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Devilseye

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Cagri has left me pretty let down. To start with, it hits calcitonin receptors that exist in the thyroid. That's not great, since calcitonin has no role in losing weight. On top of that, whatever it does lasts only a short while.

A bit of background. I was running reta alongside sema (10mg/2mg — sema because my insurance pays for it, and reta because it's a weak GLP-1R activator too), and my progress froze around 30% weight loss. For 2 months I tried to drop the final 10 pounds and got nowhere. It just sat at 30% with no movement. Cagri made little difference as well. It blunted hunger at first, but that wore off; it did help push me to 30%, yet once I stopped it, nothing changed.

Then eloralintide came along. At the starting 1mg dose my hunger was cut noticeably. By the way, 1mg was all I needed to shed those 10lbs. Clinical trials show 1mg producing 10% bodyweight loss, while 3mg only did slightly better at roughly 12.5%. Just 9mg doubled the loss to 20%, but I'll never require that much. Also, eloralintide doesn't touch the calcitonin receptor. For me it's a winner.

Overall I'm very pleased with this trial. My only wish is that more distributors carried it out of their US/Canada warehouses. I would absolutely buy. As things stand, I only find it in china warehouses.

Cheers!
 
Devilseye said:

Cagri has left me pretty let down. To start with, it hits calcitonin receptors that exist in the thyroid. That's not great, since calcitonin has no role in losing weight. On top of that, whatever it does lasts only a short while.

A bit of background. I was running reta alongside sema (10mg/2mg — sema because my insurance pays for it, and reta because it's a weak GLP-1R activator too), and my progress froze around 30% weight loss. For 2 months I tried to drop the final 10 pounds and got nowhere. It just sat at 30% with no movement. Cagri made little difference as well. It blunted hunger at first, but that wore off; it did help push me to 30%, yet once I stopped it, nothing changed.

Then eloralintide came along. At the starting 1mg dose my hunger was cut noticeably. By the way, 1mg was all I needed to shed those 10lbs. Clinical trials show 1mg producing 10% bodyweight loss, while 3mg only did slightly better at roughly 12.5%. Just 9mg doubled the loss to 20%, but I'll never require that much. Also, eloralintide doesn't touch the calcitonin receptor. For me it's a winner.

Overall I'm very pleased with this trial. My only wish is that more distributors carried it out of their US/Canada warehouses. I would absolutely buy. As things stand, I only find it in china warehouses.

Cheers!
Click to expand...

10lbs down — that's great news! Elora getting you past that plateau is awesome. EL is probably counting on exactly that.

Cagri let me down as well. I didn't figure out it wouldn't do anything for me until I'd already ordered 5 kits. Not my smartest move.

How much tirzepatide are you on, and is sema still part of your stack? Sema worked well for me and I probably should have simply stacked it.
 
Grogu said:

Devilseye said:

Cagri has left me pretty let down. To start with, it hits calcitonin receptors that exist in the thyroid. That's not great, since calcitonin has no role in losing weight. On top of that, whatever it does lasts only a short while.

A bit of background. I was running reta alongside sema (10mg/2mg — sema because my insurance pays for it, and reta because it's a weak GLP-1R activator too), and my progress froze around 30% weight loss. For 2 months I tried to drop the final 10 pounds and got nowhere. It just sat at 30% with no movement. Cagri made little difference as well. It blunted hunger at first, but that wore off; it did help push me to 30%, yet once I stopped it, nothing changed.

Then eloralintide came along. At the starting 1mg dose my hunger was cut noticeably. By the way, 1mg was all I needed to shed those 10lbs. Clinical trials show 1mg producing 10% bodyweight loss, while 3mg only did slightly better at roughly 12.5%. Just 9mg doubled the loss to 20%, but I'll never require that much. Also, eloralintide doesn't touch the calcitonin receptor. For me it's a winner.

Overall I'm very pleased with this trial. My only wish is that more distributors carried it out of their US/Canada warehouses. I would absolutely buy. As things stand, I only find it in china warehouses.

Cheers!
Click to expand...

10lbs down — that's great news! Elora getting you past that plateau is awesome. EL is probably counting on exactly that.

Cagri let me down as well. I didn't figure out it wouldn't do anything for me until I'd already ordered 5 kits. Not my smartest move.

How much tirzepatide are you on, and is sema still part of your stack? Sema worked well for me and I probably should have simply stacked it.
Click to expand...

Earlier I used tirz, but these days I run 10mg reta alongside 2mg sema and I'll keep it that way for maintenance. Since reta barely stimulates GLP1R, the two fill in each other's gaps. That combo is likely why I reached 30%. Sema came first because insurance picked up the tab. I dropped roughly 12% of my bodyweight fast, then hit a long plateau. Adding tirz 10mg to sema got me near 25%. Reta carried me past that.

Sema is a solid option. When it comes to activating GLP1R, it leaves tirz and reta far behind. Tirz and reta simply aren't in the same league as sema on that front. That's why stacking as little as 1mg on top of either one holds up biochemically. My guess is it would tack on no less than 5% additional weight loss to either.
 
Just to put it in perspective: when it comes to switching on GLP1R, semaglutide's EC50 is basically on par with native GLP1. Tirzepatide sits around 5-10 times weaker, and reta comes in at roughly 100 times weaker.

So they definitely do compliment each other, and on top of that they likely give an extra boost to glucose metrics.
 
Devilseye said:

Grogu said:

Devilseye said:

Cagri has left me pretty let down. To start with, it hits calcitonin receptors that exist in the thyroid. That's not great, since calcitonin has no role in losing weight. On top of that, whatever it does lasts only a short while.

A bit of background. I was running reta alongside sema (10mg/2mg — sema because my insurance pays for it, and reta because it's a weak GLP-1R activator too), and my progress froze around 30% weight loss. For 2 months I tried to drop the final 10 pounds and got nowhere. It just sat at 30% with no movement. Cagri made little difference as well. It blunted hunger at first, but that wore off; it did help push me to 30%, yet once I stopped it, nothing changed.

Then eloralintide came along. At the starting 1mg dose my hunger was cut noticeably. By the way, 1mg was all I needed to shed those 10lbs. Clinical trials show 1mg producing 10% bodyweight loss, while 3mg only did slightly better at roughly 12.5%. Just 9mg doubled the loss to 20%, but I'll never require that much. Also, eloralintide doesn't touch the calcitonin receptor. For me it's a winner.

Overall I'm very pleased with this trial. My only wish is that more distributors carried it out of their US/Canada warehouses. I would absolutely buy. As things stand, I only find it in china warehouses.

Cheers!
Click to expand...

10lbs down — that's great news! Elora getting you past that plateau is awesome. EL is probably counting on exactly that.

Cagri let me down as well. I didn't figure out it wouldn't do anything for me until I'd already ordered 5 kits. Not my smartest move.

How much tirzepatide are you on, and is sema still part of your stack? Sema worked well for me and I probably should have simply stacked it.
Click to expand...

Earlier I used tirz, but these days I run 10mg reta alongside 2mg sema and I'll keep it that way for maintenance. Since reta barely stimulates GLP1R, the two fill in each other's gaps. That combo is likely why I reached 30%. Sema came first because insurance picked up the tab. I dropped roughly 12% of my bodyweight fast, then hit a long plateau. Adding tirz 10mg to sema got me near 25%. Reta carried me past that.

Sema is a solid option. When it comes to activating GLP1R, it leaves tirz and reta far behind. Tirz and reta simply aren't in the same league as sema on that front. That's why stacking as little as 1mg on top of either one holds up biochemically. My guess is it would tack on no less than 5% additional weight loss to either.
Click to expand...

I'm a big fan of sema as well. Can't recall the reason I stopped adding it to my stack.

So your current combo is 10mg reta, 2mg sema and 1mg elora? Or was elora just what got you to goal, and now you're keeping the reta/sema stack?
 
Grogu said:

Devilseye said:

Grogu said:

Devilseye said:

Cagri has left me pretty let down. To start with, it hits calcitonin receptors that exist in the thyroid. That's not great, since calcitonin has no role in losing weight. On top of that, whatever it does lasts only a short while.

A bit of background. I was running reta alongside sema (10mg/2mg — sema because my insurance pays for it, and reta because it's a weak GLP-1R activator too), and my progress froze around 30% weight loss. For 2 months I tried to drop the final 10 pounds and got nowhere. It just sat at 30% with no movement. Cagri made little difference as well. It blunted hunger at first, but that wore off; it did help push me to 30%, yet once I stopped it, nothing changed.

Then eloralintide came along. At the starting 1mg dose my hunger was cut noticeably. By the way, 1mg was all I needed to shed those 10lbs. Clinical trials show 1mg producing 10% bodyweight loss, while 3mg only did slightly better at roughly 12.5%. Just 9mg doubled the loss to 20%, but I'll never require that much. Also, eloralintide doesn't touch the calcitonin receptor. For me it's a winner.

Overall I'm very pleased with this trial. My only wish is that more distributors carried it out of their US/Canada warehouses. I would absolutely buy. As things stand, I only find it in china warehouses.

Cheers!
Click to expand...

10lbs down — that's great news! Elora getting you past that plateau is awesome. EL is probably counting on exactly that.

Cagri let me down as well. I didn't figure out it wouldn't do anything for me until I'd already ordered 5 kits. Not my smartest move.

How much tirzepatide are you on, and is sema still part of your stack? Sema worked well for me and I probably should have simply stacked it.
Click to expand...

Earlier I used tirz, but these days I run 10mg reta alongside 2mg sema and I'll keep it that way for maintenance. Since reta barely stimulates GLP1R, the two fill in each other's gaps. That combo is likely why I reached 30%. Sema came first because insurance picked up the tab. I dropped roughly 12% of my bodyweight fast, then hit a long plateau. Adding tirz 10mg to sema got me near 25%. Reta carried me past that.

Sema is a solid option. When it comes to activating GLP1R, it leaves tirz and reta far behind. Tirz and reta simply aren't in the same league as sema on that front. That's why stacking as little as 1mg on top of either one holds up biochemically. My guess is it would tack on no less than 5% additional weight loss to either.
Click to expand...

I'm a big fan of sema as well. Can't recall the reason I stopped adding it to my stack.

So your current combo is 10mg reta, 2mg sema and 1mg elora? Or was elora just what got you to goal, and now you're keeping the reta/sema stack?
Click to expand...

Yep, that’s precisely my setup: 1mg elora, 10mg reta, and 2mg sema. My plan is to use up the 10mg elora vial I’m on now, then taper it out and check whether reta/sema alone can hold me in maintenance. We’ll see. It’s still too soon to say, but I’ll come back with an update in a month or two.
 
Devilseye said:

Grogu said:

Devilseye said:

Grogu said:

Devilseye said:

Cagri has left me pretty let down. To start with, it hits calcitonin receptors that exist in the thyroid. That's not great, since calcitonin has no role in losing weight. On top of that, whatever it does lasts only a short while.

A bit of background. I was running reta alongside sema (10mg/2mg — sema because my insurance pays for it, and reta because it's a weak GLP-1R activator too), and my progress froze around 30% weight loss. For 2 months I tried to drop the final 10 pounds and got nowhere. It just sat at 30% with no movement. Cagri made little difference as well. It blunted hunger at first, but that wore off; it did help push me to 30%, yet once I stopped it, nothing changed.

Then eloralintide came along. At the starting 1mg dose my hunger was cut noticeably. By the way, 1mg was all I needed to shed those 10lbs. Clinical trials show 1mg producing 10% bodyweight loss, while 3mg only did slightly better at roughly 12.5%. Just 9mg doubled the loss to 20%, but I'll never require that much. Also, eloralintide doesn't touch the calcitonin receptor. For me it's a winner.

Overall I'm very pleased with this trial. My only wish is that more distributors carried it out of their US/Canada warehouses. I would absolutely buy. As things stand, I only find it in china warehouses.

Cheers!
Click to expand...

10lbs down — that's great news! Elora getting you past that plateau is awesome. EL is probably counting on exactly that.

Cagri let me down as well. I didn't figure out it wouldn't do anything for me until I'd already ordered 5 kits. Not my smartest move.

How much tirzepatide are you on, and is sema still part of your stack? Sema worked well for me and I probably should have simply stacked it.
Click to expand...

Earlier I used tirz, but these days I run 10mg reta alongside 2mg sema and I'll keep it that way for maintenance. Since reta barely stimulates GLP1R, the two fill in each other's gaps. That combo is likely why I reached 30%. Sema came first because insurance picked up the tab. I dropped roughly 12% of my bodyweight fast, then hit a long plateau. Adding tirz 10mg to sema got me near 25%. Reta carried me past that.

Sema is a solid option. When it comes to activating GLP1R, it leaves tirz and reta far behind. Tirz and reta simply aren't in the same league as sema on that front. That's why stacking as little as 1mg on top of either one holds up biochemically. My guess is it would tack on no less than 5% additional weight loss to either.
Click to expand...

I'm a big fan of sema as well. Can't recall the reason I stopped adding it to my stack.

So your current combo is 10mg reta, 2mg sema and 1mg elora? Or was elora just what got you to goal, and now you're keeping the reta/sema stack?
Click to expand...

Yep, that’s precisely my setup: 1mg elora, 10mg reta, and 2mg sema. My plan is to use up the 10mg elora vial I’m on now, then taper it out and check whether reta/sema alone can hold me in maintenance. We’ll see. It’s still too soon to say, but I’ll come back with an update in a month or two.
Click to expand...

Absolutely, an update from you would be great.

I might toss some sema into my mix too🤔
 
I get why someone would want to stack sema with tirz or reta — sema hits GLP-1 receptors harder. There are likely cases where that approach is reasonable, especially for people who tolerate GLP-1 agonism well and see real appetite suppression without issues. But binding affinity and receptor sensitivity only tell part of the story. On top of that, many of the figures floating around online are simply wrong, based on my own reading of a pile of the early original papers and many conversations with chatgpt.

On GLP-1, sema is the most potent, then reta, then tirz. However, tirz (not reta) has biased affinity at GLP-1, so its maximal downstream effects in target cells end up bigger than the binding affinity alone would suggest. The dose is also 5-10 higher, so figuring out which one activates glp-1 the most is genuinely difficult. Once you adjust for dose and factor in the biased affinity, it could easily be tirz rather than sema or reta.

The main explanation tirz and reta cause less GI trouble than sema is their GIP agonism, which blunts some of the GLP-1 side effects. That means for most people most of the time, they are the better pick — more weight loss and fewer side effects. This holds most strongly for tirz and is probably the biggest reason it has the lowest side effect rates. The biased agonism at GLP-1 also lowers adverse effects, though I find that mechanism somewhat confusing.

Given all this, I would guess most people do better on a higher dose of tirz or reta than on lower doses with some sema thrown in. If experimentation shows otherwise, I won't argue — GLP responses really do seem individual at times, and there is surely a whole set of receptor polymorphisms in the incretin receptors plus variation in the downstream pathways.
 
lessthanhalf said:

I get why someone would want to stack sema with tirz or reta — sema hits GLP-1 receptors harder. There are likely cases where that approach is reasonable, especially for people who tolerate GLP-1 agonism well and see real appetite suppression without issues. But binding affinity and receptor sensitivity only tell part of the story. On top of that, many of the figures floating around online are simply wrong, based on my own reading of a pile of the early original papers and many conversations with chatgpt.

On GLP-1, sema is the most potent, then reta, then tirz. However, tirz (not reta) has biased affinity at GLP-1, so its maximal downstream effects in target cells end up bigger than the binding affinity alone would suggest. The dose is also 5-10 higher, so figuring out which one activates glp-1 the most is genuinely difficult. Once you adjust for dose and factor in the biased affinity, it could easily be tirz rather than sema or reta.

The main explanation tirz and reta cause less GI trouble than sema is their GIP agonism, which blunts some of the GLP-1 side effects. That means for most people most of the time, they are the better pick — more weight loss and fewer side effects. This holds most strongly for tirz and is probably the biggest reason it has the lowest side effect rates. The biased agonism at GLP-1 also lowers adverse effects, though I find that mechanism somewhat confusing.

Given all this, I would guess most people do better on a higher dose of tirz or reta than on lower doses with some sema thrown in. If experimentation shows otherwise, I won't argue — GLP responses really do seem individual at times, and there is surely a whole set of receptor polymorphisms in the incretin receptors plus variation in the downstream pathways.
Click to expand...

Your reasoning makes sense, and it's true that tirzepatide acts as a biased agonist at GLP1R — it preferentially drives the cAMP pathway and steers clear of b-Arrestin-mediated receptor internalization. Semaglutide, by contrast, is a balanced GLP1R agonist: it turns on both pathways at once, which means it does trigger receptor internalization.

Something worth factoring in: reta and tirz both trace back to the GIP peptide, whereas sema is built on GLP1. For practical purposes, sema is essentially GLP1 carrying 2 modifications that hugely extend its half-life and its albumin binding, giving steady, time-dependent GLP1R stimulation — the same way tirz and reta behave. But here's where I'd push back on what you said: even with sema's balanced agonism, every functional in vitro and in vivo measure — EC50, ki, and so on — points to sema being far more potent at GLP1R. That's also part of why larger tirz doses can be tolerated with fewer side effects: tirz is simply less efficient at GLP1R, biased agonism notwithstanding. GIPR activation doesn't carry those side effects and actually has anti-emetic properties. So in my view it's a synergy — dialed-down GLP1R activation brings less nausea, less GI stimulation, less vomiting and slower gastric emptying, while GIPR activation adds anti-emetic effects, and together that lowers the side effect burden.

That's how I read it. Obviously no one can pin down exactly which effect of tirz/reta dominates in cutting side effects, but I'd argue strong GLP1R activity is more potent at causing side effects than GIPR is at blunting them. At least that's my take on the data we have.

Regardless, in practice my combo produced a 30% weight loss — more than the average seen in participants on 12mg of reta, and I only take 10mg. I also saw bigger HbA1c drops (2.6%, which strikes me as huge).

So overall, the reta/sema combo did work for me, though I plateaued at 30% weight loss. Then adding elora 1mg got me to 35.5% weight loss, which is why I'm thrilled about it. I couldn't be happier, and I have no side effects now (early on I did get side effects like nausea and sulfur burps on sema alone, lasting roughly a month in).

Hope this is useful to anyone curious about my protocol, and thanks to lessthanhalf for raising it. Definitely a discussion worth having.

Cheers!
 
Devilseye said:

Cagri has left me pretty let down. To start with, it hits calcitonin receptors that exist in the thyroid. That's not great, since calcitonin has no role in losing weight. On top of that, whatever it does lasts only a short while.

A bit of background. I was running reta alongside sema (10mg/2mg — sema because my insurance pays for it, and reta because it's a weak GLP-1R activator too), and my progress froze around 30% weight loss. For 2 months I tried to drop the final 10 pounds and got nowhere. It just sat at 30% with no movement. Cagri made little difference as well. It blunted hunger at first, but that wore off; it did help push me to 30%, yet once I stopped it, nothing changed.

Then eloralintide came along. At the starting 1mg dose my hunger was cut noticeably. By the way, 1mg was all I needed to shed those 10lbs. Clinical trials show 1mg producing 10% bodyweight loss, while 3mg only did slightly better at roughly 12.5%. Just 9mg doubled the loss to 20%, but I'll never require that much. Also, eloralintide doesn't touch the calcitonin receptor. For me it's a winner.

Overall I'm very pleased with this trial. My only wish is that more distributors carried it out of their US/Canada warehouses. I would absolutely buy. As things stand, I only find it in china warehouses.

Cheers!
Click to expand...

Devilseye said:

lessthanhalf said:

I get why someone would want to stack sema with tirz or reta — sema hits GLP-1 receptors harder. There are likely cases where that approach is reasonable, especially for people who tolerate GLP-1 agonism well and see real appetite suppression without issues. But binding affinity and receptor sensitivity only tell part of the story. On top of that, many of the figures floating around online are simply wrong, based on my own reading of a pile of the early original papers and many conversations with chatgpt.

On GLP-1, sema is the most potent, then reta, then tirz. However, tirz (not reta) has biased affinity at GLP-1, so its maximal downstream effects in target cells end up bigger than the binding affinity alone would suggest. The dose is also 5-10 higher, so figuring out which one activates glp-1 the most is genuinely difficult. Once you adjust for dose and factor in the biased affinity, it could easily be tirz rather than sema or reta.

The main explanation tirz and reta cause less GI trouble than sema is their GIP agonism, which blunts some of the GLP-1 side effects. That means for most people most of the time, they are the better pick — more weight loss and fewer side effects. This holds most strongly for tirz and is probably the biggest reason it has the lowest side effect rates. The biased agonism at GLP-1 also lowers adverse effects, though I find that mechanism somewhat confusing.

Given all this, I would guess most people do better on a higher dose of tirz or reta than on lower doses with some sema thrown in. If experimentation shows otherwise, I won't argue — GLP responses really do seem individual at times, and there is surely a whole set of receptor polymorphisms in the incretin receptors plus variation in the downstream pathways.
Click to expand...

Your reasoning makes sense, and it's true that tirzepatide acts as a biased agonist at GLP1R — it preferentially drives the cAMP pathway and steers clear of b-Arrestin-mediated receptor internalization. Semaglutide, by contrast, is a balanced GLP1R agonist: it turns on both pathways at once, which means it does trigger receptor internalization.

Something worth factoring in: reta and tirz both trace back to the GIP peptide, whereas sema is built on GLP1. For practical purposes, sema is essentially GLP1 carrying 2 modifications that hugely extend its half-life and its albumin binding, giving steady, time-dependent GLP1R stimulation — the same way tirz and reta behave. But here's where I'd push back on what you said: even with sema's balanced agonism, every functional in vitro and in vivo measure — EC50, ki, and so on — points to sema being far more potent at GLP1R. That's also part of why larger tirz doses can be tolerated with fewer side effects: tirz is simply less efficient at GLP1R, biased agonism notwithstanding. GIPR activation doesn't carry those side effects and actually has anti-emetic properties. So in my view it's a synergy — dialed-down GLP1R activation brings less nausea, less GI stimulation, less vomiting and slower gastric emptying, while GIPR activation adds anti-emetic effects, and together that lowers the side effect burden.

That's how I read it. Obviously no one can pin down exactly which effect of tirz/reta dominates in cutting side effects, but I'd argue strong GLP1R activity is more potent at causing side effects than GIPR is at blunting them. At least that's my take on the data we have.

Regardless, in practice my combo produced a 30% weight loss — more than the average seen in participants on 12mg of reta, and I only take 10mg. I also saw bigger HbA1c drops (2.6%, which strikes me as huge).

So overall, the reta/sema combo did work for me, though I plateaued at 30% weight loss. Then adding elora 1mg got me to 35.5% weight loss, which is why I'm thrilled about it. I couldn't be happier, and I have no side effects now (early on I did get side effects like nausea and sulfur burps on sema alone, lasting roughly a month in).

Hope this is useful to anyone curious about my protocol, and thanks to lessthanhalf for raising it. Definitely a discussion worth having.

Cheers!
Click to expand...
I really appreciate you posting about this! I recently gave Eloralintide a shot and all I can say is WOW! This medication is incredible! Within 1 week I dropped 5 pounds. The only thing I noticed was a complete lack of appetite — no other side effects at all. Zero nausea, zero GI issues, absolutely nothing. It’s amazing!
 
Tinkerbell2222 said:

Devilseye said:

Cagri has left me pretty let down. To start with, it hits calcitonin receptors that exist in the thyroid. That's not great, since calcitonin has no role in losing weight. On top of that, whatever it does lasts only a short while.

A bit of background. I was running reta alongside sema (10mg/2mg — sema because my insurance pays for it, and reta because it's a weak GLP-1R activator too), and my progress froze around 30% weight loss. For 2 months I tried to drop the final 10 pounds and got nowhere. It just sat at 30% with no movement. Cagri made little difference as well. It blunted hunger at first, but that wore off; it did help push me to 30%, yet once I stopped it, nothing changed.

Then eloralintide came along. At the starting 1mg dose my hunger was cut noticeably. By the way, 1mg was all I needed to shed those 10lbs. Clinical trials show 1mg producing 10% bodyweight loss, while 3mg only did slightly better at roughly 12.5%. Just 9mg doubled the loss to 20%, but I'll never require that much. Also, eloralintide doesn't touch the calcitonin receptor. For me it's a winner.

Overall I'm very pleased with this trial. My only wish is that more distributors carried it out of their US/Canada warehouses. I would absolutely buy. As things stand, I only find it in china warehouses.

Cheers!
Click to expand...

Devilseye said:

lessthanhalf said:

I get why someone would want to stack sema with tirz or reta — sema hits GLP-1 receptors harder. There are likely cases where that approach is reasonable, especially for people who tolerate GLP-1 agonism well and see real appetite suppression without issues. But binding affinity and receptor sensitivity only tell part of the story. On top of that, many of the figures floating around online are simply wrong, based on my own reading of a pile of the early original papers and many conversations with chatgpt.

On GLP-1, sema is the most potent, then reta, then tirz. However, tirz (not reta) has biased affinity at GLP-1, so its maximal downstream effects in target cells end up bigger than the binding affinity alone would suggest. The dose is also 5-10 higher, so figuring out which one activates glp-1 the most is genuinely difficult. Once you adjust for dose and factor in the biased affinity, it could easily be tirz rather than sema or reta.

The main explanation tirz and reta cause less GI trouble than sema is their GIP agonism, which blunts some of the GLP-1 side effects. That means for most people most of the time, they are the better pick — more weight loss and fewer side effects. This holds most strongly for tirz and is probably the biggest reason it has the lowest side effect rates. The biased agonism at GLP-1 also lowers adverse effects, though I find that mechanism somewhat confusing.

Given all this, I would guess most people do better on a higher dose of tirz or reta than on lower doses with some sema thrown in. If experimentation shows otherwise, I won't argue — GLP responses really do seem individual at times, and there is surely a whole set of receptor polymorphisms in the incretin receptors plus variation in the downstream pathways.
Click to expand...

Your reasoning makes sense, and it's true that tirzepatide acts as a biased agonist at GLP1R — it preferentially drives the cAMP pathway and steers clear of b-Arrestin-mediated receptor internalization. Semaglutide, by contrast, is a balanced GLP1R agonist: it turns on both pathways at once, which means it does trigger receptor internalization.

Something worth factoring in: reta and tirz both trace back to the GIP peptide, whereas sema is built on GLP1. For practical purposes, sema is essentially GLP1 carrying 2 modifications that hugely extend its half-life and its albumin binding, giving steady, time-dependent GLP1R stimulation — the same way tirz and reta behave. But here's where I'd push back on what you said: even with sema's balanced agonism, every functional in vitro and in vivo measure — EC50, ki, and so on — points to sema being far more potent at GLP1R. That's also part of why larger tirz doses can be tolerated with fewer side effects: tirz is simply less efficient at GLP1R, biased agonism notwithstanding. GIPR activation doesn't carry those side effects and actually has anti-emetic properties. So in my view it's a synergy — dialed-down GLP1R activation brings less nausea, less GI stimulation, less vomiting and slower gastric emptying, while GIPR activation adds anti-emetic effects, and together that lowers the side effect burden.

That's how I read it. Obviously no one can pin down exactly which effect of tirz/reta dominates in cutting side effects, but I'd argue strong GLP1R activity is more potent at causing side effects than GIPR is at blunting them. At least that's my take on the data we have.

Regardless, in practice my combo produced a 30% weight loss — more than the average seen in participants on 12mg of reta, and I only take 10mg. I also saw bigger HbA1c drops (2.6%, which strikes me as huge).

So overall, the reta/sema combo did work for me, though I plateaued at 30% weight loss. Then adding elora 1mg got me to 35.5% weight loss, which is why I'm thrilled about it. I couldn't be happier, and I have no side effects now (early on I did get side effects like nausea and sulfur burps on sema alone, lasting roughly a month in).

Hope this is useful to anyone curious about my protocol, and thanks to lessthanhalf for raising it. Definitely a discussion worth having.

Cheers!
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I really appreciate you posting about this! I recently gave Eloralintide a shot and all I can say is WOW! This medication is incredible! Within 1 week I dropped 5 pounds. The only thing I noticed was a complete lack of appetite — no other side effects at all. Zero nausea, zero GI issues, absolutely nothing. It’s amazing!
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Glad to help! Just to be clear, in my view it does not substitute for GLP1s in any way, but it definitely helped me get past a really stubborn plateau!!
 
Seeing everyone discuss Elora has me pumped to give it a try, though I'm nowhere near my Reta ceiling. As of now, my approach would involve experimenting with stacking it once I reach about 8mg of Reta, but I'm taking my time increasing the dose and putting my energy into lifting and protein intake.
 
GiffMeReta said:

Seeing everyone discuss Elora has me pumped to give it a try, though I'm nowhere near my Reta ceiling. As of now, my approach would involve experimenting with stacking it once I reach about 8mg of Reta, but I'm taking my time increasing the dose and putting my energy into lifting and protein intake.
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Elora is way too expensive for me at the moment! Costs too much. I'll just wait for more choices and cheaper prices. You all can go first, though—have fun and let me know how it goes. 🤣
 
spanky2026 said:

Adding a low dose of sema to tirz is something I never would have considered. That's interesting
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Sema is something I've never used (I did reta for 2 months and my sleep was awful). These days I'm on Tirz, though I might think about adding semi...
 
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