Your acquaintance’s sad story reminds me of a short story I read a few years ago about a miracle pill that leaves about 90% of its takers perfectly slim and able to stay that way eating anything, but after a few truly disgusting days of elimination, but kills the other 10% gruesomely.

Thank you, thank you so much for sharing that. It's been a while since the last time my mind was blown away that much.

I have to admit, I would probably have taken the pill depending on how gruesome (or mitigatible) the death is. I've been obese and I've been thin, and life is not worth living when obese.

10 years ago, I was reading about nootropics and ran across an interesting piece on the ethics of drugs (that has probably been lost to time). The question it was asking was "why can we take drugs to bring us to normal, but we can't take drugs that make us better than normal?"

The interesting consequence is that it de facto forces people who don't need drugs to take them or be at a disadvantage. (think adderall at a competitive college or testosterone for lifting).

> The question it was asking was "why can we take drugs to bring us to normal, but we can't take drugs that make us better than normal?"

Because ultimately drugs make you pay one way or another, eg dependency, liver toxicity, numbness of some other facet and so on. When none of those will be true it’s the day they become the new norm

True, but the price vs the amount of effect varies hugely.

Some drugs are a bargain. Caffeine. E-nicotine. Some are hellishly expensive. Solvents will destroy your health without even giving much in the way of a high.

> why can we take drugs to bring us to normal, but we can't take drugs that make us better than normal?

Consider caffeine, which is probably entirely responsible by itself for a significant sliver of the world's total GDP.

We just don't have a lot of drugs like that because it's hard to find stuff that's performance-enhancing without serious side effects.

How does this remind you of this strange story.

Sounds a little bit like the “fatkins diet” in Makers by Cory Doctorow.

Great story. There were parts that made me think the pill was a metaphor for the covid vaccine, but this story was written several months before the vaccine was released

That is pretty unrealistic with 10% odds but I wonder what the odds would actually have to be for a drug like that to get so popular.

I take it, and when I started I got violently nauseous and had GI issues. I wasn't informed I needed to slowly ramp up.

I still have pretty big appetite suppression, and only minimal nausea sometimes if I eat too much, but what it's done to my blood glucose is AMAZING. And I lost some weight when I started which was a great bonus. It can be hard to start but it's truly worth it, just adjust the dose. I take 0.5mg as I can't handle the larger 1.0mg dose.

> I wasn't informed I needed to slowly ramp up.

In a fair world that would be considered severe malpractice :-( It's nearly common knowledge. A huge number of people are suffering under these medications because of starting at a dose to high or raising doses too quickly / too much at a time.

LY3437943 looks even more promising, with fewer side effects. Semaglutide will probably have the most side effects because it only has one action (GLP-1 agonist). Tirzepatide has slightly lower side effects because it adds a dual action (GLP-1 agonist + GIP analogue) so it can act at a lower magnitude on the GLP-1 receptors to avoid strong side effects, while still having higher efficacy due to its additional, separate, GIP action.

LY3437943 retains both the actions of Tirzepatide but adds a third action, glucagon receptor agonist. So it should be able to have higher efficacy at a lower equivalent dose than the other two (less action on GLP-1 and GIP mechanisms, fewer side effects).

>>due to the fact that eating now makes her sick.

Reminds me of the first FDA approved weight loss drug, Alli, that basically just gastrointestinally punishes you if you eat more than a few grams of fat.

https://en.wikipedia.org/wiki/Orlistat#Side_effects

> The manual for Alli makes it clear that orlistat treatment involves aversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects.

Christ. This is like Crohn's disease in pill form. One too many teaspoons of olive oil and you're in for an unpleasant evening...

I remember grabbing a pamphlet when it was new and reading their recommendation to wear dark colored pants and bring a change of clothes to work.

If shitting your pants in the break room is what gets people who can’t control their weight any other way to get to a healthy level, I think that’s worth it.

I want to frame this comment as an example of (the generalized form of) Poe's law.

It’s better to not know.

Jesus Christ on a bike, that’s beyond dystopian, that’s completely f—-ked up.

Does the fda allow that?

Yes, why would the FDA restrict what color pants you wear?

There’s huge tradeoffs people rarely talk about in Medicine. Significant risk of soiling yourself vs a statistically significant reduction in risk of early death isn’t a big deal for the FDA.

In many cases the hell that is chemo is considered acceptable for even moderate increases in expected lifespan. That’s why people started talking healthy life expectancy vs just life expectancy.

Well duh, if you discuss the side effects with patients, they won't take the drug and the drug people won't send you hookers.

Bizarrely enough, the pressure doesn't always go in that direction.

I don't have a colon (but I do still have a functioning anus). The effects from orlistat are very similar to what I experience 24/7. If you're under 30 or so, eventually your sphincter gets much, much stronger and the excess oil stops affecting you nearly as much. You can hold it in indefinitely until your normal "need to go" timing. This takes about a year or so to train, and you'll have quite a few accidents in the meantime.

I still can't eat too much salmon in one sitting though :-( I don't get diarrhea but I do get stuck on the toilet for ages after.

Never trust a fart on orlistat. The horror stories I’ve read of people soiling themselves after eating seemingly normal meals is nuts. On par with Olestra/Haribo sugar-free stories. Also it makes absorbing fat soluble vitamins a huge issue.

The so called Alli-oops.

My favorite fat loss drug along these lines is dinitrophenol. It is the true miracle fat burning drug. It interferes with cellular metabolism in such a way that the body just nonstop oxidizes fat. Fat mass loss in the order of a pound a day or more is entirely possible and some bodybuilders use it to get to a ludicrously low bodyfat percentage. Unfortunately oxidizing that much fat generates a lot of heat, so much that an overdose can be lethal because your body literally roasts itself to death and titration is extremely difficult. Oh and blindness is a common side effect. And for added fun it’s an high explosive. Needless to say it’s not FDA approved.

> And for added fun it’s an high explosive

Better not tell that to all the cardiac patients on nitroglycerin.

Also when you eat on it you are punished by heating up even more.

Permanent blindness?! Ffs

Honestly GLP-1 agonists will save lives just by being the go-to replacement for people who previously would have used DNP. GLP-1 agonists are effective enough that everyone in those circles basically stopped using DNP suddenly a couple years ago.

Is this the one? :)

https://en.wikipedia.org/wiki/2,4-Dinitrophenol#Toxicity

You want to know what's even crazier, you can literally but it over the counter. I was at kroger the other day and I saw it next to the vitamins and I did a double take.

Same experience here, gallstone attacks

You can get those from rapid weight loss, I thought. Maybe it's working TOO well if that's the case.

Ya, rapid weight loss is one of the most common triggers of gall stones. Lots of weight loss surgery patients get them as well.

Happened to me too from just generally not eating much at the time.

Ended up getting acute cholecystitis and a dead gallbladder plus sepsis after. Not too pleasant of an experience.

While others have none or barely any side effects, it is a drug after all.

For those people who tolerate the drug well, it can be revolutionary in their lives, but it's unfortunately not a good fit for everyone.

I hope your family member gets better soon.

Super weird since once you get thyroid problems, you have to drop this medication.

Not helpful. Drugs are drugs. Side effect happens. Sometimes not even related to the drug.

I don't know how you folks do it in the US, but I imagine there is a leaflet attached to the medication, and somewhere in it should be a phone number, physical address and/or an e-mail address of an institution that tracks drug side effects. If you're unlucky enough to have some weird reaction to a drug, it's good to let them know.

Right? For god sake folks, trust the randomized trials, not Internet nocebo screamers.

The risk of pancreatitis is also increased substantially [0]. And for people who may already be predisposed to pancreatitis but haven’t had an attack, severe pancreatitis has a 10-30% mortality rate [1]. But even mild acute pancreatitis will make you want to crawl out of your own skin in pain.

[0] https://www.hopkinsmedicine.org/news/media/releases/johns_ho...

[1] https://www.aafp.org/pubs/afp/issues/2007/0515/p1513.html

So I was able to find an aggregate of the study results:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294388/

out of an n of >3000 patients getting medication, 34 ended up having some form of pancreatitis. At least 12 people on placebo got pancreatitis. That's a much higher rate, but the odds are still pretty low.

I'm somewhat dubious of the severe pancreatitis mortality rates-- the issue is that most cases of severe pancreatitis are caused by very severe alcoholism, and by the time the pancreatitis shows up everything else is already failing.

That’s not entirely true. Pancreatitis, especially necrotizing pancreatitis, actually causes the broad systemic organ dysfunction. So even alcoholics with fine organs can end up with liver, lung, heart, kidney, etc complications from a severe bout of pancreatitis. Even basic things like fluid balance and endocrine function can be thrown way off by both the disease and treatment (large amounts of fluid resuscitation). I recently had severe bouts of non-alcoholic pancreatitis, the worst of which ended in a 3 month hospital stay with various periods on ventilators and various organ dysfunction. My imaging and bloodwork from 3 weeks prior were clean (I do them routinely since the pancreatitis is recurring).

Yeah, that's definitely always been my challenge with weight loss. I have zero problem with self control -- I can easily cut calories in half or less (e.g. 1000-1200 cal/day), but it's simply that my body suffers immensely. I lose all energy, can't concentrate on anything, and my immune system weakens so I start getting colds constantly.

I'm sure I'd easily lose weight with Ozempic but I'd still be suffering health issues. Not because of Ozempic itself but just because I wouldn't be getting enough calories, despite still being above a healthy weight.

You may have better success in a smaller caloric deficit. 1000-1200 calories a day is very few and that’s a very fast pace of weight loss. Try removing 500 calories or 10% of your calories. Progress will be slower, but you may feel much better.

Also, as a sibling comment alluded to, when you have fewer calories to eat, the micronutrients in the few foods you do eat matter that much more. The nutritional quality of food you need to stay healthy increases greatly when in a caloric deficit. Fruits and veggies are great for helping that, and multivitamins are cheap insurance policies to make sure you aren’t deficient in anything important, IMO. YMMV. Best of luck with your goals!

> my body suffers immensely

Does the same thing happen if you slowly wean yourself down? Are you cutting out essential nutrients that your body needs to function properly rather than the unnecessary carbs/junk? The reason I'm asking these things is that people I know who have reduced their caloric intake usually report feeling better, not worse.

That reaction may have to do with too much cutting, as another commenter alluded to, but it may also have to do with the types of nutrients you are missing when cutting.

Calories are not created equal. They are equal in physics sense, but your body is not a "bomb calorimeter" (device to measure caloric content of whatever). So maybe instead of cutting your calories in half, you cut less and replace carb calories with fat calories or protein calories. Or maybe you can even cut to 1000-1200 by replacing your calorie source with something else. For some weird reason carrots with butter work very well for me and I love the taste :-)

That sounds like a convenient excuse not to change

This is not a moral issue.

I know someone that took it and his gallbladder burst. Doctors couldn’t say if it was related to the drug, though.

As a counterpoint, I've been using it for several months and have had no side effects to speak of other than occasionally some mild reflux.

If anything, my energy levels actually went up immediately after starting it. Normally I was pretty sluggish but it felt like some extra firepower was unlocked.

Everything has risks and benefits, and might harm some people. I hope your family member gets better soon.

I’ve been on it (at 1mg, then 2mg doses) for 3-4 years now. Worst side effect for me is the tendency to have sulfur smelling burps if I have any kind of stomach upset.

did the weight stay off? Do you notice tolerance

Didn’t lose weight at 1mg. Down about 20# since the 2mg was approved.

But, also doing CrossFit 3D/wk. and now have a CGM so I can easily track blood glucose.

Second the question about tolerance! Wondering why this doesnt happen it is interesting. Most everything else causes some tolerance over time but no one mentions it for this

As a counter-counter-point I've read most (~90%) of the papers that come out of trials registered at http://clinicaltrials.gov/ for all GLP-1 agonists, including ones that haven't been approved. The vast, vast, vast majority of secondary outcomes, for things like

- blood pressure

- lipids (HDL, LDL)

- insulin sensitivity

- blood glucose

- strokes

- cardiovascular events + deaths

- myocardial infarctions

- hemoglobin A1C,

- revascularization,

- etc, etc, etc

are literally all affected positively (to the benefit of the imaginary "mean" patient) in bulk.

Note though, that doesn't mean 100% of patients are have positive results, just that each of these are, in bulk, positive across the tested subjects when averaged together. There's little in the data to suggest that cases like your family member aren't happening or couldn't happen.

There's also evidence that GLP-1 agonists increase the rate of glucose use in the brain, accelerating learning rates. (The brain accounts for 2% of body weight but up to 25% of glucose consumption, it really is fueled by glucose)

https://clinicaltrials.gov/ct2/show/NCT00256256?term=stroke&...

I started Wegovy about 5 months ago. The first couple months you feel sick but after it passes your appetite is extremely curbed (in a good way). Would highly recommend people to try it as it's made me healthier in pretty much every way.

Bold move to name their pharmaceutical like a Chinese Amazon “brand” of AliExpress-sourced electronics.

My story / anecdata.

About 6 months ago there was a posting about Ozempic and I had said something to the effect that it wasn't worth it watching some of the side effects my wife had from it. And then I went to the doctor for a check-up and lo and behold I had diabetes. Asymptomatic, but an A1C of 11. My doctor re-ran the test because he didn't believe it and it doesn't run in my family. My cholesterol had also jumped and he said he was going to put me on a statin after the initial 3 months of adjusting to the diabetes medication.

My Dr. puts me on Ozempic and I grumble about it but with that test results I had, I knew I had to do something. Fast forward 3 months, I dropped 20 pounds, and every other measurement is back in the green, including my A1C. Now, I made some serious lifestyle changes and ate a diabetic diet (limiting carbs, the types of carbs, etc), and have been keeping up with being more active but my entire relationship with food has changed because of Ozempic. Before I had a near compulsion to eat more than I should. Now, I don't because one, I feel fuller quicker and two, I know I'll feel horrible for hours if I over-eat. It only took one of those events to never want to do that again. I can't really explain why but I also don't have as strong of a desire to eat foods that are bad for me. I really thought I'd battle the cravings more after going cold turkey from "bad" foods. I can't say why it is but it's true. Side note, going to the grocery story was really difficult at first....there is so much sugar in the American food supply.

Energy wise I will say that I did struggle with low energy initially as my body adapted to lower calorie intake but I also learned that when I found the right balance of protein/complex carbs for me that my energy levels came back up and I now feel better than ever.

My doctor was shocked. I've never seen him that animated when I came back in for the 3 month follow-up. I didn't need to add any additional medications and they're slowly adjusting me back towards a single medication.

Out of curiosity, do you drink much water each day?

I'm kind of wondering if the people having a bad result don't drink enough water each day to clear out their systems? Yeah, that's a simplistic take... but still, curiosity. :)

Yeah, most of the time I think I do. I suspect it has to do more with diet and maybe water as well. Since Ozempic slows down your digestive process my current thought is that fiber / gut bacteria might have more affect on things but I haven't done a food diary to try and track what impacts me more.

Has nothing to do with it. A1c measures the percentage of hemoglobin A1 in red blood cells bound to sugars (glycated hemoglobin). Since red blood cells normally circulate for months this gives a surrogate marker for average blood glucose levels over 3-6 months.

Dehydration is not a confounder for an A1c test since the percentage is relative to the hemoglobin present. The primary confounder to A1c are blood disorders such as hemolytic anemias that lower the normal lifetime of RBCs or proportion of HbA. And this tends to falsely lower the A1c.

A person with an 11% A1c is also likely drinking quite a bit (whether they notice it or not) because at that point the chronically elevated glucose is elevating serum osmolality to increase urination.

Dehydration and kidney damage is a common side effect of Semaglutide, and they regularly test for that if you are on it. Drinking plenty of water is the way to prevent that from happening.

Perhaps I misunderstood what the GP was asking. Nevertheless GLP-1 medications appear to be kidney protective from a long term standpoint with an increased short term risk of AKI likely primarily related to GI losses with additional risk conveyed by concomitant use of “depleting” (diuretics) and nephrotoxic meds. Once on a stable dose there’s no current recommendation to monitor kidney function beyond what would normally be indicated for diabetes (usually yearly).

I have had a nearly identical experience. Thanks for sharing.

I know this isn't your family member, but if they were a 500-pound alcoholic smoking two packs of cigarettes a day, I suspect they probably felt like crap before the ozempic.