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.
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 I actually want to know is why adding glucagon agonism to an anti-obesity drug is not self-defeating, given that glucagon raises blood glucose. Numbers rather than impressions, if you have them.
Dr.GastroMayo 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.
True, and it depends on a baseline nobody has stated. Without knowing where someone started, the same number can be an excellent result or a disappointing one.
Dr.GastroMayo 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.
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Browse GL BiochemTaking the question as asked, rather than the general version of it. 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.
PurityPaulOR said:True, and it depends on a baseline nobody has stated.
Adding a me-too, because a thread of one person's experience is not much use. I had assumed I was the exception until I read this.