Posting this under the heading it deserves: Hepatic effects of glucagon receptor agonism: the mechanistic worry Everything below is what sits behind that.
Something about hepatic effects of glucagon receptor does not reconcile and I would like a second pair of eyes before I decide which half is wrong.
Two sources, both reputable, giving figures that cannot both be right unless they are measuring different quantities. My suspicion is that they are, and I cannot see how.
Triple agonism at GLP-1, GIP and glucagon receptors is the defining feature and the glucagon limb is the one people find counter-intuitive. It raises energy expenditure and promotes hepatic fat oxidation, and the incretin limbs offset the glycaemic consequence.
Happy to be corrected if someone holds better data than mine.
Whether triple agonism is additive or synergistic is an open question and the published work does not answer it. A phase 2 trial without a dual-agonist comparator arm cannot distinguish the two.
The claim is narrower than it sounds, and deliberately so.
Heart rate increased in a dose-dependent way in the phase 2 work. That is not a footnote — it is one of the specific things phase 3 exists to characterise, and it is why this subcategory is written more cautiously than the others.
I have written this out at length because the short version keeps being misread.
Discontinuation for adverse effects in phase 2 was not negligible at the higher doses. That figure belongs next to the efficacy figure whenever the efficacy figure is quoted.
I have seen it go both ways, which is why I hedge.
Glucagon receptor agonism seems paradoxical in a weight-loss compound because glucagon raises blood glucose. The paradox resolves because glucagon agonism also increases energy expenditure and promotes hepatic fat oxidation, and the incretin components offset the glycaemic effect. In diabetes trials, HbA1c improved rather than worsened.
That is the version I would defend. It is not the version I started with.
Heart rate increased in a dose-dependent way in the phase 2 work. That is not a footnote — it is one of the specific things phase 3 exists to characterise, and it is why this subcategory is written more cautiously than the others.
It is one reading of the data and not the only reasonable one.
Read the full topic (57 posts)
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Retatrutide phase 2 in type 2 diabetes: the Lancet paper
On the subject in the title: Retatrutide phase 2 in type 2 diabetes: the Lancet paper Working notes rather than a conclusion. Asking about retatrutide phase 2 in type on behalf of the question I keep seeing…
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+12 | 16 | 50k | 12mo |
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The retatrutide phase 2 obesity paper, read closely
Posting this under the heading it deserves: The retatrutide phase 2 obesity paper, read closely Everything below is what sits behind that. Retatrutide phase 2 obesity paper, from the point of view of someone…
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2 | 65k | 10mo | |
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Retatrutide dose escalation in the published trials
Posting this under the heading it deserves: Retatrutide dose escalation in the published trials Everything below is what sits behind that. An honest uncertainty about retatrutide dose escalation rather than a…
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+149 | 159 | 30k | 15mo |
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Triple agonism: additive, synergistic, or neither?
The question in the title: Triple agonism: additive, synergistic, or neither? I will give what I have already checked below so nobody repeats it. Asking about triple agonism on behalf of the question I keep…
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+71 | 80 | 38k | 11mo |
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[2026 update] What we do not know about retatrutide, listed explicitly
What we do not know about retatrutide, listed explicitly — that is the question, and I have not found it answered plainly anywhere I have looked. Putting the numbers in the first post, because a question…
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+79 | 83 | 952 | 11mo |
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Follow-up: The retatrutide phase 2 obesity paper, read closely
The retatrutide phase 2 obesity paper, read closely — setting out what I have, and where I think it stops being reliable. A follow-up question about retatrutide phase 2 obesity paper that I did not know to…
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+19 | 23 | 16k | 2d |
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Coming back to: Why a preprint's supplementary material is often the best part
Why a preprint's supplementary material is often the best part — that is the question, and I have not found it answered plainly anywhere I have looked. A question about how this site should cite something…
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+109 | 116 | 36k | 2d |
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Journal club: STEP-HFpEF and symptom endpoints — a second dataset
On the subject in the title: Journal club: STEP-HFpEF and symptom endpoints — a second dataset Working notes rather than a conclusion. Posting a small dataset on step-hfpef and symptom endpoints. It is mine,…
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+11 | 15 | 4k | 10mo |
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Second pass at: Retatrutide mass and identity: what a report should show
Second pass at: Retatrutide mass and identity: what a report should show — setting out what I have, and where I think it stops being reliable. Two things I would like separated before anyone answers on…
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+65 | 71 | 4.6k | 13mo |
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Journal club: STEP 3 and the intensive behavioural therapy floor
Posting this under the heading it deserves: Journal club: STEP 3 and the intensive behavioural therapy floor Everything below is what sits behind that. Two things I would like separated before anyone answers…
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+6 | 10 | 13k | 28d |