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tyleo · 3 months ago
Interesting. Saying, "there may not be a safe off-ramp," doesn’t feel quite right. The article describes people losing weight while on the drugs and then regaining weight after stopping them. That's not ideal, but it does imply an off-ramp, just with regressions.

Compare that to something with no real off-ramp: testosterone replacement therapy. Once you're on TRT, you can permanently suppress your body's own testosterone production, and many men won't produce enough on their own afterward.

sReinwald · 3 months ago
Strange framing, isn't it?

Bariatric surgery shows 25-65% significant regain rates depending on definition and timeframe. And regular dieting is even worse. Nobody would frame that as a safety issue. That's... just how weight loss works, not a unique GLP-1 problem.

Calling a return of symptoms (obesity) a "safety issue" is like saying insulin has "no safe off-ramp" because diabetics get hyperglycemic when they stop taking it.

Fear gets clicks, I guess.

csense · 3 months ago
At some point, somebody at the site changed the title. The old title was "GLP-1 Drugs Improve Heart Health, But Only If You Keep Taking Them."

How do I know that? The URL slug tells the tale.

> Fear gets clicks, I guess

I strongly suspect this is the reason the title was changed.

bsder · 3 months ago
It's also very strange because more than 75% had some level of sustained weight loss after several years.

That's way better than any other weight loss program. Nothing else even comes close.

m463 · 3 months ago
well, it could also be from a "do no harm" standpoint.

(although looking into it, it seems many oaths never actually say "first do no harm")

financltravsty · 3 months ago
As an experienced polysubstance researcher, that's not exactly accurate.

TRT cessation does not inherently cause men to have suppressed hormone levels after. With precautions and extra steps like HCG to maintain leydig cell/testicular function, preventing atrophy, one may safeguard against that risk.

Coming off TRT, yes you will have lower levels as your HPTA has been suppressed by exogenous hormones. One may speed up this recovery using "PCT" (post cycle therapy), which involves taking a SERM (selective estrogen receptor modulator, e.g. enclomiphene) to resensitize and restart your HPTA. However this is not always necessary, and if one takes a look at the HARLEM study, most users return to their baseline levels within a year of going cold turkey.

In the cases of true permanently lowered levels of hormones, I believe the two most common reasons are: using other AAS besides testosterone (1) and lifestyle or health factors that correlate with the need to be on TRT (2).

With 1, this can be seen in users of decadurabolin (deca), which notoriously has hormone receptor active metabolites that last around for atleast a year, continuously suppressing the system. Or trenbolone (tren/cattle bulking hormone) which is inherently neurally and endocrinically otherwise toxic.

With 2, you hop on TRT because there is some reason your hormones are not at healthy levels. Whatever the reason is, it is still there, and once you've stopped bandaiding the issue its effects resurface.

---

I have also used many GLP-1s (semaglutide, tirzepatide, and retatrutide). No there is no off-ramp, but the only effects I've noticed are a return to my baseline of appetite, and neurological state.

N.B. GLP-1s are good for impulse and behavioral disorders like ADHD, which it did help. However, I have decided to not take it due to the negative effects on personality and reward seeking behavior.

They are neuro-active in the brain, and their effects I've decided are not worth it.

apple4ever · 3 months ago
Thank you for the info on the TRT, I was getting a little worried reading some of the other comments. I'm getting on it due to years of low testosterone. I'm also getting on Zepbound due to years of obesity. The two may be linked, but I need help controlling my appetite and reducing my fatigue.
tyleo · 3 months ago
This reasoning is not flowing through for me. It feels like you are saying:

1. There is an off ramp for TRTs but some people have, “true permanently lowered levels of hormones.”

2. For GLP-1s, “there is no off-ramp, but the only effects I’ve noticed are a return to my baseline.”

To clarify my original post, I consider the ability to return to baseline to mean there is an off-ramp and permanently impacted to mean there is no off-ramp.

mrandish · 3 months ago
> GLP-1s are good for impulse and behavioral disorders like ADHD

As someone diagnosed with ADHD, I wasn't aware of this (although I haven't had reason to research GLP-1's). Is this just your N=1 or an effect proven in studies?

inhumantsar · 3 months ago
mind if I ask what personality and reward seeking effects you experienced?
neogodless · 3 months ago
> not only regained significant amounts of the weight they had lost on the drug, but they also saw their cardiovascular and metabolic improvements slip away. Their blood pressure went back up, as did their cholesterol, hemoglobin A1c (used to assess glucose control levels), and fasting insulin.

This does sound like "reversion to the mean", but saying it's "regaining weight" may be missing the bigger picture. More like "losing all previously gained health benefits."

It's less clear how "unsafe" those regressions in health markers are.

mise_en_place · 3 months ago
By what mechanism? That's not how it works. LH and FSH are suppressed when you're on TRT, but they stabilize after cessation. The question is, why would someone with clinical hypogonadism cease TRT?
Aurornis · 3 months ago
> That's not how it works. LH and FSH are suppressed when you're on TRT, but they stabilize after cessation.

The testes atrophy over time when LH and FSH are suppressed. Even if LH and FSH return (which isn’t guaranteed) the testes need to be able to respond to those hormonal signals, but atrophied testes do not respond the same.

For someone with true intractable hypogonadism this hardly matters because they weren’t capable anyway. Many people prescribed TRT today don’t actually have intractable hypogonadism, though.

Body builders have some tricks to try to reverse this, but it’s not perfectly effective and even body builders know to cycle their steroids to avoid having prolonged periods of suppressed HPG axis activity. I was involved with weightlifting in my younger years but never dabbled with steroids or TRT. Everyone I know who did try testosterone or steroids thought they were doing it the safe way (HCG, PCT, limited cycle length) but became unable to produce enough endogenous testosterone by their 40s even with SERMs.

Men on TRT for years will have considerable testicular atrophy that is not totally reversible.

> The question is, why would someone with clinical hypogonadism cease TRT?

TRT is no longer limited to men with clinical hypogonadism. Men’s health clinics that advertise on social media, TV, and radio will prescribe to anyone who contacts them (and pays cash for the prescription and gear). In some surveys of patients on TRT, 1/4 of patients didn’t even have testosterone levels measured prior to initiation of TRT.

gtirloni · 3 months ago
If you're on TRT, you are already not producing enough on your own.
Aurornis · 3 months ago
Unfortunately that’s not true any more. TRT over prescribing is a major problem right now.

Studies of TRT patients have even shown that 1/4 of TRT patients may not have had their testosterone levels measured before being prescribed TRT: (Source https://pmc.ncbi.nlm.nih.gov/articles/PMC6406807/ ) Completely unacceptable given how cheap testosterone testing is, but its happening.

TRT clinics have also become a big business. Their business model relies on prescribing TRT to anyone and then charging them monthly or quarterly to continue receiving those prescriptions, which as the parent comment noted become physically necessary after TRT causes the testes to atrophy.

The trick the clinics are using now is “diagnosing by symptoms”. They have a long list of “symptoms of low T” and the patient is basically prompted to check off enough boxes to justify TRT. It’s the same model as the medical marijuana card businesses where you can go in and the doctor will “find” a reason to give you the prescription.

It’s a real problem when combined with social media influencers who tell people that everything is a symptom of low testosterone and TRT will fix it.

tortilla · 3 months ago
Unless you went on when you weren't really low because the men's vitality clinic pushed you into a treatment protocol*

* not me but I see it with men in my age range

theptip · 3 months ago
But TRT suppresses endogenous production further, so if you go off it you’re worse than when you started.
asafira · 3 months ago
Isn't there TRT that doesn't impact your endogenous production? (HCG, SERMs)
taeric · 3 months ago
Yeah, I would fully support "easy" there, but regaining weight isn't something most people think of as danger.
fwip · 3 months ago
Many people who are losing weight are doing so because they're concerned about their health, right? Especially heart health.
observationist · 3 months ago
"Those poor people have no agency and their behaviors are outside their control!" Well, I guess we have no choice but to affirm and reinforce their lack of agency and ensure we put them on drugs for the rest of their lives!

It's ironic that one of the effects of this drug seems to be reducing the impact of impulsive behaviors, reducing cravings from other drugs and alcohol and cigarette addictions.

The hat trick for someone might be to get on one of these GLP-1 regimens, wean themselves out of whatever crisis/crises they are in, end their GLP-1 regimen with a heroic mushroom trip, and physically move to a new environment, where they don't have any of the default triggers or patterns to fall back on, and everything is fresh and can be built up from scratch.

I think the medicalization of human agency is one of the great evils of our time. The implication and impact of doctors, bureaucrats, and bean counters making sweeping policy, regulation, and legal decisions on behalf of the peasants and peons who just don't know better. The casual dismissal of fundamental basic principles is outrageous, especially in service to the politics and idiotic tribalism.

acuozzo · 3 months ago
> "Those poor people have no agency and their behaviors are outside their control!"

Our complex modern society has a daily buy-in.

Some people were born and/or raised for it and the cost for them is nothing.

Others need to soothe the pain of shoehorning themselves into it by chain-smoking while working a jackhammer or shoveling cereal into their face while programming.

Yes, these behaviors are technically within their control, but are you really going to suggest that we can solve the underlying problem(s)?

BizarroLand · 3 months ago
I think your opinion is valid from your point of view but missing an important part of the bigger picture.

Obese people typically do not try to become obese. Most obese people have tried to lose weight and find that they lack the tools and skills needed to succeed, and many of the ones that do succeed only do so temporarily.

Why is that?

It's a question with no simple answer, and no single answer.

Evolutionary biological drive to acquire calories.

Psychological dependency on food.

Inability to differentiate satisfaction from "being stuffed", likely due to environmental factors like negative education as a child or poverty mindset in parents.

The perceived difficulty of altering diets for longevity.

Self-hate.

I'm sure there are scores more reasons for this, and no single concept or mindset is large enough to fully accurately embody the breadth of reasons why people remain obese in a world that actively disincentivizes obesity in every measure of life satisfaction.

People outside of that fail to empathize with the plight of obese people. They blame them for living a life that is generally unintentionally thrust upon them.

They do not see obesity as a disease but as a choice and then mock or dismiss them for being obese, even though by all metrics it is a disease.

People tell obese people to diet like they tell alcoholics to quit drinking or drug addicts to quit using drugs and honestly believe their words have contributed value to humanity, but unlike drug addicts or alcohol, there is no cold turkey for obesity other than death.

People must eat. That includes obese people.

If you can figure out a way for a crackhead to smoke crack 3 times a day until they feel satisfied with how much crack they have smoked without remaining a crackhead, then you might be able to figure out how to get an obese person to eat 3 meals a day until they feel satisfied without remaining obese.

mgarfias · 3 months ago
Well, I didn’t produce enough T on my own anyway, so what the hell.
apple4ever · 3 months ago
Plus if you look at the numbers (found in the comments of that story):

17.5% maintained 75+% of their weight loss. 25% maintained 50-75% of their weight loss. 23% maintained 25-50% of their weight loss. 24% maintained 0-25% of their weight loss.

I mean that's pretty good!

apple4ever · 3 months ago
(Formatted better)

* 17.5% maintained 75+% of their weight loss

* 25% maintained 50-75% of their weight loss

* 23% maintained 25-50% of their weight loss

* 24% maintained 0-25% of their weight loss.

lkey · 3 months ago
The body yearns for its prior homeostasis. This is true when you lose weight with a strict diet. It's true when you lose it using a medication.

The struggle doesn't stop when you stop losing. My personal experience was that it takes about 2 years for the new 'normal' to kick in. (I lost 60lbs when I was in my early 20s and kept it off until today. The 'after' period was as taxing as the 'losing' period, but in a different way)

At that point only can you 'relax' a bit around your body's cravings for calories.

This has already been studied extensively:

https://pmc.ncbi.nlm.nih.gov/articles/PMC5764193/

It's not the worst thing in the world to be on a medication for a couple years rather than a few months, but long-term study of this class of drugs is certainly warranted and necessary.

glp1guide · 3 months ago
> Of the 308 who benefited from tirzepatide, 254 (82 percent) regained at least 25 percent of the weight they had lost on the drug by week 88. Further, 177 (57 percent) regained at least 50 percent, and 74 (24 percent) regained at least 75 percent. Generally, the more weight people regained, the more their cardiovascular and metabolic health improvements reversed.

So weight loss was actually maintained for most people -- the hard part is finding a healthy daily lifestyle which can maintain the drastic effects of GLP1s.

This information isn't new -- weight regain has been studied before and I've written about it before:

https://glp1.guide/content/do-people-regain-all-the-weight-l...

The missing piece to this article is just how bad the alternative is -- never having the cardiovascular and metabolic benefits is clearly not the best strategy (and if simply changing patterns was so easy, people would have done it already).

GLP1s don't work for everyone but they're pretty close to miraculous in effect given the balance of positive and negative side effects. Making GLP1s cheaper & more tolerable then figuring out how to actually deal with the complex web of how to keep the weight off sustainably for most people seems like the right way forward here, not avoiding potentially life-saving medication because you may not be able to get off of it as fast as you want (if you can afford it).

BTW, there is already generic Liraglutide, and legal workarounds for getting compounded Semaglutide that already mean no one pays the $1000 that was in the zeitgeist a while ago. Even Lilly Direct and similar outfits from Novo sell for $500/month, with the $150/month pricing coming soon[0].

[0]: https://glp1guide.substack.com/p/negotiations-are-underway-f...

axxto · 3 months ago

  > So weight loss was actually maintained for most people
Unless I'm mistaken, how can you interpret that from an article that claims that 57-82% of participants regained 25%-50% of their weight loss, with 24% regaining at least 75% of it? In just a bit more than a year and a half, too.

apple4ever · 3 months ago
They still lost weight from their original amount right?

That's the key. They may have come up from their lowest, but they still better off.

perelin · 3 months ago
As a GLP-1 user im really surprised that this is newsworthy. The mechanism of how these drugs lead to weight loss is appetite reduction. On GLP-1s -> less appetite, off GLPS-1s -> more appetite. Given the general health benefits that are being observed with GLP1-s the only reason to get off them is costs imo. They are absurdly expensive. Hope this will change in the next 10 years with patents running out and generics being available for cheap. The actual cost of production seem to be quite low. Gray/black market has them available for around a tenth of the otc price.
aishsh · 3 months ago
> Given the general health benefits that are being observed with GLP1-s the only reason to get off them is costs imo

There’s also the perverse incentives wrt broader society. Enabling the average person to control their physical health is orders of magnitude better for society and orders of magnitude less profitable than the current trends.

Maybe a setup where glp drugs are nationalized and only used to further understand why we have an obesity epidemic and eventually finance changes to combat it? Ideally the drug makers would do this without requiring government intervention, but I doubt they will.

SpicyLemonZest · 3 months ago
What don't we understand about the obesity epidemic? The story seems pretty clear to me at this point:

* Almost everyone has access to a wide variety of delicious food, which we on average enjoy eating more of than is required to maintain a healthy weight.

* We don't want the government to forcibly restrict people's food access.

* Research consistently shows that voluntary portion control works occasionally in the short term and not at all in the long term.

* Many people have proposed specific ingredients or nutrient classes that can be adjusted in a person's diet to resolve obesity, but none to date have checked out.

In principle, I suppose, there could be some crazy diet hack we don't yet know about. But why should we expect that to be the case? To be honest, I think a lot of the existing discourse on this topic was just wishful thinking, because before GLP-1s the bottom line was not "some people need a pharmaceutical intervention" but "some people are just gonna be obese and there's nothing we can do to help them".

perelin · 3 months ago
100% agree. But that also feels like the elephant in the room somehow. Most western pension systems are stretched to (or beyond) their limits already. I expect that having GLP1-s widely available will extend the life of a LOT of people even further. And then ... what? Im really surprised that nobody talks about that.
orwin · 3 months ago
Each time an article on glp-1 is out, I will comment:

Yes, you can loose weight without it, I did, I'm even in the healthy range now.

No, you don't have to, if you need medicine help, take it.

When I lost weight, I had my first real job that I liked so much, it didn't felt like one, 11 weeks of vacation per year, a nice enough apartment I couldn't be evicted of, great emotional support and advices and support from a doctor.

The only thing draining my willpower every day was the calorie restriction, and nothing else to worry about.

If you're in a similar spot I was, maybe trying a diet without glp-1 is better since we don't have any long term study on it yet, but if you're not: obesity will destroy your body more than any long term side effects can. Please take them if you can afford it.

The only thing I earned beside uncomfort and pain when I lost weight without drugs are internet points on hacker news, and the ability to say 'i did it' (also glp-1 didn't exist, so less long term health issues from obesity). Honestly if I had to redo it, I would take the drug despite a similar situation. Weight loss is hard, and not being able to do it without help is not an indictment on you or your character, but on your situation.

apple4ever · 3 months ago
Really really thoughtful reply, and a great counter point to the "just will it and you'll be fine!" arguments
bryanlarsen · 3 months ago
The headline doesn't seem to match the article? 20% of participants did keep the weight off and 40% kept half the weight off after stopping.

So there appears to be an off-ramp, we just don't know what it is.

NitpickLawyer · 3 months ago
> we just don't know what it is.

calories_in < calories_out seems to be a pretty good formula.

falcor84 · 3 months ago
It's almost the same as saying that the off-ramp for a cat to get off a tree is to apply a=g until h=0. It's technically correct, but I don't think it would help the cat to be aware of this.
orwin · 3 months ago
To a certain point yes, but also no. Depends on which fat you're talking about and which calories you are talking about (calories from carbs without fibers cost nothing to absorb, calories from fat cost more than half the energy they give you) (also if you have a good gut health, some calories are just never absorbed).

Calorie restriction works up to a certain point, and weirdly the benefits aren't linear, and almost flat for visceral fat(i.e: if you're using 2.6 kcal a day and eating 2.4 kcal, you will loose roughly the same amount of visceral fat than if you only ate 1.8kcal, and slightly more 'external' fat (that one you shouldn't care much if you're only interested in health)).

Calorie expenditure works linearly though, but it's hard to out-exercise your diet, and exercise while obese can be dangerous (my ankles still have to be reinforced despite me being under 24 BMI)

elevation · 3 months ago
> regained significant amounts of the weight they had lost on the drug [...] blood pressure went back up, as did their cholesterol, hemoglobin A1c [...] fasting insulin

These symptoms will be familiar for anyone who has lost weight dieting and then returned to eating junk food.

petercooper · 3 months ago
"Generally, the more weight people regained, the more their cardiovascular and metabolic health improvements reversed."

You don't say ;-) I lost 50 lbs and have kept it off for the past year while maintaining great BP. But I'm under no illusions GLP-1 medications don't have dangers and cause problems for many. It should be handled on an individual basis like any serious medication.

That said, is someone losing a lot of weight then gaining half of it back worse than them just staying where they were? I don't know the answer to that one.

quesera · 3 months ago
> losing a lot of weight then gaining half of it back

The trick, of course, is to repeat the process as you asymptotically approach your goal.

Zeno's paradox of mass.