GIP is not your friend. And why Tirzepatide is superior to Retatrutide

[trev55]

There isn't any good long term human data on these GLP-1/GIP agonist drugs, most of what we know comes from studies on rodents so I'm going to post my thoughts about why some of these drugs may be doing more harm than good, especially in lean, insulin sensitive individuals.
I'll break it into a few parts, and why Tirz is probably much safer and better over the long term than Reta.

1. GIP is not your friend.
GIP isn’t being discussed nearly as much as GLP-1 in fitness contexts, even though many of the newest incretin drugs now deliberately agonize the GIP receptor alongside GLP-1. I want to lay out why I’m not convinced this is automatically a good thing for those who aren't fat as fuck.

Before the current popularity of dual- and multi-agonist drugs — like tirzepatide and retatrutide — GIP was originally dubbed in the literature as the obesity hormone. GIP's normal physiological role after eating is to promote fat storage in adipose tissue.

In white adipose tissue, GIP signaling tends to suppress lipolysis and promote lipid storage, causing increases in white adipose fat mass under caloric excess.

There is evidence in rats that GIP shifts insulin sensitivity in a tissue specific way, reducing insulin sensitivity in muscle, liver and brown adipose tissue, and increasing insulin sensitivity in WAT.

In rodents, CNS GIP signalling has been linked to increased neuroinflammatory signalling, and reduced leptin responsiveness in appetite-regulating centers, so it is eventually de-sensitizing you to the master satiety hormone, a condition seen in obesity.

Finally GIP is described as supporting pancreatic beta-cell proliferation and survival, which is one of the reasons it’s viewed positively in diabetes treatment. However, there is also evidence that chronic overstimulation of the GIP pathway can lead to receptor desensitization and reduced effectiveness over time.

The point is that GIP's role is not a fat loss support hormone, it is a fat storage hormone which makes me question whether strong GIP agonism is helpful or actually harmful for people without existing obesity & insulin resistance.

 

[johnjay06]

An off topic aside- I’m wary of peptide hype but have tried this and it fucking worked- confirmed by before/after dexa, tailors tape, and the mirror. Jump on a couple or few months of tesamorelin. 2mg before bed is a good protocol. It’s a little spendy but not crazy if you find a good plug. And it’s a GH secretogogue with clinical trials and medically perscribed, not a sketchy research compound.

It will raise your IGF-1 to high in range values but there is something about the way it makes you pulse natural GH that specifically targets visceral fat mobilization. We all know that while fat is ugly visceral fat is dangerous to longevity and crowds your organs- it’s totally worth a try for you.

Have you compared it to HGH? I've been intrigued by the stuff and thought about giving it a go to see if it is milder on my heart rate

 

[Mfras]

Have you compared it to HGH? I've been intrigued by the stuff and thought about giving it a go to see if it is milder on my heart rate

Yeah once my visceral fat was no longer an issue I switched to generic GH and have been finishing my cut on 6.6iu/day split AM/PM. It’s hard to tell how much fat loss, recovery increase, or increased connective tissue growth it’s influenced but my hair and nails are definitely growing faster. I pretty much experienced no sides and titrated up way too fast, plus a 3 week stint on 8iu with no water retention then either.

I have bloodwork scheduled soon but I’m close to ending an epic long cut and I know igf-1 will increase when food comes back in, so when I get my current z-score if it’s above a high 2.xx I’ll adjust my dose down some. You want to keep your longterm use below 3.0 z-score to be safer from acromegaly and organ remodeling. I’ll probably blast it at 8-10ish on cycle and return to safer cruise dose with trt phases, and maybe drop to a lower longevity dose if I’m happy with my physique and chilling- important to note I’m in my late 40s, so I’m not planning to blast indefinitely.

 

[iudex]

Yeah once my visceral fat was no longer an issue I switched to generic GH and have been finishing my cut on 6.6iu/day split AM/PM. It’s hard to tell how much fat loss, recovery increase, or increased connective tissue growth it’s influenced but my hair and nails are definitely growing faster. I pretty much experienced no sides and titrated up way too fast, plus a 3 week stint on 8iu with no water retention then either.

I have bloodwork scheduled soon but I’m close to ending an epic long cut and I know igf-1 will increase when food comes back in, so when I get my current z-score if it’s above a high 2.xx I’ll adjust my dose down some. You want to keep your longterm use below 3.0 z-score to be safer from acromegaly and organ remodeling. I’ll probably blast it at 8-10ish on cycle and return to safer cruise dose with trt phases, and maybe drop to a lower longevity dose if I’m happy with my physique and chilling- important to note I’m in my late 40s, so I’m not planning to blast indefinitely.

You had a zscore of <3 with 6.6 iu?

 

[Duraclear]

An off topic aside- I’m wary of peptide hype but have tried this and it fucking worked- confirmed by before/after dexa, tailors tape, and the mirror. Jump on a couple or few months of tesamorelin. 2mg before bed is a good protocol. It’s a little spendy but not crazy if you find a good plug. And it’s a GH secretogogue with clinical trials and medically perscribed, not a sketchy research compound.

It will raise your IGF-1 to high in range values but there is something about the way it makes you pulse natural GH that specifically targets visceral fat mobilization. We all know that while fat is ugly visceral fat is dangerous to longevity and crowds your organs- it’s totally worth a try for you.

Yes, thank you. I was actually more interested in using Tesamorelin than Reta. Unfortunately, I do not have a good plug for it, and the cost from any sources I'm able to find is prohibitive, so I kind of settled for Reta. But I'll keep an eye out to see if I can find more moderately prices sources out there. Thanks for the recommendation.

 

[deuces_00]

View attachment 380937

Even when Copy pasting AI slop,

Do you carry basic common that, If GIP agonism were inherently lipogenic in vivo, the result of GLP1s we get is impossible?


Rodents and humans respond oppositely to GIP.

as soon as i saw the em-dashes i rolled my eyes and looked for someone to call it out loool

 

[bananafeet]

If I were a cynical man (which I'm not) I'd wager that smart people took advantage of the following:

1. Bodybuilders are fat phobic and reject shortcuts
2. Reta is legal to resell as a chemical

So they said it's a fat burner and played down the appetite suppression so bodybuilders didn't feel like they were common fatties. (An immoral class of out of shape gluttons).

Then the fatties felt like bodybuilders. Circle jerk to infinity.

Add cash into it and people would sell you cat piss claiming it's champagne....

 

[frenexen]

Both GIPR agonism and antagonism ultimately lead to weight loss through different mechanisms. Only GIPR agonism would enhance both fat and glycogen storage, but GIPR agonism also increases fat oxidation. Therefore, GIP agonism is advantageous for a bodybuilder. Any increased fat storage can be burned off through lipolysis and oxidation through CPT-1.

Also, I also used to think biased agonism was important for GLP-1R, but it's not. GLP-1R rapidly recycles and prevents any sort of prolonged internalization anyway. The increase in gastric emptying after prolonged usage of incretins acts downstream from GLP-1R and is, at least currently, unavoidable and due to nervous system adaptions.

To prove this point just look at biased mono-GLP1R agonists Orforglipron and Ecnoglutide. One would expect prolonged fat loss that exceeds Semaglutide, but results from studies simply don't show that happening.

 

[bananafeet]

Both GIPR agonism and antagonism ultimately lead to weight loss through different mechanisms. Only GIPR agonism would enhance both fat and glycogen storage, but GIPR agonism also increases fat oxidation. Therefore, GIP agonism is advantageous for a bodybuilder. Any increased fat storage can be burned off through lipolysis and oxidation through CPT-1.

Also, I also used to think biased agonism was important for GLP-1R, but it's not. GLP-1R rapidly recycles and prevents any sort of prolonged internalization anyway. The increase in gastric emptying after prolonged usage of incretins acts downstream from GLP-1R and is, at least currently, unavoidable and due to nervous system adaptions.

To prove this point just look at biased mono-GLP1R agonists Orforglipron and Ecnoglutide. One would expect prolonged fat loss that exceeds Semaglutide, but results from studies simply don't show that happening.

Bro what are you talking about.

I'm tired of people over complicating and over emphasizing small effects.

These drugs work by stopping you from eating by slowing stomach emptying. This reduces the glycemic effect of foods by slowing digestion.

It's not complicated. What is all this gobbledygook?

There is no "increased fat oxidation" if there was it would be a shit diabetic drug because the FFA would be turned into glucose by the liver. As is the case with HGH.

When you make these claims try to put a god damn source in.

 

[frenexen]

Bro what are you talking about.

I'm tired of people over complicating and over emphasizing small effects.

These drugs work by stopping you from eating by slowing stomach emptying. This reduces the glycemic effect of foods by slowing digestion.

It's not complicated. What is all this gobbledygook?

There is no "increased fat oxidation" if there was it would be a shit diabetic drug because the FFA would be turned into glucose by the liver. As is the case with HGH.

When you make these claims try to put a god damn source in.

I wasn't talking to you. I was talking to the OP. If you don't want to 'overcomplicate' it then don't. I was explaining to him why he was wrong both on his opinion that GIP agonism is a negative as it would increase fat storage, and that biased agonism is important.

But if you want sources then you're free to read up, but you want to simplify it so why ask?

Acute exogenous acyl-GIP treatment enhances lipid handling and fatty acid oxidation by involving brown fat - PMC

The contribution of glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling in brown adipose tissue (BAT) remains underexplored. We studied the acute effects of exogenous acyl-GIP (1 nmol/kg) administration on whole-body lipid ...

pmc.ncbi.nlm.nih.gov

"In addition, acute GIP treatment to individuals with type 1 diabetes and no onboard insulin showed an increase in supraclavicular BAT activity associated with changes in free fatty acid levels and lower respiratory exchange ratios (RER) indicative of more fatty acid oxidation (Heimburger et al, 2022)."

"Acute exogenous acyl-GIP administration promotes brown adipose tissue (BAT) lipid uptake during lipid tolerance tests, augmenting whole-body lipid handling and increases whole-body fatty acid oxidation during routine metabolism in male obese mice."

GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice - Nature Metabolism

This study, together with a companion manuscript, show that, in mice, weight loss as a result of GIP receptor antagonism requires, and potentiates, functional GLP-1 receptor signalling in the brain, explaining how both GIP receptor agonists and antagonists trigger weight loss through different...

www.nature.com

To simplify, arguing that GIP agonism is negative is like arguing that increased insulin sensitivity is negative because it allows the body to store fat.

 

[MrTexas2]

TLDR: Stick with Tirzepatide. This was my conclusion when I started studying weight loss drugs for my wife and clients. I had a female client...60 lbs overweight. She lost nearly 20 training with me but plateaued. She will exercise, but not very hard. Her diet is mediocre.

I strongly recommended Zepbound for her but she refused. Crazy, because she was a sweetheart with a nice face getting close to 35 and wanting to get married/start a family. A year later she is still single.

 

[Jason_orange12]

Anyone like stacking them?

 

[Endeavor Fitness]

I think you all are missing a massive point on why reta is considered the favourite for most of bodybuilders. Yes you read it correctly: BODYBUILDERS.

I think you all are missing a massive point on why reta is considered the favourite for most of bodybuilders. Yes you read it correctly: BODYBUILDERS.

not fat ppl, not ex obese with hunger issues that can't manage appetite on a cut for many reasons or whatever other categories you wanna fit in.

BODYBUILDERS aka ppl that when there was no reta sema tirz were able and are still able to diet down to low single digit bodyfat with mostly sheer willpower.

This is literally the gospel. Bodybuilders are using Reta purely from the muscle sparing (sometimes even using it to add muscle). The problem is when regular shmucks don't understand there is a difference the way the "Real World" uses these meds, and how the Fitness and Entertainment industry uses them.

Like you stated before GLP medications, I had to literally use sell control to get to 5% Body fat. Felt like shit, no energy, etc.. I really don't pay any attention when I see normies trying to apply "normie logic" to Fitness/Bodybuilding.

Especially when I've helped train ppl and showed them how to use BOTH. Tirzepatide doesn't spare muscle, it will pull from muscle or fat. Reta is more muscle sparing.

 

[riggspersonal]

Reta is more muscle sparing.

On the condition that your dosage is high enough for glucagon agonism, which is important to be aware of.

 

[Endeavor Fitness]

On the condition that your dosage is high enough for glucagon agonism, which is important to be aware of.

False. Doesn't matter if you're in some kind of shape. Again, clinical studies were based on fat, lazy, diabetics with fatty livers. If it took them to ramp up to 4 mg to see any effect. It takes someone in decent enough less to do it.

Again, I've seen it hundreds of times.

 

[riggspersonal]

False. Doesn't matter if you're in some kind of shape. Again, clinical studies were based on fat, lazy, diabetics with fatty livers. If it took them to ramp up to 4 mg to see any effect. It takes someone in decent enough less to do it.

Again, I've seen it hundreds of times.

That’s simply not how peptides work. Retatrutide isn't fat-soluble like most AAS, so your body fat percentage doesn't change the plasma concentration needed to actually activate the receptors. Receptor physiology doesn't change just because you're lean.

The Phase 2 trial data (NEJM) backs exactly what I'm saying. The main clinical marker for glucagon agonism is a dose-dependent spike in resting heart rate, and the data shows it doesn't clearly kick in until you hit 4mg/week.

Incidence of RHR jumping >10 bpm:

- Placebo: 2%

- 1mg: 8%

- 4mg: 15% (The inflection point)

- 8mg: 27%

- 12mg: 31%

The 4mg mark is where glucagon activity actually becomes clinically distinct. You need that specific blood concentration to agonize the receptor, regardless of whether you're a bodybuilder or an obese diabetic.

Edit: in the 1-4mg/week dosage range you're getting some glucagon agonism, and therefore some muscle sparring, but nothing material.

 

[Endeavor Fitness]

That’s simply not how peptides work. Retatrutide isn't fat-soluble like most AAS, so your body fat percentage doesn't change the plasma concentration needed to actually activate the receptors. Receptor physiology doesn't change just because you're lean.

The Phase 2 trial data (NEJM) backs exactly what I'm saying. The main clinical marker for glucagon agonism is a dose-dependent spike in resting heart rate, and the data shows it doesn't clearly kick in until you hit 4mg/week.

Incidence of RHR jumping >10 bpm:

- Placebo: 2%

- 1mg: 8%

- 4mg: 15% (The inflection point)

- 8mg: 27%

- 12mg: 31%

The 4mg mark is where glucagon activity actually becomes clinically distinct. You need that specific blood concentration to agonize the receptor, regardless of whether you're a bodybuilder or an obese diabetic.

Again, you apply "normie logic" in situations that aren't normal. There are way better coaches than me seeing the same thing. Like I said, you're comparing fat, lazy diabetics, with fatty livers to ppl in the fitness and Bodybuilding world.

How many Bodybuilders were in that study? How many are in the clinical trials?

 

[Endeavor Fitness]

Look, I'm not saying the info and clinical trials are false info. I'm saying that the info is a reflection of a certain subgroup of individuals.

I'm not starting a woman off, who is getting ready for a bikini competition, at the recommended dosage. Nor am i ramping her up at that schedule, with 16 more weeks to go. Now, if some fat person comes up to me and I see they are legit, I might use the clinical trials as a guideline.

 

[Middus]

Just wondering the exact point of this post?
What are the anecdotal harms that the OP is noticing, at least there has to be something we can hold on to, other than 'spidey sense is tingling'

 

[frenexen]

Why is glucagon accepted here as being inherently muscle sparing? Where did this idea come from? Don’t tell me it’s from DEXA alone.

The evidence that glucagon is in anyway muscle sparing is slim to none. Infusions do lead to minor decreases in RER but this does not account for amino acid breakdown. Obviously it would lower it slightly as substrate for gluconeogenesis is not carbohydrate, so if anything it’s just neutral because any decrease would represent increased fat and protein breakdown while preserving glycogen stores.

Actual benefits of glucagon agonism is a minor increase in expenditure allowing for quicker visceral fat reduction, and minor stimulant effect.

Retatrutide is arguably only preferred over Tirzepatide if you need insulin sensitivity without the appetite suppression, as it is more selective for GIPR over GLP-1R. Any other effect is so minor that it’s probably not worth the increase in RHR and potential cortisol increase from chronic GCGR activation.

If you decide to use it over Tirzepatide you theoretically want to increase protein and reduce carbohydrates, but it’s not really going to matter much imo.

 

[Elektrobot]

There isn't any good long term human data on these GLP-1/GIP agonist drugs

You lost me with your first sentence being incorrect. Why are you posting about a topic you are ignorant about?