There’s been a lot of hype on Twitter this year about how GLP-1 agonists [semaglutide/Ozempic, tirzepatide/Mounjaro] are “the miracle cure for obesity”.
God sent us ozempic and it’s going to solve every problem this country has
https://x.com/growing_daniel/status/1770888084919398847
But the clinical data and the anecdata both tell a much weaker, more mixed story.
Leo_Abstract: Seriously, though, has anyone else searched Twitter for ‘I tried Ozempic and it didn’t work for me’ stories?
I did. There are zero.
My prior on that outcome was <5%. Is Novo Nordisk running some kind of clever takedown? In the original trials it failed fully 1/3 of the time.
https://x.com/Leo_Abstract/status/1800679751704777081
[ note that “failed” here refers to “I barely lost any weight”, not “I couldn’t [ lose all the weight I wanted to and keep it off with minimal effort ]”, which is not the default outcome for GLP-1 agonists or for any weight management strategy ]
I genuinely have a hard time comprehending why the world is this way, but discourse around weight management is hyperfucked in a way no other face of health discourse is. Maybe we suck as a society at actually making there be a cure for cancer, but everyone agrees, we should want to cure it, period. End its existence. Eliminate it and all its effects from the face of the Earth. To some extent it’s also pretty easy to get people to go along with it if you start talking this way about aging. But weight loss? Not like that at all.
If there was a prophylactic drug that reduced rates of all cancers by half, even Twitter wouldn’t be cheering about how we’d conquered the cancer epidemic, and all that was left was for individuals to shape up their habits to make up the remainder of the gap.
I used to think this sort of made sense, because your weight is modulated by your willpower. Everyone knows - I’d even read Stephen Guyenet’s book, The Hungry Brain, which explains it scientifically - that some degree of overweight is an inevitable consequence of a prosperous society. Capitalism will sell you superstimuli, and your dumb lizard brain will overeat and shoot your body in the foot. It’s on you to be a responsible consumer and do some degree of dieting - unless you’d prefer to RETVRN to an environment that does the work of starving yourself to a healthy/endorsed/nice-looking/nice-feeling weight, for you. Of course it’s in-principle possible to fix the overweight of prosperity technologically - it’s in-principle possible to fix anything technologically. But fixing “my basic physiology combines with the desires of mine that I least control to produce weight gain” technologically seems to require either Solving Medicine, or wildly dangerous hunger-bypass neurosurgery, neither of which I could expect in my lifetime. So why think of it as a technological problem, instead of a willpower problem?
Then I found out that the calories-in-calories-out model of weight maintenence [“you eat 3,600 kcals over your calculated basal metabolic rate, you gain 1lb of fat”] is totally, laughably biologically false. Many sources say people ate more in the early 20th century than we do today, and yet obesity was rare [h/t Yudkowsky]. Lab rats induced by a palatable diet to “overeat” by 50% barely gain fat mass. Then I realized calories-in-calories-out was obviously insane. The units in 1lb = 3,600kcal don’t cancel [the dimensional analysis comes out to [constant]*kg on one side, energy is work [ kg m^2/s^2 ] so J = [constant]*kg m^2/s^2 on the other]. Why would your body be tracking the abstract notion of Energy, or operating on it in any way? No machine does that!
And now I’m looking at all these people cheering about how Ozempic is the cure for obesity because it helps some people lose some weight, some of which is even without conscious exertion of willpower [!], and going to myself, “. . . no, it’s not.”
You haven’t cured something until you’ve cured it. And with the way GLP-1 agonists were discovered - as a class of antidiabetic drugs that just happened to help patients lose weight rather than forcing them to gain it - we shouldn’t expect it to be a cure for overweight. We weren’t looking for a cure for overweight [we didn’t even bother trying to understand overweight!] so we didn’t find one. Exogenous insulin was first trialed as a diabetes treatment by someone who basically understood what Type 1 diabetes was - that it was a deficiency of the body’s natural insulin production - and how much insulin the body should have in it. GLP-1 agonists for weight loss are the same kind of accident as the invention of the microwave: the kind of marginally nice thing that a functioning civilization that does any R&D, spits out occasionally, but which doesn’t, by itself, fix a poorly-understood complicated problem.
Ozempic and Mounjaro activate the receptors for GLP [glucagon-like peptide hormone], for a longer period of time than the body’s natural GLP does. This has various effects that are frequently described as, approximately, “I seemed to magically lose weight”, “I feel less hungry”, “I feel full easier”, with a common side effect of “I feel less motivated to do anything”.
What is the mechanism? You would think we would know. But it’s even harder to answer the question “Why does Mounjaro [ever] work?”, than it is to answer the [also unanswered!] question “Why does Ritalin [ever] work?”.
Because GLP is one of those signal molecules like serotonin [only way more so] that actively straddles the boundary between “brain hormone” and “gut hormone”.
We know that, after eating, it’s released in the small intestine, and in the hindbrain. We know it slows digestion, raises insulin levels, and induces a feeling of satiety. Apparently it’s supposed to make [probably “hypertrophic”, ie too big instead of too numerous] fat cells divide and become smaller [which possibly helps via something something vascularization?].
But there would be simpler ways to just elevate insulin levels if that was the major problem. And leptin also induces a feeling of satiety. And fat cells are getting hypertrophied in the first place for some unknown underlying reason. And there are all these people for whom Mounjaro isn’t an overweight cure.
GLP-1 drugs have a fairly predictable directional effect on the body’s weight regulation system - a downward effect - but they’re operating on a quasi-random slice of a vast tangle of hormones and metabolic pathways that we don’t understand at all - a slice so ill-specified, the description of “cure” so Texas Sharpshooter-ed around this shot-in-the-dark that hit by sheer luck - that our slice contains both brain and digestive system, and we can’t recognize any single causal through-line at all.
Cures look different from this.
[ Praise Be To The Olive Oil, Which Works [At All] On Me. ]
People in the past ate more, yes, but obviously also expended more energy. A hundred years ago in Finland for example the average intake was like 3500 kcal per day, but then that was a society of agricultural manual labour.
The mice make for an interesting, big-if-true type of data point. I have another. I, as any gymrat is wont to do, have done a bit of a laboratory experiment on myself. When I’m cutting, my weight exactly tracks the loss expected by calories in calorie out model. At one point my diet for cutting included a package of Oreo cookies every day, which made no difference, calorie in calorie out.
My background is that I suffered of obesity all my life until I discovered that no actually if you just stop eating once you hit your daily calorie quota you can choose how much do you want to weight.
So in light of all this I hope you don’t mind my saying that calling calorie in calorie our obviously insane is, uh, obviosly insane. In fact to me it seems that Yudkowsky is emotionally very invested in believing that it is impossible to affect one’s bodyweight, and his judgement on the matter is clouded.