Revisiting: Hepatic effects of glucagon receptor agonism: the mechanistic worry

Revisiting: Hepatic effects of glucagon receptor agonism: the mechanistic worry Writing it up because I had to work it out twice and would rather nobody else did.

Session topic: SURMOUNT-OSA (N Engl J Med, 2024). Please read it before posting; the discussion is much better when everyone has.

The question I would like us to start with is what the trial set out to estimate, rather than what it found. Once that is on the table we can talk about whether the design could have answered it, and only then about the numbers.

Specific things I would like covered: the population and how far it generalises, how discontinuation was handled, whether the comparator was a fair one, and what the absolute rather than relative effect looks like.

I will summarise at the end and the summary will feed the relevant digest page.

Hepatic effects: glucagon receptor agonism promotes hepatic fat oxidation, which is mechanistically plausible for benefit in metabolic liver disease. Whether that translates to improved clinical outcomes is being tested in phase 2 work.

This follows post #2 rather than contradicting it.

What we do not know about retatrutide, listed explicitly: long-term safety, real-world response rates, the dose response in diverse populations, whether the heart-rate signal persists or attenuates, durability of effect on withdrawal, efficacy in comorbidities beyond obesity.

On the opening post — agreed on the reasoning, with one qualification.

Dose escalation in the published trials: the protocols started at lower doses and escalated by defined steps. The step sizes are documented and they may or may not match what someone self-prescribing would choose.

post #5 answers the question as asked. The question underneath it is different.

Triple agonism: is the effect additive, synergistic, or neither? A phase 2 comparison of tirzepatide (dual) to retatrutide (triple) would answer that question. The published data does not include such a direct comparison.

Mass and identity: a report on retatrutide should state the mass detected by LC-MS, not assume a theoretical mass. The theoretical mass is not published in peer-reviewed literature for retatrutide at present.

I disagree with the reply above, and I think the disagreement is substantive rather than terminological.

The distinction being drawn does not survive when you look at the published data for this specific question. I would be glad to be shown wrong on this, because the version I am arguing against is more convenient.

Why this subcategory is more cautious than elsewhere: retatrutide is investigational, phase 3 is ongoing, and the heart-rate signal in phase 2 is not negligible. Caution is proportionate to the evidence status.

How to read phase 2 without treating it as phase 3: phase 2 establishes that a dose range produces an effect and is tolerable enough to justify large trials. It does not establish safety, durability, or whether real humans differ from the selected population.

post #10 answers the question as asked. The question underneath it is different.

Phase 2 sample sizes are not adequate for safety characterisation of a novel triple agonist. Phase 3 is where that question gets answered. Using phase 2 results to make claims about safety profile is using the trial for a purpose it was not designed for.

I disagree with the reply above, and I think the disagreement is substantive rather than terminological.

The distinction being drawn does not survive when you look at the published data for this specific question. I would be glad to be shown wrong on this, because the version I am arguing against is more convenient.

TRIUMPH is phase 3 and it is ongoing. No phase 3 results exist. Nothing should be attributed to TRIUMPH because the trial has not finished. When it does, this page will update.