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 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.
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
What would genuinely help is knowing what the phase 2 dropout pattern implies about how the phase 3 tolerability will read. If the honest answer is that nobody knows, that is a useful answer and I would rather have it.
tom_AK said: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.
Right, and the exception is worth naming rather than left implied, because the exception is where people get into trouble.
tom_AK said: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.
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.
Ask again with the specifics and you will get a better answer than this one.
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Browse GL BiochemShort answer first, then the reasoning. 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.
Dr.ObesityMed said:Right, and the exception is worth naming rather than left implied, because the exception is where people get into trouble.
Second this.