GLP Non responder's

[Here2Learn]

I’ve been reading studies on GLP’s and found this interesting. Just data points. I read another one saying those who are sicker or had early childhood obesity or trauma had higher rates of non response too.

Quote from study
“Conclusions
A high HbA1c at baseline and previous non-insulin therapy were the main predictors of a greater response (optimal HbA1c and weight response) to GLP1ra in both men and women. This may aid in treatment decision-making before initiating treatment with GLP-1RAs.”

https://www.sciencedirect.com/science/article/abs/pii/S1751991822001711

 

[noteablequotable]

Nah. The theory is that peptides can be improperly made, improperly stored, or improperly reconstituted. They can bind together and turn from peptides to different compounds such as proteins. These different compounds can look like pathogens to the body, causing an immune response.

In order from best case scenario to worst, the new compounds could, in theory, cause:
1: a loss of efficacy due to peptide loss, but no immune response
2: immunity to the new compounds, but no immunity to the peptide
3: a symptomatic immune response to the new compounds, but no immunity to the peptide
4: immunity to the new compound, and the peptide, which may last indefinitely
5: a symptomatic immune response to the new compounds, and the peptide, which may last indefinitely, along with immunity to the peptide

Best ways to avoid it, according to Ghoul, are to get the best source of peptide you can, filter it, and reconstitute it with as high of a water content as possible. I guess you’d also want to keep it cold but not freezing when reconstituted, and don’t let the solution move too much.

I don’t know how likely this is to occur. As far as I’m aware it could happen in theory to HGH as well as glp-1 agonists. Yet despite underground HGH being used so much, I’ve never heard of anyone talking about an immune response to it. So it certainly can’t be very likely. Maybe because HGH is a bioidentical peptide, and exogenous glp-1 agonists are not, the body is far less likely to ever develop an immune response to HGH. I really don’t know lol

That super helpful context. I have the appropriate filters, but I've been looking for filters that are both sterile and positively charged so that they can be used to filter out endotoxins as well, but I haven't been able to find any. In any case, I'm glad to know that it helps.

 

[HUGE McBIGLARGE]

That super helpful context. I have the appropriate filters, but I've been looking for filters that are both sterile and positively charged so that they can be used to filter out endotoxins as well, but I haven't been able to find any. In any case, I'm glad to know that it helps.

I have no idea what I’m on about, so don’t trust me, but I wouldn’t worry too much about strict sterility.

I know a fella with parksonian symptoms who has been on 24/7 subq apomorphine via a syringe driver for decades. And the apomorphine comes in glass vials that are “sealed” with the loosest rubber lid known to man. They just fall off. He’s far from a clean chap, and as far as I’m aware he’s had no complications from the lack of sterility. Your skin is far from sterile, even with an alcohol wipe used.

If you want to put more effort into doing this right, focus more on proper storage than anything else. If you store your drugs and equipment right they should be fairly sterile anyway. And if you’re filtering them, bacteria would be removed. Only viruses might get in.

But again, don’t trust me. You can never do drugs too safely.

 

[Ghoul]

No one using UGL is being tested for antidrug antibodies so there's no way to determine is there's a problem or not. HGH users are constantly complaining about tons of sides, or it being bunk despite testing well, and somehow pharma is always better, even though it's the same molecule.

Neither are most bacterial infections symptomatic.

Both can silently inflict great harm, so "feels" is not exactly a great way to determine everything's fine.

Heroin addicts inject garbage brewed on a dirty spoon and filtered with a dirty cigarette butt, yet don't end up in the hospital. Does that make it safe?

 

[Ghoul]

That super helpful context. I have the appropriate filters, but I've been looking for filters that are both sterile and positively charged so that they can be used to filter out endotoxins as well, but I haven't been able to find any. In any case, I'm glad to know that it helps.

There's nothing you can do about endotoxins but minimize the presence of bacteria at every step. Once bacteria leaves behind the pieces that comprise endotoxin, they can't be removed by filtration. They can be "deactivated" by high heat, but only empty vessels are suitable for that.

That's why filtering bacteria as the last stage of brewing underground steroids is less than ideal. Compounding pharmacies and pharma manufacturers keep everything sterile to the greatest extent possible, and while they still filter sterilize as a safeguard against live bacteria. they have to meet endotoxin requirements so keep everything sterile, from ingredients to equipment, every step of the way as it's the only effective method to reduce endotoxin.

But endotoxin is a long term threat, protein aggregation and immunogenicity is far more worrisome because of what could potentially happen if just the wrong "mutant" form of the protein ends up in the body.

Yet ask any underground GLP user, or any peptide user, how they decide to dilute their peptide, and 99% of the time it's based on convenience, and they have no clue as to there being any significance to water/peptide ratio. Yet it's a VERY important factor. That's how backwards "bro science" is in regards to peptides.

 

[HUGE McBIGLARGE]

There's nothing you can do about endotoxins but minimize the presence of bacteria at every step. Once bacteria leaves behind the pieces that comprise endotoxin, they can't be removed by filtration. They can be "deactivated" by high heat, but only empty vessels are suitable for that.

That's why filtering bacteria as the last stage of brewing underground steroids is less than ideal. Compounding pharmacies and pharma manufacturers keep everything sterile to the greatest extent possible, and while they still filter sterilize as a safeguard against live bacteria. they have to meet endotoxin requirements so keep everything sterile, from ingredients to equipment, every step of the way as it's the only effective method to reduce endotoxin.

But endotoxin is a long term threat, protein aggregation and immunogenicity is far more worrisome because of what could potentially happen if just the wrong "mutant" form of the protein ends up in the body.

Yet ask any underground GLP user, or any peptide user, how they decide to dilute their peptide, and 99% of the time it's based on convenience, and they have no clue as to there being any significance to water/peptide ratio. Yet it's a VERY important factor. That's how backwards "bro science" is in regards to peptides.

Wouldn’t there be a greater risk of endotoxins from your skin? If I’m using a 25mm*0.4mm needle, that’s around 30mm^2 of surface area going through skin, collecting every contaminant along the way.

And is there an upper limit to the water/peptide ratio? I can get bacteriostatic water for free so I’m thinking of going crazy with it.

 

[Ghoul]

Wouldn’t there be a greater risk of endotoxins from your skin? If I’m using a 25mm*0.4mm needle, that’s around 30mm^2 of surface area going through skin, collecting every contaminant along the way.

And is there an upper limit to the water/peptide ratio? I can get bacteriostatic water for free so I’m thinking of going crazy with it.

Skin's a source of much worse than endotoxin. Luckily, from what I've read, the subcutaneous layer of skin has the most well developed immune system defenses, and the bacteria introduced by the needle tends to break off there and get destroyed by our immune system before it gets to the relatively undefended muscle (for IM injections). Though if it does get into the muscle, it's got a much greater chance of survivial and contributing to things like "septic arthritis", where joints are slowly destroyed, and by the time the cumulative damage is noticed, it's blamed on "old age" or "over use".

Conversely, because peptides are injected subcutaneously, the thing we most want to avoid, immunogenicity, is more likely to occur there, with the hyperactive response of our immune system to anything out of the ordinary. In fact, the best reason to sterilize the skin for a subQ injection isn't infection, but that the contaminants from the skin getting into the subQ region draw the immune systems attention to the area, making an immunogenic response to the peptide more likely.

 

[noteablequotable]

This conversation is super valuable but has definitely started off topic a bit, lol. Would love to start a thread to talk specifically about endotoxin risk because that's it's own can of worms that isn't really talked about much (at least not on the Peptide sites).

I recently did some research into non responders as part of a paper I wrote on Mazdutide. Will link some sources people might find interesting as soon as I get a few minutes.

 

[Sam312xx]

Theres a lot of misinformation being passed around regarding GLP 1 agonists.

It is very uncommon for GLP 1 agonists to cause immune responses.

GLP 1 agonists are well tolerated because they are designed to closely resemble the natural GLP 1 hormone with slight modifications for stability and efficacy.

The risk of an immune response is low, but as with any synthetic compound a rare immunogenic reaction is possible, especially with long-term use. While the ideal protocol for GLP 1 use is still being researched, cyclical dosing is being considered as an alternative to being permanently on as a way to reduce the likelihood of tolerance by allowing receptors and physiological pathways to reset during off periods.

Developing immunity or resistance to tirz or similar GLP 1 agonists is not common and is not well documented in clinical studies. They are not vaccines which intentionally provoke an immune response that would cause the body to "reject" or neutralize the medication over time.

There is no evidence to suggest that using tirz could lead to permanent immunity to the drug. Peptides like tirz are generally cleared from the body without inducing lasting immune memory, which is necessary for permanent immunity.

Developing an immunity against your own naturally produced GLP would be highly unlikely. Tirz is designed to mimic natural hormones, and there’s no evidence that it could trigger an immune response against the body’s endogenous GLP 1. The immune system typically differentiates between externally administered agents and naturally occurring hormones, especially in the case of GLP 1 agonists.

 

[HUGE McBIGLARGE]

Skin's a source of much worse than endotoxin. Luckily, from what I've read, the subcutaneous layer of skin has the most well developed immune system defenses, and the bacteria introduced by the needle tends to break off there and get destroyed by our immune system before it gets to the relatively undefended muscle (for IM injections). Though if it does get into the muscle, it's got a much greater chance of survivial and contributing to things like "septic arthritis", where joints are slowly destroyed, and by the time the cumulative damage is noticed, it's blamed on "old age" or "over use".

Conversely, because peptides are injected subcutaneously, the thing we most want to avoid, immunogenicity, is more likely to occur there, with the hyperactive response of our immune system to anything out of the ordinary. In fact, the best reason to sterilize the skin for a subQ injection isn't infection, but that the contaminants from the skin getting into the subQ region draw the immune systems attention to the area, making an immunogenic response to the peptide more likely.

It’s to my understanding that endotoxins are released when cells die or divide. Meaning your skin is going to be full of endotoxins whether you’ve sterilised your skin or not. And it’s not like these endotoxins are removed by an immune response. Of course, washing is gonna be good, but skin is far too porous for washing to be sufficient.

 

[Ghoul]

Theres a lot of misinformation being passed around regarding GLP 1 agonists.

It is very uncommon for GLP 1 agonists to cause immune responses.

GLP 1 agonists are well tolerated because they are designed to closely resemble the natural GLP 1 hormone with slight modifications for stability and efficacy.

The risk of an immune response is low, but as with any synthetic compound a rare immunogenic reaction is possible, especially with long-term use. While the ideal protocol for GLP 1 use is still being researched, cyclical dosing is being considered as an alternative to being permanently on as a way to reduce the likelihood of tolerance by allowing receptors and physiological pathways to reset during off periods.

Developing immunity or resistance to tirz or similar GLP 1 agonists is not common and is not well documented in clinical studies. They are not vaccines which intentionally provoke an immune response that would cause the body to "reject" or neutralize the medication over time.

There is no evidence to suggest that using tirz could lead to permanent immunity to the drug. Peptides like tirz are generally cleared from the body without inducing lasting immune memory, which is necessary for permanent immunity.

Developing an immunity against your own naturally produced GLP would be highly unlikely. Tirz is designed to mimic natural hormones, and there’s no evidence that it could trigger an immune response against the body’s endogenous GLP 1. The immune system typically differentiates between externally administered agents and naturally occurring hormones, especially in the case of GLP 1 agonists.

All the studies you refer to involve pharma grade compounds, and specifically, the immunogenicity studies were conducted with the specific protocol the FDA ultimately approved.

They weren't conducted with underground produced compounds, without oversight, using unknown excipients, stored and transported at random temperatures for unknown lengths of time, diluted at random strengths often using BAC of unknown origin, very very likely to contain pyrogens. and the resulting PH is random. All this in the cheapest vials available to the supplier, likely high in extractable and leachable compounds.

Every one of these conditions are linked to aggregate formation, one of the primary drivers of immunogenicity. Each unique aggregate shape is capable of inducing a unique, unknown immune reaction.

Pharma Sema and Tirz are free of all these aggregate inducing conditions, yet still generates a measurable, but low enough to be tolerable, immunogenic reaction when used once a week as directed.

UGL peptides suffer from all of the above problems, so your position that certain reactions are "rare" simply has no credibility. You almost couldn't engineer conditions more likely to induce a reaction.

So tell us, since immunogenicity problems are nearly an impossibility (despite no one being tested for antibodies), answer one simple question.

Is the random dilution rate chosen by users of GLPs, one defined by personal preference or convenience, as is the case in the overwhelming majority of instances, advisable?

 

[noteablequotable]

Links to sources of info about non responders. Lots of stuff to consider. More likely to be male, sicker, have metabolic issues, may have a history of depression or childhood trauma. Can benefit from higher doses.

1. Predictors of poor response to semaglutide for weight management | ECE2024 | 26th
European Congress of Endocrinology | Endocrine Abstracts
2. Semaglutide for weight loss: unanswered questions - PMC
3. #1696673 Weight reduction over time in tirzepatide-treated participants by early weight
loss response – post hoc analysis in SURMOUNT-1 - Endocrine Practice
4. Slow Responders to Zepbound Achieve Meaningful Weight Loss Eventually | MedPage
Today
5. Weight-loss drugs don't work for everyone. Here's why.

If you want to read my write up on Mazdutide you can find it here:

View: https://drive.google.com/file/d/1YbQce6VDrJrQCQuEv4JmiSoVCvI1sKIj/view?usp=drivesdk

 

[Ghoul]

It’s to my understanding that endotoxins are released when cells die or divide. Meaning your skin is going to be full of endotoxins whether you’ve sterilised your skin or not. And it’s not like these endotoxins are removed by an immune response. Of course, washing is gonna be good, but skin is far too porous for washing to be sufficient.

Since it's hard to go into full context with every mention of endotoxins, we're only concerned with endotoxin from gram-negative bacteria which are thankfully rarely found on the skin. The bigger threat is it building up on unsterile equipment and ingredients, then showing up in high levels in a vial of something you're injecting frequently.

 

[Ghoul]

Links to sources of info about non responders. Lots of stuff to consider. More likely to be male, sicker, have metabolic issues, may have a history of depression or childhood trauma. Can benefit from higher doses.

1. Predictors of poor response to semaglutide for weight management | ECE2024 | 26th
European Congress of Endocrinology | Endocrine Abstracts
2. Semaglutide for weight loss: unanswered questions - PMC
3. #1696673 Weight reduction over time in tirzepatide-treated participants by early weight
loss response – post hoc analysis in SURMOUNT-1 - Endocrine Practice
4. Slow Responders to Zepbound Achieve Meaningful Weight Loss Eventually | MedPage
Today
5. Weight-loss drugs don't work for everyone. Here's why.

If you want to read my write up on Mazdutide you can find it here:

View: https://drive.google.com/file/d/1YbQce6VDrJrQCQuEv4JmiSoVCvI1sKIj/view?usp=drivesdk

As far as I'm concerned, I wouldn't consider anyone a non responder until they reach max dose of Sema or Tirz. Though I see many panicking well before that point and start flailing around, potentially doing more harm than good.

 

[noteablequotable]

As far as I'm concerned, I wouldn't consider anyone a non responder until they reach max dose of Sema or Tirz. Though I see many panicking well before that point and start flailing around, potentially doing more harm than good.

That's fair, I'm just using the clinical definition for the group of people who do not respond to GLP-1 treatment as expected.

 

[Ghoul]

That's fair, I'm just using the clinical definition for the group of people who do not respond to GLP-1 treatment as expected.

I've come to appreciate one aspect of Sema that's generally considered a negative. It's "felt" much more easily than Tirz, which is far more subtle. I think that may work better for a lot of folks, and luckily, those negative effects still disappear once you're on a maintainance dose.

 

[Ghoul]

Wouldn’t there be a greater risk of endotoxins from your skin? If I’m using a 25mm*0.4mm needle, that’s around 30mm^2 of surface area going through skin, collecting every contaminant along the way.

And is there an upper limit to the water/peptide ratio? I can get bacteriostatic water for free so I’m thinking of going crazy with it.

It's better to over dilute than under. Too concentrated and aggregates form that at the least reduce the potency of the drug, and at worst, increase immunogenicity. Also, it can speed uptake of the drug to too quick a rate, potentially increasing side effects.

Over dilution decreases immunogenicity risk, but also affects pharmacokinetics. The more dilute, the longer it takes, generally, for the drug to be absorbed.

 

[Sam312xx]

All the studies you refer to involve pharma grade compounds, and specifically, the immunogenicity studies were conducted with the specific protocol the FDA ultimately approved.

They weren't conducted with underground produced compounds, without oversight, using unknown excipients, stored and transported at random temperatures for unknown lengths of time, diluted at random strengths often using BAC of unknown origin, very very likely to contain pyrogens. and the resulting PH is random. All this in the cheapest vials available to the supplier, likely high in extractable and leachable compounds.

Every one of these conditions are linked to aggregate formation, one of the primary drivers of immunogenicity. Each unique aggregate shape is capable of inducing a unique, unknown immune reaction.

Pharma Sema and Tirz are free of all these aggregate inducing conditions, yet still generates a measurable, but low enough to be tolerable, immunogenic reaction when used once a week as directed.

UGL peptides suffer from all of the above problems, so your position that certain reactions are "rare" simply has no credibility. You almost couldn't engineer conditions more likely to induce a reaction.

So tell us, since immunogenicity problems are nearly an impossibility (despite no one being tested for antibodies), answer one simple question.

Is the random dilution rate chosen by users of GLPs, one defined by personal preference or convenience, as is the case in the overwhelming majority of instances, advisable?

Yes of course I'm talking about existing literature based on pharma. What were you expecting, assumptions for UGL products?

Your recommendation to stay on GLP-1 long-term is inconsistent with your own points about the risks of UGL products. If the main goal is to minimize immune response and tolerance, the only recommendation is to avoid UGL GLP-1 agonists altogether.

You're talking about aggregation as a primary driver of immunogenicity, and conditions like improper storage, butyl rubber stoppers without ptfe coating, uncontrolled pH, and random dilution encouraging peptide aggregation. Each aggregated form can potentially look foreign to the immune system, prompting varied immune reactions.

Sticking with UGL tirzepatide long term will actually increase the chances of developing antibodies against it due to its inconsistency and lack of quality control. Long term exposure to it will make the immune response even worse as the body is repeatedly exposed to aggregate prone or contaminated compounds.

 

[noteablequotable]

I've come to appreciate one aspect of Sema that's generally considered a negative. It's "felt" much more easily than Tirz, which is far more subtle. I think that may work better for a lot of folks, and luckily, those negative effects still disappear once you're on a maintainance dose.

I've heard this as well, that Sema elicits a much stronger feeling of efficacy.

Having said that, non-responders aren't determined by self reports. Anyone who doesn't lose <5% of their body weight in 12 weeks is considered a non responder. That seems like a pretty low bar to clear, especially for people who are on an escalated titration schedule.

For what it's worth your advice is 100% in line with the general consensus: get them up to an effective dose ASAP.

 

[Intrepid]

Is reta>tirz>sema a fair statement? (Based on the increasing methods of action we observe as we go into the newer glps1)

Reta really interests me, having run sema and tirz. I find tirz to be much more effective than sema personally, so now I'm kind of curious how reta would be.

Mainly trying to offset insulin resistance from gh, keep blood glucose low/normal, and increase insulin sensitivity

 

[noteablequotable]

Is reta>tirz>sema a fair statement? (Based on the increasing methods of action we observe as we go into the newer glps1)

Reta really interests me, having run sema and tirz. I find tirz to be much more effective than sema personally, so now I'm kind of curious how reta would be.

Mainly trying to offset insulin resistance from gh, keep blood glucose low/normal, and increase insulin sensitivity

Maz is better than Reta if what you care about is WL, but otherwise you're right.