"No free lunch" is a reasonable question to ask when evaluating medication, if it would improve the evolutionary fitness of the majority of people. I think this is behind some of the skepticism. If Ozempic is so great then how come our bodies don't just produce more GLP-1? How come we aren't like chimps, with eternally shredded bodies and cheese grater abs, provided we get the protein to support them?
I would guess that getting fat in times of plenty was a feature and not a bug in the ancestral environment, and that's why we get fat today, which is obvious if you think about it. Still, it means GLP-1 agonists are smacking into quick "is it bullshit?" heuristics for a lot of people.
The second point I haven't seen discussed is that weight loss drugs prior to GLP-1 agonists include cigarettes, which (worst case) give you cancer; stimulants, which cause your heart to fail; parasitic intestinal worms, which can kill you but more importantly are just plain gross; and mitochondrial uncouplers, which set you on fire at a cellular level. That's a long history of miracle weight loss drugs which turn out to have horrible side effects. It's not reasonable to think GLP-1 is bad just because of other drugs with different mechanisms, but it certainly causes some skepticism anyway.
> If Ozempic is so great, how come our bodies don't just...
While I agree with your sentiment, your argument here assumes the human body always makes intelligent decisions for itself. My obstructive sleep apnea would like a word. After it's done choking me awake, of course.
The body is a marvelous machine, but it is far from a perfect or intelligent design. We are lucky to have what we have, but expect operating mistakes.
I agree with this criticism in the case of sleep apnoea, since the respiratory system is complicated. By intuition, it seems like the evolution of a complicated trait should require significant genetic changes, and thus be more likely to get stuck in a local maximum. I'd expect the respiratory system to be quite resistant to change: what if you've got an SNP that reduces sleep aponea but also prevents peristalsis, speech, weakens your neck, etc.? You might need a number of SNPs to all change at once in order to fix the problem.
I don't think the argument holds so strongly for questions like "why don't we produce GLP-1 hormone at a 20% higher level?" Increasing GLP-1 production levels seem like a smoother transition with fewer side effects. If higher production is better, and you've got an SNP that increases production by 5% on its own by increasing the number of L cells in your intestines (or something), that sounds like it should make you more reproductively viable in today's world and shouldn't have as high an impact on everything else as changing the shape of a throat.
Most of this is just my intuition, and I'm absolutely not an expert.
Edit: final note that I think in today's world is the key gotcha here, per the original text: "getting fat in times of plenty was a feature and not a bug", meaning that it was evolutionary advantageous for most people to put on weight until very recently, evolutionarily speaking.
> it was evolutionary advantageous for most people to put on weight until very recently
And it will perpetually remain possible for it to very abruptly and unexpectedly prove advantageous once again.
Primates in the wild really hit the nail on the head here. We clearly lost the equivalent at some point and haven't rapidly regained it. There has to be a reason for that (though it might well prove to be entirely incidental).
> The body is a marvelous machine, but it is far from a perfect or intelligent design.
And I think that we can only expect the process of evolution through natural selection to operate on traits that cause differential survival of individuals before reproduction. All sorts of new traits acquired through random mutation and recombination that only affect individuals after typical reproductive years will exist even while natural selection is still operating. The answer to “why doesn’t the human body operate like [some idealized state]?” Is either 1) insufficient time has elapsed to allow natural selection to change the gene pool, or 2) It doesn’t affect survival before or during reproductive years. (Or, I suppose a third explanation is that the required mutation that drives the change just hasn’t happened yet. Our species hasn’t been around that long after all!)
Yet women have a longer lifespan despite shorter reproductive years.
If in a hunter-gatherer society most people stop reproducing after 40 (not entirely realistic, but bear with me), me being alive and fit at 45 can still improve the survival of my genepool. I can hunt meat and gather plants to make sure my children and grand-children are well-fed and able to produce plenty of offspring, carrying my genes on. I can build shelter, care for the young (improving their survival chances and freeing up the parents to do more physically demanding work).
And my siblings share half of my genes, and my cousins a quarter (assuming no inbreeding at all, otherwise the numbers go up). So helping their children survive and proliferate is a win for the proliferation of my genes. Evolution gets less effective the more indirect the effect and the lower the gene contribution, but it doesn't completely stop working. If there is one clan where everyone dies at 30 and one where people stop reproducing at 30 but stay useful members of society until 60 then then the second clan will do better and outcompete the first
But you also take up resources, continue to decline physically, etc.
We know that there is strong selection pressure for things that occur during reproductive years. No one debates this.
How much the sort of scenarios you're discussing impact selection pressure is significantly less clear.
But it's also a moot point for this discussion - we haven't been in a world where people can get this fat so easily and in such large quantities for long enough to make significant impact to evolution even if we assumed that selection pressure works the same in said world - and again, we know it doesn't.
Grandparents are a selective advantage well after reproduction. Older members of the tribe can watch the young while fitter members engage in hunting and foraging. They can also teach the young. Most tribes around the world that still exist you see this pattern.
Correlation is not causation. Plenty of people theorize there is large selective advantage here, sure. They may even be correct! Others disagree with them on it being a large advantage.
But even if there is it doesn't mean that there is any reason whatsoever that increased GLP-1 production would be enough of an advantage to have had significant impact on evolution. We're going from A is true, B is likely true, C might maybe be true, all the way to Z is definitely true.
> Yet women have a longer lifespan despite shorter reproductive years.
After industrialized nations have reduced both maternal mortality and violent death (warfare) to small fractions of their pre-modern levels. The life tables of 1500, 500, or 5000 BC would look very different than their modern versions.
Reducing the reproductive fitness of each individual after a certain life time might even increase the reproductive fitness of the species (or tribe) as a whole, because it might reduce competition between generations and foster cooperative behavior: if parents and their children compete for the same resources – from sexual partners to food needed to raise a new generation – you'd never develop the cultural norms of life long mutual support across multiple generations.
Evolution should make intelligent choices for us but there's thousands years where a few extra pounds meant surviving a famine.
Also I bet it will kill a few people with eating disorders.
As long as you're in a 1st world country and have a BMI over ... maybe 25 (and aren't on steroids so you're both anorexic and overweight at the same time) I'd guess you're dodging a lot of the most obvious risks.
How do you define 'intelligent' and 'evolution?' I think we might differ on what those words mean, which would make this conversation difficult, so let's clarify where each of us is coming from.
My understanding (which may be slightly misguided because this is definitely not my field) is that Intelligence is the ability to use information for reasoning, decision making and achieving understanding. This ability, as a directed action, only applies to creatures with consciousness.
Regarding evolution, my understanding is closer to a process that is more akin to a passive filter, with no guidance to speak of unless we want to stretch the limits of the concept of guidance to encompass survival, which is the genetic materials of those who survive the environment getting passed on, which would also implies that sometimes garbage/noise stays in the gene pool. While information (genetic material) is being passed on, it is not being selected through reasoning or consideration, but more of a mechanical process (although there's an argument to be had that we, humans, might be changing that game).
How would you define those words? Happy to consider understanding different than my own, since I do find it interesting.
The OP said something about how the human body doesn't make "intelligent" decisions.
I was being cheeky, not using the best word for the job.
Evolution is not really passive, it's a combination of mutation (which is not intelligent, but not really passive) PLUS a passive filter, which gives the illusion of intelligence since it ends up as a kind of optimiser.
Now, due to various factors, evolution isn't perfect. For gene expression reasons (I think) the layout of mammal skeletons are not really effected much mutations, but bone sizes are; so you have giraffes with huge neck bones that are the same size as human neck bones (this isn't the best way to do it). You have bats with the same finger bones as humans (or at least very similar) acting as wings. Elephant feet are almost the same as human feet in an x-ray. Some genetic "knobs" are easier to turn than others, and it can be that shrinking something is easier than getting rid of it. Just google "vestigial structure". Actually, LLM are kind of similar (it's easier to optimise a value to zero than to remove it, even if removing a value will make the model better and faster).
It's also more adaptative than optimal. Some argue it's the "selfish gene" that "wants" to be passed on. If a gene makes you kill all the competition, that's a "fit" gene. If working in a team increases the survival rate of your cousins (who also kind of carry your genes) it's "fit". If having a certain percent of a village be gay would somehow increase survival rates (especially of their kin) then having a chance of being gay is "fit" even if the individuals themselves could be less likely to reproduce.
There's also some meta stuff about how the rate of mutations could partly be genetic.
Evolution is seen as intelligence because it solves hard problems, and IMO that's kind of the only thing intelligence needs? People who talk about "consciousness" talk a lot about how they think they think, but is how we think actually an illusion? The feeling of understanding is just a chemical pleasure hit when the brain hits the "problem solved" button. Consciousness might be an illusion, we might make a decision and wonder how we made it, then an AI in our brain quickly justifies it in some BS way that isn't actually our real thinking process.
> How come we aren't like chimps, with eternally shredded bodies and cheese grater abs, provided we get the protein to support them?
There are several reasons: Chimps have a higher density of testosterone receptors with a higher sensitivity than humans. Compared to humans, they are essentially roided out all the time.
Humans are also hairless endurance hunters so we naturally have much larger fat reserves (15-25% of body weight vs <10% for chimps) in order to retain body heat and have enough energy to hunt prey till they collapse from exhaustion.
Not to mention that we really are much more similar to chimps than they’re giving us credit for. If we ate a relatively low calorie, high protein diet, and maintained an active lifestyle, we’d all be pretty damn muscular and lean. Not roided out muscular, but far more so than I think the average person expects. Our body composition is significantly determined by relatively near-zero fitness demands in modern life and an overabundance of the wrong kinds of calories
Yes just 150+ years ago most field work was done by hand, including moving rocks from fields, plowing with an animal (and a lot of human strength too). Just clearing new roads was mostly manual work.
(Sure, you could blow up things, but then you still had to clear the bits and level the road. Yes horses existed, but mostly it was just people.)
Every activity took more physical effort, everything was maintained manually. Even if you were a bookkeeper, it was all hand written, and any math was with a slide rule or on paper, or in your head. It takes more calories to move a slide rule than work a calculator, more to write than type.
And all the while, the muscles of the arm, and the upper body are being used as you press against that paper. Moving over a page meant arm and shoulder and back and more got a bit of workout. Every little bit added up.
Now we often type without moving our upper arms or shoulders. Without a change in back or upper torso movement.
It takes more calories to read than just sit still, more calories to think deeply than not.
Even going to the bathroom meant putting on boots and coat, and walking to the outhouse.
Yes indeed. People 100 years ago were more or less jacked on average from necessity alone. Better or worse I don't know but I do like me some menial labor on the reg.
Heat retention would benefit an ambush hunter in a cold climate whereas heat exhaustion is one of the ways endurance hunters catch their prey in hot climes.
> Humans are also hairless endurance hunters
It's something we can do but the diversity of habitats, prey and techniques humans feed themselves with is far greater than what feels like an over-indexing on specific extant savannah tribes as if they are proto-human relics. Do you need to out run a fish or an oyster? Why would you run after a rabbit instead of waiting for it near it's burrow? etc.
Personally I bear little resemblance to an endurance runner so one might assume no shortage of forest/mountain dwellers in my genes given short thick legs. Built for sprinting, climbing and carrying but, to my despair, incurably injury prone at endurance running.
> Humans are also hairless endurance hunters
really? who said that? just one of many tactics we use. and obviously weve evolved to be good runners, we're bipedal. i imagine ostriches are similarly built for long distance running
> If Ozempic is so great then how come our bodies don't just produce more GLP-1?
To store calories so you don't starve. This is a failure mode of evolution and there is in fact "free lunch" when we use technology to reoptimise our bodies to calorie abundance
> when we use technology to reoptimise our bodies to calorie abundance
replace "calorie abundance" with "sedentary lifestyle" and youre there. its people eating more than they burn off because they dont exert themselves because thats what being an adult means.
For part of my life, I was extremely athletic, and after five kids, I did not have time for 6+ hours a day of exercise. Doing one hour per day seemed to do nothing to offset middle age metabolism combined with a high carbohydrate diet.
The interesting thing is that once I switched to a keto diet, my body mass changed and my health improved significantly for the better. The interesting thing is that the keto diet is actually higher calorie than the high carbohydrate one.
I suspect that telling people they need to exercise more is not helpful - most people will never be able to exercise at a level that will make a dent in their diet. A lot of people are eating 4,000+ calories a day of high carbohydrate diet burning 50-200 calories per hour. The math just doesn't work. The diet is where it is at.
I imagine a hunter gatherer doing one hour of physical activity a day would not survive for long. Your body is probably working as intended. It is your lifestyle that is incompatible not the other way around.
Plenty of ways around it. Some people have a treadmill or spin bike desk setup. Powerlifting doesn’t take much time. You can also eat less.
You can't outrun a bad diet. You can easily out-eat any exercise though. Check just how few calories stationary cycling for an hour burns. I can eat that many calories in 5 minutes.
Calorie abundance is accurate too, food has never been as cheap and delicious as it is now. Not to mention the ultra-processed high-density foods we have now.
Meaning you can easily overeat with an active lifestyle too. In fact we have entire sports in which it's beneficial to do so.
(Rugby/American Football, Strongman competitions and Sumo wrestling to name a few obvious ones)
Not just delicious...dangerously, addictively, delicious.
I don't by Doritos because for me, any size bag is one serving.
On Zepbound and it's stunning how my favorite beer...the one I craved and tasted so good 'why don't I have another?'...no longer has a hold on me. I could take two or three sips, set it down, and walk away.
I also now feel full, but not disgustingly over-stuffed now.
> replace "calorie abundance" with "sedentary lifestyle" and youre there
Our lifespans have increased with our sedentary lifestyles.
Exercise is part of it. But we’re clearly working to transcend our natural health spans in a comfortable, modern environment. That will require the application of intelligence to the problem, not just brute force.
> If Ozempic is so great then how come our bodies don't just produce more GLP-1?
Idk, why can’t we synthesise vitamin C? Why do we have a bent oesophagus prone to choking and heads bigger than womena’ hips?
We weren’t intelligently designed. To the degree we were optimised for anything it isn’t the modern environment. A lot of pushback against medicine in general seems to derive from an underlying belief in an innate perfection of human biology.
Both of your examples have no straightforward solution. Whereas we already have the mechanism in question so the question "why doesn't it just ramp up" is quite reasonable. Biology is a highly tuned system.
In humans? No. In our ancestors and every other animal around us? Yes.
> we already have the mechanism in question so the question "why doesn't it just ramp up" is quite reasonable
Our species almost got wiped out in an ice age less than a hundred thousand years ago [1]. It's possible we had the ability to ramp up GLP-1, but that it got eliminated in a famine.
> In our ancestors and every other animal around us? Yes.
Right so my point is, with no smooth optimization path towards X in a given species the question "why doesn't species just X" has a readily available answer - because biased random walks are fickle and the pathway likely convoluted. Whereas when a smooth optimization path is available it becomes reasonable to ask "then why isn't species doing X already"? Assuming a long enough timescale then there must be some selection pressure preventing it.
I agree that the ice age is a reasonable hypothesis. If we were exposed to repeated boom-bust cycles of extended duration (ie multi-generational) then it's at least plausible that we gained some mechanism dedicated to preventing us from adapting in that direction.
Still it's an entirely reasonable question that needs to be asked when considering the potential for serious side effects. If the hypothesis is that this is actively prevented for historical reasons then we should want to see the precise molecular mechanism hunted down in order to validate that. Keep in mind that an alternative hypothesis would take the general form that ramping it up causes serious deleterious side effects in the long term.
It's quite like Chesterton's fence. There must be a reason so we would do well to understand approximately what that might be before tinkering.
> I’m now beginning to question if it’s closer to a weird vitamin that we face a systemic deficit of.
There's some studies suggesting that a big part of what influences someone to naturally be fat or skinny is tied to natural production of the GLP-1 hormone. Post-prandial readings of serum level GLP-1 show significant differences in lean people vs. obese people, with obese people have much less.
We don't have an understood mechanism yet to determine if it's causative - maybe it's yet another feedback loop we have with gaining weight - but it seems very plausible that the natural level of production is a determinant factor in just how susceptible you are to packing on the pounds in today's food-rich world.
Dominant subgroups in a species are dominant because their parents survived that last set of pressures (external death inducements) at a higher rate than other subgroups -- but won't necessarily see the same results with the current set.
Even 90 years ago, there was significant loss of life due to famine, so selection was towards people who could efficiently gain and store calories in a biological Keynesian strategy. Now we have the opposite problem -- abundance of life-sustaining food produced for cheap but good quality food is expensive (in the US -- many other parts of the world have their quality food cheaper but I digress). So there hasn't been enough pressure (external-induced death) for GLP-1.
As a species with a remarkable ability to modify its environment to suit our purposes, body response to disease is just another thing to modify.
> but good quality food is expensive (in the US -- many other parts of the world have their quality food cheaper but I digress
Let's digress.
I read this frequently in various forms on this forum, and it's always "just so" justification. My own heuristic thought is that "low quality" food (high energy, long shelf-life processed foods) is very cheap because it is produced at scale and can be stored, while "high quality" (fresh products) is not cheap for the opposite reason.
The US has the cheapest food in the world [1]. Expensive food is expensive, but I would bet quality food is cheaper here than anywhere else. The "problem" is that when presented with a cheap, easy, tasty, high calorie food option against a relatively more expensive "quality" option, consumers choose the former because it's cheaper, easier, tastier, and provides more calories. I would bet this is even true when the absolute difference in price is small.
> Expensive food is expensive, but I would bet quality food is cheaper here than anywhere else.
Having lived in a few other countries with less industrialized distribution networks, no, this claim is dramatically incorrect. Fruits, vegetables, staples like rice, and basic forms of protein (fish, insects and sea critters, some chicken) are much, much cheaper relative to processed foods. Larger protein sources like beef, pork, or bushmeat is relatively more expensive, however, unless you opt for poor quality processing like cheap "corned beef" made from offal.
As an economist, I appreciate the difficulty of making apples-to-apples comparisons across countries for things like food prices, as even the acclaimed "Big Mac Index" assumes that a Big Mac has a similar relative status across countries (though the oft-misunderstood intent of the Big Mac Index is to more to compare consistent production costs). In some places a Big Mac is fancy, in the US it is considered fairly garbage but consistent.
For example, in a market in the Philippines, you have mostly cash transactions and informal capture for what the majority of people purchase. The purchasing is done more in these almost farmers-market style transfer versus grocery stores in the US. They _do_ have grocery stories, but almost uniformly for processed food distribution versus fresh food in the markets. It's much cheaper to eat healthier from the markets and through the informal distribution network of sari-sari stores versus equivalent nutrition from processed food from the grocery stores.
I'm not arguing whether fresh food tastes better or is healthier. What I want to see is evidence that "quality" food is (relatively) more expensive in the United States than it is anywhere else in the world. And then maybe some evidence that people buy junk food because "healthy food" is too expensive (my hungry teenager looks in the pantry and the refrigerator and says, "all we have is ingredients").
> my hungry teenager looks in the pantry and the refrigerator and says, "all we have is ingredients"
Matches my experience. I too would contest that reasonable quality food is more expensive. In my experience it's actually somewhat cheaper by any metric except $/calorie and even then you could just add butter or oil to the "healthy" alternative to juice the numbers.
I think the primary differentiator is convenience. Grabbing an actually rather expensive box from the cupboard beats out spending 30 minutes cooking and another 10 cleaning.
"No free lunch" is not good intuition for many biological processes. There has been near zero evolutionary pressure toward improvements that primarily manifest after age 60.
Separately, evolution took place in a very energy and calorie constrained environment which is very dissimilar to today's world. Many people do not feel spontaneous desire to fast or run laps even though these are clearly beneficial.
I'm one of those watching on the side, wishing there would be a holistic, aggregated, view on all pros/cons that highlight each results statistical relevance as well (in particular it'd be great to understand test samples).
On the natural evolution. I think it's best to think of it as a proces, with optimal state being a limit (e.g. in time, in total population), but especially in a changing environment. So, as it became easier to procure/produce fats or sugars there can be local sub-optimal states. So, in this framework, th "how come our bodies don't just produce more GLP-1?" question, can be answered with the fact that it's possible that we just haven't adapted yet. If we end up back to previous availability.— e.g. we lose farm land and "starve" again it would end up being the right evolutionary speed, if not, those that naturally produce more, may end up becomign majoritary.
The bottom line is that natural evolution is a long term process that's adapting things to long term changes and "long" here can mean many generations.
In a sense, philsophically, I wonder what prevents our own "changes" to be just a natural evolution of the natural evolution— i.e. a "conscious" evolution.
I always wondered if evolution through natural selection has essentially halted for humans for the most part. My thinking is even the previously most likely to die before child bearing has been reversed by modern society. Given that it happens at such a long time scale and modern humans and technology hasn't be around that long in the grand scheme of things it's probably not true, but I always found it interesting...
> if it would improve the evolutionary fitness of the majority of people
Evolution led to the intelligence that led to creating Ozempic. Maybe that's the mechanism by which evolution is improving evolutionary fitness. The idea that what was created by man is not part of evolution is part of the naturalism fallacy; it's the false belief that the domain of nature stops at the doors of the lab.
As I understand it, species that are really good at healing from injuries are more likely to develop cancer. So evolution has to optimize for survival via healing vs survival via not getting cancer.
Some people probably do come at it from the moral angle. But there are good reasons to assume that this time isn't different, that there is indeed no free lunch. Thankfully, everyone is free to make that risk assessment themselves. Just don't start trying to force it on anyone.
It seems like you really missed the point. Of course there are reasons we still get cancer, just like there are reasons people get fat. Evolutionarily people are way more likely to die of being under nourished than over, so the body packs on fat when it can. Evolution did not optimize for 2025
> Some people probably do come at it from the moral angle. But there are good reasons to assume that this time isn't different, that there is indeed no free lunch.
I'm struggling to understand what these sentences even mean. A medication may have side effects? Like every single medication we take? Yeah, of course it might. We don't have threads clutching their pearls about most medicines though. Tylenol can easily kill you if abused, but we don't have threads talking about how there's "no free lunch" for people using Tylenol responsibly.
> Thankfully, everyone is free to make that risk assessment themselves. Just don't start trying to force it on anyone.
Who is saying anything about forcing something on you? Is someone trying to force you to take Ozempic?
Yeah, I guess I don't really know what your point was if it wasn't to ask why we get cancer. Maybe that's my fault?
> A medication may have side effects
... beyond the initially understood ones. Tylenol has been around for a long time. When it first came out, people were probably popping it like candy until they realized the limits, and now it's pretty well understood.
And who cares if people are "clutching their pearls"? What harm does that do?
> Is someone trying to force you to take Ozempic?
Not yet, but I won't be surprised if people start pushing for it. Think about things like soda laws and seatbelt laws. If my being obese is costing you tax or insurance dollars and we have this magic pill, it's only a matter of time before the machine does its thing.
People clutched pearls about mRNA vaccines and now the US is ending all funding for them because one of those nutjobs is running HHS, this will cause an untold amount of harm and deaths. The truth matters, but unfortunately not as much as the narrative.
What does "pearl clutching" have to do with the truth? The whole point is nobody knows what the outcome will be for people being on these things for weight loss long term.
Some people think things will be great, and we've already got everything figured out. Other people are not so optimistic. Neither side knows the future. There is no "truth" here that you have exclusive access to.
This is why I said it's great that everyone can make that risk analysis themselves. If someone comes along and takes these meds off the market for no good reason, then there's something to complain about.
> The second point I haven't seen discussed is that weight loss drugs prior to GLP-1 agonists include cigarettes, which (worst case) give you cancer; [...]
Nicotine works just fine as an appetite suppressant without the carcinogenic tar you get from burning tobacco leaves. Similar for other stimulants or stimulant-like substances.
But I agree that they get a bad reputation, despite actually working pretty well, and with manageable side-effects: not worse than what I've heard about the nausea people get on GLP-1 drugs, and much better than the health effects of obesity.
Nicotine, even without the tar, reduces your nitric oxide levels leading to vasoconstriction, damages endothelial health, and can lead to atherosclerosis. You're much better off eating less and making more time to exercise instead of ingesting foreign substances to compensate for bad habits.
> "No free lunch" is a reasonable question to ask when evaluating medication, if it would improve the evolutionary fitness of the majority of people. I think this is behind some of the skepticism. If Ozempic is so great then how come our bodies don't just produce more GLP-1?
We can do science and technology on timescales vastly faster than evolution. "Why didn't evolution do it?" is just a very irrelevant question.
> The second point I haven't seen discussed is that weight loss drugs prior to GLP-1 agonists include cigarettes, which (worst case) give you cancer; stimulants, which cause your heart to fail; parasitic intestinal worms, which can kill you but more importantly are just plain gross; and mitochondrial uncouplers, which set you on fire at a cellular level. That's a long history of miracle weight loss drugs which turn out to have horrible side effects.
Cigarettes, parasitic worms, and 2,4-DNP were never medications.
Tobacco, and cigarettes in particular, has been used as a medicine for hundreds of years. And it's not just in the distant past - a friend of mine was actually prescribed cigarettes for anxiety about 30 years ago here in the US when he was 14.
There are various health benefits to smoking, believe it or not. They're just outweighed by the downsides.
I agree with you overall, but humans atrophying muscle away so rapidly, and also building muscle so quickly, is fairly unique to humans so im not sure there has to be a downside to being shredded all the time like a gorilla through some sort of medical treatment in the future. We certainly haven't figured that out now, but I wouldn't be surprised if some gene therapy and chemical cocktail couldn't allow it safely someday. From everything ive seen it seems to be just a calorie saving adaptation so more energy can go to the brain. And perhaps make more varied and specialized living strategies, made possible thanks to our brain, more efficient by not supporting large muscle groups we don't always need.
Of course maybe its not possible, but it is the default for pretty much every other animal so its not like it is trying something completely outrageous like trying to eliminate sleep.
> If Ozempic is so great then how come our bodies don't just produce more GLP-1
This strays too far into appeal to nature teritory. Evolution made us fit to reproduce not to age.
As for "no free lunch" - we do have a lot of that in medicine historically speaking: iodine salt, clean water, vitamins (C, D), iron supplements, hormone theraphy, vaccines. The field of medicine is no stranger to free lunch.
By "no free lunch" I meant that any change which evolution could easily have led to, but didn't, has likely not been evolutionarily advantageous for long enough or with great enough selective pressure to happen. Emphasis on "easily", "likely", and "long enough"/"great enough".
I don't think evolution could easily have solved most dietary deficits, manufactured clean water, prevented every endocrine condition, or designed vaccines for us. I'm not even sure what that last one would mean! These things are a nearly-free lunch because we live in industrial economies that can ship oranges around the world and build dams, but they're not an evolutionary free lunch. (And the loss of vitamin C production is argued to be an adaptation to starvation, too, just like we're arguing that lower GLP-1 is an adaptation to starvation: https://academic.oup.com/emph/article/2019/1/221/5556105)
Exactly! Further for evolution in the larger picture, it is actually necessary for living beings to die at some point, because of overpopulation. Survival instinct of the individual is only necessary to achieve enough reproduction. Death after reproduction age is necessary for evolution.
The other side of this is related to morals. People learned self-discipline by having to moderate their diet. Replacing that challenge with an injection is another example of a world in which people are not challenged to grow as people, but merely go out and buy something to make themselves feel or look better.
People who don't experience difficulties moderating their diet and could flounder their "self discipline" are now on a level field with people who did have difficulties with their diet. So they feel threatened by it.
Another example of a world in which people are not challenged to grow as people; instead of being happy that more people can get healthy they dismiss the medical advances as "moral failures" since they can no longer feel superior.
I've worked out my entire life. Always one of the strongest people in the gym. Almost always overweight. Not obese but overweight. Once I had kids I really packed on the pounds. In January I got on GLP1s and over 4 months dropped from 6'1 at 240lbs to 209lbs. I'm 46 years old with defined abs and a bench of over 405lbs. My BP has gone down and I am in a healthy range for the first time in 20+ years. My cholesterol is perfect now. I feel 20 years younger. I stopped snoring for the first time in 2 decades. My wife sleeps like a baby now which is probably the most important change. I wake up and jump out of bed fully energized and rested for the first time in decades.
Sometimes people just need a helping hand. There is no shame in that.
It appears your issue is that you just don't think its fair and that people should have to take the long way. I would argue that's a you issue and not an us one.
I'm continually frustrated with the four thousand year old history of people being surprised that other people "don't just ${something good for you} and don't just stop ${something bad for you}." Great, we've tried the "Acting surprised people do unhealthy or bad things" strategy and the "scolding people for doing unhealthy things" strategy for a couple millennia and people still do the things.
Will we continue this strategy or will we try something else now?
youre distant ancestors chased every meal they ate. your more recent centuries old ancestors probably worked 6.5 day weeks, 12 hour shifts, and had to have all the children working as well, for a pittance. YOU on the other hand have no problem finding any kind of out-of-season food and probably drive everywhere, barely lifting a finger in comparison. THIS IS THE DIFFERENCE.
Why were there no obese (poor) people 100 years ago?
Exercise is undoubtedly good and has many benefits. Unfortunately it's not a realistic way to lose weight for most people.
Our bodies are just too efficient. We can't "outrun the fork" (unless it's our full-time job). We must modify our diet. Which is not easy for many reasons.
Of course it is an option - I lost 100 lbs this way, and kept it off more than 5 yeads. As you know, that's very, very hard.
But I think these drugs are awesome. I have family members who are obese and don't seem to have whatever I have that allowed me to lose weight the old-fashioned way. I hope they'll be able to lose weight safety with the drugs.
Of course it is, and I used to basically 100% agree with you but i've changed my mind over the years. It's so wildly asymmetric that I don't think this is a useful framing anymore.
what i mean is, on one side you have huge teams of absolutely brilliant well-resourced food scientists A/B testing their products to maximize addictiveness and other related metrics. On the other side you have a stressed out parent tired from a full day of work just trying to quickly get some food for their family.
This isn't fair! It should make you angry when you see regular people who are probably a lot more like you than you think being preyed on by others
That's only relevant if socialized medicine forces you to pay for the moral failures of other people, though. Spending your own money to feel better is widely accepted behavior.
Socialized medicine forces you to pay for the victims of drunk driving accidents, for when people shoot themselves in the hand with a nail gun, for the hospital bills of vaccine deniers ending up in the emergency room, for....
At some point I think you just have to accept that the whole point of socialized medicine is to just make sure people get healthcare regardless. If you want to engage in some kind of market analysis and means testing, you can always live in America, where it's guaranteed that people get exactly as much healthcare as they deserve, since net worth and liquid cash is correlated perfectly with an individual's moral success.
Unfortunately, for those who are obese no amount of diet or exercise will give them the "perfect" body.
I see many who were overweight lose weight and get ripped, while others have no chance to reach that far. Someone with a BMI of 40 has basically ruined their body and while they may look better with a shirt, they will keep it on while on the beach because of the excessive skin.
The reward and motivation for a person with a few pounds extra and a truly obese person are simply too different. Someone who has not reached whatever weight threshold that fits their body type has a chance to look "normal", while the more obese person will reach a point where losing more weight has less impact even after plastic surgery.
This has failed though. Over 40% of Americans are obese. This costs us as a society hundreds of billions in healthcare costs, much of it federally subsidized. Being obese is a simple choice now, one can choose to be fat or choose to take a once weekly shot and not be fat.
Take Elon Musk, he is clearly overweight. Is your argument that he lacks self-discipline as a person and is as such a complete failure? Of course not, the man is clearly more disciplined and driven than most people. He just eats like crap as he has other priorities.
I am open to you explaining the argument as to why 40% of people being obese so that they have to learn self discipline in just that single area of their life and all of the associated social, health and financial costs is more beneficial to society as a whole than people taking a shot and losing weight and gaining all of the benefits that being obese robs society of.
Society evolves as its technology does. I'm sure its not the case but your argument appears to devolve to "Back in my day we didn't need a shot to be thin like you young kids, we walked up hill both ways to school with our little brother on our back. IN THE SNOW!"
Honestly, this is essentially BS. I'd say that 95% of healthy weight people stay that weight because their metabolism and appetite works properly. People who stay in shape by paying careful attention to their diet are a tiny minority.
Where I live (Spain) there’s a massive intergenerational gap between how our parents ate and how we eat and exercise. A huge number of people around me go to great lengths to control what they eat and make an effort to move. I see it at the beach, at the restaurant or at the gym. You can ask anyone in the older generations if younger people are physically healthier and you’d find an almost unanimous yes. Coincidentally we have one of the highest life expectancies in the world. None of this is given.
I am not sure I would rely on observations of gyms and beaches for whether people are healthier for fear of selection bias. Going to the beach and seeing mostly fit bathers is like going to the hospital and seeing mostly sick people and thinking that can be generalized to society.
Why would you ask old people if young people are healthier than they were? Surely, Spain compiles medical statistics.
Anyway, Spain appears to have the same weight issues as everywhere else:
> Coincidentally we have one of the highest life expectancies in the world
Those numbers are relying on how long the older generation lives. If the younger people are physically more active, how do you know that they will also live as long? It could be that modern expectations of what a "healthy" body should look like takes it too far, and that you will end up with a shorter life.
I see a lot of former athletes dying in their 60s/70s from heart failures and other conditions. Perhaps the body has limits to how much abuse it can take.
> If Ozempic is so great then how come our bodies don't just produce more GLP-1?
Because our bodies have been tuned to deal with food shortages for hundreds of thousands of years. Now we live in an age of abundance but our bodies still try to harvest each calorie they can get.
If this continues we might evolve to no longer store surplus calories as fat. Though I doubt it because the age people die from overweight related issues is way after the age most people have kids at.
But I imagine that soon we will be able to directly tune some of that evolutionary bagage that no longer applies, by gene modification.
Our bodies haven’t evolved yet to produce more GLP-1 because until recently (~70 years ago) malnutrition and hunger had been one of the top killers of humans. Frankly put, we weren’t designed to live this long.
We’re designed to consume calories and store those calories indefinitely to meet short term needs, rather than lifelong health.
But we weren’t also designed to consume microplastics, artificial sweeteners, or flavors designed in a laboratory. Yet here we are. And it’s quite probable those things contribute to obesity.
> If Ozempic is so great then how come our bodies don't just produce more GLP-1?
We don't know. But one early signal is that you lose an atypical combination of muscle mass and not just fat, which is not a good evolutionary adaptation if you are an endurance hunter.
Natural selection optimizes for long term survival of genes. Humans are probably long-lived because we have high maintenance offspring and a survival strategy built around communicating culture, but this only necessitates survival through 2-3 generations worth of time. Anything beyond that won't be selected for.
Same with health, etc. A bio professor once said "life doesn't work perfectly, it just works." There's a lot left on the table because evolution optimizes for the median case over time.
> If Ozempic is so great then how come our bodies don't just produce more GLP-1? How come we aren't like chimps, with eternally shredded bodies and cheese grater abs, provided we get the protein to support them?
Evolution favored this level of GLP1, then we invented agriculture, and cooking, and bliss points. Now it’s far easier to ingest massive numbers of calories in ways that our old world systems can’t properly signal against. Evolution hasn’t caught up and maybe never will.
I would agree, personally - I won't go near DNP, and even the newer stuff like BAM15 that is supposed to be incredibly selective I am quite suspicious of.
But you still see people losing tons of weight on GLP-1s wanting it to go faster, drop more pounds, etc.
I'm a big proponent of them - and I have enough risk tolerance that I'm on grey market retatrutide - but I see a lot of people that want to just keep adding more and more chemicals to the equation to solve the issue. I've taken the time to significantly modify my food and exercise habits, and believe that I'll be able to maintain my weight loss if I were to go off of the GLP-1. But a lot of people haven't. They eat the same bad food, just in lower quantities, don't increase their protein and fiber intake, don't exercise, and just up the dose or add a new compound when their rate of weight loss doesn't satisfy them.
There's tons of interest in BAM15, clenbuterol, and all sorts of experimental substances. Tons of people taking things like tesamorelin and ipamorelin too.
I think the GLP-1s are basically miracle drugs that have allowed a lot of people, including myself, to totally revamp their approaches to diet and fitness. But there's a lot of people that are going to be more than happy to increase their cocktail with anything they think will get them skinny faster.
Uncouplers are particularly useful to make sure your metabolism doesn’t slow down, which makes getting off those drugs when reaching the right body fat percentage without regaining everything way easier
Losing weight through any method will make your metabolism slow down - fat is metabolically active. Uncouplers won't change this. Even if 100% of your weight loss is fat, your BMR is going to drop. The amount of metabolic adaptation from caloric deficits is grossly overstated by many people, and the "starvation mode" adaptation is temporary. Just reaching a maintenance level of calories for a relatively short period of time is enough to reset it - but this change is minor to begin with. The majority of any metabolism slowing will occur purely as a function of weight loss.
The issue with regaining weight after coming off these drugs is that people don't change their habits, and once they are off, they no longer have the limited appetite, and return to eating like they did before, which just results in the problem reoccurring. Uncouplers won't change this.
If people want to sustain their weight loss, they either need to change their lifestyle and eating habits, or they need to stay on the drugs, and potentially even both.
Let’s be real: both of us have no idea of how it would play out. Pharma companies will try to add them to their stack at some point, and then the real world data we currently lack will decide for everyone
we get fat because of the american diet, priori to which people in the world were actually not that fat
the lack of fermented food, the epidemics of ultra-processed, ultra-rich and grotesquely fat and sugary food is why people have gotten fat, which is a relatively recent phenomenon (and which is not as widespread in culture that resist the American diet the most like the French and the Japanese)
none of the things you cited are “miracle weight loss drugs.” they are things people did to lose weight. these are the first class of drugs that actually cause people to lose weight.
Amphetamine is actually a very effective weight loss drug. And it's sort of orthogonal to the fact that it's a stimulant. Stimulants in general can cause an acute reduction in appetite and temporary weight loss. This tends to stabilise with tolerance, however. As someone with obesity and ADHD, thus was my experience with methylphenidate treatment. And I used to think the weight loss effects of amphetamine were analogous until recently.
Amphetamine and methyphenidate(MPH) have very different ways of acting as stimulants. MPH is an inhibitor of the dopamine transporter(DAT) and the norepinehrine transporter(NET). These cross-membrane proteins essentially "suck up" the dopamine or norepinehrine after neurotransmission, thus regulating the effect. MPH inhibits this process, increasing the effect. This is called a norepinephrine/dopamine reuptake inhibitor(NDRI). Cocaine also works like this, as well as the antidepressant wellbutrin(bupropion).
Amphetamine on the other hand, is a bit more complicated. It interacts with DAT/NET as well, as a substrate, actually passing through them into the neuron. Inside the neuron, it has a complex series of interactions with TAAR1, VMAT2, and ion concentrations, causing signaling cascades that lead to DAT reversal. Essentially, enzymes are activated that modify DAT in such a way that it pumps dopamine out of the neuron instead of sucking it up. How that happens is very complicated and beyond the scope of this comment, but amphetamine's activity at TAAR1 is an important contributor. As such, amphetamine is a norepinephrine-dopamine releasing agent(NDRA). Methamphetamine, MDMA, and cathinone(from khat) also work like this.
Anyway, recently I was reading about TAAR1 and learned something new, namely that TAAR1, besides being and internal receptor in monoaminergic neurons, is also expressed in the pancreas, the duodenum, the stomach, and intestines and in these tissues, TAAR1 activation will increase release of GLP-1, PYY, and insulin, as well as slow gastric emptying.
So in essence, there may be some pharmacological overlap between ozempic and amphetamine(I'm still looking for data on how significantly amphetamine reaches TAAR1 in these tissues, so unclear what the relevance is. But amohetamine is known to diffuse across cellular membranes, so it's likely there is an effect).
Also interesting, amphetamine was recently approved as a treatment for binge eating disorder. Not only because it causes weight loss, but because it improves functioning in the prefrontal cortex(crucial to its efficacy in ADHD), which is apparently implicated in the neuropsychological aspects of BED as well.
There is a mixed picture on this. I see a lot reports of reports of it causing binging in the evenings despite no prior issues.
The issue is that therapeutic doses are not the multi-day bender of a speed-freak that forgoes sleep to keep their blood-concentration permanently high. Instead it's a medicated window of 6-12 hours with a third or more of their waking hours remaining for rebound effects to unleash stimulation-seeking demons that run wilder than ever.
The American Tobacco Company marketed cigarettes for women's weight control in the 1920's. Lucky Strikes 'Reach for a Lucky" campaign was a big example of this as well, although they marketed it as an appetite suppressant rather than simply a miracle weight loss cure.
Keeping in theme, Ozempic specifically has already been marketed off label as an appetite suppressant, rather than a pure weight loss drug. That's a more modern construct in its brief history.
I would guess that getting fat in times of plenty was a feature and not a bug in the ancestral environment, and that's why we get fat today, which is obvious if you think about it. Still, it means GLP-1 agonists are smacking into quick "is it bullshit?" heuristics for a lot of people.
The second point I haven't seen discussed is that weight loss drugs prior to GLP-1 agonists include cigarettes, which (worst case) give you cancer; stimulants, which cause your heart to fail; parasitic intestinal worms, which can kill you but more importantly are just plain gross; and mitochondrial uncouplers, which set you on fire at a cellular level. That's a long history of miracle weight loss drugs which turn out to have horrible side effects. It's not reasonable to think GLP-1 is bad just because of other drugs with different mechanisms, but it certainly causes some skepticism anyway.