightly reducing their intake, or increase their expenditure of calories. There‘s many ways to do that - becoming taller, more restless, less hungry, decreasing intestinal uptake, reduced enjoyment of food (loss of taste/smell) etc
Fertility is one of those things that's dropped faster than obesity has increased in most places and will have a much greater impact on future generations.
> If it was that simple, why didn't the human body just evolve
That's easy to answer. We exist today in a very different environment to that we evolved in.
It makes perfect sense that there could be a hormone that wouldn't provide a net reproductive benefit to hunter-gatherers or subsistence farmers but provides an immense health benefit to sedentary humans eating unlimited food. In fact, it would be surprising if there wasn't.
> If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists? Or modify GLP-1 itself?
Replace "GLP-1" with any of: aircraft, computers, buildings, WiFi, ...
Some things are easy for nature to find and some things aren't!
And even of the things that are easy for nature to find, and that we would have found useful even in the environment of evolutionary adaptation, they might not confer overall fitness if they are too costly.
Go to the glp-1 related Subreddits and you'll see they aren't all wealthy educated people. Hell I read a story of a girl on the Manjaro subreddit who couldn't get her meds and ate herself into the ER in two days.
My sister takes Ozempic and is the proto-typical obese white girl with way too many kids she can't afford and only eats trash. It probably saved her life.
I'm putting increasing probability on the idea that there's something in our modern environment that's disrupting the GLP-1 metabolism (or a related system), these drugs are counteracting that effect.
When it was just appetite suppression, that made sense, we're not adapted to a modern degree of plenty. Not sure that explains the other positive effects, if these results reproduce.
The lactose adaption took a couple thousand years to develop, no? While the last famines in developed countries took place less than 100 years ago. Feeling less hungry does feel like an elegant solution to the blatant oversupply humans are facing now.
> My suspicion is that at least some of these medical record review studies are just driven by confounding - people who find out about GLP-1 agonists are better educated, wealthier, or have behavioral/lifestyle traits that explain many of the apparent benefits.
This exactly. There was a recent paper about Ozempic and (IIRC) dementia that saw that the drug acted implausibly quickly to prevent illness -- the Kaplan Meier curves were literally separated at day 0. [1]
Confounding is rampant in this area. The people who published the paper I linked below should not be scientists. It's embarrassing. Anyone who cites it in support of Ozempec as a miracle drug has revealed that they don't know what they're doing, and should be ignored, with prejudice [2].
More generally, it's depressing that so many people are piling on here to tell you that you're wrong, based on little more than their "knowledge" that obesity is bad. The fact is that most of the science around GLP-1 agnoists and anything other than obesity is weak, to say the least.
Those graphs are incredible. Literally. As in impossible to credit.
What sort of other things would we have to conclude if we took them seriously? Insulin causes AD, starting the day you get the prescription? The mind (assuming it's turned on and operating) boggles.
GLP-1 of course is the GLP-1 agonist created by the body.
I don't think that humans eat to obesity by default. People have had adequate food for quite long and not grown fat.
Maybe there is something in out environment or our foods that are blocking the GLP-1 receptor? If a modern food company discovered something like that they'd immediately realize that (unintentionally) they sell better, probably without realizing what they had created.
> People have had adequate food for quite long and not grown fat.
That's revisionist, both in terms of "for quite long" (food insecurity was common in America until about World War II, and massive food surplus available at consumer-cheap prices begins a little later; other countries still suffer from food insecurity today) and that people haven't grown fat when able to do so. Being wealthy enough to the point of being able to be fat has been A Thing for a thousand years. We know this because the medieval Catholic Church felt that they had to preach moderation; if they had to preach it, it's because it wasn't happening as a universality.
A good amount of GLP-1 is made in the intestines, and production is heavily affected by interactions between those cells and gut bacteria. So anything that caused dysbiosis of the gut microbiome could potentially be causing problems with natural GLP-1 emissions, e.g., antibiotics in the food supply, emulsifiers, etc.
Obesity is itself an across-the-board impairment to health. Anything with a positive impact on obesity will be, therefore, an across-the-board improvement to health.
There’s no evolutionary benefit to eating as little as possible any time in human history, other than the past few decades. We’re barely into the third generation where calory overconsumption is an issue. It takes a few hundreds of thousands more to evolve something this complex, with a population as global as ours
I'm not really sure what you're arguing, because the initial claim was there's no evolutionary benefit to undereating. Yes you can store visceral fat and I'm not arguing there isn't a benefit for that, just that there's a clear benefit for undereating as well.
It's not that there isn't a benefit to under eating. Demonstrably there is.
Nor is there a strict disadvantage to overeating sometimes - it keeps you alive and is a great way to store food.
It's just that we probably regularly did both. We probably ate a lot, then very little, either on daily, monthly, or annual cycles. So it just so happened that beneficial things took advantage of those cycles as the right time to do beneficial things.
Think of it this way: I need to defrag my hard drive, but I cannot do that when I'm playing games. It's not that there's a benefit to stopping playing games, it's just that that's when I can defrag. It's probably similar with all the autophagy benefits of fasting - we were probably regularly not eating so we did it then. During eating we can't really do all that good stuff.
And conversely, I really need to build muscle and brain tissue, and that's probably easier to do when I'm calorie rich. It's just the right time, and I can count on a calorie-reduction later to do the other stuff.
Overeating doesn’t cause any issues to any animals during their average reproductive period (younger ages). Longer lifespans and calory deficits lead to lower quality offsprings. Nothing “demonstratable” there.
Yeah but lifespan benefits usually come after the animal has had a lot of chances to have offspring. Also undereating is much more likely to kill you in times of famine.
I think it's important to call out that it's actually constantly increasing amount to increase the results.
As patients lose weight, they need to eat fewer and fewer calories to continue to lose weight, as the BMR decreases. This isn't because of the medication, but rather because it requires fewer calories to maintain their mass, so they burn fewer calories at rest.
Increasing the dose further decreases hunger signals, which further decreases their desire to eat as much.
It's not "increasing to maintain the same results" its "increasing to increase results".
Ex.
Patient A currently weighs 330lbs. Has a BMR of 3300 Calories.
- Initial dose, they eat 2,800 calories a day instead of 3,500 calories they used to.
- Loses weight. Now weighs 250lbs.
- BMR is roughly now weighs 250lbs, and has a BMR of roughly 2500 calories, but dose still has them eating around 2,800 calories.
- Dose is increased, patient is now eating around 2,000 calories.
- Patient A reaches 200lbs, BMR is roughly 1,800 calories, but is still eating 2,000 calories.
- Dose is increased, Patient A is now eating 1600 calories.
That's incorrect. It's a titrated drug similar to blood pressure meds. If you have effectiveness at a 1mg dose for example, you stay at that. The drugs have maximum doses.
>If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists? Or modify GLP-1 itself?
Honestly? I'm not much of a physiologist, but based on the effects regarding addictions like tobacco or narcotics that cannot be causally downstream just of diet, I'd wonder if GLP-1 agonists aren't actually impacting stress-interoception systems rather than just hunger and metabolism. Under that hypothesis, the evolutionary reason would be: because we evolved to undergo stress mostly in physically strenuous, energy-burning situations, while high loads of cognitive and emotional stress without physical effort are a novelty to post-industrial lifestyles.
Of course, saying "fat people should simply eat less" is by no means novel. It's the same as "have you tried _not_ being addicted to [drug]?" or "Why doesn't he just [obvious but impossible action]? Is he stupid?"
For some people, "eat less" is easier said than done. Their body, for whatever reason, makes them suffer when they don't eat. Maybe it's easy – or hard, but possible – for you, and that's great. But don't assume that simply because you've never experienced it as impossible, doesn't mean others don't (or that they simply lack some kind of strength that you possess).
If anything, the effectiveness of this medicine appears to demonstrate that – much like other "chemical imbalances" such as ADHD or depression – obesity might be a symptom of biology that simply doesn't make enough of a certain chemical, or makes too much of another.
Also, I see you posting your website link on a bunch of threads. I read it. This isn't the place for a discussion about it, but I do want to point out a major rhetorical flaw: you appear to assume that _no_ patented invention is _ever_ actually useful. I think this nullifies most of your argument, because it's demonstrably untrue.
Most people ate quite poorly before the 1800s, routinely suffering from various nutrient deficiencies depending on what the local staple food lacked. The few people who were rich enough to get abundant food could and did become obese.
Eating less food and keeping your body from knowing it seems to be a big part of why it works.
On GLP-1 agonists, you don’t get nearly the counterbalancing reduction in energy expenditure you usually see with caloric restriction. Your body keeps happily releasing lipid stores, assuming they will be replenished, but they aren’t. Hunger hormones remain untriggered, cortisol stays low, and insulin keeps shuttling glucose into cells to be burned.
If you aren’t metabolically deranged, your body does this anyway. But many people have totally decompensated metabolically due to excess energy intake over time, and essentially cannot recover without some kind of treatment.
GLP-1 is just the beginning — future compounds will do a better job maintaining muscle mass, for example. But this is looking like an absolute miracle, and once patent protection ends (especially for oral formulations), we’re going to be living in a very different world health-wise.
Losing muscle mass is just what happens when you're in a calorie deficit. The same thing happens if you're in a calorie deficit without the aid of a GLP-1.
Making sure each meal contains substantial protein will help negate this.
Right, it’s not something specific to GLP-1 treatment, but there are myostatin and activin A modulators under investigation to specifically counteract muscle loss related to caloric deficit more generally.
Patent protection for the early versions has already ended. Teva is making generic versions of liraglutide and it's been available in the US for a few months. The other GLP-1 agonists will be protected for a few more years though.
True but imagine the price and availability impact when the oral formulations go off-patent. The autoinjectors are inherently expensive to make and ship, and some people have a needle phobia. Oral daily seems like the endgame here.
> On GLP-1 agonists, you don’t get nearly the counterbalancing reduction in energy expenditure you usually see with caloric restriction
And that's mostly related to how much you move. If the body needs to reduce energy expenditure, there isn't much it can cut that's non essential that will make a difference, other than activity and movement in general. So you feel like laying on the couch all day.
I haven't tried GLP-1 myself, but reports seem to indicate that GLP-1 drugs make you feel _tired_, which is basically the same thing. So I am not sure the body is fooled that easily.
> many people have totally decompensated metabolically
Around 88% of americans have some level of metabolic dysfunction so that tracks. Numbers worldwide are trending up.
> and essentially cannot recover without some kind of treatment.
They can. Going back to a healthy food intake will fix anything that's not permanently damaged(and if it is permanently damaged, there isn't much medicine can do either). That can be sped up with other measures, such as fasting.
I am a bit skeptical of trying to fix a problem that was mostly created by the food industry with medication. GLP-1 isn't without side effects.
Cutting sugars and simple carbs in general has very similar effects and will decrease your hunger hormones as well. I think everybody should try that first before relying on medical interventions.
Besides, carbs tend to make you retain a lot of liquid. Drastically cutting them usually improves fluid retention, people see changes pretty quickly in the scale, and that can motivate them to continue. Do that long enough and even eating habits will change and so will your palate. A soda becomes unbearable.
>but reports seem to indicate that GLP-1 drugs make you feel _tired_,
I know a few people that take one of the name brands, and they really don't complain about this issue. What they do talk about is having more energy after dropping weight because they just don't feel compelled to eat much anymore.
I'm not overweight myself, but I am a Type 1 diabetic from a young age. "Sugar noise" is not something that is easy to ignore. Especially in the case where you have excess insulin in your bloodstream but not active enough for your body to use it. Your body will scream at you to eat something sweet/carby. In people that are overweight this can be caused by insulin resistance. Until you experience it, it's really easy to say "People should try", but it's about as easy as telling someone to drop meth or heroin.
I am overweight. That food and sugar noise thing is real and brutal. Your parent comment should really factor that in the discussion. I know it's hard because (fortunately) they may not have experienced this themselves, but it's horrible.
My body SCREAMS for me to eat something sweet/carby all fucking day long. All day. Never realized the extent of it until using GLP-1s. I tried many things: full strict diets with macro counting, IF, more lenient and "natural-feeling" diets where you just try to eat whole foods that are filling and tasty. With or without weight lifting, sometimes cardio. Yeah they work, big surprise! But the entire time you are fighting against that urge, doesn't matter if you've gone a full month with perfect "discipline". Eventually it gets you. And I was miserable the entire time trying _not_ to think about food.
As public health policy though, just telling people to do the things you describe doesn't work because dieting sucks and your body doesn't want you to do it.
Some people can do it but they're usually not among the huge percentage of obese people in the population.
With GLP-1 agonists it doesn't even feel like you're fighting your body because you just automatically don't want to eat too much (just like people who don't have problems managing their weight).
I think it's basically a good thing that modern day civilization has cheap and available calories because no one has to go hungry, but this is an environment that evolution just hasn't prepared us for and many many people are just not calibrated right for it. Maybe we can finally fix that.
I've been taking Ozempic or Zepbound for a couple months as a personal experiment and the effects have been nothing short of life-changing.
I have been somewhat of a "casual bio hacker" for the past 25 years and have done things like quitting alcohol or caffeine cold turkey and staying off it for years, or tracking every calorie I ate for 10+ years. I've had periods of eating really healthy, I've had periods of eating whatever but staying in calorie deficit, I've had periods of just not eating much at all, I've had periods of eating anything and not caring. I've tried a variety of more extreme body modifications just to try it and note the results. I find messing with the body (or food intake or whatever) to be like trying to reverse engineer an unknown binary, or like trying to write a keygen but for your mood and health. It's been a little hobby of mine for a long time.
These medications are WAY different. There is no way to describe it. You just feel... better, in almost every way. As someone once posted on another thread, their relationship with food changed. I noticed my relationship with food changed as did my relationship with other minor vices; my "screen time" is down. My anxiety is almost entirely gone, my mood is better, and I feel like I sleep better.
Even as the weight loss rate decreased (which was dramatic at first but has mostly stopped as I didn't increase my dosage of the medications to see what would happen), I just feel... better.
No amount of eating better or healthy lifestyle that I've tried (and documented) in the past two decades has produced anything nearly as profound as the impact that Ozempic has, both on my mental and physical health. Which seems crazy, and I thought that people who were crowing about an off-label diabetes drug were crazy as you probably think I am. But I agree with these types of articles - GLP-1 drugs are just the first step in some kind of next step in health, and obviously right now the focus is on "lose weight, undo the damage of processed foods!" but I think we are going to find that GLP-1's are just the first of many new discoveries that could extend or improve our lives beyond the aesthetic reasons that people take them today.
Regarding side effects, I have a lot of people ask me or comment about this. I think just like any drug, you only hear about the people with bad side effects. 8% of American adults are taking a GLP-1 drug right now, yet CVS Pharmacy doesn't have a section dedicated to managing the side effects (but they do for opioid side effects like constipation), which would be my gauge as to how it's really going.
I did have some dehydration (far less than something like scopolamine gives me) on the first couple days after my first self injection, but increasing my water and electrolyte intake fixed that and it seems to have gone away (I've even tried lowering my water and electrolyte intake and it didn't come back). I am not more tired, nor do I have more (or fewer) digestive issues than before. I think people who do have increased digestive issues have just never experienced (or not recently) what happens when you are really full and just overeat, because their bodies are so used to higher calorie or sugar consumption. Just like how Thanksgiving dinner can make you tired or make you have to wait in the family line for the bathroom, I suspect that GLP-1's are causing some people's "normal" meals to feel to their body like a "Thanksgiving dinner" because they effectively are (by comparison). I have noticed some slight muscle loss in my non-dominant arm that is of mild concern but nothing that I am worried about at this time.
This is anecdotal yes and it's just my personal account of these medications but I was skeptical until I tried them, like you are, as I thought "oh, just eat healthy, why needs a shot".
I will update this post when it's determined that GLP-1's cause some crazy or horrible disease but for now I am enjoying this experiment with them.
What are you referring to here? The muscle-preserving medication? Are GLP-1s actively reducing your muscle mass, or is it the fact that people on them ate very little and didn't tend to exercise?
Assuming you're going to fix a extremely complex system like the human body by just taking a pill is what some people call the bias of Illusion of Control.
You don’t believe the medicine that billions of people take to treat diseases that would’ve otherwise demonstrably killed them is “accumulated knowledge” enough? From insulin to antibiotics, we have sufficient evidence that many types of medicine DO work. Nobody is “playing god” (whatever that means), it’s just reproducible and consistent data
Modern medicine does have magic pills for many illnesses; for example, antibiotics are magical for many bacterial infections, many vaccines are almost magical too.
OTOH, many pills will have undesired side-effects, and the body is in a complex dynamic equilibrium, so it may happen that blocking GLP-1 may have side effects.
Eventually, we'll all die, but I'm optimistic that GLP-1 will lead to a better equilibrium. Preliminary evidence says it will. I'm not as confident as the author though :)
Like I asked, where's our cutoff? If obesity on average kills you a couple of decades earlier than otherwise, does treatment for that meet your approval?
Cool. How about cancer treatment? Some of those you can live with for some months/years. We allowed to treat anyway when the outcomes are better?
> Staying obese into old age carries risks. There are multiple ways to manage that risk. None of it is as exigent as other conditions.
And why should this not be one of the ways to manage that risk? The biggest difference seems to be that it actually works, on average, unlike some other common treatments like telling people to eat less and exercise more.
Does eating less food reduce addiction to tobacco, alcohol and other substances? Because there is mounting (but not conclusive) evidence that GLP-1 agonists do just that.
Sample of only a half dozen people close enough to me to talk intimately about it - but for drinking it’s been absolutely proven in my mind for some people.
I have one friend in particular who started a GLP-1 drug solely to assist in drinking less - she certainly does not need to lose any weight. It worked like a light switch for her and turned moderately problematic drinking into easily achieved light social drinking. No impact on appetite since she is on a very low dose.
I have had the same experience, even though I took it for weight loss to start with.
I do know that drinking can be downright unpleasant for me if I push through the aversion after my first drink and try to go for a few more. I have noticed a strong correlation to drinking and my blood sugar crashing rapidly afterwards while on Tirzepatide while wearing a glucose monitor.
A single cold beer on hot day with friends is still quite pleasant. Sitting in a bar for hours on end drinking heavily is simply downright uninteresting now before you get into any unpleasant side effects.
> Is this based on your survey or her self assessment?
Both? Being around her, and her self-assessment. Not sure how else one could interpret such a statement. This is all anecdotal evidence and should be taken as such.
> Yet it used to be? You don't find this situation suspect?
Yes, it used to be moderately interesting sometimes with the right people. Suspect in what manner? That it removes the desire to get inebriated? Perhaps so, since we do not understand the mechanism at play. What we don't know can certainly hurt us.
Overall the desire to drink less seems very similar to the impact it has on appetite and hunger levels. In that way, it is not so surprising to me.
>In the current study, the researchers demonstrated that semaglutide reduced binge-like alcohol drinking in both male and female mice, and that the effect was dose-dependent (i.e., greater amounts of semaglutide led to greater reductions in binge alcohol intake). The researchers also tested semaglutide in rats that were made dependent on alcohol through long-term exposure to alcohol vapor. They found that semaglutide reduced alcohol intake in this animal model, again with no sex differences.
It is not documented, so no, it is not. Which is why I questioned if it was entirely based on self assessment or not and left the door open either way as the question was based out of curiosity and if his anecdote was public I wanted the answer to be as well. Is that not fair?
> when those pieces of data come together it provides evidence.
When you properly document them it literally stops being an anecdote and then becomes evidence.
> The researchers also tested semaglutide in rats that were made dependent on alcohol through long-term exposure to alcohol vapor.
So.. what are we actually measuring then? Isn't alcoholism a disease and not some acquired exposure based dependency? The idea that "GLP-1 for Everything" is even floated in this way is unusual in and of itself. I'm uncomfortable with all this and am once again annoyed at the way we use rats in research.
I wonder if it's about more stable glucose levels hence avoidance of cravings. Anecdotally, alcohol and nicotine cravings seem to pass me whenever I have a particularly fast acting (low osmolality) carbohydrate supplement.
There is no known link between how much you eat and Alzheimers, substance abuse, etc. If it was as simple as eating less makes these issues go away, we would've figured that out a long long time ago.
Alzheimer's is now being referred as type 3 diabetes for a reason.
Human metabolism is sensitive to the type of food you eat.
Check https://www.metabolicmind.org/ as a starting point and follow the rabbit hole to understand the link between what you eat and mental and metabolic illness.
Also, GLP-1 also eliminates muscle - your heart is a muscle.
GLP-1 reduces calorie intake and puts many people on a deficit (typically on purpose). This of course will reduce muscle just like any other calorie deficit anyone runs long term.
This goes against all evidence I have seen for folks who have lost a drastic amount of weight very rapidly. Bodybuilders seem to see the same effect as well when on cuts.
When you are losing 5% of your bodyweight per month (as I was, and many do) a substantial portion of that is simply going to be mean muscle mass. You can counteract some, but not all, of this by heavy resistance training. It's very difficult to not lose muscle mass while losing weight - it takes extreme measures for most folks (e.g. athletes) to do so.
I think it's a fair bit of a stretch to broadly say that this study shows an association.
> Conclusion: Higher intake of calories and fats may be associated with higher risk of [Alzheimer Disease] in individuals carrying the apolipoprotein E ϵ4 allele.
> The hazard ratios of [Alzheimer Disease] for the highest quartiles of calorie and fat intake compared with the lowest quartiles in individuals without the apolipoprotein E ϵ4 allele were close to 1 and were not statistically significant.
For the general population, there was no correlation. Identifying specific genetic outliers where there may be a connection is still useful, but far from a general result.
Exactly. There are lots of skinny alcoholics and drug addicts. Unfortunately many of them are homeless.
The real surprise I learned is that GLP-1 may discourage other addictions as well, including gambling. Source: A nurse I talked to who works with GLP-1 trials.
As others have already stated, it’s starting to become mainstream science that there is a strong correlation between obesity/poor body composition and Alzheimers. It’s not settled science yet, but the correlation is starting to look a whole lot like causation at a society level.
Not to cite anecdotal evidence, but my father-in-law was skinny as a rail and got severe, early-onset Alzheimer's. Obesity might be one potential cause of Alzheimer's, but it's among many.
>If it was as simple as eating less makes these issues go away, we would've figured that out a long long time ago.
You can't get people in large enough quantities to do that reliably and for long enough as part of a study. Best you can do is a small quantity of lab rats.
The data is already rolling in as part of prescribed out-patient data.
No, there are a number of effects of GLP-1 RAs that are not directly related to their initial research and development associated with insulin response, beta cells, etc or recent research associated with appetite suppression. For instance, there is growing research and speculation around dopamine systems in humans.
It might be awhile before the research propagates to the realm of popular science.
IMO, it kind of represents how incredibly blind we are to supposedly safe compounds, and how arrogant others are for calling for less regulation. When attention is high, suddenly so much more is revealed.
I don't think we know conclusively yet. That probably explains quite a lot of it, yes. It's unclear how that would lead to the substance (ab)use results, though.
Do we know? I think that's the question being asked here. Using these drugs seems to improve a bunch of indicators and we're not sure why.
It's really interesting to me that there's some evidence for Metformin -- a diabetes drug that suppresses glucose production and appears to do other things we don't fully understand -- having general health benefits and possible life extending benefits in healthy people. Normally it's just used to treat some forms of diabetes.
Feels like we're on the cusp of figuring something out about inflammation, aging, and metabolism.
Polyunsaturated fatty acids (PUFAs), whether from plants or animals, are most susceptible to oxidative damage because they have multiple double bonds that can react with oxygen. Each double bond creates a potential site for oxidation.
Societies consuming high amounts of oxidized oils (repeatedly heated cooking oils, whether plant or animal) show increased rates of cardiovascular disease
Populations with high fresh fish consumption (like traditional Japanese diets) show better health outcomes despite high PUFA intake, likely due to immediate consumption and minimal oxidation
Modern food processing/storage methods increase exposure to oxidized fats
Fast food consumption correlates with higher intake of oxidized fats due to repeated oil heating
Socioeconomic factors influence exposure - processed foods with oxidized fats are often cheaper and more accessible
Oxidation status of fats may be as important as the traditional saturated/unsaturated classification
> if you limit them you tend to live longer due to the decrease in oxidative damage
Can you elaborate on that? Aren't animal fats, particularly dairy, rather rich in saturated fats? And saturated fats oxidize less easily than unsaturated fats precisely because they lack weak double bonds.
Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.
This is probably what’s going to get us over the 80 years life estimate plateau. The main killers now are overwhelmingly cardiovascular diseases and cancers.
It feels more likely to me that there's some sort of condition we don't have a widely known name for that is caused long-term by a combination of predisposition in genetics and something in western diets that is, I'm not sure, forcing us to overproduce ghrelin (possible links to puberty occurring earlier in both young boys and girls?), or underproduce certain classes of incretins (possible links to excessive blood sugar levels in larger percentages of the population historically over time?).
It would be boring to learn that it's just caused by excessive exposure to fructose.
But what do I know, I'm just a dumb HN reader.
Seems neat that there's ongoing work in this area and it'll be cool to read about new knowledge in that space when something is discovered.
It's interestingly disingenuous that many claim of GLP-1 agonist miraculous effects on all kinds of health problems, where the same problems are "simply" solved by getting on a calorie deficit and lean. Liver, kidneys, heart, etc. If you have a non-alcoholic fatty liver disease and are obese, getting leaner will heal it. All those impressive results are on obese or diabetic people. So it is not only not a surprise, but also dishonest marketing or ignorance.
Don't get me wrong - those are miraculous drugs. First real non-stimulant low side effect appetite suppresion that will help millions. But let's wait for honest research on lean people before spreading marketing on how it improves overall health.
Also, how nobody mentions the need for increasing the dosage and tolerance build-up (just check reddits how much people end up having to take after months of continuous use). You cannot be on it "for life".
The increasing dosage is to tritrate up to a dose not because you gain tolerance. There are patients on GLP-1 for over a decade. Also maintenance and weight loss dosages are different: see the dosing charts for ozembic vs wegovy which are exactly the same drug.
Even if folks gain tolerance that doesn’t seem overly concerning. Mental health drugs also have tolerance issues and changing medicines every few years, while it has challenges for the patient, is an accepted part of long term psychiatric treatment.
Just a narrow comment, but type 2 diabetes certainly isn't limited to the obese. Many lean people develop issues with blood sugar that can't be controlled with diet alone.
A friend's son, who is an EMT, was recently diagnosed with type 2 diabetes at the age of 21. He doesn't drink or eat sweets, except on holidays, and works out five days a week. Suddenly, he started feeling sick, was vomiting, and ended up in the ER, all within three days. It can really hit you like a truck.
This is my #1 question on GLP-1: are we just seeing how humans do much, much better by being lean vs. the direct result of the drug?
A lean current-epoch human -- with our food abundance, access to modern medicines, higher standards of life, lower risks of injury, etc -- is likely going to be markedly healthier than a non-lean current-epoch human or a lean human from a prior age where medicine/food/etc was worse.
> where the same problems are "simply" solved by getting on a calorie deficit and lean
Except that there apparently is mounting evidence that GLP-1 agonists also address some issues that are not generally addressed by just restricting calories. TFA touches on this briefly: "The weight loss involved with GLP-1 agonist treatment is surely a big player in many of these beneficial effects, but there seem to be some pleiotropic ones beyond what one could explain by weight loss alone."
I seem to recall seeing claims that they reduce COVID-19 mortality even controlling for BMI (possibly because they inhibit systemic inflammation), reduce alcohol consumption, and even (though I think just anecdotally) may help overcome gambling addiction.
I don't know that you have to be disingenuous to both be enthused about these medications AND wish we'd never created the super-processed, super-sugary, make-people-crave-them-and-overeat-them modern American diet. Once you fuck with your gut biome for long enough it's not "simple" to solve it. It's incredibly difficult both discipline and metabolism-wise.
Born too late to die in infancy, born too early to see immortality.
I imagine parents in the 1890s felt the same way. Our children will see a new and different world than we can imagine. I love this topic of moving past “health” and towards something better. To quote an 1890s thinker: “it’s time to find out what value our values really had”.
This does remind me of the superconductor stuff tho - I’m too excited - it will be interesting to see what focused clinical studies show us here, particularly around GLP-1’s effects on addiction.
The most important question in the world right now is: which generation will be the first to live indefinitely? It is clear to me that we are on a trajectory to achieve indefinite lifespan extension, but unlike Kurzweil et al I don't see a real possibility that it will happen soon enough for me personally. Maybe my kids, or maybe one or two generations further.
Will it happen soon enough to prevent population collapse due to plummeting fertility rates? Will fertility rates go even lower or will the population start to rise again as deaths fall? Will we see stagnation due to older brains being stuck in their ways, or will we be able to fix that too?
I used GLP-1 to prepare my taxes last week, it was such a stress-free experience.
Then as I was coding I kept hitting context window limitations with o1-preview. so on a lark I just fired up my local Ozempic and submitted the same prompts and bam: spit out a whole working iOS app first try.
I heard that before they nerfed it with RLHF, Mounjaro not only treated diabetes but also made you charming in conversation and sublimely compassionate towards all beings.
The best way that I can describe what Semaglutide has done for me is that I feel like almost nothing in my life has changed (other than being down 45lbs, suddenly having normalized liver enzyme levels and blood pressure.) Before starting it, I generally ate until I was satiated, almost never over full. From time to time I'd maintain a caloric deficit, but it meant a large part of my attention was consumed, day and night, by a nagging distraction of food.
Today, I still just eat a normal diet until I'm satiated - but 1/3 of the food is left on the plate. I have a little less of an interest in alcohol and coffee, but other than that it's like nothing has changed.
My point is that there's still a common sentiment that these drugs are some sort of a shortcut for people who want the ability to over-indulge, when in reality that couldn't be further from the truth.
I think what I feel like on a GLP-1 is what most people feel like without one. If you want to know what I feel like without a GLP-1, try not eating until your mind is constantly nagging you to do so - then try staying like that forever. That's what a lot of people propose to anyone who has a problem with their weight.
This is my issue. I have lost 40-60lb many times in the past 15 years, but I always gain it back because the root cause is not fixable. I always have a lingering hunger, and I don't want to spend my entire life hungry.
It seems like there's growing medical acceptance of the idea that everyone has a natural weight that they seem to plateau at (which in some cases is overweight.) 1mg of semaglutide reset my natural plateau from 225 to 180. You are exactly right though - being overweight is either a daily physical battle or an hour by hour mental battle if you are trying to restrict calories.
I assume you are also on weekly doses. How does it work for you?
I feel like I go through cycles of:
Day 1: no change
Day 2: can go whole day without eating, a bit nauseous
Day 3-5: feeling bloated, food doesn’t digest fast, not eating much, biggest weight loss
Day 6-7: Slowly getting back to eating reasonable portions
I'm on 1mg of compounded semaglutide, where I've been for the past 4 months. I have a similar arc in terms of days 2-5 being the strongest effect, but I haven't experienced any nausea (except the smallest bit during the first couple of weeks at 0.5mg.) I was briefly at 1.5mg but was brought down because I started losing weight faster than needed. My weight has been rock steady since coming back to 1mg.
I feel like I have an almost optimal reaction to the drug, which I kind of feel bad about, given all the side effects other people seem to have. My experience mostly matches yours, except without bloating or nausea. I do have a slight urge to drink on day 6 and 7 -- well not an urge, more like an acceptance of it -- kind of hard to explain. I don't even think about alcohol on the other days.
I am injecting the Hims formulation of semaglutide. I had no side effects on my first two injections, so my next two (which were supposed to be the same as the first two) I increased the dosage slightly. I am pretty happy with how I feel so I'm not sure how aggressively I'll ramp up to the full dose.
I’m on Zepbound and I had no side effects for my 2.5mg and 5mg doses. It’s starting to be more prevalent with 7.5mg - and I haven’t moved to higher dose yet.
Ah, ok so my experience parallels yours.
Are you eating "healthier"? What I've found is I prefer "simpler" meals to more complex/layered/richer dishes. I forgo pasta dishes or sandwiches for simple meals like eggs + a vegetable + fruit. I've actually had to throw out a bunch of ingredients that went bad that I never would have had to before. I've had to adjust my grocery shopping quite a bit, including frequency.
Yes, simpler is better. More specifically, I no longer can do Thai food. To spicy now.
That's usually how it works for me too. I find that days 2-5 I start feeling not very good. I wouldn't say bloated, but almost weird blood sugar levels.
Usually about 6pm in the evening is when I start feeling terrible. Kinda makes me want to eat less.
It works much better, in my experience, to cut the dose in half and take it twice a week. I do Sunday and Thursday, 2.5mg of tirzepatide per injection.
>If you want to know what I feel like without a GLP-1, try not eating until your mind is constantly nagging you to do so - then try staying like that forever. That's what a lot of people propose to anyone who has a problem with their weight.
Ironically- not eating- is what solved this issue for me. I imagine it is what people on GLP-1 feel like all the time.
I spent a long time food fixated, frequently nagged by hunger, until I started practicing going without. Now I can go 2-3 days without eating and have to force myself to eat something.
I encourage most people to try going 2-3 days without food and seeing how it changes their relationship to it.
Going days without eating for nonreligious reasons is a Hallmark indicator of an eating disorder.
I'm sure it is in some cases, but overall I think having self control over when and how much one eats is a good thing.
I would be more concerned about unrestrained compulsive eating disorders.
It is interesting that compulsive eating to the point of exhaustion, obesity, loss of mobility, and organ failure is normal, but skipping a few meals is considered strange.
The former is a leading cause of death, while the later is perfectly safe and may even have a number of benefits.
Indicator, not proof. If you're an illegal spy (no diplomatic cover), paranoia isn't a maladaptive behavior. If you're overweight, going days without eating isn't necessarily a sign that you have swapped one bad relationship with food for another - it could just be a way to lose weight. Effective weight loss methods absolutely depend on reining in hunger. Fasting happens do that for some people.
If you weigh 40 kg as an adult and you don't eat for days, you probably have an eating disorder. If you weigh 140 kg as an adult and you don't eat for days, meh?
bingo. As I understand it, disorder is characterized by harm and lack of control. spending time lifting weights for health is usually OK, staying up all night throwing things at invisible monsters is not.
You’ve been eating the wrong things all your life. Animals aren’t obese in the wild, nor would you be if you didn’t eat slop.
What an insightful and additive point of view that I've never considered before.
Humans aren’t obese in the wild, either.
The main difference between GLP-1 agonists and telling people to eat less/better is that one works and one doesn't.
That is because the advice around eating less is focused on old paradigms that have clearly failed.
Those drugs let people experience intermittent fasting and fasting by reducing hunger and snacking.
The danger of suppressing hunger signals is that hunger could've been a important que for nutritional needs.
Muscle loss is severe danger of gpl-1, And muscle size is tied to longevity.
So although promising it's not without danger. And there are other paradigms but those are not yet explored yet the underlying mechanisms work the same.
Edit: Let's keep HN a place where discussion can be held without just kneejerk down voting.
Edit2: great discussion thanks all.
If people are obese, they’re not getting the right hunger signals anyways. Obesity is heavily tied to longevity. GLP1s cause muscle loss because when you lose weight, some of your caloric deficit will be supplemented by your muscles.
The article suggests that non-weight loss side effects of GLP1s are also worth considering taking the medication for. If you’re maintaining a healthy weight, while taking the drug, you shouldn’t experience the muscle atrophy.
Also, muscle size isn’t tied to longevity, usable muscle and a certain strength and physical ability is tied to longevity. Muscle size is a convenient proxy. Also cardiovascular ability in a related way. You basically just need to be able to move and carry things and act in your environment in a responsible way at an old age so you don’t fall or hurt yourself.
Your points are just reforcing my initial point. Old paradigms of nutrition have clearly failed. If we could acknowledge that we could move forward and be open to very promosing alternative paradigms.
Which currently are not studied enough, to create clear nutritional guidelines for the public.
Gpl1 and those paradigms work through the same mechanisms action (autophagy, ketones, reducing food intake).
If there is acute problem with health such as (morbidly)obesity then gpl-1 could be a great intervention.
But its not long term solution, nutrition and a healthy relationship with food and lifestyle is.
Muscles are very important for health, but let's not go into that. For muscle size I linked to meta study about muscle size and all cause mortality (longevity)
> Conclusions: Low SMI(skeletal muscle mass Index) was significantly associated with the increased risk of all-cause mortality.
https://pubmed.ncbi.nlm.nih.gov/37285331/
> Old paradigms of nutrition have clearly failed. If we could acknowledge that we could move forward and be open to very promosing alternative paradigms.
> Which currently are not studied enough, to create clear nutritional guidelines for the public.
We have very clear, very obvious nutritional guidelines for the public, and we have lots of research on the healthy food to eat. The TLDR guidelines that would have a positive impact on most people is "eat less". Doesn't seem to work, and it's not an informational problem.
(1) its not long term solution, nutrition and a healthy relationship with food and lifestyle is.
The reality is that plenty of people will just never have this. Some people are "weak" or "genetically predisposed" or "addicted" or "impoverished" or any other number of things that people use to explain poor diet. No amount of nutritional guidelines will fix this. That's just the (unfortunate) reality. Now what do we do?
(2) GLP-1 medication (according to the article) have other benefits beyond nutrition, eg addiction, Alzheimer's, kidney health, etc. These benefits could be very real (some are still being studied). If they turn out real, how does our relationship with the drug change, how that its not just a replacement for a "healthy relationship with food and lifestyle"?
You've mentioned muscle being a proxy for health. Do you consider going to the gym and working out to be a "long term solution"? Why is spending an hour a day performing an artificial activity (lifting weights) generally considered a healthy lifestyle, but taking safe preventative medication not considered part of a healthy lifestyle?
(Generally) society considers vaccines to be safe and healthy, and we recommend them for everyone from a young age. They're obviously quite artificial, and they trick our body by stimulating certain biological pathways artificially.
What is different about certain medication like GLP1 meds that keep us from considering it part of a safe, healthy lifestyle?
The health benefits of eating less and fasting such as autophagy, ketones occurs with or without gpl1. That is how gpl1 is healthy, because eating less and fasting is healthy.
You don't have to go to the gym to activate and stimulate muscles. But our bodies are made for daily usage of muscles.
We always had downtrodden, poor, weak people, in any society. But in the 1970's they were not obese.
We dont take daily vaccins they are a intervention. Gpl1 could be intervention for obesity patients.
The danger of long term usage of gpl1 is that our bodies emerged ecosystems that we don't understand yet. By reducing hunger signals that their motivate a person to get nutrition such as protein, vitamins and minerals, etc Leads to malnutrition, muscle loss and other diseases.
Your point is that there is no problem with current paradigm of nutrition while at the same time promoting a agent that stops the addictive nature of our current nutritional paradigm.
If you use gpl-1, And it works for you that is great and we should be grateful that gpl-1 is available. My only advice would be, to lift weights or callisthenics to keep your muscle size and strength. And to explore other nutritional paradigms that can help you maintain the weight loss without gpl-1.
> That is how gpl1 is healthy, because eating less and fasting is healthy.
These medications do so much more than this. First, they have all sorts of direct metabolic benefits beyond just eating less, and secondly, studies are linking them to non-metabolic benefits too.
You don’t have to go to the gym to stimulate your bodies, but most people require it because they won’t do it naturally in their life. You don’t need GLP1s to regulate your metabolism, but it seems most people aren’t doing it naturally in their life.
In 1970s, people died of hunger. We’re also not in the 70s and won’t be going back. Our society has a surplus of unhealthy food and an uneven distribution of healthy food. The food is engineered in labs to be addictive. Our society doesn’t make room for regular physical exercise. So many things wrong, and until we start regulating the food industry, the best we can do is correct mistakes.
I’m also not sure there is any real evidence that the GLP1s are causing malnutrition because of “hunger signals”. But ensuring proper nutrition of vitamins and micronutrients is not that hard to monitor.
I’ve never used a GLP1 antagonist. I’m not one to brag to strangers on the internet, but I view myself as rather healthy and athletic. It’s a lot of work, it’s not that fun, it takes a lot of time. I just don’t believe that the only right way to be healthy is waste an hour in the gym every morning and do “hard work”. If there was a CrossFit pill, I’d be here supporting that too.
Some things (working out, vaccines) are basically just a net-good on the health of society. Why isn’t it possible that this is included in that list?
I came here to basically say this.
People who tout the dangers of glp1 - and there ARE risks! - are also ignoring the "what did you do instead of a glp1" and the answer is.... remain overweight, which has many risks!
Yes glp1 might increase the risk of a certain kind of cancer. But guess what, it also reduces the risks of many other cancers tied to obesity!
It's hard for me to take hand-wringing over glp1s seriously. Appeals to "JUST do x" are lost in the "just" - hello if people could just do intermittent fasting, or eat less calories, well then there would be less obesity. The obesity epidemic is literally a rebuttal to any of these arguments.
> Those drugs let people experience intermittent fasting and fasting by reducing hunger and snacking.
This shows you haven't tried GLP-1s. I've been doing IF for ten years, doesn't stop me from being overweight. GLP-1s do.
First of all congratulations with your succes, and not take away from that. But IF nor fasting is a silver bullet.
Reducing food intake, and insuline while keeping hunger down is.
Important aspect is keeping hunger down. And if your fasting/excersicsing you can experience the same.
The discussion on weight unfortunately almost always focused on total weight.
But we would like to retain our muscles, and reduce adipose tissue(fat).
With gpl1 people are able to fast, stop snacking and reduce food intake because hunger signals are blocked.
But a fasting lifestyle, which goes further then just IF. And a focus on nutrition(vitamins, minerals, quality sources) could the same.
Furthermore the effects of lowering inflammation of gpl1 is only logical reduction in food intake/fasting will lead to autophagy.
IF/Fasting and other new nutritional paradigms are still new and uncharted. It's not clear yet what the full effects are, and how to implement them correctly.
Yeah, but at the end of the day, it either works, or it doesn't. You can say "you're holding it wrong" all you want, but if it's easy to hold the thing wrong, it's the thing's fault.
GLP-1s work for many more people than any other diet advice we've ever had.
I dont think this is an either or situation. People still need tools in their toolbox if they dont want to be be on a biologic for the rest of their lives.
Fasting is just one such tool.
"Oh you don't want to be on a statin for the rest of your life, do you?"
Yes! I do! It lowers the risk of stroke and heart attack!
who are you talking to?
I dont think making up quotes and responding to yourself is a productive way to carry on a conversation.
IF is not well understood, nor explained.
So in that aspect we agree completely. A few years ago people would call you mad for fasting, and now we have drug that allows people to life the fasting lifestyle.
And if there is a medical reason I'm not making the argument against. I'm making the argument that it's a intervention and that healyhy nutrition, healthy relationship with food will is the long-term solution.
And order todo that we would need to explore other nutritional paradigms than the current one.
Edit: - Fasting lifestyle, like omad(eat once a day) removes the feeling of hunger and thoughts about food, until it's the moment to eat.
> So in that aspect we agree completely. A few years ago people would call you mad for fasting, and now we have drug that allows people to life the fasting lifestyle.
It's nothing like the fasting lifestyle, it just quiets the food noise.
> I'm making the argument that it's a intervention and that healyhy nutrition, healthy relationship with food will is the long-term solution.
That's like saying "I'm making the argument that diabetes medication is an intervention, and that producing healthy amounts of insulin is the long-term solution". Yeah, it's all well and good, except it doesn't work.
You can yell at people for not <insert favorite reason here>, but, at the end of the day, people have tried diet, they've struggled with it, and it's failed. No matter how much yelling you do, they won't stop. It's like trying to talk a meth addict out of their addiction.
Doctors have long said, "Diet and Exercise", but they couldn't really address the pain aspect of hunger until the last few years.
And hunger is painful.
Hunger is something that is left to the patient to cope with -- usually badly. Sure there could be support groups and exercise groups, but nobody is going to be there in your bed when you're trying to fall asleep with hunger pains.
This thread is kind of painful because it's full of people who have no problem with their weight telling others to "just don't have a problem too!".
I don't eat because I'm hungry. I eat because food is there, or because I remembered that food exists, or because I have nothing better to do, or because stuff tastes good. I can't remember the last time I was hungry.
The weird thing is I can go a really long time without food. I can go 36 hours easily without eating something, hunger doesn't bother me at all. After 36 hours, I think "huh, I should probably eat something".
Such situations where I forget to eat are really, really, really rare. I have to basically be on my own and working on something fun, because that's when I both don't have food in the house and don't want to spend the two minutes it takes to order something.
Exactly.
Kids who went hungry at school had behavioral problems, and couldn't focus on schoolwork. The solution was to give the kids breakfast, not to tell them to cope with hunger until they got home.
You don't lose weight when IF if you eat your maintenance calories during the period you're not fasting.
Depending on ones metabolism, IF with no caloric deficit doesn't guarantee weight loss.
Right and caloric deficit is just diet.
On one side, sure GPL-1 may have side effects, maybe bad ones. On the other hand, overweight in the sense of excessive adipose tissue, correlates with a huge number of very bad health problems (both mental and physiological), with an abundance of proof around causality for many of these.
I’m thinking, whatever negative side effects we find for GPL-1 in the future, they will have to be pretty massive to offset all these benefits.
A GLP-1 drug trial 12 years ago by a major pharma company was stopped because of increased suicide risk (2 in 10,000) among the cohort.
We will see what happens long term the second time around.
"Compared with those prescribed lifestyle intervention for obesity, adolescents prescribed either liraglutide (Saxenda; Novo Nordisk) or semaglutide (Wegovy; Novo Nordisk) had a 33% lower risk of suicidality over 12 months of follow-up after controlling for potential baseline confounders."[1]
[1]https://www.tctmd.com/news/defying-earlier-glp-1-data-study-...
It's not even the second time around now, liraglutide was approved a decade ago.
I'm fine with GPL-1 agonists, they seem great, not trying to argue against them.
This is an age old problem in the obesity treatment and research community. It never seems to go away. It's come up with bariatric surgery, with other methods, and now GPL1- agonists.
The issue for me is that "telling people to eat less" is sort of a strawman in some ways. It doesn't work.
What does work, however, at least according to evidence I've seen, is giving people strategies for losing weight, therapy, support, and so forth. It doesn't work for everyone but it does for some.
I would rather people try that first as it can be self-sustaining and doesn't require medication.
I'm not opposed to the medication or people using it, in fact I think it's a good thing, but it seems a little dangerous to me to create a culture where people are just told "take this pill, pay lots of money for it, because nothing else will work" which is not actually true. I don't think we're at that point but it's easy for me to imagine.
It's tricky because losing weight can take a mental load off, it's just getting there that's hard. Once you get there you gain confidence, people treat you differently, doctors take you more seriously, exercise becomes easier (less weight to throw around and less strain on joints), etc.
Eating less works, if taking a drug that makes you eat less, well, works.
That's a bad read of what they said. They didn't say that eating less doesn't work, they said that telling people to eat less doesn't work.
I am tempted to make a snide remark, but I suppose that won't do any good.
I think the post is as hostile to GLP-1 as you feel it is.
Eating less works. Telling people to eat less and exercise self control doesn't work very often.
Except adherence to taking GLP-1 agonists isn't a given, especially with dosing regimens that are shorter than a week.
Obesity rates are not consistent across the world or time. Neither work. They just hide symptoms of the larger problem.
The problem is the human existing in a modern environment that is hostile to it. GLP-1s enable the human to more effectively operate in said environment. It patches malfunctioning reward centers (addiction and food compulsion), it reduces overall inflammation, it provide cardiovascular protective properties.
As kubectl_h mentions [1], the future is better understanding and fine tuning the mechanisms responsible. I think gene therapy is the end goal (permanent fix vs chronic maintenance with GLP-1s), but others have indicated in previous threads that might not be possible. We need more information and research. This is only the beginning of the "Aha!" moment (The most exciting phrase to hear in science, the one that heralds new discoveries, is not “Eureka” but “That's funny...” —Isaac Asimov).
[1] https://news.ycombinator.com/item?id=41989101
> in a modern environment that is hostile to it.
Our ancient environment was hostile as well.
> It patches malfunctioning reward centers
It has an impact on them. It does not "patch" them. This is not a rational way to describe any drug.
> it reduces overall inflammation
It can inhibit certain inflammatory pathways.
> it provide cardiovascular protective properties.
It reduces the number of cardiovascular events. Whether that number is normal to begin with is not considered here.
> We need more information and research.
You certainly do.
You're free to your opinion (legit, no snark intended), the market will deliver to the demand. The cost benefit ratio is obvious, even accounting for potential side effects at scale.
https://www.axios.com/2024/01/18/ozempic-wegovy-weight-loss-...
https://www.axios.com/2024/01/19/weight-loss-drugs-america-o...
https://recursiveadaptation.com/p/the-growing-scientific-cas...
https://www.jpmorgan.com/insights/global-research/current-ev...
Edit: I simply do not understand the hostility towards this simple intervention, my apologies.
> You're free to your opinion
Oh. Thank you. That's very generous. I assumed we started from that position but apparently not.
> the market will deliver to the demand.
Yes, because our healthcare market is perfect, and we should acquiesce to it's demands. The same could be said of opioid pain killers.
> The cost benefit ratio is obvious
Which entities cost benefit ratio, exactly? The patients? Are you _sure_ you have data which allows you to say that?
> even accounting for potential side effects at scale.
You're free to your opinion. The market will repeat history.
You seem hostile to this possible solution. Can you explain why?
Obesity rates aren't consistent because access to cheap calories is not consistent across the globe. I don't mean to be glib, there are certainly other factors, but as a first order approximation obesity rates of a region or country are going to be proportional to how easy calories are to access, followed by how satiating those calories are
Japan and Colorado have just as much access to cheap calories as Louisiana, but notably less obesity. Also, obesity rates have increased faster than access to calories has; it's a surprisingly recent problem.
Even in the eighties, household spending on food was nearly 50% higher relative to overall consumption than today.[0] Japanese households today actually spend 16%(!) of their household income on food, compared to only 7% in the US.[1]
Obviously there are multiple factors, as I said I think the relative satiety of food also plays a role. US food spending has been more or less static over the last two decades while obesity rates have continued to climb so cost can't explain everything (though as an aside, I do think lower costs probably take some time to have an effect). But even if there are multiple factors at play, cost really should not be discounted as a huge driver, especially if we're taking a public health approach to addressing the problem. If we just attribute obesity to individual moral failings, as some are wont to do, I think we're really doing a disservice to ourselves
[0] https://www.cepr.net/in-the-good-old-days-one-fourth-of-inco...
[1] https://www.cia.gov/the-world-factbook/field/average-househo...
'problem' is a loaded word. The data is coming in saying that this class of drugs provides potentially massive benefits. If I get a lot of benefit but didn't fully address the root 'problem', I still get a lot of benefit.
As long as the supply chain correctly functions for the entire time you plan on being on the drug.
Yes, obviously. As long as the drug is available and the earth exists, etc etc
Therapies are contingent on being available. That’s uniform. What’s unique about glp-1s is that they are very effective in weight loss and many other things. As compared to alternatives that aren’t.
One, going off GLP-1 for all I know doesn't have bad side effects, other than going back to your bad diet.
If we are back at the point of supply chain issues that interrupt GLP-1 for any significant amount of time you're starting to look at issues like we had during covid that are going to have all kinds of other effects.
From my understanding getting the pre-compounded components isn't that difficult, and that India and China are making versions of it now.
Obesity rates consistently increase as people get more access to calories.
Yes, but that’s an incomplete view on the obesity epidemic in the West, imo. It’s not just that there’s “more access to calories,” it’s that access to healthy foods is getting more difficult for a large portion of the population. People working multiple jobs don’t have time to cook a complete, nutritious meal. Also, due to our ever-increasing wealth inequality, it’s harder for people to afford healthy food. A whole chicken, a vegetable, and a starch will always cost more than getting something at Wendy’s. Similarly, a jar of jelly is cheaper and lasts longer than a box of strawberries.
I'm Brazilian, but whether you consider Latin America western or western-adjacent, here healthy food is definitely not cheaper than processed food at all. Yet, you can see populations and regions dropping from food insecurity directly into obesity as soon as people do have access to more food.
The time argument might be relevant, but even then, most Brazilians do have cheap and easy access to a very healthy lunch in restaurants or to-go meals, purchased or prepared, with rice, beans, meat, salad... The breakfast is probably bread, but I'd say most people don't eat a lot of that in the morning. Getting proper nutrition at night will probably be problematic, but it's also a smaller window...
But, like I said, processed food is quite expensive here. For instance, a 1 kg of chicken breast goes by less than a third the price of a McDonald's combo. A pack of cookies or snacks will be like double the price of a 1 kg of bananas...
I can only speak for my culture so thank you for the perspective and insights on yours. Just checked and it seems like bananas are 27.5% cheaper in Brazil than America. Chicken fillets are a shocking 71% cheaper! I'm sure I'm not taking a lot of things into account here like the average income levels, but still, that's crazy.
How do you explain why Japanese and Koreans are so thin? There is so little obesity in those countries. For most other countries, I agree.
This is like saying that driving doesn't work because people still walk and the real problem is transportation. It simply doesn't matter. It's not an argument.
I'm pointing out the problems of considering this a valid on term "solution." It's simply not. You need a plan to eventually be rid of this compromise.
That GLP-1 has benefits is good. That we could possibly rearrange our food system so we don't need it anymore is better.
You can acknowledge both without hurting _anyone_. You entirely lack an argument.
>That we could possibly rearrange our food system so we don't need it anymore is better.
Ya so you want to change a system that involves millions of selfish actors and corporations looking to profit and that have entrenched themselves, and are protected by freedom of association versus a choice between a doctor and a patient.
I can tell you which one will be more successful.
This is a textbook case of letting better stand in the way of good.
I'd love to re-imagine our food of food production and consumption, but it sounds like you're arguing that because food production and consumption is a better solution, we shouldn't be promoting GLP-1 agonists.
Sorry, but one is exists in reality and the other exists in our imaginations. When we let our imaginations take precedence over reality, we live in a fantasy and the consequence is that we get neither. Effectively this argues for neither, and that's a bad deal for everyone.
"The [food system] can remain irrational longer than you can remain [alive]."
> It's simply not. You need a plan to eventually be rid of this compromise.
because..?
> That we could possibly rearrange our food system so we don't need it anymore is better.
Will this be before or after we fix capitalism/finish building communism?
I don't understand your point. Many common medications - ibuprofen, albuterol, insulin injections - function entirely by hiding symptoms of an underlying problem. If the symptoms being hidden are worse than the side effects of the medication, what's the concern?
Solving symptoms and not root causes is how you get band-aid fixes that wind up being inadequate to the task in the end. I would've thought everyone here would be aware of the danger of treating symptoms rather than the underlying issues, given it's such a common pitfall in the computer field.
I think if you reflect on the purpose of a bandaid a little bit, you would come to understand why your own analogy is bad.
Again, I genuinely don't understand the point. There's a large and well-funded segment of the nutrition industry dedicated to solving the root causes - Weight Watchers alone has over a billion dollars in annual revenue. We just haven't invented a diet-based solution which works as well as GLP-1 agonists without requiring you to compromise on palatability and feel hungry all day.
It'll be great if we do, although I don't know of any promising research avenues and I lean towards the hypothesis that the average human metabolism is simply tuned to mild obesity under conditions of widespread food availability.
The point, which seems to be routinely massively downvoted on here, is that both things can be true at once:
- these drugs are good and a paradigm shift in the treatment of obesity (and have other benefits)
- we must not lose sight of the need to address a thoroughly sick food industry that necessitate so many people needing to use these. Junk food advertising, lack of subsidies for fresh vegetables, HFCS, food deserts, etc.
Chile is experimenting with banning junk food ads to children and is seeing some early behaviour changes.
The point which people seem to be wilfully missing is that we can have both these drugs and advocate for cracking down on a food system that deliberately poisons everyone in society. Having everyone be on this drug because we shrug and say "free market innit" while big corps continue to feed us crap is not a solution, obviously.
"Fixing" the food industry isn't possible for as long as they have billions to sink into influencing politics. Trying to find a market or political solution has failed. Full stop. The fact that you're still trying to find some way to make it work is embarrassing and depressing. It's time to attack the problem from another direction, one that will also ensure these companies either go bankrupt, lose relevance and power and/or evolve into a form that's less parasitic and more beneficial to us as a species. GLP-1 can be one tool to help us do that.
We can only crack down on a "food system that deliberately poisons everyone in society" if such a system actually exists.
* Food deserts are a problem, but the vast majority of Americans don't live in one. We just don't typically want to eat a pile of fresh veggies when there's other options available.
* Criticisms of HFCS are, as far as I can tell, entirely viral misinformation - not once have I seen someone point to concrete evidence that HCFS is worse than table sugar.
It seems to me that this entire idea of a poisonous food system is an epicycle to avoid the obvious conclusion, that our bodies are calibrated on average to eat ourselves into obesity when we have the means to do so. If you don't start from the premise that there must be an external reason we're getting heavier, it's very hard to explain why potato chips should be any more unhealthy than a traditional breakfast of potatoes and bacon.
IIRC food deserts are a demand issue, not supply. The reason healthy food doesn't exist in those neighborhoods is because it closed because people didn't go there.
I've heard that too, but even if true it's still a problem for the minority of people in the area who would have liked to get fresh veggies and such.
I haven't seen any comments on the topic of chronic inflammation. I am not knowledgeable on this topic, but we do know that chronic inflammation is linked to a huge number of disease end points. GLP-1 may be reducing (or preventing) systemic inflammation.
https://en.wikipedia.org/wiki/Systemic_inflammation
What about people who, with their current habits, are on the bottom range of what is considered "normal" weight (in the BMI sense) or already underweight?
Wouldn't taking GLP-1 agonists (for potential non-weight-loss benefits) be potentially harmful as it may reduce eating even further and lead to being significantly underweight?
> Wouldn't taking GLP-1 (for potential non-weight-loss benefits) be potentially harmful as it may reduce eating even further and lead to being significantly underweight?
Almost certainly at the weight loss dosages people are taking now, but semaglutide (at least) can be tuned up and down for effect. Time will tell what kind of dosage is required for these non-weight-loss benefits.
That said, I think it's more important to focus on how this drug works -- it works in the brain and in specific areas of the brain that we now know are important for weight loss/addiction/inflammation(?) (because of these emergent miracle drug effect). It doesn't seem outside the realm of possibility that drug companies will be able to target these systems with more finesse in the future as opposed to superdosing engineered stable GLP-1 molecules that flood the system.
It is the future understanding of what this drug does that is the real promise for all people -- we are just in the early stages of understanding what we've found.
Sure, it would probably not be helpful to give these people medical anorexia unless there was some huge, huge, more-than-offsetting other benefit. (Less than 2% of the US population is considered underweight by BMI: https://www.kff.org/other/state-indicator/distribution-of-bo... . )
Obviously subject to conversation with their doctor, but my endocrinologist suggested against this class of drugs for blood sugar control.
They just need to take GLP+1, instead.
It's the number one recommended supplement by the American Society for Cannibals. The flavor is in the fat!
If it really is inflammation, exercise targets that just as well, and also acts as a miracle drug that seems to reduce the risk of just about everything, somewhat paradoxically even orthopedic injuries over a long enough timescale (because you stave off age-related muscle and bone mineral loss).
But that puts us back in the "telling people to exercise doesn't cause them to actually do it" at the public health level. For you yourself, you can simply live a less risky, healthier life. For all yous, probably we need something like a once-weekly pill or injection that doesn't require drastic habit changes. For all of society on a forever timescale, of course, we can ignore the fact that adults won't change their ways and focus on instilling lifelong athlete habits in kids. Doesn't seem to be the direction we're going in, though.
Things like GLP-1 can give a near immediate bodily response that can lead to people starting to work out. When you have inflammation issues I can promise the last thing you want to do is put stress on your body from working out. Especially when most people don't know how to do it properly.
Love that word "pleiotropic", nice vocab builder.
So it looks like GLP-1 may have positive side-effects beyond what can be explained as consequences of weight loss. Surprising linkages between biochemistry/hormones and temperament.
I am slowly (1 kilogram per month) losing weight by eating nothing but meat 2-3 days per week. My understanding is that the extra GLP-1 secreted by the gut when digesting lots of protein leads to appetite suppression. It works, and is surprisingly easy to do (no feelings of hunger).
So will I also be getting the beneficial side effects of GLP-1? If so, high-protein dieting becomes the smart way to lose weight.
> FTA: So we're not only going to be treating (or outright preventing) a number of diseases, we're going to be learning more about the cause of these diseases than we ever did before.
Ultra processed foods (UPF) needs a hard look IMO. It's the leading cause of many diseases stated in the article and several others including cancer and dementia.
Color me a bit skeptical on the "GLP-1 is the cure for everything" hype. These drugs are clearly a game-changer for obesity and T2D, and possibly a few other conditions, but it strikes me as unlikely that a chemical exists that is more or less an across-the-board improvement to health, with no downsides. If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists? Or modify GLP-1 itself?
The best argument against is "starvation was a human universal" and that survival through famines totally dominated the evolutionary trend in GLP-1 related things in the body. But even something as simple as lactose tolerance responded quite quickly to changes in human dietary structure in different areas of the world.
My suspicion is that at least some of these medical record review studies are just driven by confounding - people who find out about GLP-1 agonists are better educated, wealthier, or have behavioral/lifestyle traits that explain many of the apparent benefits.
(still, part of me is still holding out for the "miracle drug" explanation)
> If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists? Or modify GLP-1 itself?
Because evolutionary fitness doesn't care about what we care about, and even if it did it operates so slowly it hasn't yet finished adapting to us having invented cooking.
That said, I share your skepticism. This kind of story feels almost exactly like the old Victorian (literal) snake oil advertising: https://commons.m.wikimedia.org/wiki/File:Clark_Stanley%27s_...
True, but (a) maybe it would evolve "naturally" given enough time, and (b) the things that humans create are a product of evolution too, no? Albeit not directly through the mechanism of natural selection.
> True, but (a) maybe it would evolve "naturally" given enough time,
You could say the same for myopia. But we still make glasses for people, which breaks the natural selection process that would drive that evolution.
The obesity epidemic is only 50 years old. GLP-1 seems to be a “thing that fixes your satiety balance”, that is applying to more than just food, but maybe also help you regulate yourself when you have way too much access to alcohol, drugs, etc.
In short: the reason that the human body wouldn’t have evolved to make more GLP-1 automatically yet is because evolution causes populations of organisms (not individuals) to change, over generations, to be better suited to their environment.
And 50-100 years is nothing in terms of evolution. We spent 500k years evolving to optimize gathering every calorie we can. And then yesterday it turned out that maybe it is in fact possible to have too much.
Also, the human body does make some GLP-1 itself. Maybe it was just getting started.
> If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists?
Because we haven't had the infinite years required to "just evolve" every possible bodily improvement?
I don't know if it's an ideal wonder drug or also has downsides we haven't found yet or some of the positives are misinterpreted but if "why didn't we just evolve it" was meaningful it could be an argument against ANYTHING being good in the way presented.
To be fair, we don’t need infinite years/generations to select for favorable traits.
Such a selection process might already be underway - obesity lowers fertility, so there is pressure towards not being obese. IMO the next generation will already be either slightly reducing their intake, or increase their expenditure of calories. There‘s many ways to do that - becoming taller, more restless, less hungry, decreasing intestinal uptake, reduced enjoyment of food (loss of taste/smell) etc
Fertility is one of those things that's dropped faster than obesity has increased in most places and will have a much greater impact on future generations.
> If it was that simple, why didn't the human body just evolve
That's easy to answer. We exist today in a very different environment to that we evolved in.
It makes perfect sense that there could be a hormone that wouldn't provide a net reproductive benefit to hunter-gatherers or subsistence farmers but provides an immense health benefit to sedentary humans eating unlimited food. In fact, it would be surprising if there wasn't.
> If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists? Or modify GLP-1 itself?
Replace "GLP-1" with any of: aircraft, computers, buildings, WiFi, ...
Some things are easy for nature to find and some things aren't!
And even of the things that are easy for nature to find, and that we would have found useful even in the environment of evolutionary adaptation, they might not confer overall fitness if they are too costly.
Well said. Diseases that affect the elderly don’t get a lot of consideration from nature. Natural selection really only cares about us reproducing.
On top of all that, our current environment and diet are quite a bit different from the norm over the past few million years.
Go to the glp-1 related Subreddits and you'll see they aren't all wealthy educated people. Hell I read a story of a girl on the Manjaro subreddit who couldn't get her meds and ate herself into the ER in two days.
My sister takes Ozempic and is the proto-typical obese white girl with way too many kids she can't afford and only eats trash. It probably saved her life.
I'm putting increasing probability on the idea that there's something in our modern environment that's disrupting the GLP-1 metabolism (or a related system), these drugs are counteracting that effect.
When it was just appetite suppression, that made sense, we're not adapted to a modern degree of plenty. Not sure that explains the other positive effects, if these results reproduce.
My bet is on the HFCS in the processed food.
Look at all countries that are having rapid increases in obesity and see how many use HFCS to see if you're on the right track.
The lactose adaption took a couple thousand years to develop, no? While the last famines in developed countries took place less than 100 years ago. Feeling less hungry does feel like an elegant solution to the blatant oversupply humans are facing now.
> My suspicion is that at least some of these medical record review studies are just driven by confounding - people who find out about GLP-1 agonists are better educated, wealthier, or have behavioral/lifestyle traits that explain many of the apparent benefits.
This exactly. There was a recent paper about Ozempic and (IIRC) dementia that saw that the drug acted implausibly quickly to prevent illness -- the Kaplan Meier curves were literally separated at day 0. [1]
Confounding is rampant in this area. The people who published the paper I linked below should not be scientists. It's embarrassing. Anyone who cites it in support of Ozempec as a miracle drug has revealed that they don't know what they're doing, and should be ignored, with prejudice [2].
More generally, it's depressing that so many people are piling on here to tell you that you're wrong, based on little more than their "knowledge" that obesity is bad. The fact is that most of the science around GLP-1 agnoists and anything other than obesity is weak, to say the least.
[1] I believe it was this paper. Certainly, the KM curves in this are ridiculous: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz...
[2] Sadly, this appears to include the "Alzheimer's Association"...though you sort of understand why they're biased in favor of miracles.
EDIT: I am just now realizing that Derek Lowe is citing this paper. Oy vey.
Those graphs are incredible. Literally. As in impossible to credit.
What sort of other things would we have to conclude if we took them seriously? Insulin causes AD, starting the day you get the prescription? The mind (assuming it's turned on and operating) boggles.
One of the disappointing things in my life has been the discovery of how much "medical science" is based on statistical illiteracy.
drop the "medical", it's cleaner.
GLP-1 of course is the GLP-1 agonist created by the body.
I don't think that humans eat to obesity by default. People have had adequate food for quite long and not grown fat.
Maybe there is something in out environment or our foods that are blocking the GLP-1 receptor? If a modern food company discovered something like that they'd immediately realize that (unintentionally) they sell better, probably without realizing what they had created.
> People have had adequate food for quite long and not grown fat.
That's revisionist, both in terms of "for quite long" (food insecurity was common in America until about World War II, and massive food surplus available at consumer-cheap prices begins a little later; other countries still suffer from food insecurity today) and that people haven't grown fat when able to do so. Being wealthy enough to the point of being able to be fat has been A Thing for a thousand years. We know this because the medieval Catholic Church felt that they had to preach moderation; if they had to preach it, it's because it wasn't happening as a universality.
A good amount of GLP-1 is made in the intestines, and production is heavily affected by interactions between those cells and gut bacteria. So anything that caused dysbiosis of the gut microbiome could potentially be causing problems with natural GLP-1 emissions, e.g., antibiotics in the food supply, emulsifiers, etc.
Not really. Being fat was a sign of being rich back then, because only rich people could even have enough surplus calories to get fat.
>an across-the-board improvement to health
Obesity is itself an across-the-board impairment to health. Anything with a positive impact on obesity will be, therefore, an across-the-board improvement to health.
Why didn't evolution make us smart enough to not overeat?
There’s no evolutionary benefit to eating as little as possible any time in human history, other than the past few decades. We’re barely into the third generation where calory overconsumption is an issue. It takes a few hundreds of thousands more to evolve something this complex, with a population as global as ours
> There’s no evolutionary benefit to eating as little as possible any time in human history
In multiple organisms we see that under-eating and fasting extends lifespan, so I'm not sure that's the case.
https://www.nature.com/articles/s41392-022-01163-z
https://www.science.org/content/article/why-eating-less-mean...
https://www.nature.com/articles/d41586-024-03277-6
Humans (and other mammals) starve to death way more often than died of calorie overconsumption, since the first little mammal climbed a tree
Eating at little as possible means enough to live, though. That's what the "as possible" means, otherwise it would be "not eating"
And then you store the rest of the food cache you found… where again? A prehistoric fridge?
Oh wait that’s called fat cells, one of the best evolutionary advancements ever! Overeating really pays off.
I'm not really sure what you're arguing, because the initial claim was there's no evolutionary benefit to undereating. Yes you can store visceral fat and I'm not arguing there isn't a benefit for that, just that there's a clear benefit for undereating as well.
No evolutionary benefit.
But there's a demonstrable one - a longer lifespan. In most animals (including mammals) a longer lifespan gives more time for reproduction.
Jumping in to try to settle on common ground.
It's not that there isn't a benefit to under eating. Demonstrably there is.
Nor is there a strict disadvantage to overeating sometimes - it keeps you alive and is a great way to store food.
It's just that we probably regularly did both. We probably ate a lot, then very little, either on daily, monthly, or annual cycles. So it just so happened that beneficial things took advantage of those cycles as the right time to do beneficial things.
Think of it this way: I need to defrag my hard drive, but I cannot do that when I'm playing games. It's not that there's a benefit to stopping playing games, it's just that that's when I can defrag. It's probably similar with all the autophagy benefits of fasting - we were probably regularly not eating so we did it then. During eating we can't really do all that good stuff.
And conversely, I really need to build muscle and brain tissue, and that's probably easier to do when I'm calorie rich. It's just the right time, and I can count on a calorie-reduction later to do the other stuff.
We just never have that calorie deficit anymore.
Overeating doesn’t cause any issues to any animals during their average reproductive period (younger ages). Longer lifespans and calory deficits lead to lower quality offsprings. Nothing “demonstratable” there.
Yeah but lifespan benefits usually come after the animal has had a lot of chances to have offspring. Also undereating is much more likely to kill you in times of famine.
This was a rhetorical question.
Not to everyone, clearly
Is it addictive at all?
In the sense that you need a constantly increasing amount to maintain the same results: yes.
I think it's important to call out that it's actually constantly increasing amount to increase the results.
As patients lose weight, they need to eat fewer and fewer calories to continue to lose weight, as the BMR decreases. This isn't because of the medication, but rather because it requires fewer calories to maintain their mass, so they burn fewer calories at rest.
Increasing the dose further decreases hunger signals, which further decreases their desire to eat as much.
It's not "increasing to maintain the same results" its "increasing to increase results".
Ex.
Patient A currently weighs 330lbs. Has a BMR of 3300 Calories. - Initial dose, they eat 2,800 calories a day instead of 3,500 calories they used to. - Loses weight. Now weighs 250lbs. - BMR is roughly now weighs 250lbs, and has a BMR of roughly 2500 calories, but dose still has them eating around 2,800 calories. - Dose is increased, patient is now eating around 2,000 calories. - Patient A reaches 200lbs, BMR is roughly 1,800 calories, but is still eating 2,000 calories. - Dose is increased, Patient A is now eating 1600 calories.
That's incorrect. It's a titrated drug similar to blood pressure meds. If you have effectiveness at a 1mg dose for example, you stay at that. The drugs have maximum doses.
> If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists?
Have you read the submission before writing your comment? An answer to this question is given in one of the few short paragraphs.
>If it was that simple, why didn't the human body just evolve to excrete GLP-1 agonists? Or modify GLP-1 itself?
Honestly? I'm not much of a physiologist, but based on the effects regarding addictions like tobacco or narcotics that cannot be causally downstream just of diet, I'd wonder if GLP-1 agonists aren't actually impacting stress-interoception systems rather than just hunger and metabolism. Under that hypothesis, the evolutionary reason would be: because we evolved to undergo stress mostly in physically strenuous, energy-burning situations, while high loads of cognitive and emotional stress without physical effort are a novelty to post-industrial lifestyles.
[flagged]
Of course, saying "fat people should simply eat less" is by no means novel. It's the same as "have you tried _not_ being addicted to [drug]?" or "Why doesn't he just [obvious but impossible action]? Is he stupid?"
For some people, "eat less" is easier said than done. Their body, for whatever reason, makes them suffer when they don't eat. Maybe it's easy – or hard, but possible – for you, and that's great. But don't assume that simply because you've never experienced it as impossible, doesn't mean others don't (or that they simply lack some kind of strength that you possess).
If anything, the effectiveness of this medicine appears to demonstrate that – much like other "chemical imbalances" such as ADHD or depression – obesity might be a symptom of biology that simply doesn't make enough of a certain chemical, or makes too much of another.
Also, I see you posting your website link on a bunch of threads. I read it. This isn't the place for a discussion about it, but I do want to point out a major rhetorical flaw: you appear to assume that _no_ patented invention is _ever_ actually useful. I think this nullifies most of your argument, because it's demonstrably untrue.
> much like other "chemical imbalances" such as ADHD or depression
Interesting that the examples you bring up are also things that turned out to be misunderstood and were not actually chemical imbalances.
> you appear to assume
Where do I appear to assume this?
Most people ate quite poorly before the 1800s, routinely suffering from various nutrient deficiencies depending on what the local staple food lacked. The few people who were rich enough to get abundant food could and did become obese.
This exact line of reasoning is the cover story on the Economist this week:
Briefing: https://www.economist.com/briefing/2024/10/24/glp-1s-like-oz...
Leader (opinion piece): https://www.economist.com/leaders/2024/10/24/its-not-just-ob...
(sorry, paywalled)
https://archive.today/D06ZN
https://archive.today/YgiWx
This can also be viewed as advertising - there are board members in common between The Economist's holding company and Novo N.
Isn’t this just eating less food is good for everything?
Eating less food and keeping your body from knowing it seems to be a big part of why it works.
On GLP-1 agonists, you don’t get nearly the counterbalancing reduction in energy expenditure you usually see with caloric restriction. Your body keeps happily releasing lipid stores, assuming they will be replenished, but they aren’t. Hunger hormones remain untriggered, cortisol stays low, and insulin keeps shuttling glucose into cells to be burned.
If you aren’t metabolically deranged, your body does this anyway. But many people have totally decompensated metabolically due to excess energy intake over time, and essentially cannot recover without some kind of treatment.
GLP-1 is just the beginning — future compounds will do a better job maintaining muscle mass, for example. But this is looking like an absolute miracle, and once patent protection ends (especially for oral formulations), we’re going to be living in a very different world health-wise.
Losing muscle mass is just what happens when you're in a calorie deficit. The same thing happens if you're in a calorie deficit without the aid of a GLP-1.
Making sure each meal contains substantial protein will help negate this.
Right, it’s not something specific to GLP-1 treatment, but there are myostatin and activin A modulators under investigation to specifically counteract muscle loss related to caloric deficit more generally.
Patent protection for the early versions has already ended. Teva is making generic versions of liraglutide and it's been available in the US for a few months. The other GLP-1 agonists will be protected for a few more years though.
True but imagine the price and availability impact when the oral formulations go off-patent. The autoinjectors are inherently expensive to make and ship, and some people have a needle phobia. Oral daily seems like the endgame here.
> On GLP-1 agonists, you don’t get nearly the counterbalancing reduction in energy expenditure you usually see with caloric restriction
And that's mostly related to how much you move. If the body needs to reduce energy expenditure, there isn't much it can cut that's non essential that will make a difference, other than activity and movement in general. So you feel like laying on the couch all day.
I haven't tried GLP-1 myself, but reports seem to indicate that GLP-1 drugs make you feel _tired_, which is basically the same thing. So I am not sure the body is fooled that easily.
> many people have totally decompensated metabolically
Around 88% of americans have some level of metabolic dysfunction so that tracks. Numbers worldwide are trending up.
> and essentially cannot recover without some kind of treatment.
They can. Going back to a healthy food intake will fix anything that's not permanently damaged(and if it is permanently damaged, there isn't much medicine can do either). That can be sped up with other measures, such as fasting.
I am a bit skeptical of trying to fix a problem that was mostly created by the food industry with medication. GLP-1 isn't without side effects.
Cutting sugars and simple carbs in general has very similar effects and will decrease your hunger hormones as well. I think everybody should try that first before relying on medical interventions.
Besides, carbs tend to make you retain a lot of liquid. Drastically cutting them usually improves fluid retention, people see changes pretty quickly in the scale, and that can motivate them to continue. Do that long enough and even eating habits will change and so will your palate. A soda becomes unbearable.
>but reports seem to indicate that GLP-1 drugs make you feel _tired_,
I know a few people that take one of the name brands, and they really don't complain about this issue. What they do talk about is having more energy after dropping weight because they just don't feel compelled to eat much anymore.
I'm not overweight myself, but I am a Type 1 diabetic from a young age. "Sugar noise" is not something that is easy to ignore. Especially in the case where you have excess insulin in your bloodstream but not active enough for your body to use it. Your body will scream at you to eat something sweet/carby. In people that are overweight this can be caused by insulin resistance. Until you experience it, it's really easy to say "People should try", but it's about as easy as telling someone to drop meth or heroin.
I am overweight. That food and sugar noise thing is real and brutal. Your parent comment should really factor that in the discussion. I know it's hard because (fortunately) they may not have experienced this themselves, but it's horrible.
My body SCREAMS for me to eat something sweet/carby all fucking day long. All day. Never realized the extent of it until using GLP-1s. I tried many things: full strict diets with macro counting, IF, more lenient and "natural-feeling" diets where you just try to eat whole foods that are filling and tasty. With or without weight lifting, sometimes cardio. Yeah they work, big surprise! But the entire time you are fighting against that urge, doesn't matter if you've gone a full month with perfect "discipline". Eventually it gets you. And I was miserable the entire time trying _not_ to think about food.
This is life changing.
As public health policy though, just telling people to do the things you describe doesn't work because dieting sucks and your body doesn't want you to do it.
Some people can do it but they're usually not among the huge percentage of obese people in the population.
With GLP-1 agonists it doesn't even feel like you're fighting your body because you just automatically don't want to eat too much (just like people who don't have problems managing their weight).
I think it's basically a good thing that modern day civilization has cheap and available calories because no one has to go hungry, but this is an environment that evolution just hasn't prepared us for and many many people are just not calibrated right for it. Maybe we can finally fix that.
I've been taking Ozempic or Zepbound for a couple months as a personal experiment and the effects have been nothing short of life-changing.
I have been somewhat of a "casual bio hacker" for the past 25 years and have done things like quitting alcohol or caffeine cold turkey and staying off it for years, or tracking every calorie I ate for 10+ years. I've had periods of eating really healthy, I've had periods of eating whatever but staying in calorie deficit, I've had periods of just not eating much at all, I've had periods of eating anything and not caring. I've tried a variety of more extreme body modifications just to try it and note the results. I find messing with the body (or food intake or whatever) to be like trying to reverse engineer an unknown binary, or like trying to write a keygen but for your mood and health. It's been a little hobby of mine for a long time.
These medications are WAY different. There is no way to describe it. You just feel... better, in almost every way. As someone once posted on another thread, their relationship with food changed. I noticed my relationship with food changed as did my relationship with other minor vices; my "screen time" is down. My anxiety is almost entirely gone, my mood is better, and I feel like I sleep better.
Even as the weight loss rate decreased (which was dramatic at first but has mostly stopped as I didn't increase my dosage of the medications to see what would happen), I just feel... better.
No amount of eating better or healthy lifestyle that I've tried (and documented) in the past two decades has produced anything nearly as profound as the impact that Ozempic has, both on my mental and physical health. Which seems crazy, and I thought that people who were crowing about an off-label diabetes drug were crazy as you probably think I am. But I agree with these types of articles - GLP-1 drugs are just the first step in some kind of next step in health, and obviously right now the focus is on "lose weight, undo the damage of processed foods!" but I think we are going to find that GLP-1's are just the first of many new discoveries that could extend or improve our lives beyond the aesthetic reasons that people take them today.
Regarding side effects, I have a lot of people ask me or comment about this. I think just like any drug, you only hear about the people with bad side effects. 8% of American adults are taking a GLP-1 drug right now, yet CVS Pharmacy doesn't have a section dedicated to managing the side effects (but they do for opioid side effects like constipation), which would be my gauge as to how it's really going.
I did have some dehydration (far less than something like scopolamine gives me) on the first couple days after my first self injection, but increasing my water and electrolyte intake fixed that and it seems to have gone away (I've even tried lowering my water and electrolyte intake and it didn't come back). I am not more tired, nor do I have more (or fewer) digestive issues than before. I think people who do have increased digestive issues have just never experienced (or not recently) what happens when you are really full and just overeat, because their bodies are so used to higher calorie or sugar consumption. Just like how Thanksgiving dinner can make you tired or make you have to wait in the family line for the bathroom, I suspect that GLP-1's are causing some people's "normal" meals to feel to their body like a "Thanksgiving dinner" because they effectively are (by comparison). I have noticed some slight muscle loss in my non-dominant arm that is of mild concern but nothing that I am worried about at this time.
This is anecdotal yes and it's just my personal account of these medications but I was skeptical until I tried them, like you are, as I thought "oh, just eat healthy, why needs a shot".
I will update this post when it's determined that GLP-1's cause some crazy or horrible disease but for now I am enjoying this experiment with them.
> But this is looking like an absolute miracle
What are you referring to here? The muscle-preserving medication? Are GLP-1s actively reducing your muscle mass, or is it the fact that people on them ate very little and didn't tend to exercise?
Assuming you're going to fix a extremely complex system like the human body by just taking a pill is what some people call the bias of Illusion of Control.
https://en.wikipedia.org/wiki/Illusion_of_control
You’re going to have to be more specific, because I am sure you are not arguing against the concept of medicine.
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Try telling a type 1 diabetic patient to eat like it's the 1800s
> a type 1 diabetic patient
Are you sure there is such a thing?
Yes.
And what biological test can one conduct that proves this, and is unchangeable over time?
I argue that medicine still does not have enough accumulated knowledge about the complexity of the human body to be playing God with a single pill.
You don’t believe the medicine that billions of people take to treat diseases that would’ve otherwise demonstrably killed them is “accumulated knowledge” enough? From insulin to antibiotics, we have sufficient evidence that many types of medicine DO work. Nobody is “playing god” (whatever that means), it’s just reproducible and consistent data
There is no god. So I argue that medicine is at least just as potent as nothing.
You may begin your argument now
Any single pill? Or is your objection specific to this one? (That iirc is actually an injection, not a pill, but w/e)
Maybe ... maybe not.
Modern medicine does have magic pills for many illnesses; for example, antibiotics are magical for many bacterial infections, many vaccines are almost magical too.
OTOH, many pills will have undesired side-effects, and the body is in a complex dynamic equilibrium, so it may happen that blocking GLP-1 may have side effects.
Eventually, we'll all die, but I'm optimistic that GLP-1 will lead to a better equilibrium. Preliminary evidence says it will. I'm not as confident as the author though :)
You're right, but the way you're going about it isn't.
Are diabetics biased in this way when they take insulin? Or where is your cutoff?
How many average person years does an intervention need to save before it meets your approval?
Untreated diabetics can die within a week. Are we facing the same sort of problem here?
No, but same thing with different numbers.
Like I asked, where's our cutoff? If obesity on average kills you a couple of decades earlier than otherwise, does treatment for that meet your approval?
> No, but same thing
They're either the same or they're different.
> Like I asked, where's our cutoff?
Exigency of loss of life.
> kills you a couple of decades earlier
Staying obese into old age carries risks. There are multiple ways to manage that risk. None of it is as exigent as other conditions.
> does treatment for that meet your approval?
Universally? No.
>> Like I asked, where's our cutoff?
> Exigency of loss of life.
Cool. How about cancer treatment? Some of those you can live with for some months/years. We allowed to treat anyway when the outcomes are better?
> Staying obese into old age carries risks. There are multiple ways to manage that risk. None of it is as exigent as other conditions.
And why should this not be one of the ways to manage that risk? The biggest difference seems to be that it actually works, on average, unlike some other common treatments like telling people to eat less and exercise more.
Does eating less food reduce addiction to tobacco, alcohol and other substances? Because there is mounting (but not conclusive) evidence that GLP-1 agonists do just that.
Sample of only a half dozen people close enough to me to talk intimately about it - but for drinking it’s been absolutely proven in my mind for some people.
I have one friend in particular who started a GLP-1 drug solely to assist in drinking less - she certainly does not need to lose any weight. It worked like a light switch for her and turned moderately problematic drinking into easily achieved light social drinking. No impact on appetite since she is on a very low dose.
I have had the same experience, even though I took it for weight loss to start with.
I do know that drinking can be downright unpleasant for me if I push through the aversion after my first drink and try to go for a few more. I have noticed a strong correlation to drinking and my blood sugar crashing rapidly afterwards while on Tirzepatide while wearing a glucose monitor.
A single cold beer on hot day with friends is still quite pleasant. Sitting in a bar for hours on end drinking heavily is simply downright uninteresting now before you get into any unpleasant side effects.
Add me to that sample set, I drink far, far less with it
> turned moderately problematic drinking into easily achieved light social drinking.
Is this based on your survey or her self assessment?
> Sitting in a bar for hours on end drinking heavily is simply downright uninteresting
Yet it used to be? You don't find this situation suspect?
> Is this based on your survey or her self assessment?
Both? Being around her, and her self-assessment. Not sure how else one could interpret such a statement. This is all anecdotal evidence and should be taken as such.
> Yet it used to be? You don't find this situation suspect?
Yes, it used to be moderately interesting sometimes with the right people. Suspect in what manner? That it removes the desire to get inebriated? Perhaps so, since we do not understand the mechanism at play. What we don't know can certainly hurt us.
Overall the desire to drink less seems very similar to the impact it has on appetite and hunger levels. In that way, it is not so surprising to me.
FFS. An anecdote is one piece of data, when those pieces of data come together it provides evidence.
For example we see the same behaviors in mice
https://www.niaaa.nih.gov/news-events/research-update/semagl...
>In the current study, the researchers demonstrated that semaglutide reduced binge-like alcohol drinking in both male and female mice, and that the effect was dose-dependent (i.e., greater amounts of semaglutide led to greater reductions in binge alcohol intake). The researchers also tested semaglutide in rats that were made dependent on alcohol through long-term exposure to alcohol vapor. They found that semaglutide reduced alcohol intake in this animal model, again with no sex differences.
> An anecdote is one piece of data
It is not documented, so no, it is not. Which is why I questioned if it was entirely based on self assessment or not and left the door open either way as the question was based out of curiosity and if his anecdote was public I wanted the answer to be as well. Is that not fair?
> when those pieces of data come together it provides evidence.
When you properly document them it literally stops being an anecdote and then becomes evidence.
> The researchers also tested semaglutide in rats that were made dependent on alcohol through long-term exposure to alcohol vapor.
So.. what are we actually measuring then? Isn't alcoholism a disease and not some acquired exposure based dependency? The idea that "GLP-1 for Everything" is even floated in this way is unusual in and of itself. I'm uncomfortable with all this and am once again annoyed at the way we use rats in research.
I wonder if it's about more stable glucose levels hence avoidance of cravings. Anecdotally, alcohol and nicotine cravings seem to pass me whenever I have a particularly fast acting (low osmolality) carbohydrate supplement.
There is no known link between how much you eat and Alzheimers, substance abuse, etc. If it was as simple as eating less makes these issues go away, we would've figured that out a long long time ago.
Alzheimer's is now being referred as type 3 diabetes for a reason.
Human metabolism is sensitive to the type of food you eat.
Check https://www.metabolicmind.org/ as a starting point and follow the rabbit hole to understand the link between what you eat and mental and metabolic illness.
Also, GLP-1 also eliminates muscle - your heart is a muscle.
GLP-1 reduces calorie intake and puts many people on a deficit (typically on purpose). This of course will reduce muscle just like any other calorie deficit anyone runs long term.
Fasting increases growth hormone release (dramatically, in the case of extended fasting), which counters muscle loss. Does this happen with GLP-1?
This goes against all evidence I have seen for folks who have lost a drastic amount of weight very rapidly. Bodybuilders seem to see the same effect as well when on cuts.
When you are losing 5% of your bodyweight per month (as I was, and many do) a substantial portion of that is simply going to be mean muscle mass. You can counteract some, but not all, of this by heavy resistance training. It's very difficult to not lose muscle mass while losing weight - it takes extreme measures for most folks (e.g. athletes) to do so.
> Alzheimer's is now being referred as type 3 diabetes for a reason.
No it's not.
Some are referring to it that way
https://pmc.ncbi.nlm.nih.gov/articles/PMC2769828/#:~:text=We....
What you eat is a very different concept to the amount you eat. Especially on topics like these, the distinction is critical.
There have previously been associations between caloric intake and Alzheimer Disease or Cognitive Aging, for example:
https://jamanetwork.com/journals/jamaneurology/fullarticle/7... https://www.pnas.org/doi/10.1073/pnas.0808587106
I think it's a fair bit of a stretch to broadly say that this study shows an association.
> Conclusion: Higher intake of calories and fats may be associated with higher risk of [Alzheimer Disease] in individuals carrying the apolipoprotein E ϵ4 allele.
> The hazard ratios of [Alzheimer Disease] for the highest quartiles of calorie and fat intake compared with the lowest quartiles in individuals without the apolipoprotein E ϵ4 allele were close to 1 and were not statistically significant.
For the general population, there was no correlation. Identifying specific genetic outliers where there may be a connection is still useful, but far from a general result.
Exactly. There are lots of skinny alcoholics and drug addicts. Unfortunately many of them are homeless.
The real surprise I learned is that GLP-1 may discourage other addictions as well, including gambling. Source: A nurse I talked to who works with GLP-1 trials.
As others have already stated, it’s starting to become mainstream science that there is a strong correlation between obesity/poor body composition and Alzheimers. It’s not settled science yet, but the correlation is starting to look a whole lot like causation at a society level.
Not to cite anecdotal evidence, but my father-in-law was skinny as a rail and got severe, early-onset Alzheimer's. Obesity might be one potential cause of Alzheimer's, but it's among many.
Yep, just like there are skinny as rails type 2 diabetics. My grandfather was one.
There is also a huge correlation between obesity and type 2 diabetes as well.
I imagine they share similarities, but that’s pure speculation.
>If it was as simple as eating less makes these issues go away, we would've figured that out a long long time ago.
You can't get people in large enough quantities to do that reliably and for long enough as part of a study. Best you can do is a small quantity of lab rats.
The data is already rolling in as part of prescribed out-patient data.
No, there are a number of effects of GLP-1 RAs that are not directly related to their initial research and development associated with insulin response, beta cells, etc or recent research associated with appetite suppression. For instance, there is growing research and speculation around dopamine systems in humans.
It might be awhile before the research propagates to the realm of popular science.
IMO, it kind of represents how incredibly blind we are to supposedly safe compounds, and how arrogant others are for calling for less regulation. When attention is high, suddenly so much more is revealed.
I don't think we know conclusively yet. That probably explains quite a lot of it, yes. It's unclear how that would lead to the substance (ab)use results, though.
Depends on who you are and if you have an eating disorder.
Do we know? I think that's the question being asked here. Using these drugs seems to improve a bunch of indicators and we're not sure why.
It's really interesting to me that there's some evidence for Metformin -- a diabetes drug that suppresses glucose production and appears to do other things we don't fully understand -- having general health benefits and possible life extending benefits in healthy people. Normally it's just used to treat some forms of diabetes.
Feels like we're on the cusp of figuring something out about inflammation, aging, and metabolism.
Yes. Turns out everyone should have just been eating fats all along.
hmm, ahem no!
veg fats okay, animal fats no so much as if you limit them you tend to live longer due to the decrease in oxidative damage.
Polyunsaturated fatty acids (PUFAs), whether from plants or animals, are most susceptible to oxidative damage because they have multiple double bonds that can react with oxygen. Each double bond creates a potential site for oxidation.
Societies consuming high amounts of oxidized oils (repeatedly heated cooking oils, whether plant or animal) show increased rates of cardiovascular disease
Mediterranean populations consuming fresh, minimally processed olive oil show better cardiovascular outcomes
Populations with high fresh fish consumption (like traditional Japanese diets) show better health outcomes despite high PUFA intake, likely due to immediate consumption and minimal oxidation
Modern food processing/storage methods increase exposure to oxidized fats
Fast food consumption correlates with higher intake of oxidized fats due to repeated oil heating
Socioeconomic factors influence exposure - processed foods with oxidized fats are often cheaper and more accessible
Oxidation status of fats may be as important as the traditional saturated/unsaturated classification
> if you limit them you tend to live longer due to the decrease in oxidative damage
Can you elaborate on that? Aren't animal fats, particularly dairy, rather rich in saturated fats? And saturated fats oxidize less easily than unsaturated fats precisely because they lack weak double bonds.
What's GLP-1?
In this context it's shorthand for "GLP-1 receptor agonist."
https://en.wikipedia.org/wiki/GLP-1_receptor_agonist
Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.
This is probably what’s going to get us over the 80 years life estimate plateau. The main killers now are overwhelmingly cardiovascular diseases and cancers.
It feels more likely to me that there's some sort of condition we don't have a widely known name for that is caused long-term by a combination of predisposition in genetics and something in western diets that is, I'm not sure, forcing us to overproduce ghrelin (possible links to puberty occurring earlier in both young boys and girls?), or underproduce certain classes of incretins (possible links to excessive blood sugar levels in larger percentages of the population historically over time?).
It would be boring to learn that it's just caused by excessive exposure to fructose.
But what do I know, I'm just a dumb HN reader.
Seems neat that there's ongoing work in this area and it'll be cool to read about new knowledge in that space when something is discovered.
It's interestingly disingenuous that many claim of GLP-1 agonist miraculous effects on all kinds of health problems, where the same problems are "simply" solved by getting on a calorie deficit and lean. Liver, kidneys, heart, etc. If you have a non-alcoholic fatty liver disease and are obese, getting leaner will heal it. All those impressive results are on obese or diabetic people. So it is not only not a surprise, but also dishonest marketing or ignorance.
Don't get me wrong - those are miraculous drugs. First real non-stimulant low side effect appetite suppresion that will help millions. But let's wait for honest research on lean people before spreading marketing on how it improves overall health.
Also, how nobody mentions the need for increasing the dosage and tolerance build-up (just check reddits how much people end up having to take after months of continuous use). You cannot be on it "for life".
The increasing dosage is to tritrate up to a dose not because you gain tolerance. There are patients on GLP-1 for over a decade. Also maintenance and weight loss dosages are different: see the dosing charts for ozembic vs wegovy which are exactly the same drug.
Even if folks gain tolerance that doesn’t seem overly concerning. Mental health drugs also have tolerance issues and changing medicines every few years, while it has challenges for the patient, is an accepted part of long term psychiatric treatment.
Just a narrow comment, but type 2 diabetes certainly isn't limited to the obese. Many lean people develop issues with blood sugar that can't be controlled with diet alone.
A friend's son, who is an EMT, was recently diagnosed with type 2 diabetes at the age of 21. He doesn't drink or eat sweets, except on holidays, and works out five days a week. Suddenly, he started feeling sick, was vomiting, and ended up in the ER, all within three days. It can really hit you like a truck.
This is my #1 question on GLP-1: are we just seeing how humans do much, much better by being lean vs. the direct result of the drug?
A lean current-epoch human -- with our food abundance, access to modern medicines, higher standards of life, lower risks of injury, etc -- is likely going to be markedly healthier than a non-lean current-epoch human or a lean human from a prior age where medicine/food/etc was worse.
Or is it, in fact, the direct result of the drug?
> where the same problems are "simply" solved by getting on a calorie deficit and lean
Except that there apparently is mounting evidence that GLP-1 agonists also address some issues that are not generally addressed by just restricting calories. TFA touches on this briefly: "The weight loss involved with GLP-1 agonist treatment is surely a big player in many of these beneficial effects, but there seem to be some pleiotropic ones beyond what one could explain by weight loss alone."
I seem to recall seeing claims that they reduce COVID-19 mortality even controlling for BMI (possibly because they inhibit systemic inflammation), reduce alcohol consumption, and even (though I think just anecdotally) may help overcome gambling addiction.
See, for example:
https://pmc.ncbi.nlm.nih.gov/articles/PMC8425441/ [COVID-19]
https://www.ncbi.nlm.nih.gov/search/research-news/19361/ [Addiction]
I don't know that you have to be disingenuous to both be enthused about these medications AND wish we'd never created the super-processed, super-sugary, make-people-crave-them-and-overeat-them modern American diet. Once you fuck with your gut biome for long enough it's not "simple" to solve it. It's incredibly difficult both discipline and metabolism-wise.
Born too late to die in infancy, born too early to see immortality.
I imagine parents in the 1890s felt the same way. Our children will see a new and different world than we can imagine. I love this topic of moving past “health” and towards something better. To quote an 1890s thinker: “it’s time to find out what value our values really had”.
This does remind me of the superconductor stuff tho - I’m too excited - it will be interesting to see what focused clinical studies show us here, particularly around GLP-1’s effects on addiction.
The most important question in the world right now is: which generation will be the first to live indefinitely? It is clear to me that we are on a trajectory to achieve indefinite lifespan extension, but unlike Kurzweil et al I don't see a real possibility that it will happen soon enough for me personally. Maybe my kids, or maybe one or two generations further.
Will it happen soon enough to prevent population collapse due to plummeting fertility rates? Will fertility rates go even lower or will the population start to rise again as deaths fall? Will we see stagnation due to older brains being stuck in their ways, or will we be able to fix that too?
Born just in time to live too long and outlive your savings while modern monetary policy infinitely reduces the value of your local currency!
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No. Some of the positive effects of GLP-1s are seen before the actual weight-loss occurs.
A healthy diet and lifestyle lead to increased GLP-1 levels.
Were there actually any studies on their effect on healthy and fit people?
Loss of muscle mass is already recognized:
https://pubmed.ncbi.nlm.nih.gov/38937282/
And probably especially bad in people without fat reserves.
Guys hear me out. The next VC funded killer idea:
ChatGLP!
I used GLP-1 to prepare my taxes last week, it was such a stress-free experience.
Then as I was coding I kept hitting context window limitations with o1-preview. so on a lark I just fired up my local Ozempic and submitted the same prompts and bam: spit out a whole working iOS app first try.
I heard that before they nerfed it with RLHF, Mounjaro not only treated diabetes but also made you charming in conversation and sublimely compassionate towards all beings.
The future is now