Writing this once so I can stop repeating it across threads. It is about retatrutide, and it is deliberately narrow — everything I am not confident about is marked as such.
What is actually established
The glucagon component looks paradoxical and is not. Glucagon receptor agonism raises energy expenditure and drives hepatic fatty-acid oxidation, and its hyperglycaemic tendency is offset by the GLP-1 arm's insulin secretagogue effect. Net result: intake down from GLP-1/GIP, expenditure up from glucagon, glycaemia neutral or improved. It is a balancing act, and it is why the liver-fat results are the most interesting part of the dataset.
The condition it depends on
Phase 2 tolerability figures rarely survive contact with phase 3 scale. Triple agonism means three receptor systems generating adverse events, and the dropout column is the one I would read first when the larger trials report.
The practical version
For anyone tracking the class: GLP-1 alone gets you appetite, GLP-1 plus GIP adds tolerability and lipid handling, and adding glucagon adds expenditure and liver-fat reduction. Each addition also adds a receptor system that can generate side effects.
What I am not sure about
So the question, as narrowly as I can put it: what the phase 2 dropout pattern implies about how the phase 3 tolerability will read. I have searched first, so if this is covered somewhere point me at it and I will read it.
Dr.GastroMayo said:The glucagon component looks paradoxical and is not.
No disagreement, though the timescale matters more than the mechanism here. Most of what looks like a difference in kind turns out to be a difference in how long somebody waited.
Dr.GastroMayo said:The glucagon component looks paradoxical and is not.
I would rather people stopped quoting the 24% as if it were a licensed outcome. It is a phase 2 result in a few hundred participants with no cardiovascular endpoint and no long-term safety data, and this board has a habit of treating pipeline numbers as settled.
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Browse GL BiochemAnswering the narrow version, because the broad one does not have a single answer. The phase 2 numbers were about 24% mean weight loss at 48 weeks on the top dose, with the curve still descending at the end of the study. A curve that has not flattened is a real finding, but it also means the true plateau is unknown, and phase 2 populations are small and selected.
PurityPaulOR said:No disagreement, though the timescale matters more than the mechanism here.
Can confirm. Same sequence, different timescale. I had assumed I was the exception until I read this.