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

 

[IronMetal_2]

So a small lesson for the geeks regarding immunogenicity for GLP meds, using Tirz as an example.

This is a from a study using pharma Tirzapetide, with every factor, from PH to the materials used in its container, carefully controlled to prevent aggregates from forming and minimize immunogenicity to the greatest degree possible. It's in a different league compared to UGL.

View attachment 300634

nGIP and nGLP-1 are native GIP and GLP hormone.

"Cross reactive" means an immune reaction against the natural hormone induced by the peptide that's mimicking it, IE, Tirz.

ADA, anti drug antibodies, in layman's terms, speeds elimination of the native hormone from the body, reducing its effectiveness.

NAb, neutralizing antibodies, for all intents, destroys the hormone.

I highlighted the percentages of subjects, around 5000 in this study, who developed these antibodies after 40 weeks, on the right.

Luckily, the levels of immunogenicity induced ADAs and NAbs, using PHARMA tirz, on the pharma protocol, didn't rise to the level of reducing effectiveness of the synthetic peptide + native hormones during the 40 week study.

However, it's clear immunogenicity is induced not only against the peptide, but against natural GLP and GIP as well.

UGL peptides are a mess by comparison, with all the ingredients in place for large quantities of aggregates to form, coupled with improper reconstitution, more frequent dosing by Dr. Reddit's protocol, and poor storage conditions.

Much higher levels of ADAs, and NAbs at the least will weaken effectiveness of treatment, including to future use of Tirz (and possibly other drugs), but at worst, potentially induce a long lasting immunity to our natural GIP and GLP hormones with yet to be studied outcomes.

We are in uncharted territory. It's prudent to proceed with caution, and minimize the immunogenic potential of these compounds by controlling what we can.

For a layman, reading this doesn't sound too great lol. Should those who use Pharma Tirzepatide be worried at all? I mean even 33.9% and 14.2% really doesn't sound great at all.

How about semaglutide? is it any lower there?

 

[HUGE McBIGLARGE]

I just got some vials off of Amazon that are covered in glitter. I tried googling if glitter affects peptide aggregation and it’s coming up blank. Am I taking on additional risk by using this, or will I just be more stylish?

seriously though, where am I meant to get proper vials? I’m sending these “vials” back, but where am I meant to get properly made ones?

And thanks, Ghoul, for all the material to read

 

[bigMoJo]

Which previous post of mine are you referring to?

This one bro...

The terms you use like “speeds elimination” and “destroys the hormone” exaggerate the severity, as this doesn't occur in all cases. ADAs can lead to faster clearance, but this depends on the type and level of ADAs present as not all ADAs are neutralizing. NAbs can interfere with hormone function but may not always “destroy” the hormone. The terminology that you use oversimplifies how ADAs and NAbs function and their actual impact on efficacy.

Also, it's theoretically possible that cross reactive antibodies could lead to long lasting immunity against natural GLP1 and GIP, but this is neither confirmed or well documented in the scientific literature.

The idea that UGL induced antibodies could result in permanent immunity to natural hormones is just speculation. Most studies including the one you are referencing suggest that even cross reactive antibodies do not necessarily result in long lasting immunity at the relatively low levels seen with pharma grade products. UGL peptides could have higher immunogenicity and therefore a higher theoretical risk of this outcome but it is theoretical.

 

[Ghoul]

For a layman, reading this doesn't sound too great lol. Should those who use Pharma Tirzepatide be worried at all? I mean even 33.9% and 14.2% really doesn't sound great at all.

How about semaglutide? is it any lower there?

Most peptides induce an immune reaction. The focus is on keeping it low enough that it doesn't have a negative effect.

Let's say immunogenicity was measured using a single number.

Hypothetically a once a week shot:

After an injection, it jumps to 15.

A week later it's dropped to 10.

Next injection it's back to 15.

A week later it's dropped to 10.

That's sustainable.
--------

Let's consider a twice a week protocol:

Initial injection it's jumped to 15

3 days later it's dropped to 12

Take another injection it's 18

3 days later it's dropped to 15

Take another injection it's 20

You can see the problem.
--------------

This is a very oversimplified analogy, but I'm sure you get the point. It's got to be kept manageable and stable.

In the real world they measure the blood level of the peptide and related hormones. If they start dropping, despite not changing the dose, that's a sign the immune system is "clearing" it faster and a strengthening. immune reaction is developing.

If the drug was left at room temp for 2 days, and lots of aggregates formed, that initial immune reaction level might have been 30, for instance. Or if you increased frequency to daily injections, the number could keep building higher.

At some point, it will get high enough to be "clinically significant.".

So like pharma, if one is going to use UGL peptides, the best strategy is minimizing the factors within our control, and avoid the factors that make immunogenicity worse.

In the case of HGH, about 2% of children develop such high levels of antibodies their growth becomes impaired. There have been a handful of pharma peptides for rare diseases that became disasters for some patients who developed seemingly permanent immunity to them. That's why the FDA became hyperfocused on this issue.

If pharma changes anything, from the materials used to make self injecting pens. to the injection frequency, they have to demonstrate immunogenicity isn't a problem under the new conditions.

 

[noteablequotable]

I just got some vials off of Amazon that are covered in glitter. I tried googling if glitter affects peptide aggregation and it’s coming up blank. Am I taking on additional risk by using this, or will I just be more stylish?

seriously though, where am I meant to get proper vials? I’m sending these “vials” back, but where am I meant to get properly made ones?

And thanks, Ghoul, for all the material to read

Find a good medical supply company.

 

[Ghoul]

I just got some vials off of Amazon that are covered in glitter. I tried googling if glitter affects peptide aggregation and it’s coming up blank. Am I taking on additional risk by using this, or will I just be more stylish?

seriously though, where am I meant to get proper vials? I’m sending these “vials” back, but where am I meant to get properly made ones?

And thanks, Ghoul, for all the material to read

Sterile, *pyrogen free*, teflon (ptfe) coated
stopper.

Like this or similar:

https://www.medical-and-lab-supplies.com/ultra-spec-sterile-5ml-20mm-neck-clear-sealed-glass-vial-qty-1.html

 

[jj89]

Hey Ghoul, on the subject of using GLPs indefinitely.

What if I went from using tirzepatide and switched to reta for a period of time. Would that count as far as staying "on" or are you risking blunting the effectiveness.

I guess I'm asking does it matter what specific drug you use as long as you use one of them.

 

[iris]

Sterile, *pyrogen free*, teflon (ptfe) coated
stopper.

Like this or similar:

https://www.medical-and-lab-supplies.com/ultra-spec-sterile-5ml-20mm-neck-clear-sealed-glass-vial-qty-1.html

I think he is in the UK or maybe in Europe, somewhere

Are you @HUGE McBIGLARGE ?

 

[Ghoul]

Hey Ghoul, on the subject of using GLPs indefinitely.

What if I went from using tirzepatide and switched to reta for a period of time. Would that count as far as staying "on" or are you risking blunting the effectiveness.

I guess I'm asking does it matter what specific drug you use as long as you use one of them.

Once again I'm going to preface this by we have a lot to learn, as even medical researchers and clinicians don't understand the underlying mechanisms of what's a growing body of "observational evidence".

The lessened sensitivity has been observed in people who used significantly different GLP drugs years before, stopped for a long time, and started Tirz. Docs have noticed this with patients who went off Sema, regained weight, and went back onto Sema or Tirz.

So my guess is that whatever's causing the decreased sensitivity, is related to the receptors, the immune system, or something else involved in metabolic regulation, and independent of the specific GLP drug used.

Based on that, I'd expect a switch to Reta would count as "continuous exposure" and avoid the developing this problem.

 

[Middus]

Just to chime in, immunogenicity doesn't always correlate to the compound being destroyed. Sometimes the body just creates antibodies that cling onto the peptide and do nothing. An Tesamorelin for example. immunogenicity in over 2/3 of those using, with little or no correlation to lack of therapeutic effect.

 

[Ghoul]

Just to chime in, immunogenicity doesn't always correlate to the compound being destroyed. Sometimes the body just creates antibodies that cling onto the peptide and do nothing. An Tesamorelin for example. immunogenicity in over 2/3 of those using, with little or no correlation to lack of therapeutic effect.

That's true, While Neutralizing antibodies "kill" the target, Anti drug antibodies cling to the target. Neither are a concern until and unless they rise to a level they impact clinical outcomes.

Obviously Neutralizing antibodies negate some of the drug, so a lot of that makes you "immune" to one degree or another to the peptide.

However, while the clinging Antidrug antibodies don't stop the drug from working, it makes them more recognizable and cleared more quickly from your system, reducing the drug's half life, making it less effective.

In fact the FDA advises drug makers to monitor PK (pharmacokinetics), ie, the speed of drug clearance, rather than antibodies (difficult to measure), as the first sign of immunogenicity problems developing.

 

[jj89]

Once again I'm going to preface this by we have a lot to learn, as even medical researchers and clinicians don't understand the underlying mechanisms of what's a growing body of "observational evidence".

The lessened sensitivity has been observed in people who used significantly different GLP drugs years before, stopped for a long time, and started Tirz. Docs have noticed this with patients who went off Sema, regained weight, and went back onto Sema or Tirz.

So my guess is that whatever's causing the decreased sensitivity, is related to the receptors, the immune system, or something else involved in metabolic regulation, and independent of the specific GLP drug used.

Based on that, I'd expect a switch to Reta would count as "continuous exposure" and avoid the developing this problem.

Thanks bro.

I've been curious how something like reta might make a lean bulk more effective, so I'll be a bit of a guinea pig I guess. I'll be continuing tirz at a low dose for the first few months then switching to reta for the latter half and see if anything noteworthy happens.

 

[Sam312xx]

This one bro...

I think you misunderstood my point. I didn’t mean to suggest that there’s an absence of aggregates that would eliminate concerns about efficacy or immunogenicity.

The original post I replied to significantly exaggerated the risks associated with UGL peptides by implying a near certainty of severe immunogenic reactions, including long lasting immunity against natural GLP1 and GIP hormones. While it’s true that UGL peptides lack the rigorous quality control of pharma, the issue is much more nuanced than what he portrayed.

Most instances of ADA and NAb formation do not result in complete or permanent neutralization of the natural hormones, and long lasting immunity is far from guaranteed. The reality is that while immunogenicity is possible, the extreme outcomes suggested are rare and not conclusively supported by current evidence.

Both the doomsayers and the non-believers are wrong at this point in time, the right approach is a balance between caution and evidence. The potential immunogenic risks associated with UGL peptides are higher, but require a balanced understanding, because severe lasting immune responses is speculative.

 

[HUGE McBIGLARGE]

Some crystal clear peptide solutions completely clog a 13mm filter with less than .5ml liquid passed through .

How can you tell when the filter is clogged?

I plunge the reconstituted solution through the filter into a new vial, and eventually the filter gives some “pushback”. This isn’t from the vial, as if I try plunging into air it still gives pushback.

I can get water through, but not air. What gives?

Here’s a video after I disconnected the syringe, filled it with air, and tried getting it through the filter


View attachment IMG_3082.mov

 

[Ghoul]

How can you tell when the filter is clogged?

I plunge the reconstituted solution through the filter into a new vial, and eventually the filter gives some “pushback”. This isn’t from the vial, as if I try plunging air it still gives pushback.

I can get water through, but not air. What gives?

It becomes difficult, then completely stops allowing any flow whatsoever, regardless of how much pressure I apply on the 3ml syringe. I have to replace the 13mm filter with another, or, once I realized this was a constant problem with certain, but not all, peptides, I got 25mm filters which have 5x the filter area. and are enough to filter the entire 3ml.

Meanwhile, other peptides can be filtered with the 13mm and suffer no slowdown, never mind blockage at all.

There's definately a ton of >.2um particulates in the peptide, whether "proteinaceous" aggregates or other stuff, or both. None of it's good or desirable, especially that large. They tend to be the most pip inducing peptides. I've noticed a massive reduction in site reactions after filtration, fwiw.

 

[HUGE McBIGLARGE]

It becomes difficult, then completely stops allowing any flow whatsoever, regardless of how much pressure I apply on the 3ml syringe. I have to replace the 13mm filter with another, or, once I realized this was a constant problem with certain, but not all, peptides, I got 25mm filters which have 5x the filter area. and are enough to filter the entire 3ml.

Meanwhile, other peptides can be filtered with the 13mm and suffer no slowdown, never mind blockage at all.

There's definately a ton of >.2um particulates in the peptide, whether "proteinaceous" aggregates or other stuff, or both. None of it's good or desirable, especially that large. They tend to be the most pip inducing peptides. I've noticed a massive reduction in site reactions after filtration, fwiw.

So if I can get the water through, does that mean it’s not blocked? Because it sure seems blocked when I fiddle around with it in empty air.

I put 10mg/5ml of pt141 through a 0.22micron 33mm filter

 

[Ghoul]

So if I can get the water through, does that mean it’s not blocked? Because it sure seems blocked when I fiddle around with it in empty air.

If water can get through it's not completely blocked, however, I push air through to get the last bit of holdback liquid into the vial, so straight air should go through. (air takes a little more force, but shouldn't be impossible).

You may want to presoak the filter by running .5ml BAC through it before use, and see if that makes a difference, or just push harder.

 

[HUGE McBIGLARGE]

If water can get through it's not completely blocked, however, I push air through to get the last bit of holdback liquid into the vial, so straight air should go through. (air takes a little more force, but shouldn't be impossible).

You may want to presoak the filter by running .5ml BAC through it before use, and see if that makes a difference, or just push harder.

Thanks. My syringes are 2.5ml, so I do 2.5ml of the peptide solution, then flush it with another 2.5ml of bac to make the whole mix 5ml.

I’ll follow a “if the water goes through it’s not blocked” rule

 

[Ghoul]

Thanks. My syringes are 2.5ml, so I do 2.5ml of the peptide solution, then flush it with another 2.5ml of bac to make the whole mix 5ml.

I’ll follow a “if the water goes through it’s not blocked” rule

Yeah, mine becomes a damn brick wall. I was pissed because I didn't want to go through $8 worth of filters for one 5 dose vial. Now I know better and a single 25mm is good enough. If that ever clogs on one vial I should probably consider throwing. that batch in the trash lol

 

[HUGE McBIGLARGE]

Yeah, mine becomes a damn brick wall. I was pissed because I didn't want to go through $8 worth of filters for one 5 dose vial. Now I know better and a single 25mm is good enough. If that ever clogs on one vial I should probably consider throwing. that batch in the trash lol

thanks for all of the help!