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

 

[Grey Spartan]

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.

View attachment 300587

This still your recommendation?

For Sema it's .5ml for doses up to 2.4mg. So a 10mg vial should be diluted with at least 2ml.

No less than .5ml for Tirz up to 10mg, .75ml for 12.5mg and 15mg.

 

[bigMoJo]

Curious...
Since UGL GLPs can be "compounded" by the "user," technically any dosage may be administered. Hypothetically, assuming proper dilution, what are the negatives of titrating unlike pharma protocol? For example, starting at 2.5mg Tirz. for 4 weeks, but increasing to 4mg at week 5 instead of 5mg. We discuss dosages of AAS by the tens of milligram's (10, 50, 100, 200), is that applicable with GLPs?

 

[Ghoul]

This still your recommendation?

For Sema it's .5ml for doses up to 2.4mg. So a 10mg vial should be diluted with at least 2ml.

No less than .5ml for Tirz up to 10mg, .75ml for 12.5mg and 15mg.

That's backwards. I corrected it in a subsequent post.

.5ml for Tirz doses to 15mg

.5ml for Sema to 1mg,
.75ml for Sema 1.7mg and 2.4mg

 

[Ghoul]

Curious...
Since UGL GLPs can be "compounded" by the "user," technically any dosage may be administered. Hypothetically, assuming proper dilution, what are the negatives of titrating unlike pharma protocol? For example, starting at 2.5mg Tirz. for 4 weeks, but increasing to 4mg at week 5 instead of 5mg. We discuss dosages of AAS by the tens of milligram's (10, 50, 100, 200), is that applicable with GLPs?

I don't see any particular issue titrating in smaller increments, as long as you keep in mind full strength of a given dose takes 4 weeks to develop, so be careful thinking "not enough" until at least two weeks have passed, imo.

 

[AlexDavis43]

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.

Who is considering this, specifically? PubMed, Reddit, blog post, or what/who

 

[17SS]

Has anyone used the Tirz/Sema 60/3 combination? Feel like I’m plateauing on Tirz 5mg/week and have to bump it to 10mg/week.

Will get reta next time.

Still have a script for Tirz 5mg/week that runs $25/month but the wife has been using it.

 

[Ghoul]

Has anyone used the Tirz/Sema 60/3 combination? Feel like I’m plateauing on Tirz 5mg/week and have to bump it to 10mg/week.

Will get reta next time.

Still have a script for Tirz 5mg/week that runs $25/month but the wife has been using it.

You're supposed to plateau. If you gained weight back at the same dose the appetite suppressing effects would kick in again. Why not stick with tirz? The next titration level is 7.5mg. Ideally, youi'd reach goal weight at 12.5 or 15, and could use those for your maintainance dose, where you'd feel nothing, and benefit from the long list of non-weight related health benefits of GLP/GIP agonists.

I strongly advise against mixed peptides.

 

[bigMoJo]

I don't see any particular issue titrating in smaller increments, as long as you keep in mind full strength of a given dose takes 4 weeks to develop, so be careful thinking "not enough" until at least two weeks have passed, imo.

I'm considering UGL GLP for someone very close to me, pays over $500/month currently for a clinic that "compounds" their own Sema. Insurance does not cover at all, and $500/month is ridiculous. I want to make sure I have all my ducks in a row before I divulge the possibility of low cost alternative, where it comes from, what the negatives are, etc.

 

[Ghoul]

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.



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.

 

[Sam312xx]

Who is considering this, specifically? PubMed, Reddit, blog post, or what/who

A Canadian institution that is active in metabolic health and diabetes research is looking into alternative dosing protocols, such as cyclical or pulsatile. GLP 1 is a novel domain, we don't really know much.

 

[Ghoul]

I'm considering UGL GLP for someone very close to me, pays over $500/month currently for a clinic that "compounds" their own Sema. Insurance does not cover at all, and $500/month is ridiculous. I want to make sure I have all my ducks in a row before I divulge the possibility of low cost alternative, where it comes from, what the negatives are, etc.

UGL will be no worse, and possibly safer than compounder's product. I say that because often, compounders are adding things like Vitamin B, for legal reasons (ie, making their product "custom" so they can't be sued for copying the pharma drug), which is ill advised, like any admixture, due to the effects it can have on the Sema.

If you go this route, you'll need to monitor them closely for a while, because if anything goes wrong, you'll be on the hook. Perhaps consider doing the reconstitution for them to reduce the chance of dosing errors. I almost did the same for someone I know, but frankly lost my nerve and decided against it.

 

[bigMoJo]

UGL will be no worse, and possibly safer than compounder's product. I say that because often, compounders are adding things like Vitamin B, for legal reasons (ie, making their product "custom" so they can't be sued for copying the pharma drug).

If you go this route, you'll need to monitor them closely for a while, because if anything goes wrong, you'll be on the hook. Perhaps consider doing the reconstitution for them to reduce the chance of dosing errors. I almost did the same for someone I know, but frankly lost my nerve and decided against it.

That's exactly where I'm at. If something goes south, I'd feel responsible. Likely, I will reconstitute, and stay involved for a while.

 

[Ghoul]

Here are some highlights from a presentation to the FDA regarding what's been found in bootleg sema found in med spas, small, less regulated compounding pharmacies (not the larger, FDA controlled "manufacturing" compounders), and of course what we get from underground labs:





Peptide formulations can be run through computer simulations, that predict all the ways a peptide is expected to degrade, and the immunogenic risk it poses in a worst case scenario. This is called "in silico" testing. Properly manufactured sema is considered low risk when run through this simulation. Unfortunately, the copies we use are not identical, and when those peptides are run through the same simulation, demonstrate a much higher potential for immunogenicity:

 

[Ghoul]

That's exactly where I'm at. If something goes south, I'd feel responsible. Likely, I will reconstitute, and stay involved for a while.

I would've done it if they were close, but it was more of an acquaintance, and I could see her relatives coming after me if she got bad sides or even something unrelated to sema, but decided to use it as an excuse to sue, even if she didn't.

 

[Sam312xx]

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.

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.

 

[bigMoJo]

I would've done it if they were close, but it was more of an acquaintance, and I could see her relatives coming after me if she got bad sides or even something unrelated to sema, but decided to use it as an excuse to sue, even if she didn't.

It's tough. For me it's a sibling. I wouldn't get sued, but never forgive myself if something were to happen. But, $500/month is money they don't have, would be nice to save that burden for them. By the way, pharma Sema was over $1000/month. I think it was going to be like $1800 at some point.

The FDA presentation is a great share ("another one"). As you stated, Compounder looks no better than UGL. I wish I could run my own in silico, accounting for proper dilution and 5um filter spikes. Assuming that would cut down on subvisible particles, there would still be the .01 to 4.99um that gets through. What would be the impact of such small impurities? Would it be enough to degrade half life, or worse, bring about immunogenicity? Is pharma even capable of filtering down to .01um?

 

[Sam312xx]

Filtering down to 5 µm would reduce larger particles, subvisible particles are small enough to escape filtration and could still contribute to aggregate formation. Aggregates in this size range are still linked to increased immunogenicity because they can be recognized as foreign bodies by the immune system and potentially triggering an antibody response.

Aggregates and small impurities don’t necessarily degrade the half-life directly, but they can affect bioavailability or lead to faster clearance if the immune system targets them. So immunogenicity is a more immediate concern.

In pharma filters used to remove subvisible particles usually reach 0.2 µm, which is standard for sterilizing. There are some advanced filtration systems like ultrafiltration that can reach as low as 0.1 µm but filtration below 0.1 µm is difficult and hardly doable for large scale ops.

 

[bigMoJo]

Filtering down to 5 µm would reduce larger particles, subvisible particles are small enough to escape filtration and could still contribute to aggregate formation. Aggregates in this size range are still linked to increased immunogenicity because they can be recognized as foreign bodies by the immune system and potentially triggering an antibody response.

Aggregates and small impurities don’t necessarily degrade the half-life directly, but they can affect bioavailability or lead to faster clearance if the immune system targets them. So immunogenicity is a more immediate concern.

In pharma filters used to remove subvisible particles usually reach 0.2 µm, which is standard for sterilizing. There are some advanced filtration systems like ultrafiltration that can reach as low as 0.1 µm but filtration below 0.1 µm is difficult and hardly doable for large scale ops.

Oh, that's right, oils can be filtered down to .22um, so pharma can do .2 no problem. The filter spike's are really just sifting rubber stopper matrial and potentially glass shards.

Is it safe to assume UGL can filter the peptide down to at least .22?

Going off your previous post, I understood it to mean that there just isn't enough aggregates, even with UGL, to reduce efficacy or promote immunogenicity. Essentially, those who were studied are the numerical "one-offs" who developed immunogenicity. And, what Ghoul stated about

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.

would be more prevalent in those conditions, right?

 

[Ghoul]

Oh, that's right, oils can be filtered down to .22um, so pharma can do .2 no problem. The filter spike's are really just sifting rubber stopper matrial and potentially glass shards.

Is it safe to assume UGL can filter the peptide down to at least .22?

Going off your previous post, I understood it to mean that there just isn't enough aggregates, even with UGL, to reduce efficacy or promote immunogenicity. Essentially, those who were studied are the numerical "one-offs" who developed immunogenicity. And, what Ghoul stated about

would be more prevalent in those conditions, right?

Aggregates form after reconstitution. They "incubate" over time at a rate determined by a number of factors. The more degraded the peptide is in lyophilized form, for instance like the degradation we see in some QSC group buys, dropping in purity during shipping, the more aggregate prone "pieces" are floating around.

If the PH is off even slightly, they can be generated at 10x the rate. When was the last time you heard someone mention controlling the PH of their reconstitution? Silicon used to lubricate the syringe barrel form microscopic droplets while you're injecting BAC that become aggregate producing factories.

Factors affecting the physical stability (aggregation) of peptide therapeutics - PMC

The number of biological therapeutic agents in the clinic and development pipeline has increased dramatically over the last decade and the number will undoubtedly continue to increase in the coming years. Despite this fact, there are considerable ...

pmc.ncbi.nlm.nih.gov

We discuss some basic ways to prevent degeneration of peptides here, including filtration. .2um or .22um filters are recommended by peptide manufacturers for sterilization, and studies show it can also be useful for removing the largest, most immunogenic inducing aggregates. I filter my peptides now. Some crystal clear peptide solutions completely clog a 13mm filter with less than .5ml liquid passed through .

Post in thread 'Retatrutide'

Oct 13, 2024

By the time the peptide gets to you, the 99% could be 94% and the 97% could still be 97%, so don't concern yourself too much with that. 96% or above imo is fine.

Pharma reconstituted GLPs (pens) last for two years under refrigeration. That's under perfect conditions you cannot replicate.

User reconstituted pharma proteins in multi dose containers, using the specific BAC they supply, are universally instructed to be discarded after 28 days.

No one can say for certain how long before a UGL peptide degrades. On top of all the variables, each batch will vary in stability as well.

What...

• Ghoul

• 

Anyone trying to sell the idea this is not an issue, and merely some irrelevant, abstract concept that has no real world impact is misinformed, and perhaps exercising some wishful thinking. Like the "bros" who insist concern over sterility of injectables isn't an issue because they haven't had to rush to the hospital with some terrible infection. It's not much of an issue for pharma, because they expend a great amount of effort to minimize it. Since no one monitors antibody levels in UGL peptide users there's no problem to see. Only peptides that "stopped working" and side effects that can be attributed to any number of things.

I'll leave you with some pretty aggregates of GLP-1 intentionally grown by inducing peptide "stress" conditions.

 

[Sam312xx]

Oh, that's right, oils can be filtered down to .22um, so pharma can do .2 no problem. The filter spike's are really just sifting rubber stopper matrial and potentially glass shards.

Is it safe to assume UGL can filter the peptide down to at least .22?

Going off your previous post, I understood it to mean that there just isn't enough aggregates, even with UGL, to reduce efficacy or promote immunogenicity. Essentially, those who were studied are the numerical "one-offs" who developed immunogenicity. And, what Ghoul stated about

would be more prevalent in those conditions, right?

It’s possible for UGLs to filter peptides down to 0.22 µm with the right equipment, as 0.22 µm filters are commonly available and affordable.

It's not just about the filter though, it's about quality control. The end results might be different between UGL's and pharma even if both use the same filters because of sterility and filtration consistency. UGLs often lack the sterile environments, advanced equipment, and process controls necessary to filter peptides as effectively, which increases the risk of contamination despite using a 0.22 µm filter.

Which previous post of mine are you referring to?