Giant Semaglutide Thread (and other GLP-1 / GIP agonists)

[Doodle]

Wanted to create a thread where everyone can post their experiences with different sourced Semaglutide.

Who are you using?
Pharma vs non?
Dosage?
How long have you been taking it?
What are your thoughts?
Have you lost weight?
Side effects?
Oral vs injection?
Tests?

 

[egruberman]

There are a few off the top of my head. Atrial structure improvement, that is the reversal of long term damage from stresses, is pronounced in normal weight, non-diabetics but not the obese.

If you can think of any that tease apart the effect independent from weight loss and metabolic improvement I’d like to see them.

To be clear, he made the assertion and it was qualified. I am passing it along as a point of interest, but may be interpreting his statements incorrectly.

 

[Musmadar]

While much of the conversation surrounding these drugs focuses on their ability to suppress appetite, there is far more to their benefits. For those dedicated to optimizing their health and performance, tirzepatide and retatrutide offer a range of metabolic improvements that go beyond simple caloric restriction:

One of the most important effects of both tirzepatide and retatrutide is their role in improving insulin sensitivity, improved insulin sensitivity means better glucose uptake by muscle cells, leading to more efficient use of carbohydrates consumed post-exercise. This promotes faster recovery, greater glycogen replenishment, and enhanced muscle growth over time.

When the body is more sensitive to insulin, less of the hormone is required to keep blood sugar levels stable, which in turn reduces the risk of insulin resistance—a precursor to type 2 diabetes, this means that they can maintain higher energy levels during workouts and optimize muscle growth, while simultaneously reducing the risk of developing metabolic diseases.

In addition to enhancing insulin sensitivity, tirzepatide and retatrutide can significantly improve how the body processes and uses carbohydrates. Proper carbohydrate metabolism ensures that glucose is effectively used during exercise, delaying the onset of fatigue and allowing for longer, more intense sessions.

Moreover, post-exercise, efficient carbohydrate utilization aids in faster glycogen restoration in muscles, which is essential for recovery and the ability to perform optimally in subsequent workouts. This improvement in metabolic function means that the nutrients consumed are put to better use in fueling performance and muscle repair.

While the appetite-suppressing effects of tirzepatide and retatrutide are often highlighted, their impact on fat loss goes far beyond simply reducing caloric intake. These drugs can promote fat loss by improving overall metabolic health. By increasing insulin sensitivity and optimizing carbohydrate use, the body becomes more efficient at burning fat for energy, especially in a caloric deficit.

Moreover, these drugs may enhance the body's thermogenic capacity, further supporting fat loss. By increasing the energy expenditure even at rest, tirzepatide and retatrutide allow individuals to burn more calories throughout the day, contributing to a leaner physique over time.

Another key benefit of tirzepatide and retatrutide is their ability to reduce inflammation, which is crucial for both short-term performance and long-term health. Intense exercise, particularly in strength training or endurance sports, can lead to temporary increases in inflammation. While this is a natural part of the recovery process, chronic inflammation can hinder progress and increase the risk of injuries or illnesses.

By improving insulin sensitivity and stabilizing blood sugar levels, tirzepatide and retatrutide help reduce chronic inflammation. This supports faster recovery, improved joint health, and greater resilience in training. Additionally, these drugs have been shown to improve lipid profiles and cardiovascular health, reducing the risk of heart disease—a critical point for anyone involved in long-term bodybuilding.

These medications address the root causes of metabolic dysfunction, offering improvements in insulin sensitivity, carbohydrate utilization, fat loss, and inflammation management.

 

[Sampei]

Tirz is better on paper and the general anecdotal consensus is that it just lacks the HEAVY appetite suppression Sema has. So it depends what you want to use it for, appetite control and some health benefits or maximum efficacy on the health and medium appetite control?

To me the complete opposite sema gas some appetite control at first but after just a bit I get used to it and it gives me no side at all plus the glycemic control of sema Is superior for me.

Tirz destroyed my gastric emptiness, I could feel full for hours after eating just a little snack. Food craving? 0. Appetite average but as I felt full all the time I didn't want to eat.
Glycemic control of tirz on 5mg? Not that great.

 

[HB_22]

I

would really like to get the binding affinity for each nailed down on a relative basis to one another. Feel like I saw it somewhere but could never find it again.

Please dont mix up binding affinity with receptor activation. You can have a very strong binding affinity but still very low to almost no receptor activation, as this is how most antidotes work.

 

[Trenbolonetax]

Please dont mix up binding affinity with receptor activation. You can have a very strong binding affinity but still very low to almost no receptor activation, as this is how most antidotes work.

I did mix those up. Thank you for the correction! If I could find that, I would be very happy.

No other reason than curiosity. So far, I am having my best experience on Reta.

 

[Sampei]

My understanding is that reta has a greater binding affinity to GLP1 and GIP than tirz, in addition to the glucagon effect.



Semaglutide has a much greater binding affinity to GLP1 than tirzepatide and retatrutide. Theoretically then, one could add it in to a stack, but there are potential downsides to this and nothing in the literature that supports it. As @Ghoul stated, it's probably best to stick with a single compound for as long as its effective, which for most, should be indefinitely.

Peter Attia just did an AMA on GLP-1 agonists:

#320 – AMA 64: New insights on GLP-1 agonists (Ozempic, Wegovy, Mounjaro) - efficacy, benefits, risks, and considerations in the rapidly evolving weight-loss drug landscape - Peter Attia

"If you're taking these drugs, really, really pay attention to your protein consumption and your resistance training. . .that's obviously going to be an important part of being on the right side of that body composition curve.” — Peter Attia

peterattiamd.com

It's an interesting summary of the literature. The only point that I found particularly interesting was that there is no evidence (according to him) of any health benefit of a GLP1 agonist independent of the effect on body composition and metabolic improvements.

Some other points:
There's more safety data and nothing to suggest any issues with these compounds.
Most likely they should be taken indefinitely and there's no real observed reduction in efficacy, provided they aren't used intermittently.

He points to the SELECT trial which shows no weight regain with semaglutide when continued over the course of four years:

Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial - Nature Medicine

A prespecified analysis of the SELECT trial revealed that patients assigned to once-weekly subcutaneous semaglutide 2.4 mg lost significantly more weight than those receiving placebo and showed improvements in various anthropometric indices.

www.nature.com

There's some other stuff in there. It's a good listen if you have a subscription, but I think nothing that would surprise any of us.

What's the downside for example of using 0.5mg sema and 2.5mg of Tirz instead of maybe 1mg sema alone or 5mg Tirz alone?

 

[Sampei]

While much of the conversation surrounding these drugs focuses on their ability to suppress appetite, there is far more to their benefits. For those dedicated to optimizing their health and performance, tirzepatide and retatrutide offer a range of metabolic improvements that go beyond simple caloric restriction:

One of the most important effects of both tirzepatide and retatrutide is their role in improving insulin sensitivity, improved insulin sensitivity means better glucose uptake by muscle cells, leading to more efficient use of carbohydrates consumed post-exercise. This promotes faster recovery, greater glycogen replenishment, and enhanced muscle growth over time.

When the body is more sensitive to insulin, less of the hormone is required to keep blood sugar levels stable, which in turn reduces the risk of insulin resistance—a precursor to type 2 diabetes, this means that they can maintain higher energy levels during workouts and optimize muscle growth, while simultaneously reducing the risk of developing metabolic diseases.

In addition to enhancing insulin sensitivity, tirzepatide and retatrutide can significantly improve how the body processes and uses carbohydrates. Proper carbohydrate metabolism ensures that glucose is effectively used during exercise, delaying the onset of fatigue and allowing for longer, more intense sessions.

Moreover, post-exercise, efficient carbohydrate utilization aids in faster glycogen restoration in muscles, which is essential for recovery and the ability to perform optimally in subsequent workouts. This improvement in metabolic function means that the nutrients consumed are put to better use in fueling performance and muscle repair.

While the appetite-suppressing effects of tirzepatide and retatrutide are often highlighted, their impact on fat loss goes far beyond simply reducing caloric intake. These drugs can promote fat loss by improving overall metabolic health. By increasing insulin sensitivity and optimizing carbohydrate use, the body becomes more efficient at burning fat for energy, especially in a caloric deficit.

Moreover, these drugs may enhance the body's thermogenic capacity, further supporting fat loss. By increasing the energy expenditure even at rest, tirzepatide and retatrutide allow individuals to burn more calories throughout the day, contributing to a leaner physique over time.

Another key benefit of tirzepatide and retatrutide is their ability to reduce inflammation, which is crucial for both short-term performance and long-term health. Intense exercise, particularly in strength training or endurance sports, can lead to temporary increases in inflammation. While this is a natural part of the recovery process, chronic inflammation can hinder progress and increase the risk of injuries or illnesses.

By improving insulin sensitivity and stabilizing blood sugar levels, tirzepatide and retatrutide help reduce chronic inflammation. This supports faster recovery, improved joint health, and greater resilience in training. Additionally, these drugs have been shown to improve lipid profiles and cardiovascular health, reducing the risk of heart disease—a critical point for anyone involved in long-term bodybuilding.

These medications address the root causes of metabolic dysfunction, offering improvements in insulin sensitivity, carbohydrate utilization, fat loss, and inflammation management.

Sema has a great glycemic control too and it last 7 days something that Tirz can't do as it's 5 days half life really decrease the glycemic control on the last few days before the new dose is injected.

Diabetic friends report a lot better glycemic control and less need of insulin on semaglutide 1mg for example compared to Tirz at 7.5mg.

I believe we are forgetting about sema just because ppl are getting hyped up on Tirz and reta.

Sema price is super low at the moment compared even to Tirz and ppl in my opinion should first see if sema works for them before jumping on the tirz bandwagon

 

[Ghoul]

What's the downside for example of using 0.5mg sema and 2.5mg of Tirz instead of maybe 1mg sema alone or 5mg Tirz alone?

While part of me appreciates the willingness of people to make themselves human guinea pigs, once again my question, without any ability to quantify the risk of using these drugs together, what is it that the thoroughly tested, safe protocols of using one fails to provide? As eguberman pointed out, over 3+ years of use, they're more effective for 99.9% of users than could've been dreamed of a decade ago.

What are you gaining by trying random combinations of these molecules?

As far as specific risks, I could put theoretical ones out there, based on facts, but no one's out there conducting these experiments, since there's still so much to learn about the compounds individually.

 

[Musmadar]

Sema has a great glycemic control too and it last 7 days something that Tirz can't do as it's 5 days half life really decrease the glycemic control on the last few days before the new dose is injected.

Diabetic friends report a lot better glycemic control and less need of insulin on semaglutide 1mg for example compared to Tirz at 7.5mg.

I believe we are forgetting about sema just because ppl are getting hyped up on Tirz and reta.

Sema price is super low at the moment compared even to Tirz and ppl in my opinion should first see if sema works for them before jumping on the tirz bandwagon

Sema was the first reson for me to dive into the Glp's agonists waters....

After years of trying almost all the others insulin sensitivity related enhancers like:
metformin, chromium, berberine, cinamon, sibutramine, intermitent fasting....you name it,
when I tryed sema I could almost feel it's effect like a pumping effect to all my muscles and extremities....I knew it's something very good happening.

I didn't mind the little nausea either because of its others beneficial effects.

You are right: with the actual lowered price it's, maybe the best choice among the other glp's agonists.

 

[Ghoul]

Sema was the first reson for me to dive into the Glp's agonists waters....

After years of trying almost all the others insulin sensitivity related enhancers like:
metformin, chromium, berberine, cinamon, sibutramine, intermitent fasting....you name it,
when I tryed sema I could almost feel it's effect like a pumping effect to all my muscles and extremities....I knew it's something very good happening.

I didn't mind the little nausea either because of its others beneficial effects.

You are right: with the actual lowered price it's, maybe the best choice among the other glp's agonists.

Sema is incredible bang for the buck. About $2 a week at the max dose. I expect it'll mostly obsolete insulin sooner or later, except for Type 1 diabetics.

Tirz is a "premium" option in my mind, much gentler, though the majority of non weight related benefits really seem to require the 15mg dose, so it's $15-20 a week at the best current prices.

 

[Sampei]

Sema is incredible bang for the buck. About $2 a week at the max dose. I expect it'll mostly obsolete insulin sooner or later, except for Type 1 diabetics.

Tirz is a "premium" option in my mind, much gentler, though the majority of non weight related benefits really seem to require the 15mg dose, so it's $15-20 a week at the best current prices.

yes that's the issue for me with tirz, if you want to use it for weight loss and appetite suppression it works great (even better then sema 100% at least for me) but all those health benefit are not there unless you ramp up the dosage to 10/15mg and that means if I only want the health benefit and glycemic control I gotta destroy my appetite and slow my gastric emptiness at a level it's not good for bodybuilding.

Instead when I was using sema after a while at 1mg I had no side effect and had fantastic insuling sensitivity and glycemic control.

So for a bodybuilding perspective I believe semaglutide is a lot better IF one don't get nasty side effect from it.

For example I never got bad side from sema, tirzepatide on the other hand gave me a lot more sides at a 5mg dosage, acid reflux and burps first of all, something I never experienced on sema.

I'm off both right now but if I ever jump back on one for health benefit, it will be sema or a new one maybe that has no appetite suppression and gastric slowness but great glycemic control, it will probably never be synthetizes as what brings money is the appetite suppression for all the obese ppl around but if for once they will ever think of diabetic ppl and not only the fatties and how to milk them, a GLP able to give us insulin sensitivity plus other benefits without any impact on stomach/appetite, it will be the best substance ever for a BB.

 

[Trenbolonetax]

yes that's the issue for me with tirz, if you want to use it for weight loss and appetite suppression it works great (even better then sema 100% at least for me) but all those health benefit are not there unless you ramp up the dosage to 10/15mg and that means if I only want the health benefit and glycemic control I gotta destroy my appetite and slow my gastric emptiness at a level it's not good for bodybuilding.

Instead when I was using sema after a while at 1mg I had no side effect and had fantastic insuling sensitivity and glycemic control.

So for a bodybuilding perspective I believe semaglutide is a lot better IF one don't get nasty side effect from it.

For example I never got bad side from sema, tirzepatide on the other hand gave me a lot more sides at a 5mg dosage, acid reflux and burps first of all, something I never experienced on sema.

I'm off both right now but if I ever jump back on one for health benefit, it will be sema or a new one maybe that has no appetite suppression and gastric slowness but great glycemic control, it will probably never be synthetizes as what brings money is the appetite suppression for all the obese ppl around but if for once they will ever think of diabetic ppl and not only the fatties and how to milk them, a GLP able to give us insulin sensitivity plus other benefits without any impact on stomach/appetite, it will be the best substance ever for a BB.

I’m prettty surprised that folks are getting better glycemic control with sema than tirz. I’ve never tried sema, and I’m going to ask a pretty stupid question / comment I hope to be corrected as I sit in the toilet.

Isn’t the GIP component of Tirz responsible for most of the BG lowering? I need to find the study, but it wasn’t so much the increase in insulin secretion as it was the rate of insulin independent glucose clearance.

At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg (84.0%) (P < .05). There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1 mg (5.1%) (P < .05). Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C–peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P < .05). HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile.

Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUCinsulin divided by AUCglucose. Insulin sensitivity (SI) and glucose effectiveness (SG) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUCinsulin versus AUCglucose was increased 7-fold by tirzepatide from 0.014 ± 0.004 with glucose only to 0.099 ± 0.016 (P < 0.001). SI was not affected by tirzepatide, whereas SG was increased by 78% (P < 0.001). The increase in SG contributed to an increase in KG by 74 ± 4% after glucose alone and by 67 ± 8% after glucose+ tirzepatide, whereas contribution by SI times AUCinsulin insulin (i.e., disposition index) was 26 ± 4% and 33 ± 8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.

 

[Ghoul]

yes that's the issue for me with tirz, if you want to use it for weight loss and appetite suppression it works great (even better then sema 100% at least for me) but all those health benefit are not there unless you ramp up the dosage to 10/15mg and that means if I only want the health benefit and glycemic control I gotta destroy my appetite and slow my gastric emptiness at a level it's not good for bodybuilding.

Instead when I was using sema after a while at 1mg I had no side effect and had fantastic insuling sensitivity and glycemic control.

So for a bodybuilding perspective I believe semaglutide is a lot better IF one don't get nasty side effect from it.

For example I never got bad side from sema, tirzepatide on the other hand gave me a lot more sides at a 5mg dosage, acid reflux and burps first of all, something I never experienced on sema.

I'm off both right now but if I ever jump back on one for health benefit, it will be sema or a new one maybe that has no appetite suppression and gastric slowness but great glycemic control, it will probably never be synthetizes as what brings money is the appetite suppression for all the obese ppl around but if for once they will ever think of diabetic ppl and not only the fatties and how to milk them, a GLP able to give us insulin sensitivity plus other benefits without any impact on stomach/appetite, it will be the best substance ever for a BB.

You could try Liraglutide. I believe it's as effective for insulin sensitivity but only 1/3 as strong for weight loss as Sema.

Daily shots though, and expensive. Not sure why QSC doesn't offer this and other suppliers do.

 

[Sampei]

You could try Liraglutide. I believe it's as effective for insulin sensitivity but only 1/3 as strong for weight loss as Sema.

Daily shots though, and expensive. Not sure why QSC doesn't offer this and other suppliers do.

Fuck me, Daily shot I ain't doing that. I'm already shooting GH ED and it's a chore.

But thanks for the suggestion!

 

[Sampei]

I’m prettty surprised that folks are getting better glycemic control with sema than tirz. I’ve never tried sema, and I’m going to ask a pretty stupid question / comment I hope to be corrected as I sit in the toilet.

Isn’t the GIP component of Tirz responsible for most of the BG lowering? I need to find the study, but it wasn’t so much the increase in insulin secretion as it was the rate of insulin independent glucose clearance.

I don't know, maybe I haven't stayed enough time with tirzepatide because it wrecked my appetite so much I had to stop it but a friend of mine that is diabetic report he has a lot better glycemic control with 1mg of sema vs 7.5mg of Tirz and he has a CGM so he can really tell what is doing what plus his insulin use it's a lot less with sema.
What he says is that sema as well keeps him well for 7 days until the new shot but tirz halflife of 5 days is bad for him on the last few days he has to increase insulin a lot more because tirz become a lot less effective.

So probably better shoot 2x a week Tirz Vs once a week sema.

 

[Trenbolonetax]

I don't know, maybe I haven't stayed enough time with tirzepatide because it wrecked my appetite so much I had to stop it but a friend of mine that is diabetic report he has a lot better glycemic control with 1mg of sema vs 7.5mg of Tirz and he has a CGM so he can really tell what is doing what plus his insulin use it's a lot less with sema.
What he says is that sema as well keeps him well for 7 days until the new shot but tirz halflife of 5 days is bad for him on the last few days he has to increase insulin a lot more because tirz become a lot less effective.

So probably better shoot 2x a week Tirz Vs once a week sema.

He’s a type 2 on insulin, or type 1 insulin dependent?

I’m not discounting your experience or his, I’m sincerely trying to figure out really how the fuck the all work, especially when you start layering in other mechanisms than GLP1.

For me, it’s not intuitive that adding glucagon action would help BG control (Reta), but would certainly help fat mobilization and loss.

I’ve gone round and round and round convincing myself every single way lol.

The only experience and data I have to draw in from a BG lowering perspective is 15mg of tirz on 16 and 27iu of GH. My fasting insulin came back 2.5, and A1C 5.1. During this 3 month look back, I ate over 100 pints of ice cream…

I also understand these are context dependent. I’ve seen some information suggesting that the long term of activation of GIPR can help store adipose tissue in a fed state, but liberate in a fasted state…so interesting.

 

[Sampei]

He’s a type 2 on insulin, or type 1 insulin dependent?

I’m not discounting your experience or his, I’m sincerely trying to figure out really how the fuck the all work, especially when you start layering in other mechanisms than GLP1.

For me, it’s not intuitive that adding glucagon action would help BG control (Reta), but would certainly help fat mobilization and loss.

I’ve gone round and round and round convincing myself every single way lol.

The only experience and data I have to draw in from a BG lowering perspective is 15mg of tirz on 16 and 27iu of GH. My fasting insulin came back 2.5, and A1C 5.1. During this 3 month look back, I ate over 100 pints of ice cream…

I also understand these are context dependent. I’ve seen some information suggesting that the long term of activation of GIPR can help store adipose tissue in a fed state, but liberate in a fasted state…so interesting.

How could you eat on 15mg Tirz???

 

[Sampei]

He’s a type 2 on insulin, or type 1 insulin dependent?

I’m not discounting your experience or his, I’m sincerely trying to figure out really how the fuck the all work, especially when you start layering in other mechanisms than GLP1.

For me, it’s not intuitive that adding glucagon action would help BG control (Reta), but would certainly help fat mobilization and loss.

I’ve gone round and round and round convincing myself every single way lol.

The only experience and data I have to draw in from a BG lowering perspective is 15mg of tirz on 16 and 27iu of GH. My fasting insulin came back 2.5, and A1C 5.1. During this 3 month look back, I ate over 100 pints of ice cream…

I also understand these are context dependent. I’ve seen some information suggesting that the long term of activation of GIPR can help store adipose tissue in a fed state, but liberate in a fasted state…so interesting.

He is type2

 

[Ghoul]

How could you eat on 15mg Tirz???

Remember it only feels like an appetite suppressant until you hit the weight homeostasis for that dose.

It's not a diet pill that reduces appetite regardless of weight.

If the room temperature (weight) and the thermostat (glp) are matched, nothing is happening. That's what a maintainance dose is. You feel normal. There's no appetite suppression. Drop more weight and appetite fires up to bring weight back up. Gain weight, and appetite suppression returns.

GLPs turn the thermostat down.

This is the mechanism of action people can't seem to grasp. It's not even specific to the drug, it's the body's natural weight regulation system.

But in the absence of this knowledge, that the body seeks to maintain energy homeostasis, and weight issues, underweight and overweight are usually attributable to a malfunction in this system, it's a paradigm shift in thinking that's going to be difficult to grasp.