This is the version of the explanation I wish somebody had given me, written down before I forget what confused me. It is about retatrutide, and it is deliberately narrow — everything I am not confident about is marked as such.
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.
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.
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.
The bit I cannot resolve on my own is what the phase 2 dropout pattern implies about how the phase 3 tolerability will read. Not looking for reassurance. Looking for the part I have got wrong.
wanda_boise said:The glucagon component looks paradoxical and is not.
Correct as far as it goes. The part it does not cover is what to do when the honest answer is "not enough data", which is more often than anyone likes.
Correct me if the detail matters more than I have assumed.
wanda_boise 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 BiochemTaking the question as asked, rather than the general version of it. 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.
Dr.ObesityLA said:The part it does not cover is what to do when the honest answer is "not enough data", which is more often than anyone likes.
Same pattern here, and in the same order. The detail I would add is minor and it is already implied above.