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greyenlightenment  investments: META/FBL, TSLA, TQQQ, TECL, MSFT ...  1yr ago (npr.org)   2639 thread views

Eli Lilly releases data for a new weight-loss drug to tackle obesity : Shots - Health News : NPR

npr.org

This drug is a true gamechanger

In the SURMOUNT-1 study, people who took the highest dose of tirzepatide, most of whom had a BMI of about 30 or higher but did not have diabetes, lost about 21% of their body weight during the 72 week study. As researchers point out, for people who have bariatric surgery, typical weight loss is about 25% to 30% of their weight, one or two years after the surgery. In the tirzepatide study, 36% of people taking the highest dose lost 25% or more of their body weight.

this is comparable to bariatric surgery

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This is what I was afraid of. As more evidence mounts that the obesity epidemic is caused by something environmental (either a change in dietary composition or a toxin of some sort), a "cure" has arrived just before the root cause has been proven. Instead of targeting the root cause and removing whatever is causing obesity from the environment, slimness will now be sold to those who can afford it. I think even if researchers identified the cause of obesity, there would be a lot of incentive to keep the obesity train rolling, to everyone's detriment.

And obesity is just the most visible symptom of metabolic disease. Could we still be at increased risk of cancer, heart disease, etc even with these miracle drugs?

I'm not suggesting any explicit conspiracy here, but I can't help notice a terrifying convergence of incentives. One corporation makes money by selling us cheap, addictive, poisoned food. Another corporation makes money by selling us a partial cure for the poison in our food. The incentives align to never, ever find a better solution to this problem, and to suppress it if it is discovered.

The environment is super-calorie dense ultra palatable food. compare a food store today to 70 years ago.

According to your theory, what is the path from tasty calorie-dense food to a decrease in basal energy expenditure (BEE)?

the problem is the "CI" side of "CICO"...a tiny cookie has 70 calories. It would be effortless for a typical person to overeat them.

But why is the typical person storing the calories as fat, instead of raising their temperature by .3 degrees or making them energetic? And if they are overeating, why are they not feeling satiated? When I'm satiated (not just "full" or "no longer hungry") I have no desire to eat anything at all. The idea of eating becomes repulsive.

You seem really confident that people are eating more now than is historically normal. Outside of war or famine, I've seen evidence that people in the past consumed many more calories.

Did the French eat less than Americans in the 30 year period when the obesity epidemic was exploding in America? The answer is absolutely not! The french “disappeared” an additional 214 calories per day per person during this time. This means that a 50 year old living in America in 1990 would be four times as likely to be obese as a French person despite being responsible for disappearing 2.4 MILLION less calories between the ages of 20 and 50.

It also looks like the median American ate around 3500 calories a day in 1939.

Do you have any evidence you've seen that we are actually eating more calories today?

I've presented evidence that the calories out side has changed, not due to activity going down, but due to people's basal calorie expenditure going down. The amount of calories someone in 2020 burns just by sitting on the couch is less than the amount of calories someone in 1920 burnt by sitting on a couch, and according to the researcher, "The surprising conclusion is we spend less energy when resting now than individuals did 30-40 years ago! The magnitude of the effect is sufficient to explain the obesity epidemic."

Even if we are eating more calories today, and this is due to increased convenient "hyperpalatable" foods, do you have any explanation for the decrease in basal calorie expenditure? (Keep in mind, this is not referring to total energy expenditure, it cannot be explained by saying we're less active today because that is not what is being measured.)

because humans store excess energy as fat, unlike other animals, which do this more poorly. This seems more possible than humans somehow having a slower metabolism over timeframes that cannot be explained by evolution

I am sorry if I gave the impression that I believed there was an evolutionary selection pressure to lower BEE. However, now might be a good time to point out that the earliest mammals had ways to store fat and enter a state called Torpor - low body temperature, high fat storage, low energy expenditure, higher hunger levels. Echidnas are one of the older branches from the mammal family tree - they lay eggs and exude milk from their skin instead of concentrating it in a nipple. They enter a state of torpor. Bears famously enter a state of torpor. It seems to be common to mammalian metabolism and remnants of it remain in most mammals. It is almost universally useful, for humans included, to lower metabolism during famine, dry periods, winters, etc.

When mammals are not in torpor, they store body fat in a specific ratio: Saturated, Mono Unsaturated, and Poly Unsaturated fats are 4:5:1. When it is time to enter into torpor, mono-unsaturated foods become more available and body fat becomes more unsaturated, closer to 2:7:1

There are a lot of mechanisms that go on inside a cell that can cause a metabolism bottleneck. Once the bottleneck occurs, they body can no longer expend the calories as energy and instead has to store them as fat. I'm not going to go into it here and now. When I get around to it, I will write an effort post on this and will tag you.

I think it is more likely that this is an effect of the other major cause of obesity: A Decrease in physical activity.

It sounds like you didn't read the twitter thread in my first post, but Active Energy Expenditure (AEE) has actually increased over time. Basal Energy Expenditure is the amount of energy you use just to keep alive. Adjusted for body composition (it's known that muscle expends more basal energy than fat), the amount of Basal Energy Expenditure has decreased over time.

How do we get back, then?

That is the question, isn't it? This playlist looks into a lot of what might have gone wrong. His primary theory is substituting poly-unsaturated fats (PUFA) for saturated fats, but there are a few other things we could be looking at.

Unfortunately that just tells us how to stop digging the hole, it doesn't tell us how to fix it. There are people who report removing PUFA and increasing Saturated fats stopped weight gain, but it didn't make their weight go down significantly. However, it did make their temperature go up, which might be an indicator their BEE went up as well.

In any event, someone's paying for them. It's a huge inefficiency. We're paying somewhere for food or a toxin that makes us metabolically diseased, then paying someone else for a drug to get rid of one of the symptoms. Besides that, obesity is becoming a problem even in poorer countries, countries where the government cannot afford to pay for medication for each of their citizens.

It also worries me from a health perspective that we are treating it as an overeating problem, and solving it by making people less hungry, instead of addressing the fact that our basal metabolic rate has decreased a significant amount in the past century.

Can the decline in BEE be explained by us just being unfit skinnyfats?

They say that it has been adjusted for body composition and age. Also, look at this comparison. Female athletes in 1986 had a lower BEE than the average woman in 1919.

Excellent. Since these drugs work by suppressing appetite the government should fund the creation of a related GLP-1 agonist that it owns the patent on then distribute them for free to everyone in the country on demand (cheap since gov owns patent). The people taking the drugs will be significantly better off, the savings on food stamps etc. will be enough to make up the few billion development costs in a few years and as a side effect there will be fewer ugly people on the street. Win win for everyone.

Put it in the toothpaste. (Yes, it's a reference.)

As NPR has reported, when patients can't afford to stay on obesity medications, they are likely to gain much of the weight back.

If I were Eli Lilly and Company, I would invest into food science, trying to make as many different hyperpalatable foods aimed at teenagers and young adults as possible. The more people have BMI of 30 by the time they are 30, the bigger the market for their drug is. Imagine the government first handing out food stamps to poor Americans, then paying for their obesity treatment via Medicaid.

I'd guess that if the drugs are really effective and the collective societal BMI starts going down, it eventually creates a feedback cycle where obesity generally becomes less and less acceptable and thus there's going to be less people having BMI 30 by 30.

Alternatively people are going to start pigging out even more because now calories are consequence-free until, miracle drug or no, something gives.

As I understand, the miracle drug in question is an appetite suppressant, not something that supercharges your metabolism like the drug in Doctorow's Makers.

Maybe one day, we'll get that crazy food pill thing like in Naruto where it instantly burns all your fat for a rush of energy.

Can't decide if I'm relieved or disappointed.

i doubt it. type 2 diabetes can be attenuated with diet modification yet society tolerates it. Down Syndrome is tolerated even though it can be prevented with prenatal screening.

Neither of those is a particularly good comparison. Down Syndrome is not something you can "fix" anyway, there's never going to be a miracle drug for it. Type 2 diabetes is not immediately visible (conditions like obesity that are visible make it more likely, but being obese does not guarantee you have diabetes and having diabetes does not necessarily mean you are obese).

What I mean here is that I suspect that simply having more obese people all around us has made us more tolerant of obesity in general (personally or in others) than we would be otherwise, or society would have been some decades past when obesity was less common, and having actually effective weight loss drugs available would then mean less obese people around us and the pre-00s greater-than-current disdain for obese persons returning.

I don't think this will change anything. Trans people, for example, are just 1% of population yet trans rights/inclusion has exploded

What do you mean by Down syndrome is tolerated? We do screen all pregnancies for Down syndrome and terminate pregnancy in case of positive test. Sometimes the screening test is not done or the test fails but those are exceptions and not the norm.

who is we? where? this is not true in the US. that is the decision of the mother.

It always should be. But the idea is that almost always the decision is made to terminate the pregnancy. That's the point of making the test. Maybe in some countries that percentage is still not sufficiently high due to poorly understood information and we should think how to improve that.

Who do you mean by "we"? My understanding is that the rate of abortions after testing for Down Syndrome vary pretty heavily from country to country (googling around, seeing USA around 67%, France around 77% and Denmark around 98%, though that's from 2011).

Though I guess the real issue here is referring to "society" tolerating something when of course what "society" tolerates varies a great deal from one part of the world to the other (for now, at least).

Down Syndrome is tolerated even though it can be prevented with prenatal screening.

Statements like this really make you appreciate how hard AI alignment will be. We can't even get humans to reliably differentiate between "prevent illness" and "kill sick people and replace them with healthy people".

Down Syndrome people aren't 'sick'. Having Down Syndrome is their default state. It's not a sickness, it's congenital.

Now, why are we equivocating between abortion and murder?

Alignment is easy. Agreement is hard. The Bailey is «aligning the AI to the generic mode of operation where it makes sure the user's intent is understood correctly and does not go all monkey's paw». The Motte is «having the AI align the future to your preference, very much not obliging the user when the instruction is against my preferences».

This is the general problem of politics.

Body-positive cultural genocide.

Are "whales" really where McDonald's makes its money, as if it's like a company putting out free-2-play games for PCs and smartphones? I remember the iconic message you'd sometimes see spelled out on those signs outside: "Over 1 Billion Served." I'd assume that McD's business model relies less on sporadic-yet-still-plentiful gluttons and more on the literal billions of average joes who might choose the convenience of a double cheeseburger, fries, and a drink at least every once in a while.

That said, I'll acknowledge that your basic point might still be right, that this might be at least a small disaster for certain parts of the food and drink industry.

"Billions served" wasn't about the number of unique customers. By the time they stopped posting the counter in the 90s, they were up to 100 billion. It was the number of orders served.

Even so, I think they didn't get to that number by skimming for the obsessives.

You don't have to be a whale to be a regular customer. A Big Mac, a small serving of fries and a diet soda is a perfectly cromulent lunch. A bit high in fats and tastes like nothing, but generally fine if you're an office worker. Hell, you can have the same setup for dinner and an Egg McMuffin Meal for breakfast and you'll be fine as a "thrice a day customer".

Of course, upgrading to medium fries adds 90 Cal per serving, a single packet of ranch is 110 Cal more, a small soda is 150 Cal, boom, you're eating 700 extra calories and putting on weight without being a "whale" that eats ten burgers every day. And that's without any other snacks and creamy sugary coffees the same person might have throughout the day.

but the way that their discounting/deals are structured suggests a keen awareness of this in practice

That wasn't my initial read of what the coupon books and occasional mobile discount appear to be for; I believe that's more to convince the semi-regular customers to find it worth coming to the store (given that they're basically 2/5ths off what a single person would want to buy). Sure, it's still perfectly possible to go full whale at that point, but I'm not sure what the amount of crosstalk is between coupon users and those who spend 40 for one big meal.

Or maybe those milkshakes are far more popular than I think they are, since that's probably the cheapest way to maximize calories.

The sheer difference in revenue between a 'twice a day' customer and a 'twice a year, when drunk'

There's a lot of middle missing in that statement; people who are too lazy or busy to pack a lunch or cook dinner tend to be people who visit fast food places semi-regularly. They're also the ones that respond well to those discounts. (Maybe it's a universal human experience to consider this a failure?)

I'm relatively certain that (though my sample size is small) with respect to "whales" the source of their size is diffuse factors and not from any one source in particular; I think packaged candy/chocolate/potato chip manufacturers will be most impacted because people don't need to re-buy them as much. Fast food tends to be people going from 0 meal to 1, less 1 meal to 2, so it's not "a magic drug that makes people stop going out to eat" and more "they only buy one meal's worth of food where they might otherwise buy 1.5-2x", thus they'll not likely be affected as much.

I think there's a large market of once a week customers (though I haven't gone to McDonalds in a long time.) Does McDonald's near you have a play gym? My mom would bring us there about once a week so that we could let out some energy.

It's an inexpensive meal for people who were running late and needed to get something on the way to work. Or couldn't go grocery shopping on the weekend due to a sick kid. The drive through has a huge appeal, especially when there's a one year old in the backseat.

I wouldn't eat at McDonalds (I can afford better options) but I can see the appeal. I would bet a large segment of the market is poorer families with young kids.

It's a disaster for weight loss industry . weight watchers, Adkins, nutrisystem, slimfast, and so on

These industries were never very large anyway (comparatively).

Now hold on, I'm pre-registering the prediction that it will have a tangible effect, but I'm skeptical it will be a wonder-pill that will send multiple industries into a downward spiral.

At least one industry (weight loss centres) is already feeling the effect:

https://www.cnn.com/2023/04/28/business/jenny-craig-weight-loss-ozempic/index.html

the drugs are expensive and the rollout will be slow. And even then, a 250+ lb person who slims 20% is still going to be eating a lot. Investing in Eli Lilly and and McDonald's mean I win either way

In the NEJM tirzepatide study, they reported a final fat-to-lean ratio of 0.7, which means that the subjects were still about 0.7/1.7 = 40% body fat.

That's why we need EMH to protect people from making simple mistakes like that. :)

Eli Lily can and will make good money on tirzepatide but it is a big company with tens of different drugs on the market. Some of them will be unprofitable which makes it hard to predict the final stock price of this company.

Also, it doubtful that it will make a noticeable dent in McDonald's profits. McDonald's is not the only fast food chain. People buy food in supermarkets too and throw out about half of it for whatever reason. It is very hard to predict what impact the appetite loss in a number of fat people will have.

Plenty of companies are already doing that. Doubtful that Eli Lilly's contribution would move the needle much.

By the way, do you have the same reaction to companies that produce cancer drugs -- that they should invest in causing as much cancer as possible to expand their addressable market?

Good question, thanks. I certainly have this reaction to companies that produce ART drugs: I would expect them to celebrate gay lifestyle and talk how the government should treat HIV in IV drug users "for free", but stay silent about distributing clean needles in safe injection centers or combating the overprescription of opioids.

I guess the difference between these two cases and cancer drugs is twofold:

  • obesity and AIDS are "vice" illnesses, while cancer is only partially so

  • cancer treatment either saves you or you die, you aren't expected to have regular chemotherapy for the rest of your life

cancer treatment either saves you or you die, you aren't expected to have regular chemotherapy for the rest of your life

Cancer treatment is extremely expensive and cancer patients (especially those caught after Stage I) are often medicalized for life even in the cases where they live for decades afterward.

Moreover what does the duration of the treatment matter? Why should the pharma company's incentives be different as between a therapeutic that is extremely expensive over the short term and a therapeutic that is moderately expensive over the long term, if the NPVs are the same?

Shouldn't your theory predict, for example, that pharma companies selling expensive therapeutics for lung cancer should oppose smoking cessation efforts?

They wouldn't do that because it would be so obvious conflict of interest that the outrage would follow and the government would simply shut the company or fined them billions.

We have done this to companies for much smaller conflicts of interests. For example, the company that misleadingly advertised opioids as non-addictive got liquidated (https://en.wikipedia.org/wiki/Purdue_Pharma).

Hmm... My model is a bit different.

I think it matters which individuals have control of these things and what their incentives are.

And my model is that if I'm a sociopathic CEO I really only care about maximizing the bottom line for the next few years.

I'm not going to bother to dump microplastics into the water supply because the ROI on the cancer rate increase is way too far in the future to benefit me.

cancer treatment either saves you or you die

The vast majority of cancer therapy will boost your expected lifespan on the order of months to a few years. Cures are quite rare and usually surgical in nature except for some slower growing cancers or newer immunotherapies.

Pharma companies just change their prices accordingly if you're only taking the drug for a few months. It's unfortunately arbitrary and pretty disconnected from actual benefit conferred to the patient.

TIL that "ART" in the context of medicine could mean either "assisted reproductive technology" (like IVF) or "antiretroviral therapy" (like HIV drugs). I feel bad for people with both HIV and fertility issues!

Invest in both McDonald's stock and Eli Lilly.

Literally was talking to a friend on what’s the indirect buy on these drugs. Said the exact same thing Pepsi and McDonald’s.

Wait, no. The point of these drugs is that they kill your appetite. McDonald's is going to get wrecked.

Fortunately, they don't really work.

Why do you consider that fortunate?

(Or was it an auto-co-wreck for "Unfortunately"?)

A good look at the picture I'm using here will reveal roughly what the answer is.

I'm afraid I don't see what you're getting at; can you explain more clearly?

You have looked it its original size, and you still don't get it ?

When your comment is this opaque and low effort, it's probably a bad comment.

I'm afraid I don't.

He likes big butts and he cannot lie.

It's dilemma. Either be too personal or just eat the downvotes.

I'll eat the downvotes, I guess.

That’s a pretty strong claim, do you have any evidence that ozempic or this drug doesn’t actually work?

What I mean is they won't eliminate overweight people, as the results aren't that good.

Moreover, it was natural for people not to become obese with very few exceptions. The drug is merely fixing the issues that we have created in recent years. It is not an improvement, merely preventing more harm that we are causing to ourselves.

That's the hope.

It'll be absolutely fascinating to see the social changes that accompany a family of drugs that make obesity, if not optional, then at least curable. Particularly if national health services subsidize these drugs to make them affordable.

I'm envisioning a situation where a GLP-1 agonist prescription is as normal as eyeglasses for the middle aged. Obese people could become as unusual a sight as they were a century ago.

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