Stacking GLP's

[BP_6]

I know it has been done. Just asking for more personal anecdotes. Has anyone ever stacked for example Tirz and Reta. Like I don't know, 4mg Reta, 5mg Tirz? Probably doesn't make much of a difference or any point to really doing that. Just curious. Also would like to hear about other stacks.

 

[Sera]

Also interested

 

[tomvet93]

I think the only honest answer is noone knows.

I did a small amount of reta on top of tirzepatide for a month (lots of people on reddit do it). After reading up on it more I decided to just up the tirzepatide.

Theoretically there's some concern about the balance of gip glp and glucagon is quite specific with reta and might be upset by adding a different compound.

Tbh no-one has ever specified (that I've found) what those risks are.

I anecdotally felt better on the mix and lots of people on reddit have been doing it now for probably a year.

But I didn't feel that much better (better appetite control and energy with less nausea) that I felt it was worth fucking about with long term.

In the end I've frozen a year's supply of reta and once I've hit my goal of weight loss will probably taper off the tirzepatide and then add reta for maintaining. (If I hadn't already bought the reta I would probably stick with low dose tirzepatide)

In summary I think no-one knows. Probably not worth messing about with and just titrate up the one you're on.

I'm even debating swapping to sema long long term as I can get pharma for cheap enough that it worth sticking with. Only moved to ugl tirzepatide and reta when the price of mounjaro shot up in the UK.

(Currently down 25kg in 4 months on tirzepatide)

 

[sionnach]

I've done tirz and reta together, and reta with cagri. Cagri didn't do anything noticeable at all. Tirz with reta did offer more hunger suppression than reta alone. But I''ve been at target weight for months and didn't see the point as my diet's already locked down, so now I just do reta for the metabolic benefits.

 

[Deadpool99]

I've done tirz and reta together, and reta with cagri. Cagri didn't do anything noticeable at all. Tirz with reta did offer more hunger suppression than reta alone. But I''ve been at target weight for months and didn't see the point as my diet's already locked down, so now I just do reta for the metabolic benefits.

Interesting, I'm using reta rn, and 4mg cagri, I am very shitty responder to glp1/cagri but as soon as I hit the 3mg dose, holy shit do u feel it.

I also have some Zepbound in the fridge idm using it.

May I ask what reta dose did u max out and how much tirz did u add? Interested in stacking them myself

 

[ackmack78]

I used Sema on top of Reta since Reta didn't give me much appetite suppression. Worked fine

 

[sionnach]

May I ask what reta dose did u max out and how much tirz did u add? Interested in stacking them myself

I first did it transitioning from tirz to reta, ie 6:2, 4:4, 2:6 but I also added tirz back in to a reta routine later at about 4:5. Like I said, there's more hunger suppression, but I didn't really need it. On a pretty steady ~6mg of reta for good now, no plans to change it.

I used Sema on top of Reta since Reta didn't give me much appetite suppression. Worked fine

This is probably the better route to go vs tirz/reta or cagri/reta (or even "ghetto reta") if you want the GIP and GCG effects but also have trouble with diet.

 

[Deadpool99]

I first did it transitioning from tirz to reta, ie 6:2, 4:4, 2:6 but I also added tirz back in to a reta routine later at about 4:5. Like I said, there's more hunger suppression, but I didn't really need it. On a pretty steady ~6mg of reta for good now, no plans to change it.


This is probably the better route to go vs tirz/reta or cagri/reta (or "ghetto reta") if you want the GIP and GCG effects but also have trouble with diet.

Oh you never truly maxed out the reta dose?

Debating tirz vs sema, but also thinking of switch to tirz fully once my reta runs out. I think tirz and reta will possible add better BG control to then going Reta + Sema.

However sema would probably be stronger in appetite.

 

[Ghoul]

@tomvet93

Retatrutide depends on a precisely tuned receptor ratio, roughly GLP-1 : GIP : glucagon = 1 : 1 : 0.3 that keeps glucagon driven fuel burning balanced by incretin driven fuel storage.

This balance lets the liver make and use glucose in harmony, providing energy without needing to break down protein for fuel.

Adding tirzepatide breaks that balance.

Its GLP-1 and GIP receptor activity is several times stronger than Retatutride’s (about 2× at GLP-1 and 5× at GIP).

When both drugs are present, Tirzepatide dominates the shared receptors, so Retatrutide’s incretin (GLP/GIP) side gets drowned out.

That leaves Retatrutide’s glucagon receptor as the only part still working at full strength. Now the perfectly calibrated push/pull of these hormones is lost.

Glucagon, fully active, tells the liver to make and release glucose (and oxidize it for energy).

Tirzepatide makes the body extremely sensitive to increases in blood glucose, and sends the opposite signal via a rapid, amplified insulin release, ie, “stop producing glucose and store energy”. This makes Tirz excellent for glucose control, but when glucagon is continuously stimulating glucose production in the liver, you don’t want insulin response to be quite this strong.

Normally those two signals are never sent to the liver at the same time.

It’s like pressing the accelerator and brake pedal. The engine (your liver) strains, burning fuel inefficiently.

Glucose release is now impaired by insulin, and when the liver can’t produce glucose properly, it switches fuels from carbs. First to fatty acids, and then to amino acids taken from muscle.

This “substrate shift” creates a catabolic state. The body starts breaking down muscle protein to feed the liver’s glucose production and energy needs.

The liver continues oxidizing fat and amino acids but still can’t efficiently release glucose.

Plasma amino acids fall, nitrogen waste rises, and ALT/AST increase.

Muscle tissue becomes a primary substrate source for liver glucose production. (aka hepatic gluconeogenesis) accelerating lean mass loss.

This mechanistic instability, glucagon drive with simultaneous amplified insulin release is what led to earlier GLP-1/glucagon dual-agonists (e.g., MEDI0382, PF-06291874) to be abandoned for safety and effectiveness failures, causing liver stress, enzyme elevation, and catabolism. .

Retatrutide broke the “glucagon curse” through 20 years of experimentation to find the perfect balance of GLP/ GIP/ Glucagon receptor binding proportionality that works and is safe.

Until Dr. Reddit decided the most effective weight loss compounds ever known to man don’t work well enough, so they throw them together in random combinations, yet few, if any, ever seem to achieve the success rate that patients in the trials using one do.

 

[Sera]

Its GLP-1 and GIP receptor activity is several times stronger than Retatutride’s (about 2× at GLP-1 and 5× at GIP

Minor correction, retatrutide is roughly nine fold more potent at the GIP receptor than tirzepatide.

 

[Ghoul]

Minor correction, retatrutide is roughly nine fold more potent at the GIP receptor than tirzepatide.

Damn missed the edit window, though it doesn’t make a difference for the overall point, it should’ve read:

“Its GLP-1 receptor activity is roughly 2× stronger than Retatrutide’s, while its GIP receptor activity is about 5 to 9 times weaker (but once attached has a longer “residence time” than Reta GIP).“

Even though Reta has stronger potency at the GIP receptor, its faster off-rate and shorter residence time mean it binds, signals, and releases quickly.

When Tirz is sitting on those receptors Reta can’t simply bump it off, it just has to wait for a receptor to free up. Since Tirz dissociates slowly, very few openings appear and Tirz still monopolizes GIP sites,

Tirz also has a stronger albumin binding mechanism, and a steady, continuous rate of release. Reta detaches and reattaches much more dynamically (this gives Reta some kind of pulsatile advantage over Tirz I don’t quite understand yet), but it also means Tirz’s steadier plasma concentration is another reason it dominates shared receptors when both are in your system at the same time, throwing off Reta’s balance.

 

[ackmack78]

I don't know all the sciencey shit but sema and reta got me to 6.5%bf, without muscle loss. Technically I gained muscle while cutting but that's only because I had a 2 month layoff from lifting after surgery. I'll take that as a win

 

[ineffectual]

@tomvet93

Retatrutide depends on a precisely tuned receptor ratio, roughly GLP-1 : GIP : glucagon = 1 : 1 : 0.3 that keeps glucagon driven fuel burning balanced by incretin driven fuel storage.

This balance lets the liver make and use glucose in harmony, providing energy without needing to break down protein for fuel.

Adding tirzepatide breaks that balance.

Its GLP-1 and GIP receptor activity is several times stronger than Retatutride’s (about 2× at GLP-1 and 5× at GIP).

When both drugs are present, Tirzepatide dominates the shared receptors, so Retatrutide’s incretin (GLP/GIP) side gets drowned out.

That leaves Retatrutide’s glucagon receptor as the only part still working at full strength. Now the perfectly calibrated push/pull of these hormones is lost.

Glucagon, fully active, tells the liver to make and release glucose (and oxidize it for energy).

Tirzepatide makes the body extremely sensitive to increases in blood glucose, and sends the opposite signal via a rapid, amplified insulin release, ie, “stop producing glucose and store energy”. This makes Tirz excellent for glucose control, but when glucagon is continuously stimulating glucose production in the liver, you don’t want insulin response to be quite this strong.

Normally those two signals are never sent to the liver at the same time.

It’s like pressing the accelerator and brake pedal. The engine (your liver) strains, burning fuel inefficiently.

Glucose release is now impaired by insulin, and when the liver can’t produce glucose properly, it switches fuels from carbs. First to fatty acids, and then to amino acids taken from muscle.

This “substrate shift” creates a catabolic state. The body starts breaking down muscle protein to feed the liver’s glucose production and energy needs.

The liver continues oxidizing fat and amino acids but still can’t efficiently release glucose.

Plasma amino acids fall, nitrogen waste rises, and ALT/AST increase.

Muscle tissue becomes a primary substrate source for liver glucose production. (aka hepatic gluconeogenesis) accelerating lean mass loss.

This mechanistic instability, glucagon drive with simultaneous amplified insulin release is what led to earlier GLP-1/glucagon dual-agonists (e.g., MEDI0382, PF-06291874) to be abandoned for safety and effectiveness failures, causing liver stress, enzyme elevation, and catabolism. .

Retatrutide broke the “glucagon curse” through 20 years of experimentation to find the perfect balance of GLP/ GIP/ Glucagon receptor binding proportionality that works and is safe.

Until Dr. Reddit decided the most effective weight loss compounds ever known to man don’t work well enough, so they throw them together in random combinations, yet few, if any, ever seem to achieve the success rate that patients in the trials using one do.

They always seem to start adding, stacking before coming even close to current approved max dose.

 

[tomvet93]

@tomvet93

Retatrutide depends on a precisely tuned receptor ratio, roughly GLP-1 : GIP : glucagon = 1 : 1 : 0.3 that keeps glucagon driven fuel burning balanced by incretin driven fuel storage.

This balance lets the liver make and use glucose in harmony, providing energy without needing to break down protein for fuel.

Adding tirzepatide breaks that balance.

Its GLP-1 and GIP receptor activity is several times stronger than Retatutride’s (about 2× at GLP-1 and 5× at GIP).

When both drugs are present, Tirzepatide dominates the shared receptors, so Retatrutide’s incretin (GLP/GIP) side gets drowned out.

That leaves Retatrutide’s glucagon receptor as the only part still working at full strength. Now the perfectly calibrated push/pull of these hormones is lost.

Glucagon, fully active, tells the liver to make and release glucose (and oxidize it for energy).

Tirzepatide makes the body extremely sensitive to increases in blood glucose, and sends the opposite signal via a rapid, amplified insulin release, ie, “stop producing glucose and store energy”. This makes Tirz excellent for glucose control, but when glucagon is continuously stimulating glucose production in the liver, you don’t want insulin response to be quite this strong.

Normally those two signals are never sent to the liver at the same time.

It’s like pressing the accelerator and brake pedal. The engine (your liver) strains, burning fuel inefficiently.

Glucose release is now impaired by insulin, and when the liver can’t produce glucose properly, it switches fuels from carbs. First to fatty acids, and then to amino acids taken from muscle.

This “substrate shift” creates a catabolic state. The body starts breaking down muscle protein to feed the liver’s glucose production and energy needs.

The liver continues oxidizing fat and amino acids but still can’t efficiently release glucose.

Plasma amino acids fall, nitrogen waste rises, and ALT/AST increase.

Muscle tissue becomes a primary substrate source for liver glucose production. (aka hepatic gluconeogenesis) accelerating lean mass loss.

This mechanistic instability, glucagon drive with simultaneous amplified insulin release is what led to earlier GLP-1/glucagon dual-agonists (e.g., MEDI0382, PF-06291874) to be abandoned for safety and effectiveness failures, causing liver stress, enzyme elevation, and catabolism. .

Retatrutide broke the “glucagon curse” through 20 years of experimentation to find the perfect balance of GLP/ GIP/ Glucagon receptor binding proportionality that works and is safe.

Until Dr. Reddit decided the most effective weight loss compounds ever known to man don’t work well enough, so they throw them together in random combinations, yet few, if any, ever seem to achieve the success rate that patients in the trials using one do.

Good explanation thanks appreciate it

 

[tomvet93]

They always seem to start adding, stacking before coming even close to current approved max dose.

To be fair increasing doses although effective definitely cause more side effects.

I'm currently down to around 120kg from 145kg aiming to get to around 100kg.

When I started 1.25mg of tirzepatide was like a miracle had no side effects and no cravings.

As I've lost more weight I've had to increase the dose as it became less effective. But now have fairly frequent nausea.

Most pharmaceuticals do stack well and often are synergistic with desired effect whereas often have different side effects that don't stack. It's just unfortunate that isn't the case with these