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

 

[Ghoul]

The previous "non-insulin" therapy is referring to those who've used the old short acting daily dose GLPs that predated Sema.

It's being increasingly observed that any exposure to GLPs, even other types, followed by a gap in treatment, leads to decreased efficacy of Sema and Tirz.

This "immunity" was noted, coincidentally, in a study of Tirz by some researchers that found the diabetics that used another GLP, even those who stopped years before, didn't respond as well.

More recently clinicians are observing those who "take a break" and return to treatment later require higher doses and not achieving the same level of weight loss.

I've been beating the drum on this here, hoping to save at least some folks from ending up with this problem, by just sticking as closely to pharma protocols as possible. We know that after four years of using Sema, and three years of Tirz, no loss of efficacy has been observed.

These aren't diet pills or steroids. They're complex proteins that can induce an immunogenic response that can cause you to develop immunity to these drugs, like a vaccine. And like a vaccine, the possibility exists for long term, or even lifetime immunity. Even worse, fucking around could lead to developing an immunity against your own naturally produced GLP.

I'm a few years, things will certainly be interesting with all these GLPnauts for whom the incredibly rapid weight loss these drugs provide just wasn't fast enough.

 

[noteablequotable]

The previous "non-insulin" therapy is referring to those who've used the old short acting daily dose GLPs that predated Sema.

It's being increasingly observed that any exposure to GLPs, even other types, followed by a gap in treatment, leads to decreased efficacy of Sema and Tirz.

This "immunity" was noted, coincidentally, in a study of Tirz by some researchers that found the diabetics that used another GLP, even those who stopped years before, didn't respond as well,

More recently clinicians are noting those who "take a break" and return to treatment later require higher doses and not achieving the same level of weight loss.

I've been beating the drum on this here, hoping to save at least some folks from ending up with this problem, by just sticking as closely to pharma protocols as possible. We know that after four years of using Sema, and three years of Tirz, no loss of efficacy has been observed.

These aren't diet pills or steroids. They're complex proteins that can induce an immunogenic response that can cause you to develop immunity to these drugs, like a vaccine. And like a vaccine, the possibility exists for long term, or even lifetime immunity. Even worse, fucking around could lead to developing an immunity against your own naturally produced GLP.

I'm a few years, things will certainly be interesting with all these GLPnauts for whom the incredibly rapid weight loss these drugs provide just wasn't fast enough.

So it sounds like the general take aways are "get on and stay on" and "use the lowest effective dose", is that right?

Would you mind sharing your sources? I'd like to read through them. I'm a non responder to Tirz who checks basically all of the boxes for reasons why a person might be a non-responder.

I've been wondering if I should move to Maz or Reta because of how they boost energy expenditure, or just wait for a more effective GLP-1 to come along.

 

[Ghoul]

So it sounds like the general take aways are "get on and stay on" and "use the lowest effective dose", is that right?

Would you mind sharing your sources? I'd like to read through them. I'm a non responder to Tirz who checks basically all of the boxes for reasons why a person might be a non-responder.

I've been wondering if I should move to Maz or Reta because of how they boost energy expenditure, or just wait for a more effective GLP-1 to come along.

Before I go into this for the umpteenth time, which is not your fault, I'll have to ask you to indulge my intellectual curiosity by answering a few questions that will lay the groundwork for you to have a better understanding of the information I give you.

What were the doses of previous GLPs you've used, in mg and ml?

 

[noteablequotable]

Before I go into this for the umpteenth time, which is not your fault, I'll have to ask you to indulge my intellectual curiosity by answering a few questions that will lay the groundwork for you to have a better understanding of the information I give you.

What were the doses of previous GLPs you've used, in mg and ml?

I am on the prescription stuff because I have good insurance and I qualify for it.

Tirzepatide only. 2.5 and 5. Moving up to 7.5 soon on a very accelerated time table. I've been injecting every 5 days instead of 7 (with doctor approval). It hasn't quite been 12 weeks yet but I haven't lost a pound and we both recognize that is a bad sign l.

 

[Ghoul]

I am on the prescription stuff because I have good insurance and I qualify for it.

Tirzepatide only. 2.5 and 5. Moving up to 7.5 soon on a very accelerated time table. I've been injecting every 5 days instead of 7 (with doctor approval). It hasn't quite been 12 weeks yet but I haven't lost a pound and we both recognize that is a bad sign l.

OK, there goes my narrative, lol. I thought you had used underground lab peptides

Hope is not lost. I know multiple men, and they're all men, who appeared to be non-responders to Zepbound until they hit 10mg. It's not uncommon.

In fact I'll note 2.5mg is useless for the majority of males, in my experience. I think for men, 5mg should be the starting dose, since males and females have different response sensitivity for very clear biological reasons,

How tall are you, and weight (no judgement here)?

 

[noteablequotable]

OK, there goes my narrative, lol. I thought you had used underground lab peptides

Hope is not lost. I know multiple men, and they're all men, who appeared to be non-responders to Zepbound until they hit 10mg. It's not uncommon.

How tall are you, and weight (no judgement here)?

NP. 5' 10" 413. I happen to be a woman with metabolic and reproductive issues I've had since childhood so there are some complications making the WL difficult. I know the inbody is controversial, but per my last results my smm is very good (100.8lbs) and my ww is acceptable (133.8lbs). I'm just holding onto a lot of fat that my body doesn't want to metabolize.

 

[Ghoul]

NP. 5' 10" 413. I happen to be a woman with metabolic and reproductive issues I've had since childhood so there are some complications making the WL difficult. I know the inbody is controversial, but per my last results my smm is very good (100.8lbs) and my ww is acceptable (133.8lbs). I'm just holding onto a lot of fat that my body doesn't want to metabolize.

Another assumption down the tubes lol!

Ok, the theory put forth in an early study of GLPs is that response for appetite suppression purposes is dependent on the total proportion of GLP receptors agonized.

Keep in mind the doses prescribed by pharma are universal, and designed to apply to the majority, but ideally they would be personalized based on the number of receptors an individual has.

Men have a higher density, so all other factors being equal, require a higher dose for a similar effect. (hence my comment above).

More body mass=more receptors.

In the clinical studies, the number of non-responders shrinks as dose increases. Some don't even respond until 15mg.

So don't lose hope.

It also takes 4 injections to reach maximum blood concentration, and therefore maximum effect for a particular dose.

Also, even absent the appetite suppression, metabolic health is still being gradually improved.

It's HIGHLY unlikely you'll be a non responder above 10mg.

You may find that the weight loss at 15mg, once you plateau at that dose, is insufficient to meet your goal. Should that be the case, within 6 months the new, higher doses of Wegovy (up to 7.2mg) should be approved, and you can transition to that, which will almost certainly be more than sufficient.

When you get the ability to send direct messages. please send me a message and I'll give you some additional info. (click my username and "Message"). And feel free to ask whatever you want to here in the forum.

 

[noteablequotable]

Another assumption down the tubes lol!

Ok, the theory put forth in an early study of GLPs is that response for appetite suppression purposes is dependent on the total proportion of GLP receptors agonized.

Keep in mind the doses prescribed by pharma are universal, and designed to apply to the majority, but ideally they would be personalized based on the number of receptors an individual has.

Men have a higher density, so all other factors being equal, require a higher dose for a similar effect. (hence my comment above).

More body mass=more receptors.

In the clinical studies, the number of non-responders shrinks as dose increases. Some don't even respond until 15mg.

So don't lose hope.

It also takes 4 injections to reach maximum blood concentration, and therefore maximum effect for a particular dose.

Also, even absent the appetite suppression, metabolic health is still being gradually improved.

It's HIGHLY unlikely you'll be a non responder above 10mg.

You may find that the weight loss at 15mg, once you plateau at that dose, is insufficient to meet your goal. Should that be the case, within 6 months the new, higher doses of Wegovy (up to 7.2mg) should be approved, and you can transition to that, which will almost certainly be more than sufficient.

When you get the ability to send direct messages. please send me a message and I'll give you some additional info. (click my username and "Message"). And feel free to ask whatever you want to here in the forum.

Thank you for the offer! I will definitely reach out once I have permissions to. Even though I have been prescribed Tirz I've been thinking about Maz and Reta for the glucagon agonism. I wonder if the pool of non-responders to those drugs will be smaller because in theory even people who have suboptimal metabolic health should benefit from the forced consumption of glycogen and increased production of glucose from non-carbohydrate sources. I'd hate to burn out my receptors and develop immunity on Tirz when I'd really benefit more from other drugs.

 

[Ghoul]

Thank you for the offer! I will definitely reach out once I have permissions to. Even though I have been prescribed Tirz I've been thinking about Maz and Reta for the glucagon agonism. I wonder if the pool of non-responders to those drugs will be smaller because in theory even people who have suboptimal metabolic health should benefit from the forced consumption of glycogen and increased production of glucose from non-carbohydrate sources. I'd hate to burn out my receptors and develop immunity on Tirz when I'd really benefit more from other drugs.

You can't "burn out receptors", I assure
you. Please don't start playing with other compounds from underground sources until you've exhausted your pharma options.

What you can do is develop an immunity as a result of using substandard underground sourced GLP drugs, something nearly impossible if you stay on legit Zepbound.

Please, wait until you get to 15mg before deciding it's ineffective. It's very likely you'll find it works even before getting to that dose. Consider having access to a legit pharma option a blessing.

 

[AlexDavis43]

NP. 5' 10" 413. I happen to be a woman with metabolic and reproductive issues I've had since childhood so there are some complications making the WL difficult. I know the inbody is controversial, but per my last results my smm is very good (100.8lbs) and my ww is acceptable (133.8lbs). I'm just holding onto a lot of fat that my body doesn't want to metabolize.

Welcome to Meso. Check out the New Member Introduction thread.

 

[Here2Learn]

@noteablequotable I am female and struggled to get my WL going with Sema. Outside of the GLP protocol I have been working hard on bringing my body back online. I feel like I turned a switch off for a long time and I am actually getting my functions to come back on. I think women may understand what I mean more than men, but I could be wrong there.

I didn’t understand when I first started. I have a lot to loose and my weight just wasn’t moving, it did help with inflammation though. I am a fast responder to medication and alcohol so I assumed this would be the same. It hasn’t been at all. I am not sure what all you feel comfortable with discussing openly but we could DM, discuss here or not at all. Just reach out if you have questions.

@Ghoul has all the info you need on peptide protocol.

 

[noteablequotable]

You can't "burn out receptors", I assure
you. Please don't start playing with other compounds from underground sources until you've exhausted your pharma options.

What you can do is develop an immunity as a result of using substandard underground sourced GLP drugs, something nearly impossible if you stay on legit Zepbound.

Please, wait until you get to 15mg before deciding it's ineffective. It's very likely you'll find it works even before getting to that dose. Consider having access to a legit pharma option a blessing.

Ah, I haven't seen your full theory but is it something like:

People are injecting GLP-1s that are contaminated with harmful microorganisms causing some kind of immune response. Eventually this leads GLP-1s, regardless of their quality, to also generate an immune response causing them to be less effective over time?

I know the grey unapproved stuff isn't the best, but it's tempting. I think these drugs will make a difference for me, but I'll heed your advice for now.

 

[noteablequotable]

@noteablequotable I am female and struggled to get my WL going with Sema. Outside of the GLP protocol I have been working hard on bringing my body back online. I feel like I turned a switch off for a long time and I am actually getting my functions to come back on. I think women may understand what I mean more than men, but I could be wrong there.

I didn’t understand when I first started. I have a lot to loose and my weight just wasn’t moving, it did help with inflammation though. I am a fast responder to medication and alcohol so I assumed this would be the same. It hasn’t been at all. I am not sure what all you feel comfortable with discussing openly but we could DM, discuss here or not at all. Just reach out if you have questions.

@Ghoul has all the info you need on peptide protocol.

I'm shocked at how nice everyone here is. I was led to believe that steroid use would make you all a bunch of grumps.

 

[Middus]

NP. 5' 10" 413. I happen to be a woman with metabolic and reproductive issues I've had since childhood so there are some complications making the WL difficult. I know the inbody is controversial, but per my last results my smm is very good (100.8lbs) and my ww is acceptable (133.8lbs). I'm just holding onto a lot of fat that my body doesn't want to metabolize.

Keep using tirz till max dose for about 12 weeks.
That being said, if you have been obese since childhood and don't respond to GLPs or they aren't helping, you might need to switch to setmelanotide. Pharma setmelanotide is hella expensive though

 

[Grey Spartan]

I'm shocked at how nice everyone here is. I was led to believe that steroid use would make you all a bunch of grumps.

 

[Sam312xx]

The previous "non-insulin" therapy is referring to those who've used the old short acting daily dose GLPs that predated Sema.

It's being increasingly observed that any exposure to GLPs, even other types, followed by a gap in treatment, leads to decreased efficacy of Sema and Tirz.

This "immunity" was noted, coincidentally, in a study of Tirz by some researchers that found the diabetics that used another GLP, even those who stopped years before, didn't respond as well.

More recently clinicians are observing those who "take a break" and return to treatment later require higher doses and not achieving the same level of weight loss.

I've been beating the drum on this here, hoping to save at least some folks from ending up with this problem, by just sticking as closely to pharma protocols as possible. We know that after four years of using Sema, and three years of Tirz, no loss of efficacy has been observed.

These aren't diet pills or steroids. They're complex proteins that can induce an immunogenic response that can cause you to develop immunity to these drugs, like a vaccine. And like a vaccine, the possibility exists for long term, or even lifetime immunity. Even worse, fucking around could lead to developing an immunity against your own naturally produced GLP.

I'm a few years, things will certainly be interesting with all these GLPnauts for whom the incredibly rapid weight loss these drugs provide just wasn't fast enough.

How did you come up with the conclusion that the reduced responsiveness is due to an immunogenic response?

 

[IronMetal_2]

FWIW: my Hb1Ac before starting tirz wasn't bad at all (5,2%) and I still lost a bunch of weight easily and quickly on a mere 5 mg, approaching 10% weight loss soon.

Just try it and titrate up until it works. For some, 5mg is all they need, some need 15 mg. And there's nothing wrong with going up, besides cost...

 

[noteablequotable]

FWIW: my Hb1Ac before starting tirz wasn't bad at all (5,2%) and I still lost a bunch of weight easily and quickly on a mere 5 mg, approaching 10% weight loss soon.

Just try it and titrate up until it works. For some, 5mg is all they need, some need 15 mg. And there's nothing wrong with going up, besides cost...

I do worry that escalating to larger doses will increase my risk of the more extreme side effects like pancreatitis and gastroparesis. People who have poor metabolic health have probably already stressed their pancreas out a bit.

 

[HUGE McBIGLARGE]

People are injecting GLP-1s that are contaminated with harmful microorganisms causing some kind of immune response. Eventually this leads GLP-1s, regardless of their quality, to also generate an immune response causing them to be less effective over time?

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