Why Some Patients Do Not Respond to GLP-1 Therapies

[BNLFL]

I need to go through this whole thread tomorrow, because my wife has simply plateaued. She began stacking Tirz 3 weeks ago, and I have to get her progress details out of her.

 

[A_random_gal]

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.

You may well be correct that the drugs will continue to improve and that we can keep purchasing gray. But if the medications you already have stored work well for you, does that really matter? Suppose that at some future point you have reached your target weight on Tirz and/or Reta, and your side effects have faded long ago (which is where we all hope to end up) — would it matter to you that a new, shiny drug can produce 40% weight loss reduction? Nah, I'll just keep going with my Tirz freezer stash.

 

[Just A Cat]

Skidude recently shared an excellent poster showing how many GLP-1 options are in the development pipeline. I would have reposted it in this thread if I could locate it.

FartfulCodger said:

For what it's worth, I suspect my 24-year-old son is a slow responder, at least where Tirz is concerned. His weight is trending the right way, but the change is far less striking than what I experienced (male, age 60). My wife, who is 5'4", also saw quicker results despite being on her small dose.

Tirz simply doesn't appear to blunt his appetite to the same degree. He stands 6'2" while I'm 5'9", in case that matters. Though it shouldn't matter, should it? From what I've read, GLPs are "brain drugs," unlike many other medications, and ought to work regardless of body size or blood volume; since our hypothalamuses (hypothalami?) are all roughly the same size, appetite suppression should in theory be consistent on that front. Perhaps age and metabolism come into play. He usually notices mild appetite suppression the day after his injection, but it fades fairly fast. I've been raising his dose gradually, though I may also try split-dosing.

Reading between the lines of that study, the non-responders frequently lacked the delayed stomach emptying that responders typically showed.

Until further data comes along, I will personally connect a normal stomach emptying time with a strong likelihood of GLP-1 resistance.

 

[RetCurious]

ladyj779 said:

Thanks for sending me down yet another rabbit hole!

Back in 2021, a single day's dose of 1 mg carried a price tag of $330.

Setmelanotide - Wikipedia

en.wikipedia.org

 

[tekkit]

A_random_gal said:

You may well be correct that the drugs will continue to improve and that we can keep purchasing gray. But if the medications you already have stored work well for you, does that really matter? Suppose that at some future point you have reached your target weight on Tirz and/or Reta, and your side effects have faded long ago (which is where we all hope to end up) — would it matter to you that a new, shiny drug can produce 40% weight loss reduction? Nah, I'll just keep going with my Tirz freezer stash.

Sure, that's an option. It's the same logic as having a freezer stocked with sema from before tirz came along and simply continuing to use it. That said, tirz performs better and produces greater weight loss for most people. Reta goes a step further still. If someone has a freezer full of sema, they might feel drawn to "upgrade" by picking up reta instead — I know I would.

Picture a future drug that improves on reta even further: not just more potent for weight loss, but able to target fat more precisely while doing more to protect muscle. Perhaps it could even promote muscle gain (with exercise, naturally) while burning fat.

What lies ahead, and which of these things is or isn't achievable, is unknown to us. Still, given how many companies are conducting research, I doubt reta is where this ends. Better drugs are coming.

 

[tekkit]

Just A Cat said:

Skidude recently shared an excellent poster showing how many GLP-1 options are in the development pipeline. I would have reposted it in this thread if I could locate it.



Reading between the lines of that study, the non-responders frequently lacked the delayed stomach emptying that responders typically showed.

Until further data comes along, I will personally connect a normal stomach emptying time with a strong likelihood of GLP-1 resistance.

That image does ring a bell — I think it's the one @Skidude posted:

Where it originated, I can't say for certain, but this is where I came across it:

Four Strategies for Competing in the Crowded Obesity Drug Marketplace - The Dedham Group

Here are four strategies for manufacturers to stand out in the crowded anti-obesity medication market.

dedhamgroup.com

Since that piece is nearly 2 years old at this point, my guess is that both the count of companies and the count of drugs in development have grown since then — maybe by a lot.

Edit: Grammar.

 

[ladyj779]

Tirz works well in my case. Stacking reta with tirz works even better. Add sema to that mix and it improves further still.

Elora is next on my list to add.

I'll keep tweaking the stack along with other variables, and likely plenty of new options that emerge over the coming 30 years or so

This isn't zero sum. Very few things are.

 

[ThatNextGril]

tekkit said:

Sure, that's an option. It's the same logic as having a freezer stocked with sema from before tirz came along and simply continuing to use it. That said, tirz performs better and produces greater weight loss for most people. Reta goes a step further still. If someone has a freezer full of sema, they might feel drawn to "upgrade" by picking up reta instead — I know I would.

Picture a future drug that improves on reta even further: not just more potent for weight loss, but able to target fat more precisely while doing more to protect muscle. Perhaps it could even promote muscle gain (with exercise, naturally) while burning fat.

What lies ahead, and which of these things is or isn't achievable, is unknown to us. Still, given how many companies are conducting research, I doubt reta is where this ends. Better drugs are coming.

Ah, but hold on—claiming "reta is better" without qualification is somewhat misleading. Suppose reta gave me awful sleep, a higher resting heart rate that felt uncomfortable, and allodynia that nearly drove me insane; for me it clearly isn't "better" in any sense (and yes, all of that really happened). On the other hand, if tirz fits my body like a glove—virtually no side effects—and keeps my food noise suppressed (which is what I care about most from the glp1 benefits), then in my book tirz is unquestionably better. At my current dose I have a little more than 8 years of tirz stocked away, and given what I spent over the year while selectively building that supply, should another option appear that satisfies those same criteria, it's my choice whether to go for it. That's the key distinction. Saying better drugs will arrive isn't incorrect, but presuming we'd all abandon our stashes for the latest shiny API is exactly that—a presumption.

 

[tekkit]

ThatNextGril said:

Ah, but hold on—claiming "reta is better" without qualification is somewhat misleading. Suppose reta gave me awful sleep, a higher resting heart rate that felt uncomfortable, and allodynia that nearly drove me insane; for me it clearly isn't "better" in any sense (and yes, all of that really happened). On the other hand, if tirz fits my body like a glove—virtually no side effects—and keeps my food noise suppressed (which is what I care about most from the glp1 benefits), then in my book tirz is unquestionably better. At my current dose I have a little more than 8 years of tirz stocked away, and given what I spent over the year while selectively building that supply, should another option appear that satisfies those same criteria, it's my choice whether to go for it. That's the key distinction. Saying better drugs will arrive isn't incorrect, but presuming we'd all abandon our stashes for the latest shiny API is exactly that—a presumption.

Absolutely. In my earlier comment I already noted that sticking with tirz is a perfectly valid option — much like how someone sitting on a ten-year supply of sema could keep using sema even with tirz and reta on the market today.

That said, if you did give a newer drug a try and found it worked better for you minus the side effects, you'd be faced with a choice... continue working through your tirz stockpile that isn't as effective, or shell out more money for the upgrade. That's exactly why I'm not stockpiling. Running out of supply doesn't worry me in the slightest. I've got a couple of years' worth on hand — plenty to weather any short-term disruptions — but not so much that switching to a newer drug down the line would be difficult once they hit the market.

 

[Calm Logic]

tekkit said:

Absolutely. In my earlier comment I already noted that sticking with tirz is a perfectly valid option — much like how someone sitting on a ten-year supply of sema could keep using sema even with tirz and reta on the market today.

That said, if you did give a newer drug a try and found it worked better for you minus the side effects, you'd be faced with a choice... continue working through your tirz stockpile that isn't as effective, or shell out more money for the upgrade. That's exactly why I'm not stockpiling. Running out of supply doesn't worry me in the slightest. I've got a couple of years' worth on hand — plenty to weather any short-term disruptions — but not so much that switching to a newer drug down the line would be difficult once they hit the market.

Another option is to combine the new with the old, pass the old along by selling or donating it, or simply switch to the new while holding on to the old as a fallback.

 

[Just A Cat]

My prediction: the Reta versus Tirz argument is going to keep raging for several years to come.

 

[reta-stacker]

Calm Logic said:

That's true, though it's fair to wonder who will be supplying those vendors down the road.

As for stockpiling, what worries me is choosing on price alone rather than picking product that comes with more testing behind it. My preference would be kits that are in stock and already tested — LCMS, endos, and sterility included.

Wouldn't the issue in that case be the vial expiring?

 

[SVT810E]

Just A Cat said:

Skidude recently shared an excellent poster showing how many GLP-1 options are in the development pipeline. I would have reposted it in this thread if I could locate it.



Reading between the lines of that study, the non-responders frequently lacked the delayed stomach emptying that responders typically showed.

Until further data comes along, I will personally connect a normal stomach emptying time with a strong likelihood of GLP-1 resistance.

In this trial, gastric emptying showed no correlation with food intake.

Appetite Suppression by GLP‐1 Receptor Agonists: Role of Delayed Gastric Emptying - PMC

This study aimed to evaluate relationships between delayed gastric emptying and appetite suppression during treatment with liraglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA). We conducted a secondary data analysis from a 16‐week ...

pmc.ncbi.nlm.nih.gov

As far as I understand it, other studies examining this question have for the most part likewise reported no meaningful effect. Early gastric emptying (prior to tachyphylaxis) might indicate overall responsiveness to GLP-1 therapy, but this mechanism does not appear to matter much for weight loss over the long term.

 

[reta-stacker]

tekkit said:

That image does ring a bell — I think it's the one @Skidude posted:

/

Where it originated, I can't say for certain, but this is where I came across it:

Four Strategies for Competing in the Crowded Obesity Drug Marketplace - The Dedham Group

Here are four strategies for manufacturers to stand out in the crowded anti-obesity medication market.

dedhamgroup.com

Since that piece is nearly 2 years old at this point, my guess is that both the count of companies and the count of drugs in development have grown since then — maybe by a lot.

Edit: Grammar.

My hope is that Efocipegtrutide, Nimacimeb and Clafutriben stay out of the middle spot ahead of the rest. Retatrutide took roughly a month before I could pronounce it without tripping over the syllables.

 

[Skidude]

tekkit said:

That image does ring a bell — I think it's the one @Skidude posted:

/

Where it originated, I can't say for certain, but this is where I came across it:

Four Strategies for Competing in the Crowded Obesity Drug Marketplace - The Dedham Group

Here are four strategies for manufacturers to stand out in the crowded anti-obesity medication market.

dedhamgroup.com

Since that piece is nearly 2 years old at this point, my guess is that both the count of companies and the count of drugs in development have grown since then — maybe by a lot.

Edit: Grammar.

reta-stacker said:

My hope is that Efocipegtrutide, Nimacimeb and Clafutriben stay out of the middle spot ahead of the rest. Retatrutide took roughly a month before I could pronounce it without tripping over the syllables.

The part that interests me is the black diamonds labeled "other"

"cagrisema" appears to be one of them.

 

[Calm Logic]

reta-stacker said:

Wouldn't the issue in that case be the vial expiring?

Since my freezer is a standard one rather than a manual-defrost unit or a deep freeze, I play it safe and insulate all of it. Stored that way, I figure reta should hold up for a decade at minimum. Tirz and sema even more so, given that they are hardier about surviving less-than-ideal conditions. A lab freezer running at considerably lower temperatures would be the ideal setup.

 

[reta-stacker]

Calm Logic said:

Since my freezer is a standard one rather than a manual-defrost unit or a deep freeze, I play it safe and insulate all of it. Stored that way, I figure reta should hold up for a decade at minimum. Tirz and sema even more so, given that they are hardier about surviving less-than-ideal conditions. A lab freezer running at considerably lower temperatures would be the ideal setup.

What I had in mind was stretching an RT30 kit over several weeks. Doesn't potency fall off a cliff once a month has passed? My assumption was that those larger vials are meant for people on maximum doses, and at that rate a 30 would be used up within a few weeks regardless.

 

[Calm Logic]

reta-stacker said:

What I had in mind was stretching an RT30 kit over several weeks. Doesn't potency fall off a cliff once a month has passed? My assumption was that those larger vials are meant for people on maximum doses, and at that rate a 30 would be used up within a few weeks regardless.

After reconstitution, my bigger concern is sterility rather than degradation. A number of people have reported that their reta still works well even months later. There are also some test results on degradation following recon:

/community-link/thread/23489/

 

[Just A Cat]

Just A Cat said:

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.

Just A Cat said:

Skidude recently shared an excellent poster showing how many GLP-1 options are in the development pipeline. I would have reposted it in this thread if I could locate it.



Reading between the lines of that study, the non-responders frequently lacked the delayed stomach emptying that responders typically showed.

Until further data comes along, I will personally connect a normal stomach emptying time with a strong likelihood of GLP-1 resistance.

SVT810E said:

In this trial, gastric emptying showed no correlation with food intake.

Appetite Suppression by GLP‐1 Receptor Agonists: Role of Delayed Gastric Emptying - PMC

This study aimed to evaluate relationships between delayed gastric emptying and appetite suppression during treatment with liraglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA). We conducted a secondary data analysis from a 16‐week ...

pmc.ncbi.nlm.nih.gov

As far as I understand it, other studies examining this question have for the most part likewise reported no meaningful effect. Early gastric emptying (prior to tachyphylaxis) might indicate overall responsiveness to GLP-1 therapy, but this mechanism does not appear to matter much for weight loss over the long term.

So essentially we're on the same page — it's a tomato/tomat-oh kind of argument.

The "effect" I was referring to means a higher dose will be needed before it works. If someone begins at a low dose and feels nothing in their stomach, that signals they'll likely need to go higher than others.

Take this example: you and your best friend start the same day from the same vial. You get no stomach-slowing effects while they feel it right away. Chances are you'll need a higher dose than they will to lose the same amount of weight.

Look at dose response and there's a difference.

Look only at weight loss and there's none.

For decades, weight management was treated as nothing but willpower and behavior (calories in vs. calories out). We now have evidence showing that premise was false.

 

[Skidude]

Calm Logic said:

After reconstitution, my bigger concern is sterility rather than degradation. A number of people have reported that their reta still works well even months later. There are also some test results on degradation following recon:

/community-link/thread/23489/

/

That same graphic has been posted by me on numerous occasions.

Not long ago I came across this over on peppys

Freeze/thaw cycles did not sit well with it

Retatrutide: The Complete Stability Picture

We put retatrutide through eight extended-duration stability studies, spanning refrigerator, room temperature, freezer, freeze-thaw, 130 °F heat, and bacteriostatic versus ultrapure water, and put the results in one place to show how it holds up over time and under stress.

www.peprecon.com