Hacker News Reader

> 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.

Time is the key for evolutionary concepts here; abundant food (sugar), abundant sedentary lifecycle availability, abundant antibiotics / vaccines, -- are mostly still in their first generation of generational "study" -- in the developed world; ie an American born post World War 2.

And that's being generous, because the food industrialization (removal of fiber, concentration of sugars), and cultural norm of consistent fast food is much more in line with the tail end of millennials than any generation before.

Of course we're not seeing evolutionary pressures for diabetes, when, at the same time we've generally increased life expectancy past reproductive years.

Most basic factoid: Insulin was discovered in 1921 before Penicillin in 1928, before the Polio vaccine in 1950.

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.

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.

> 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.

Also revisionist is sedentary lifestyle, which still isn't as true in many regions of the world.

In the past 50 years, we have the normalization of computers / fax machines, fast food, fast commercial air travel.

In the past 75 years, we have the normalization of suburbs, television, and personal automobiles, personal phones.

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.

Modern food companies did discover this; through concentrated sugars and reduced fiber, arguably with increased use of oils too.

Side effects:

- Additional Consumption (sugar, HFSS, caffeine, etc)

- Lack of Satiation (less fiber)

- Quicker to Grow food (less fiber)

- Longer shelf life (less fiber, more oil)

> 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.

>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.

>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.

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.

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.

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.