Why Some Patients Do Not Respond to GLP-1 Therapies

[Just A Cat]

Why Some Patients Do Not Respond to GLP-1 Therapies​#-why-some-patients-do-not-respond-to-glp-1-therapiesA Commentary in Pharmacy Times.

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www.pharmacytimes.com

Table from article:

Link 2 in the footnotes is worth a look as well: roughly 1 in 10 individuals could carry resistance to GLP-1 diabetes drugs. Source: Stanford Medicine, April 10, 2026, accessed June 2, 2026.

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med.stanford.edu

Quoted passage: These genetic variants, present in about 10% of the general population, produce an unexpected and still unexplained effect that scientists call GLP-1 resistance: the hormone GLP-1 (glucagon-like peptide-1), which assists in controlling blood sugar, is present at higher levels yet has less biological effect.

 

[Skidude]

Just A Cat said:

Why Some Patients Do Not Respond to GLP-1 Therapies​#-why-some-patients-do-not-respond-to-glp-1-therapiesA Commentary in Pharmacy Times.

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www.pharmacytimes.com

Table from article:





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Link 2 in the footnotes is worth a look as well: roughly 1 in 10 individuals could carry resistance to GLP-1 diabetes drugs. Source: Stanford Medicine, April 10, 2026, accessed June 2, 2026.

Loading…

med.stanford.edu

Quoted passage: These genetic variants, present in about 10% of the general population, produce an unexpected and still unexplained effect that scientists call GLP-1 resistance: the hormone GLP-1 (glucagon-like peptide-1), which assists in controlling blood sugar, is present at higher levels yet has less biological effect.

It also appears that those affected by this may be overrepresented, statistically speaking, among people who are overweight — a consequence of their inherent resistance.

 

[plant_lady]

My heart goes out to those who don't respond to these medications — that has to be a really difficult spot to be in. For a while I didn't tell anyone I was taking Tirz, since I feared it might simply fail to work for me (that I'd turn out to be a non-responder).

 

[Schwossy]

People who are GLP-1 resistant ought to still see a response from at least Cargi and Elora, I'd think... Either way, newer work is heading in the direction of agonists that hit 4 or 5 targets.

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www.medscape.com

 

[tekkit]

Schwossy said:

People who are GLP-1 resistant ought to still see a response from at least Cargi and Elora, I'd think... Either way, newer work is heading in the direction of agonists that hit 4 or 5 targets.

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www.medscape.com

The reason I'm not laying in years & years of tirz & reta is precisely because these upcoming drugs seem so much more promising. In time, better options will arrive. This one may not pan out, but a huge amount of research and testing is underway.

 

[FartfulCodger]

tekkit said:

The reason I'm not laying in years & years of tirz & reta is precisely because these upcoming drugs seem so much more promising. In time, better options will arrive. This one may not pan out, but a huge amount of research and testing is underway.

That said, a stockpile could eventually let you sell "fine aged craft reta."

 

[A_random_gal]

tekkit said:

The reason I'm not laying in years & years of tirz & reta is precisely because these upcoming drugs seem so much more promising. In time, better options will arrive. This one may not pan out, but a huge amount of research and testing is underway.

My guess is that a lot of us — me included — share a concern that the gray market could get shut off at some point. The reasons could be Chinese or domestic crackdowns, shipping failures, or some form of worldwide disruption. There's no telling what might happen. After all, even with the world falling apart, we still want to be skinny!

 

[spanky2026]

One in ten — you would figure most of us would have a friend or relative in that group. I personally know plenty of people taking GLPs, and some of them respond slowly, yet I have not met a single non-responder. Curious.

 

[Skidude]

spanky2026 said:

One in ten — you would figure most of us would have a friend or relative in that group. I personally know plenty of people taking GLPs, and some of them respond slowly, yet I have not met a single non-responder. Curious.

Plenty of people, from what I gather, combine multiple GLP1s along with amylin agonists.

Then you have others who never reach therapeutic dosing levels.

And in between sit those who follow the standard pharma titration schedule.

A spectrum, it appears.

 

[Just A Cat]

The piece never claimed that GLP-1 fails to produce weight loss — its point was that a larger amount may be required before the effect shows up.

As for the study design, it focused on the insulin arm of the GLP-1 picture. Compared with people who lack the genetic variant, insulin control was impaired at lower doses.

tldr: GLP-1 resistance means you need a higher dose to be effective.

 

[justdabbling]

At least the wording points to a weaker response to GLP-1 rather than none at all. Add a larger dose, along with some tirz or reta to bring in the extra gip /gluca receptors, plus some elora, and you would have a route toward weight loss

 

[SVT810E]

Schwossy said:

People who are GLP-1 resistant ought to still see a response from at least Cargi and Elora, I'd think... Either way, newer work is heading in the direction of agonists that hit 4 or 5 targets.

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www.medscape.com

A lot hinges on the specific nature of the resistance and on how these medications function. One possibility is that downstream pathways converge, so a single resistance mechanism could blunt both drugs; another is that neither drug actually targets what is driving obesity in a given patient.

I've been digging into my own recurring problem with intense hunger after substantial weight loss. Cagri at 0.25mg, escalated to 2mg within under a month, felt no different from injecting water. Setmelanotide, by contrast, did work. My leptin levels turned out to be essentially crashed, and setmelanotide could sidestep the appetite effects of that, though it wasn't a complete solution. For that particular problem cagri was simply the wrong drug aimed at the wrong target, and while reta can bring me down to weight, it too appears to stop doing much once I get there.

 

[GirtxC]

My heart goes out to those for whom it doesn't work.

That said, hang around the Reddit forums long enough and you'll notice a different group it doesn't work for... the ones who believe these are magic fat-burning drugs. They keep eating 2000 calories at every meal and claim that they don't work.

 

[tekkit]

A_random_gal said:

My guess is that a lot of us — me included — share a concern that the gray market could get shut off at some point. The reasons could be Chinese or domestic crackdowns, shipping failures, or some form of worldwide disruption. There's no telling what might happen. After all, even with the world falling apart, we still want to be skinny!

“Congratulations to drugs for winning the war on drugs.”

Not even the supply of genuinely illegal substances can be shut down, and the enormous trade in counterfeit bags and watches hasn't been stopped either. Meanwhile, "gear" has been banned in plenty of countries for decades, yet it still appears to be easy to obtain.

Availability may hit a few short-lived snags, but grey market peptides aren't disappearing. If you've got a stockpile covering a couple of years, you're fine. Truly.

Superior drugs that you'll want to switch to will show up over the coming years. We're going to see plenty of people wondering what to do with their 10-year reta supply once XYZ becomes available and turns out to be so much better.

 

[ladyj779]

SVT810E said:

A lot hinges on the specific nature of the resistance and on how these medications function. One possibility is that downstream pathways converge, so a single resistance mechanism could blunt both drugs; another is that neither drug actually targets what is driving obesity in a given patient.

I've been digging into my own recurring problem with intense hunger after substantial weight loss. Cagri at 0.25mg, escalated to 2mg within under a month, felt no different from injecting water. Setmelanotide, by contrast, did work. My leptin levels turned out to be essentially crashed, and setmelanotide could sidestep the appetite effects of that, though it wasn't a complete solution. For that particular problem cagri was simply the wrong drug aimed at the wrong target, and while reta can bring me down to weight, it too appears to stop doing much once I get there.

Thanks for sending me down yet another rabbit hole!

 

[ladyj779]

tekkit said:

“Congratulations to drugs for winning the war on drugs.”

Not even the supply of genuinely illegal substances can be shut down, and the enormous trade in counterfeit bags and watches hasn't been stopped either. Meanwhile, "gear" has been banned in plenty of countries for decades, yet it still appears to be easy to obtain.

Availability may hit a few short-lived snags, but grey market peptides aren't disappearing. If you've got a stockpile covering a couple of years, you're fine. Truly.

Superior drugs that you'll want to switch to will show up over the coming years. We're going to see plenty of people wondering what to do with their 10-year reta supply once XYZ becomes available and turns out to be so much better.

My parents are Boomers, and my grandparents lived through the Depression. After my grandparents died, my mom, her siblings and a couple of my cousins were puzzled that my grandparents — who were very financially secure — had stocked the basement with home-canned goods enough to last years. I got it, though; as a kid I had helped my grandmother can some of it.

Every last bit of my reta stash is getting used

 

[Calm Logic]

tekkit said:

“Congratulations to drugs for winning the war on drugs.”

Not even the supply of genuinely illegal substances can be shut down, and the enormous trade in counterfeit bags and watches hasn't been stopped either. Meanwhile, "gear" has been banned in plenty of countries for decades, yet it still appears to be easy to obtain.

Availability may hit a few short-lived snags, but grey market peptides aren't disappearing. If you've got a stockpile covering a couple of years, you're fine. Truly.

Superior drugs that you'll want to switch to will show up over the coming years. We're going to see plenty of people wondering what to do with their 10-year reta supply once XYZ becomes available and turns out to be so much better.

I have my doubts. The SSRIs marketed as "me too" versions following Prozac didn't offer much improvement on side effects. And they weren't any more effective either.

 

[tekkit]

Calm Logic said:

I have my doubts. The SSRIs marketed as "me too" versions following Prozac didn't offer much improvement on side effects. And they weren't any more effective either.

The market for GLP-1 drugs used for weight loss is already roughly 4x larger than the anti-depressant market (all SSRIs included), and this GLP-1 weight loss segment is both fairly young and expanding fast.

Among approved products, tirz has already overtaken sema — the "Prozac" of GLP-1 weight loss meds — while in the grey market both tirz and reta have done so. That leaves aside cagri and elora. The development pipeline is nowhere near its end; in fact, things are only getting started.

The best is yet to come.

 

[frogfrog123]

spanky2026 said:

One in ten — you would figure most of us would have a friend or relative in that group. I personally know plenty of people taking GLPs, and some of them respond slowly, yet I have not met a single non-responder. Curious.

Sema and tirz did nothing for me — I went up to the max dose of each and saw zero response. It was incredibly disheartening, and my doctor stared at me as if I were from another planet. Reta was the turning point; once I began it, everything changed.

 

[Calm Logic]

tekkit said:

The market for GLP-1 drugs used for weight loss is already roughly 4x larger than the anti-depressant market (all SSRIs included), and this GLP-1 weight loss segment is both fairly young and expanding fast.

Among approved products, tirz has already overtaken sema — the "Prozac" of GLP-1 weight loss meds — while in the grey market both tirz and reta have done so. That leaves aside cagri and elora. The development pipeline is nowhere near its end; in fact, things are only getting started.

The best is yet to come.

Will there still be fat people in the future?

If GLPs weren't available to me, I'd give Jardiance a try as a way to help keep my weight in check. Cost Plus Drugs carries Farxiga, another drug from that same class, for $8.