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

[Nmcoyote1]

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

 

[Zydeceltico]

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?

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

Here are 2 legit long term studies returned by Gemini:

Clinical studies on the long-term effects of tirzepatide (the active ingredient in Mounjaro and Zepbound ) have expanded significantly as of 2026. While the drug is relatively new, researchers have now released data from trials spanning three to four years , offering a better understanding of its sustained safety and effectiveness.

1. Three-Year Weight Management and Diabetes Prevention​[archived internal link]
The SURMOUNT-1 trial is one of the longest completed studies to date, following participants for 176 weeks (roughly 3.4 years).

Weight Loss Maintenance: Participants on the highest dose (15 mg) achieved and maintained an average weight reduction of 22.9% over the three-year period.

Diabetes Risk Reduction: In adults with pre-diabetes and obesity, tirzepatide reduced the risk of progressing to type 2 diabetes by 94% compared to a placebo.

Health Reversal: Nearly 99% of participants treated with the drug remained diabetes-free at the end of the 176-week treatment period.

2. Four-Year Cardiovascular and Mortality Outcomes​[archived internal link]
The SURPASS-CVOT trial, published in late 2025, followed over 13,000 patients with type 2 diabetes and established cardiovascular disease for a median of 4 years .

Heart Protection: The study confirmed that tirzepatide is as effective as other leading treatments (like dulaglutide) in preventing major cardiovascular events, such as heart attacks and strokes.

Survival Benefits: Results showed a significant reduction in all-cause mortality (8.6% vs 10.2%) over the four-year period.

Kidney Health: Long-term use was also associated with slowing the decline of kidney function in high-risk patients.

3. Long-Term Safety and Side Effects​[archived internal link]
Data from these multi-year trials indicate that the safety profile remains consistent over time.

Common Issues: Gastrointestinal symptoms (nausea, diarrhea, and constipation) are the most frequent side effects. These are typically most severe during the initial dose-escalation phase but can persist for some users.

Serious Risks: Rare but serious events monitored in long-term studies include pancreatitis (occurring in <1% of participants) and gallbladder-related issues.

Warnings: It remains contraindicated for individuals with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

4. Ongoing "Lifetime" Research​[archived internal link]
Because tirzepatide is often intended for chronic use, researchers are using 10-year and lifetime simulation models based on current trial data to predict future health gains. These models suggest that long-term use may continue to generate substantial health benefits by preventing long-term complications of obesity and diabetes.

 

[blueandazure]

GLP-1s have been used for so long that sema's patent is about to expire. I think the only long term effects are positive ones.

 

[Zydeceltico]

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?

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

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​[archived internal link]
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​[archived internal link]
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​[archived internal link]
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.

 

[Gr33dyOctopus]

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.

 

[Grogu]

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

That “exposure to unstable compounded formulations” is the typical trashing of compounded glp-1s in the popular press. The cynic in me thinks that Eli Lilly probably paid the author to include that in the article.

I don’t think that peptides or grey peptides are any more unstable than brand name. I’ve been using compounded tirz that was compounded over a year ago and it’s working great. I actually liked it better than brand zepbound.

As far as the crux of the article, I’m not sure what people are really expecting as far as “long-term” studies. Clinical studies aren’t going to track patients for decades. The long-term clinical study is millions of patients actually taking the medication in the real world. Sema started being prescribed in Dec 2017 to people with T2DM, that’s 8 years of real world data on its effectiveness.

 

[Chili777]

And those studies haven't touched on one of the biggest benefits to me which is alcohol control/suppression or whatever you want to call it. I thought I read that there is, or will be, a trial to study the effects of Tirz on that subject. I know that from the day I started Reta, I haven't wanted a drink (well, I did have a single beer at a Christmas party and it took me an hour to finish) and the presence of alcohol as a driver of my existence simply vanished.

I've heard other anecdotal stories of the same thing for meth and other habit forming substances. I'll be on some amount of Reta for the foreseeable future for that reason alone. Every time I think of that, I want to order more.

 

[Nmcoyote1]

That “exposure to unstable compounded formulations” is the typical trashing of compounded glp-1s in the popular press. The cynic in me thinks that Eli Lilly probably paid the author to include that in the article.

I don’t think that peptides or grey peptides are any more unstable than brand name. I’ve been using compounded tirz that was compounded over a year ago and it’s working great. I actually liked it better than brand zepbound.

As far as the crux of the article, I’m not sure what people are really expecting as far as “long-term” studies. Clinical studies aren’t going to track patients for decades. The long-term clinical study is millions of patients actually taking the medication in the real world. Sema started being prescribed in Dec 2017 to people with T2DM, that’s 8 years of real world data on its effectiveness.

I've seen ongoing discussion in the grey community about Mutagenasis from contaminates causing reactions to grey peptides. Those reactions include itching, redness or peptides not working. Some are recommending that we filter grey. I'm not sure what to think?

 

[Nmcoyote1]

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.

That is common with any diet, GLP-1 use or weight loss surgery where you lose lots of weight.

 

[randompersonrandom]

We should be filtering grey because we have no real idea of the manufacturing conditions and because filtering costs like a buck and if you're using pens, doesn't really add extra effort.

I'm not sure "because scary mutagenics" even needs to be factored into that part; you had me at "we don't know if the lab was inspected for fruit flies."

 

[tubby]

Here are 2 legit long term studies returned by Gemini:

Clinical studies on the long-term effects of tirzepatide (the active ingredient in Mounjaro and Zepbound ) have expanded significantly as of 2026. While the drug is relatively new, researchers have now released data from trials spanning three to four years , offering a better understanding of its sustained safety and effectiveness.

1. Three-Year Weight Management and Diabetes Prevention​
The SURMOUNT-1 trial is one of the longest completed studies to date, following participants for 176 weeks (roughly 3.4 years).

Weight Loss Maintenance: Participants on the highest dose (15 mg) achieved and maintained an average weight reduction of 22.9% over the three-year period.

Diabetes Risk Reduction: In adults with pre-diabetes and obesity, tirzepatide reduced the risk of progressing to type 2 diabetes by 94% compared to a placebo.

Health Reversal: Nearly 99% of participants treated with the drug remained diabetes-free at the end of the 176-week treatment period.

2. Four-Year Cardiovascular and Mortality Outcomes​
The SURPASS-CVOT trial, published in late 2025, followed over 13,000 patients with type 2 diabetes and established cardiovascular disease for a median of 4 years .

Heart Protection: The study confirmed that tirzepatide is as effective as other leading treatments (like dulaglutide) in preventing major cardiovascular events, such as heart attacks and strokes.

Survival Benefits: Results showed a significant reduction in all-cause mortality (8.6% vs 10.2%) over the four-year period.

Kidney Health: Long-term use was also associated with slowing the decline of kidney function in high-risk patients.

3. Long-Term Safety and Side Effects​
Data from these multi-year trials indicate that the safety profile remains consistent over time.

Common Issues: Gastrointestinal symptoms (nausea, diarrhea, and constipation) are the most frequent side effects. These are typically most severe during the initial dose-escalation phase but can persist for some users.

Serious Risks: Rare but serious events monitored in long-term studies include pancreatitis (occurring in

 

[Gr33dyOctopus]

That is common with any diet, GLP-1 use or weight loss surgery where you lose lots of weight.

Oh yea, im not blaming the glp1, it was a lot of factors im sure.

 

[Ragnar]

I appreciate you trying to be helpful by sharing your chatbot output, but at present "AI" lacks proper critical thinking skills and is going to give false confidence when answering these kinds of questions. This is because to a chatbot "safety" is just a word and a vague concept. It looks for studies involving GLP and "safety" and paraphrases those outputs, without understanding the proper context of what the term means in a research setting.

Let me explain:

Any GLP study centered around diabetes cannot inform on long-term safety for GLP use in non-diabetics. The way these studies determine safety is by comparing bad things that happen to people receiving the GLP against bad things that happen to people in the control group (no GLP). Since we're dealing with diabetics, that means the control group is going to be poorly controlled diabetics, which is one of the least healthy groups on the planet.

If Gemini were remotely competent here it would have answered: Long-term studies indicate that GLP drugs are safer than living with poorly controlled diabetes. That's a good thing, but doesn't really tell us one way or the other if they're safe for non-diabetics, which is presumably what OP was asking.

I guess I don't follow on how SURMOUNT-1 is not a long-term study that looks at tirzepatide in adults with obesity and that do not have diabetes?

https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

"The present trial , SURMOUNT - 1 , evaluated the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes"

It seems like a valid comparison to me.

 

[tubby]

I guess I don't follow on how SURMOUNT-1 is not a long-term study that looks at tirzepatide in adults with obesity and that do not have diabetes?

https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

"The present trial , SURMOUNT - 1 , evaluated the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes"

It seems like a valid comparison to me.

The answer to that is right in the abstract and I've bolded the relevant part:

In this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary end points were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population.

When people say "long-term" they're usually asking about 5-10 years or longer, not 72 weeks.

To be clear, I'm not arguing that GLPs are unsafe. I have no reason to believe that. I'm just pointing out that nobody knows the answer to OP's question one way or the other and anyone claiming to know is misleading you.

And this isn't any sort of nefarious plot. Just about all drug trials are like this because the alternative (studying GLPs for 10 years before releasing them) would be way too expensive and would keep people who need them from accessing them sooner. In practice the way this plays out is that population-level health data is monitored after the drug is approved in the so-called "post-marketing" period. If a safety signal emerged there later on it gets investigated and if it's strong enough the approval for the drug may be later pulled.

 

[Zydeceltico]

And this isn't any sort of nefarious plot. Just about all drug trials are like this because the alternative (studying GLPs for 10 years before releasing them) would be way too expensive and would keep people who need them from accessing them sooner. In practice the way this plays out is that population-level health data is monitored after the drug is approved in the so-called "post-marketing" period. If a safety signal emerged there later on it gets investigated and if it's strong enough the approval for the drug may be later pulled.

All true.

And?

 

[miss-sanne]

Yes we do know a lot.

I have prescribed glp-1 to my diabetes patients for more than 15 years, and it's been around for even longer, 20 maybe ??

 

[JoonyO]

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 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

 

[tubby]

Yes we do know a lot.

I have prescribed glp-1 to my diabetes patients for more than 15 years, and it's been around for even longer, 20 maybe ??

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

 

[Zydeceltico]

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

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

 

[miss-sanne]

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

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.