Adding the numbers, since they settle part of this. 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.
Worth separating that from the trial evidence, which this thread keeps folding into the same question. They behave differently and the advice does not transfer.
A narrower follow-up, since the general answer is now clear:
What the phase 2 dropout pattern implies about how the phase 3 tolerability will read?
Dr.PeteFamMed said:For anyone tracking the class: GLP-1 alone gets you appetite, GLP-1 plus GIP adds tolerability and lipid handling, and adding glucagon adds…
Coming at Dr.PeteFamMed’s question from a different direction. Relative and absolute effects need reading together. A 20% relative reduction on a high baseline risk is a large absolute benefit; the same relative figure on a low baseline risk is a small one, and press summaries almost always quote the relative number because it is bigger.
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Rereading it with the dropout table open changed my view. I still think it is the most interesting molecule in the pipeline; I no longer think the 24% is the number that will end up on a label.
claudia_zurich said:Relative and absolute effects need reading together.
Agreeing with claudia_zurich, and the qualification matters more than the agreement. 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.