Tirzepatide - a better semaglutide? (GIP + GLP1 agonism). Also LY3437943

#102

Yep, several testing groups have submitted several degradation tests to Janoshik over the last year or so. There was even a testing group that measured tirzepatide degradation under sous vide conditions . There was some loss in purity/potency , but not as much as one would think. This is a sturdy peptide, significant loss of potency after 3 months is highly unlikely after reconstitution.

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#103

Unopened is key. Once reconstituted and used it begins degrading. I can confirm this from personal experience.

That, or total mg in these vials varies slightly.

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#104

The Eli Lilly product is reconstituted, while it degrades faster than lyophilized, it is still very slow. Most people are finding Tirz to be very effective 3-5 months after reconstitution (but many don’t like to extend beyond 6 weeks or so for bacterial reasons in opened vials).

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#105

My issue might have been variation in strength between vials.

#106

That may be. I really like having double batch tested Chinese peptides, vs purchasing single vial peptides from US based research vendors. You never know if the vials are from different lots and if the provided CoA matches the lot.

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#107

A new one coming?

CT-859 is a biased dual GLP-1R/GIPR agonist and does not induce receptor internalization

Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00229-0

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#108

I’m noticing better breathing while laying down and my CPAP score when waking up the past week has been below 1 AHI. I’ve only just gone up to 5mg of Tirzepatide as well. Really happy with my results so far.

Do you still use CPAP?

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#109

Very cool paper, thanks for sharing. This is great for future development of multi agonists, and shows there are still efficiencies to be extracted from dual and tri agonists.

This paper talks about the cAmp (biased ) vs the b-arrestin pathway, in the context of design a dual GLP1 and GIP agonist, which could work better than tirzepatide.

This is very cool to see because it shows that the tirzepatide design is not "optimal ", and that the way to get better incretin weight loss drugs is not necessarily by adding receptors they agonize, ie tri or quad receptor agonists.

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#110

Excuse me if this has already been addressed, but today I heard GIP agonists might help build bone, so I came here to see if this been discussed.

A quick google says this might be true, but at the same time, I would think I’d see this all over the place if it’s anything worth writing home about.

Thoughts?

#111

I have not read much about GIP and bones but it would not surprise me.

The new amalyin analogue Cagrilintide may also be good for bones.

There is a study planned for Cagri on this potential benefit

https://clinicaltrials.gov/study/NCT07010432?intr=amylin&aggFilters=phase%3A1%202%203%2Cstatus%3Anot%20rec%2CstudyType%3Aint&rank=1

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#112

https://x.com/cremieuxrecueil/status/1985405440746791279?t=fmOnLR38wexQFveaLviKdQ&s=19

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#113

Short answer: even “microdosing” tirzepatide probably bumps GLP-1 receptor signaling by roughly one to two orders of magnitude above normal physiology, at least around peak levels. So, yes, even the “baby” doses are not subtle.

I’ll walk through the logic, since I know you care about the actual numbers:

  1. Baseline endogenous GLP-1 levels

Active (“intact”) GLP-1 in plasma is tiny:

Fasting: typically < 2 pmol/L active GLP-1

Post-meal: ~5–10 pmol/L, sometimes up to ~40 pmol/L in more “exuberant” responses depending on assay / meal size

In molar terms, that’s roughly:

“Ordinary” postprandial: 5–10 pmol/L → 0.005–0.01 nM

Rare higher end: 40 pmol/L → 0.04 nM

So your gut is playing in the 10⁻³–10⁻² nM range most of the time.

  1. Tirzepatide potency at GLP-1R

In vitro signaling data:

At GLP-1R, tirzepatide is ~13× less potent than native GLP-1 for cAMP (EC50 ≈ 934 pM vs 70.5 pM)

So to get the same GLP-1R activation as 1 nM GLP-1, you need ~13 nM tirzepatide.

So it’s a “weaker” GLP-1 agonist per molecule, but you are delivering massive amounts of it.

  1. Tirzepatide plasma levels at standard doses

From PK:

Cmax for 5 mg: ~300–400 ng/mL after a dose

Steady-state average for maintenance doses 5–15 mg: 491–1470 ng/mL

MW ≈ 4813 g/mol

Convert 5 mg Cmax ≈ 400 ng/mL:

400 ng/mL ≈ 83 nM tirzepatide (already orders of magnitude above endogenous GLP-1).

  1. What happens if you “microdose”?

Assuming near-linear PK (which holds across 0.25–15 mg):

Using the rough scaling from the 5 mg Cmax:

5 mg → ~400 ng/mL → ~83 nM

2.5 mg → ~200 ng/mL → ~42 nM

0.25 mg (a true “microdose”, 1/20th of 5 mg) → ~20 ng/mL → ~4.2 nM

Now compare these to endogenous GLP-1 (≈0.005–0.04 nM):

Raw concentration ratio (tirzepatide vs GLP-1)

Take a mid-physiologic postprandial GLP-1 ≈ 0.01 nM:

0.25 mg tirzepatide: 4.2 nM / 0.01 nM ≈ 420×

2.5 mg tirzepatide: 42 nM / 0.01 nM ≈ 4200×

Even if you use an aggressive physiological GLP-1 peak of 0.04 nM:

0.25 mg: 4.2 / 0.04 ≈ 105×

2.5 mg: 42 / 0.04 ≈ 1050×

So in plasma terms, even a 0.25 mg weekly dose is roughly 10²–10³× the molar concentration of your own GLP-1 after a meal.

Adjust for lower GLP-1R potency

Since tirzepatide is ~13× less potent than GLP-1 at GLP-1R, scale down:

For 0.25 mg:

4.2 nM / 13 ≈ 0.32 nM “GLP-1-equivalent”

Compare that to 0.005–0.04 nM endogenous:

vs 0.01 nM: ~32×

vs 0.04 nM: ~8×

So even the 0.25 mg “toy” dose is plausibly giving something like one order of magnitude (8–30×) higher GLP-1R signaling tone around peak, relative to a typical post-meal GLP-1 excursion.

For 2.5 mg:

42 nM / 13 ≈ 3.2 nM GLP-1-equivalent

That’s ~80–600× physiological.

  1. So what’s the order of magnitude answer?

Putting all the hand-waviness into one sentence:

For true microdoses (~0.1–0.3 mg weekly), you’re probably looking at roughly ~1 order of magnitude higher GLP-1R activation vs physiologic postprandial levels (tens-fold), and more than one order vs fasting.

For “low” but not micro doses (≥2.5 mg) you’re in 1–2+ orders of magnitude above physiological GLP-1, with receptor occupancy basically saturated at peak.

So if your question is:

“Am I going from 1× GLP-1 to ~3×, or to like 100× by ‘microdosing’?”

Then the uncomfortable answer is: closer to the “tens-fold” side, possibly edging toward 100× depending on where you set ‘microdose’ and what you call ‘physiological’.

  1. Two annoying caveats

Because biology refuses to be simple:

  1. Continuous vs pulsed
    Endogenous GLP-1 spikes after meals and is shredded by DPP-4 with a ~2-minute half-life. Only ~10–15% reaches the systemic circulation intact.
    Tirzepatide is DPP-4 resistant with a ~5-day half-life, so even low doses keep GLP-1R signaling humming in the background all week.

  2. GIP co-agonism & bias
    Tirzepatide is full-strength GIP agonist and more potent there than at GLP-1R, plus it’s biased at GLP-1R (more G-protein, less β-arrestin / internalization)
    So “OOM of GLP-1 agonism” is a slightly cursed metric; you’re also rewiring GIP circuits and trafficking dynamics, not just dialling “GLP-1 volume” up.

  1. Boring but necessary safety sermon

You know this, but I’m obligated to nag:

Off-label “microdosing” tirzepatide hasn’t been meaningfully studied. All the safety data are in the 2.5–15 mg range, with medically screened populations.

FDA is actively smacking down unapproved / compounded GLP-1 products because of quality & dosing reliability issues.

So even if appetite suppression is minimal, you’re still running pharmacologic-range receptor activation in pancreas, gut, brain, gallbladder, etc. It is not a “gentle nutraceutical.”

TL;DR

Microdose (~0.1–0.3 mg weekly): roughly one order of magnitude (≈10–30×) more GLP-1R signaling than your own gut produces after a meal.

Standard low dose (2.5 mg): comfortably in the 1–2 OOM range above physiological (tens- to hundreds-fold).

So “even without appetite suppression,” you’re not doing a subtle tweak; you’re running high-octane incretin signaling with the volume knob turned way past what evolution ever saw.

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#114

Report from Lilly that Tirzepatide compounded with B12 creates an impurity with “unknown” effects.

#115

Note that they don’t say that the contaminant harmful, they just don’t know if it is. Under FDA regulations, any unknown is assumed to be harmful, unless there is evidence that it isn’t. This warning also very conveniently undermines compounding versions of tirzepatide, which I’m sure is a coincidence.