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c/retatrutide·posted 2 years ago by u/andres_sorensen

unpopular opinion: most of what gets said here about glucagon is guesswork

Trial Data Long Haul ×8 Cold Box ×3 Well Actually ×1

unpopular opinion: most of what gets said here about glucagon is guesswork, and I am aware this is a minority view on this board.

Where the evidence actually stands, since every thread here assumes a different answer.

Phase 2 reported a large mean body weight change at 48 weeks across a few hundred participants with a slow, protocol-driven escalation. The effect size was striking. The confidence intervals were wide, the population was small, and the duration was under a year.

Phase 3 is running. Until it reports, everything else — including the ranking arguments this board loves — is extrapolation from a small study. That is not a criticism of the compound; it is a description of the evidence.

What the glucagon arm is doing, as best anyone can say from public data.

GLP-1 and GIP agonism cover appetite and insulin secretion in ways that are now reasonably well characterised. Glucagon receptor agonism is the third leg and it is associated with increased energy expenditure and with effects on hepatic fat.

Mechanistically that is why this compound reads as a different proposition rather than a stronger version of a dual agonist. Clinically, the size and durability of that difference in humans is precisely what is not yet established, and anyone telling you otherwise is filling a gap with confidence.

The standing caveat, written out properly because it keeps getting compressed into a footnote.

Nothing containing this compound is approved by any regulator. Research-use-only material is not approved for human use. That is not a legal formality on this board — it is why there is so little independent data, why the escalation schedules people post are invented, and why nobody here can answer a dosing question.

What this board can usefully do is read the published trials carefully, log independent purity results, and be honest about how thin the evidence base is. Everything else belongs somewhere with a clinician in it.

Research-use-only material is not approved for human use and nothing here should be read as a recommendation to use it.

9,484 up / 2,117 down82% upvoted34 commentsid 1bls2q6 Oct 2023

34 comments

29 in this archive, depth 5

best — the order this archive was captured in

u/ledger_modMOD707 points·2 years ago

Removed the escalation schedule. There is no published protocol for members to follow and inventing one here is exactly what this board does not do.

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u/hugo_pires493 points·2 years ago

Increases in heart rate have been reported across this receptor class. The magnitude and clinical significance are exactly what phase 3 is powered to establish.

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u/ferran_krastev174 points·2 years ago

small trial, big effect, wide error bars

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u/andres_sorensenOP109 points·2 years ago·edited

Correction: TRIUMPH is the phase 3 programme. The number you are quoting is from the phase 2 readout, which is a different trial.

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u/incretin_ivypharmacology66 points·2 years ago

Correction: TRIUMPH is the phase 3 programme.

Adding the standing caveat: none of this is approved anywhere and research material is not for human use.

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u/devils_advocate_d0 points·2 years ago

Nothing containing this compound is approved anywhere. Research-use-only material is not approved for human use, and that is a statement of fact rather than a disclaimer.

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u/nikhil_lindqvist0 points·2 years ago

Nothing containing this compound is approved anywhere.

This is the sentence the rest of the board should read first. Phase 2 is not a label.

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u/cagrilintide_enthusiast1 point·2 years ago·edited

Glucagon receptor agonism is associated with increased energy expenditure and with hepatic effects. That is a mechanistic story with strong preclinical support and limited phase 2 human data.

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u/cormac_roos1 point·2 years ago·edited

Push back: quoting the phase 2 headline as an expected outcome is not a fair reading of a small trial with wide intervals.

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u/employer_carveout276 points·2 years ago

The constipation profile felt different rather than worse. Hard to describe and impossible to quantify, so take it as an impression.

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u/careful_gradient_again192 points·2 years ago

Right, and it bears repeating that nothing here is approved anywhere and research material is not for human use.

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u/ledger_modmod · vetting313 points·2 years ago

phase 2 data only, and people quote it like it is a label

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u/farid_molnar77 points·2 years ago·edited

Yes — the glucagon arm is what makes it a different proposition rather than a stronger version of the others.

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u/reta_and_regret240 points·2 years ago

Is that the 48-week figure or an earlier readout?

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u/andres_sorensenOP143 points·2 years ago·edited

Has anyone posted an independent test on this compound recently?

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u/ferran_krastev107 points·2 years ago

Which phase 2 arm are you quoting, and at what week?

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u/nikhil_lindqvist-33 points·2 years ago

It is a triple agonist at the GLP-1, GIP and glucagon receptors. The glucagon arm is the genuinely novel component and it is the one with the least human outcome data behind it.

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u/nikhil_lindqvist124 points·2 years ago

Read the phase 2 paper twice before ordering anything. Recommend that to anyone in this board: the error bars are the interesting part.

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u/isabela_nilsen61 points·2 years ago

Read the phase 2 paper twice before ordering anything.

Agreed, and the glucagon arm is exactly why the comparison threads do not work.

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u/rui_only_ro21 points·2 years ago

a lot of the confident posting here is extrapolation

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u/aa_analysis_andy27 points·2 years ago·edited

the energy-expenditure story is mechanistically interesting and clinically unproven

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u/andres_sorensenOP33 points·2 years ago

Small fix — three receptors, not two. GLP-1, GIP and glucagon, and the third one is the reason this compound gets its own board.

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u/cagrilintide_enthusiast140 points·2 years ago

Phase 2 estimates effect and finds a dose range. Phase 3 estimates it precisely in a bigger population and catches what phase 2 was too small to see. Treating them as the same tier of evidence is the recurring error here.

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u/endotoxin_elliemicro97 points·2 years ago

Watched heart rate on a wearable across twelve weeks because the threads said to. It moved a little and I have no idea whether that means anything.

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u/careful_gradient_notes166 points·2 years ago

dose escalation in the trials was slow for a reason

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u/ismael_eriksen36 points·2 years ago

research-use-only material is not approved for human use, full stop

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u/hassan_nilsen11 points·2 years ago

the glucagon component is why the metabolic story reads differently

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About c/retatrutide

Retatrutide: GIP/GLP-1/glucagon triple agonism, the TRIUMPH programme, and the fact that most people discussing it are handling research-grade material with no human-use approval anywhere. Dose-response, heart-rate signal, and the unusually steep phase-2 weight curves get argued about here weekly.

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