Follow-up: Retatrutide phase 2 in type 2 diabetes: the Lancet paper

Retatrutide phase 2 in type 2 diabetes: the Lancet paper Writing it up because I had to work it out twice and would rather nobody else did.

I have seen SURPASS-4 (Lancet, 2021) cited in support of a claim I do not think it supports, twice this month, so I would like to work through what it actually shows.

My reading is that the trial is sound for its own question and is being stretched to answer a different one. I might be wrong about that, which is why this is a topic rather than a correction.

What I would like from this discussion: someone who disagrees with me to say why, with the section of the paper they are relying on.

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

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.

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.

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.

Worth separating two things that the opening post runs together.

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.

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.