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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.
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.
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.
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.
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")
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.
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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.
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.
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.
> 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?
mind if I ask what personality and reward seeking effects you experienced?
> 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.
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?
> 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.
If you're on TRT, you are already not producing enough on your own.
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.
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
Yeah, I would fully support "easy" there, but regaining weight isn't something most people think of as danger.
"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.
Well, I didn’t produce enough T on my own anyway, so what the hell.
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!
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.
> 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...
> So weight loss was actually maintained for most people
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.
> 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.
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.
Really really thoughtful reply, and a great counter point to the "just will it and you'll be fine!" arguments
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.
> we just don't know what it is.
calories_in < calories_out seems to be a pretty good formula.
> 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.
"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.
> 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.
>have unhealthy habits that causes weight gain
>stop taking weight loss drug
>regain weight
>there is no safe off-ramp for GLP-1
I guess taking weight loss drugs don't really teach healthy eating habits.
Same is true for: insulin, Levothyroxine, Antiretroviral Therapy (HIV), Enzyme Replacement Therapy ( Pompe Disease or Gaucher Disease, antipsychotic medications for severe schizophrenia. And many others. And here’s the interesting twist, the closer the Number Needed to treat is to 1, the more helpful the medication should be viewed. All these medications have an extremely low NNT, including GLP1s.
> "this new class of drugs should be rebranded from “weight loss” drugs to “weight management” drugs, which people may need to take indefinitely."
I suspect the manufacturers view this as a feature not a bug. :-) More seriously, I find the article's conclusions to be pretty much what I'd expect. Most medicines aren't permanent cures and obesity results from a variety of factors with lifestyle and diet being major elements.
I was seriously obese for decades and about 9 years ago, hovering on the edge of becoming diabetic and other serious obesity-related health issues (high BP, IBS/GERDS, chronic apnea, etc), I decided I had to do something. GLP-1's weren't available then but none of the other typical approaches, including medically supervised diets worked more than a few months. Doing my own research, I discovered keto (this was before keto became big) and decided to try it. It was hard at first but also remarkably effective. I lost over 100 pounds in 8 months, becoming fit and seeing abs for the first time in my life. As I lost the weight, all the other health issues resolved too. But I knew if I returned to my previous diet and habits, I'd eventually grow obese again. Many people will take GLP-1s, lose weight but then stop and regain the weight because they didn't change their underlying behavior. Just like many people do with dieting, keto or any other intervention. But any intervention that works can be an invaluable for the few willing to understand, use it as a tool and do the work.
I stayed strict keto for 5 years. Long enough to train my body and mind how to be fit and healthy as normal (not a temporary diet). Then I started a rigorous process of gradually transitioning away from strict keto over a period of two years and that's also worked. I still eat a pretty low carb diet averaging less than 100g or less a day and will for life because there is no "Eat whatever junk you want and stay fit", at least for my metabolism. Reading that article, the criticisms of GLP-1s would also apply to keto or just "eat less, move more". If you stop the intervention, the system returns to state. However, for me keto helped me break an insidious pattern driven by habit, metabolism and blood sugar levels. I was then able to adopt new patterns. I suspect GLP-1s could help others in a similar way. Obviously, there is no magic drug that "cures" obesity by making you immune to bad habits and the physics of calories in/calories out.
For comparison, there also doesn't seem to be a "safe off-ramp" for obese patients from other weight loss interventions either: https://pmc.ncbi.nlm.nih.gov/articles/PMC4396554
It’s the same as any other intervention to reduce weight. I worked out and ate better for a year and lost 35lbs.
Then, I stopped working out, and gained 15lbs. Exercise: no safe off-ramp for some.
It’s the perfect pharmaceutical miracle drug: a shot that cures the root cause for thousands of diseases (obesity) with a whole bunch of unexpected benefits (like reductions in substance abuse, fewer migraines), with mild symptoms and rare complications. But you’re stuck on it for life or else return to your pre GLP1 body.
The fact it spun of of research on Gila monsters is still crazy to me.
By the same logic we could say that there is no safe off-ramp from any diet or exercise protocol.
When the treatment is ceased, the benefits go away.
Or an alternative title: "36 months of tirzepatide permanently treated obesity in 17.5% of patients."
I think that it is quite unsurprising that without the drug a large amount of people revert to their previous behavior and with that will revert to their previous weight.
Indefinitely, not permanently
It’s no different from people who undergo gastric bypass surgery. Those with food addictions/habits manifest them elsewhere such as gambling, or if they are seriously addicted, they continue to eat which bursts their band.
My wife is back devouring cookies after being on mounjaro for 4 months. Thankfully she lost most weight all by herself so wasn’t totally reliant on the medication. But it’s crazy how noticeable the difference of one’s eating habits when on and off it.
There doesn’t need to be an off-ramp they just have to take it for life. Why would someone think they would keep the weight off? If they could they would have before Ozempic.
> Why would someone think they would keep the weight off? If they could they would have before Ozempic.
I think the intuition many people have--which I am not at all defending as correct, but it certainly isn't so obviously wrong that we should scoff at someone for thinking it works this way--is more like "if my weight was stable before I did this intervention, I just need to lose the weight and then my weight will once again be stable after it"; in this mental model, one would assume you only need lots of willpower to lose weight: after, you only will need as much willpower as you already know you have to not gain it back, as it isn't as if you are gaining weight currently.
I could see it building habits that persist even when no longer using the drugs. They've found other things to fill their time instead of eating, and things which would previously trigger them to start eating now trigger them to do other things.
There's of course a risk that when they stop the drugs that hunger will drive them to re-establish those habits, but now that they have new habits that fight that hunger they are in a much better position to resist it than they were when they'd initially established their eating patterns.
> take it for life
That's literally the implication of these findings.
But one can always hope for a miracle drug that you can take for a bit, then stop, and have its effects last. Now we know that Ozempic is not that drug.
I imagine the idea for some is "if I can just get myself healthier, I can then stay motivated to maintain the healthier lifestyle required to stay skinny without the drugs"