We Still Don’t Know Much About Grey GLP Use or long-term outcomes of GLP use

[miss-sanne]

Yes, we know a lot, but the question was specifically about safety, which was what I was speaking to.

sorry tubby, I misread. I do believe safety is high, though. Rare side effects can happen. With any medicine.

 

[Zydeceltico]

I think this too.

But we should really not close our eyes (pun intended) about NAION.

One of my best friends got it from glp-1, and now he has no drivers license and exhausted because he lost a lot of his vision.

Also the pancreatitis is often very serious, I recently lost a 50 y old male to that, it was because of gall stones, but same patophysiology.

Do you happen to know if incidence of NAION is dose-dependent? I know that there are other risk factors like sleep apnea, hypertension, etc. Just wondering if dosage is indicative.

 

[miss-sanne]

Do you happen to know if incidence of NAION is dose-dependent? I know that there are other risk factors like sleep apnea, hypertension, etc. Just wondering if dose-dependence is indicative.

No it's not. Not to my knowledge. Any low dose can do it.

We do talk a lot about it here in Denmark, because yes Novo is our economy-baby.

It's rare 1:10.000

It's based on observation.

I was very sorry for my friend, only 9 patients in Denmark has been diagnosed, so he was very unlucky !

He was on a low dose, 0,25-0,5 mg.

 

[woundcarping]

I think this too.

But we should really not close our eyes (pun intended) about NAION.

One of my best friends got it from glp-1, and now he has no drivers license and exhausted because he lost a lot of his vision.

Also the pancreatitis is often very serious, I recently lost a 50 y old male to that, it was because of gall stones, but same patophysiology.

First I'd heard of NAION in general, much less in reference to GLP1. I assume it affected him bilaterally?

 

[miss-sanne]

First I'd heard of NAION in general, much less in reference to GLP1. I assume it affected him bilaterally?

Yes both eyes for him.

Novo put in on their list of side effects last year, and it was recognized as a very rare side effect in October 2025, I think.

We started to hear about it in Denmark last spring, when patients talked about it. So I got my eyes checked out with eye doctor, when I started using Tirz.

 

[tubby]

I am not the first to say it by any means and to rely on @miss-sanne ' s direct report as a small "n" of vailidity, I suggest that "silence is golden." In other words, as has been said countless times, if there were inherent serious safety issues, the rabid, sensationalist media would have long ago jumped all over them and demonized the living shit out of them to terrify every "Karen" into signing up for the witch hunt.

I have not seen any "Jerry-Springer-fied" national headlines and it has been a long while sooooooooo

We seem to be arguing past each other for some reason that I don't understand.

You're referring to short-term safety concerns. I (and numerous studies) agree with you that these drugs seem to be fairly safe in the short-term, aside from rare side effects like @miss-sanne has brought up.

What OP asked about was LONG-TERM safety. We have no information on long-term safety other than the studies and post-marketing data in diabetic populations, which has the limitations I explained above.

I want these drugs to be safe long-term just as much as anyone else here, but that desire doesn't justifying lying. They're probably safe long-term. And even if it turns out there's an issue that emerges after a decade of use, there's a good chance that thing is less dangerous than a decade of being morbidly obese. That's the gamble we're all making and I think it's a good gamble, but it's important to be clear about that. If some 20-year old wants to take GLPs to lose 15 pounds to look better in a bikini, that's a different kind of gamble where if we're lying about what is known and what isn't known, it could cause them to make a decision they might not have.

 

[Gr33dyOctopus]

Had I known that mine was f'd up BECAUSE of my diet I would have TRIED to make changes and tried to save it. I was fed so much misinformation... I had ten more attacks before relenting to surgery after the initial attack. I couldn't take the idea of going through another couple hours ( at least ) of that kind of pain.

On the other hand I rather enjoy messing with people now and saying, " I'm part human. Not 100%."

I look for something "positive" in everything. lol

Yep agree. I had no idea my gallbladder was actively

We seem to be arguing past each other for some reason that I don't understand.

You're referring to short-term safety concerns. I (and numerous studies) agree with you that these drugs seem to be fairly safe in the short-term, aside from rare side effects like @miss-sanne has brought up.

What OP asked about was LONG-TERM safety. We have no information on long-term safety other than the studies and post-marketing data in diabetic populations, which has the limitations I explained above.

I want these drugs to be safe long-term just as much as anyone else here, but that desire doesn't justifying lying. They're probably safe long-term. And even if it turns out there's an issue that emerges after a decade of use, there's a good chance that thing is less dangerous than a decade of being morbidly obese. That's the gamble we're all making and I think it's a good gamble, but it's important to be clear about that. If some 20-year old wants to take GLPs to lose 15 pounds to look better in a bikini, that's a different kind of gamble where if we're lying about what is known and what isn't known, it could cause them to make a decision they might not have.

I agree, im in my 50s and was over 330 pounds, couldnt tie my shoes and barely wipe.my own ass. Im way more willing to put my future health potentially on the line in exchange for less chance of a heart attack, stroke or diabetes.

But some kid teying to lose a few pounds to cut weight. Not ok. Wish they wouldnt risk it

 

[BH_LOVER]

My gallbladder shit the bed while losing my first 40 pounds in less than two months. Its at 4 percent. Having it out very soon.

Had mine out almost 2 years ago. Had lost about 30lbs at that point. All of a sudden one night I wound up in the ER with surgery 2 days later. Worst pain of my life

 

[JoonyO]

Had mine out almost 2 years ago. Had lost about 30lbs at that point. All of a sudden one night I wound up in the ER with surgery 2 days later. Worst pain of my life

They compare the pain to that of child birth...so after birthing 10 chillenses I couldn't stand the thought of doing it again!

 

[lessthanhalf]

The thing that really stands out to me from the research is convincing and repeatable evidence that semaglutide and tirzepatide reduce overall death rates. The younger and healthier the population involved in the studies the harder it will be to see this signal, and it requires lots of patients over a long time. The longest term studies show reduced chances of heart attack, stroke and death, by around 25 to 30%. They reduce the chances of a lot of other things, the development of diabetes in those with impaired glucose tolerance is reduced by about 90%. The results on cancers is more complex but there is pretty good evidence of reduced chances of developing many of the most common cancers. For Alzheimer's the evidence so far is mixed, population studies show significantly reduced risks, but prospective trials ( which are more accurate ) so far have not shown any benefit. They improve quality of life, mobility and arthritis mainly due to weight loss. This post would be pages long if I tried to include them all. The number of studies being published on these sort of related consequences is enormous ( many hundreds to a 1000 per year in 2025 ), and over the next few years the picture will slowly get clearer.

Shorter term negative effects are very common and cause a fairly high percentage of people to stop taking them, mainly nausea and vomiting diarrhoea and constipation, as well as skin sensory symptoms. Most of these type side effects peak at months 2 to 4 after starting and then improve, but not for everyone. Most of these effects are not severe, but some people develop dehydration and subsequent renal failure from gi side effects, and some die, most at risk are older physically and medically frail persons and diabetics with multimorbidity.

Are there negative effects in the long term - yes Gallstones are a consequence of any type of weight loss, sudden improvements in diabetic control can cause neuropathy, pancreatitis, nerve compression syndromes due to weight loss, NAION, plus many more, but I think the important issue is that the sum of all of the negative long term consequences is quite small, and the sum of the positive ones is very large, in terms of order of magnitude effects positive effects outweigh negative ones by more than 10 to 1. The fact that overall chances of death go down, essentially means that there are no hidden or unknown negative effects that increase your chances of death. A lot of the studies I have seen that emphasise the long term negative effects or concern about unknown long term effects, as far as I am concerned seem to be mostly ignoring the large amount of evidence that already exists, and mostly seem to be coming from areas of medicine where their whole job is questioned by glp's mainly dietitians ( whose treatments for obesity do not work over the long term as far as I am concerned ) and weight loss surgeons ( whose treatments do work and very well, but are expensive, have limited access, have significant adverse effects, and whose treatment method is being questioned by increasingly effective glp medications )

TLDR These medicines make you significantly less likely to die while taking them, this alone massively outweighs any long term known or unknown harms.

 

[tubby]

The thing that really stands out to me from the research is convincing and repeatable evidence that semaglutide and tirzepatide reduce overall death rates. The younger and healthier the population involved in the studies the harder it will be to see this signal, and it requires lots of patients over a long time. The longest term studies show reduced chances of heart attack, stroke and death, by around 25 to 30%. They reduce the chances of a lot of other things, the development of diabetes in those with impaired glucose tolerance is reduced by about 90%. The results on cancers is more complex but there is pretty good evidence of reduced chances of developing many of the most common cancers. For Alzheimer's the evidence so far is mixed, population studies show significantly reduced risks, but prospective trials ( which are more accurate ) so far have not shown any benefit. They improve quality of life, mobility and arthritis mainly due to weight loss. This post would be pages long if I tried to include them all. The number of studies being published on these sort of related consequences is enormous ( many hundreds to a 1000 per year in 2025 ), and over the next few years the picture will slowly get clearer.

Shorter term negative effects are very common and cause a fairly high percentage of people to stop taking them, mainly nausea and vomiting diarrhoea and constipation, as well as skin sensory symptoms. Most of these type side effects peak at months 2 to 4 after starting and then improve, but not for everyone. Most of these effects are not severe, but some people develop dehydration and subsequent renal failure from gi side effects, and some die, most at risk are older physically and medically frail persons and diabetics with multimorbidity.

Are there negative effects in the long term - yes Gallstones are a consequence of any type of weight loss, sudden improvements in diabetic control can cause neuropathy, pancreatitis, nerve compression syndromes due to weight loss, NAION, plus many more, but I think the important issue is that the sum of all of the negative long term consequences is quite small, and the sum of the positive ones is very large, in terms of order of magnitude effects positive effects outweigh negative ones by more than 10 to 1. The fact that overall chances of death go down, essentially means that there are no hidden or unknown negative effects that increase your chances of death. A lot of the studies I have seen that emphasise the long term negative effects or concern about unknown long term effects, as far as I am concerned seem to be mostly ignoring the large amount of evidence that already exists, and mostly seem to be coming from areas of medicine where their whole job is questioned by glp's mainly dietitians ( whose treatments for obesity do not work over the long term as far as I am concerned ) and weight loss surgeons ( whose treatments do work and very well, but are expensive, have limited access, have significant adverse effects, and whose treatment method is being questioned by increasingly effective glp medications )

TLDR These medicines make you significantly less likely to die while taking them, this alone massively outweighs any long term known or unknown harms.

That's all good stuff, but you're leaving out one key detail in your analysis. GLPs reduce death (not to mention all the other factors you brought up) relative to poorly controlled diabetes . So if someone has poorly controlled diabetes then your analysis is absolutely correct, since that is what we currently have long-term data on. If someone doesn't have diabetes, it's quite possible GLPs will be found to reduce death, but that's still speculative at this point.

A similar logical error was made a few years back when it was announced that diabetics on metformin monotherapy lived longer on average than the general population. This was a correct observation, but people erroneously took it to mean that metformin more generally had life-extension properties. When metformin use in non-diabetics was studied, it was found that it didn't appear to lead to life-extension in non-diabetics.

Now, I'll grant you that one key difference with GLP1s is that they also serve to reduce other intermediate markers (e.g. inflammation, lipids, BMI, etc.) in non-diabetics, which supports the idea that they'll be beneficial in non-diabetics. I want it to be true just as much as you do, but unfortunately our desires are not a replacement for long-term data in non-diabetics.

 

[mlke6]

https://chat.peppys.org/u/nmcoyote1

There is a lot to unpack here. So I will have to think about different sections and reread it. But they mentioned “exposure to unstable compounded formulations” being a possible cause of things like immunogenisis. Hmmmm I wonder if that’s a thing and if it could be why we see different feels… excetra? Are peptides/ grey peptides really unstable? Should we be filtering grey peptides to prevent inmogenisis/ skin reactions

We Still Don’t Know Much About Long-Term GLP Use

How do GLP-1s affect the brain? Why does weight loss taper? Does long-term use lead to tolerance? All these questions remain unclear.

www.medscape.com

A guy over at meso talks about immunogenissis and aggregates often. Or at least he did.

 

[JoonyO]

IMO most obesity surgeons/physicians will do what's in their OWN interest. Unless they want to find another occupation. GLPs negate their necessity as "cures" for being overweight. You don't need a gastric sleeve ( and the possibility of death under anesthesia ) when you have GLPs as a proven alternative to allowing yourself to be opened up like a chicken and have parts removed or altered.

In other words I believe fear mongering will be used the same way BP is doing with CN grey.

But hey, what do I know? Just speculative on my part.

 

[jw717us]

IMO most obesity surgeons/physicians will do what's in their OWN interest. Unless they want to find another occupation. GLPs negate their necessity as "cures" for being overweight. You don't need a gastric sleeve ( and the possibility of death under anesthesia ) when you have GLPs as a proven alternative to allowing yourself to be opened up like a chicken and have parts removed or altered.

In other words I believe fear mongering will be used the same way BP is doing with CN grey.

But hey, what do I know? Just speculative on my part.

I'll take that another step and liken it to plumbing. If you spend time in plumbing forums you'll see professional plumbers ridicule PEX and Sharkbite style connectors as a "$20000 insurance incident waiting to happen" even though the fittings are proven, in building code, etc.....

Why? Any home owner can go spend $150 on the tools for PEX and easily replumb their own home. Check it with the go/no-go gauge and you are good to go. A single faucet or valve? 5 minutes of work for a C grade level home DIY person. That cuts into a LOT of work for real plumbers.

I once had an emergency when I was leaving town. I had my spouse call a plumber to replace a valve that was broken. I let them know on the phone it was a copper line and I wanted it replaced with a copper fitting and sweated in. They did the work, charged $350 for it. When I got home I saw they cut the copper and used a $25 Sharkbite slip fitting. We had words about that one.

Soooooo when a homeowner does it to save money it's a big no no waiting to blow. When they do it to shave time of the job it's perfectly good work.

I think we are seeing that same mentality here. Heck my doc just gave me an Rx with no real guidance. It wasn't till I found grey that I saw great guides on proper diet and advice on how to handle GI issues!

 

[DjJoshua]

More from Gemini regarding the 4 year study's findings on the effect of tirzepatide and atherosclerosis:

Clinical studies released in late 2025 and early 2026 have confirmed that tirzepatide (Mounjaro, Zepbound) provides robust protection against atherosclerotic cardiovascular disease (ASCVD) . These benefits appear to stem from both significant weight loss and direct biological effects on the vascular system.

1. Landmark Atherosclerosis Trial: SURPASS-CVOT​
The SURPASS-CVOT trial , published in January 2026, is the definitive study for tirzepatide's impact on atherosclerosis.

Cardioprotection: In over 13,000 patients with type 2 diabetes and established ASCVD, tirzepatide was non-inferior to dulaglutide (an established cardioprotective drug) in preventing major adverse cardiovascular events (MACE), such as heart attack and stroke.

Composite Risk Reduction: An expanded measure including cardiovascular death, heart attack, stroke, or coronary revascularization showed a significant reduction in risk compared to the active treatment group.

Survival: The trial observed a 16% lower rate of all-cause mortality compared to those taking dulaglutide.

2. Effects on Plaque and Vessel Health​
Recent data highlights that tirzepatide goes beyond weight management to directly improve arterial health :

Plaque Stabilization: Ongoing studies like the T-PLAQUE trial are using advanced imaging to investigate how tirzepatide may slow or even reverse the buildup of coronary artery plaques.

Vascular Repair: The drug stimulates endothelial progenitor cells , which helps repair damage to blood vessel linings.

Inflammation: Long-term use significantly reduces C-reactive protein (hsCRP) levels by roughly 32.9% , a key marker linked to atherosclerosis and stroke risk.

3. Predicted 10-Year ASCVD Risk​
Research based on three-year data shows that tirzepatide significantly lowers predicted long-term risk:

Risk Score Reduction: Participants on the 15 mg dose saw their 10-year predicted ASCVD risk drop by nearly 9.2% , while the placebo group's risk increased by over 50% due to aging and weight.

Impact of BMI: Reaching a healthy BMI (below 25 kg/m²) through treatment was linked to a 39.4% reduction in predicted 10-year risk compared to those who remained in the overweight or obese range.

WOW, Very good information, I did not know this.

 

[yml1966 12231]

More from Gemini regarding the 4 year study's findings on the effect of tirzepatide and atherosclerosis:

Clinical studies released in late 2025 and early 2026 have confirmed that tirzepatide (Mounjaro, Zepbound) provides robust protection against atherosclerotic cardiovascular disease (ASCVD) . These benefits appear to stem from both significant weight loss and direct biological effects on the vascular system.

1. Landmark Atherosclerosis Trial: SURPASS-CVOT​
The SURPASS-CVOT trial , published in January 2026, is the definitive study for tirzepatide's impact on atherosclerosis.

Cardioprotection: In over 13,000 patients with type 2 diabetes and established ASCVD, tirzepatide was non-inferior to dulaglutide (an established cardioprotective drug) in preventing major adverse cardiovascular events (MACE), such as heart attack and stroke.

Composite Risk Reduction: An expanded measure including cardiovascular death, heart attack, stroke, or coronary revascularization showed a significant reduction in risk compared to the active treatment group.

Survival: The trial observed a 16% lower rate of all-cause mortality compared to those taking dulaglutide.

2. Effects on Plaque and Vessel Health​
Recent data highlights that tirzepatide goes beyond weight management to directly improve arterial health :

Plaque Stabilization: Ongoing studies like the T-PLAQUE trial are using advanced imaging to investigate how tirzepatide may slow or even reverse the buildup of coronary artery plaques.

Vascular Repair: The drug stimulates endothelial progenitor cells , which helps repair damage to blood vessel linings.

Inflammation: Long-term use significantly reduces C-reactive protein (hsCRP) levels by roughly 32.9% , a key marker linked to atherosclerosis and stroke risk.

3. Predicted 10-Year ASCVD Risk​
Research based on three-year data shows that tirzepatide significantly lowers predicted long-term risk:

Risk Score Reduction: Participants on the 15 mg dose saw their 10-year predicted ASCVD risk drop by nearly 9.2% , while the placebo group's risk increased by over 50% due to aging and weight.

Impact of BMI: Reaching a healthy BMI (below 25 kg/m²) through treatment was linked to a 39.4% reduction in predicted 10-year risk compared to those who remained in the overweight or obese range.

Wow! This is staggering! Thanks for sharing!