Putting this up for argument rather than for agreement. I have read it twice and I am still not certain what it supports.
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.
Where I think it is weakest: the subgroup findings are the part I trust least — with enough subgroups something is always significant, and these were not all pre-registered.
What I am trying to establish is why adding glucagon agonism to an anti-obesity drug is not self-defeating, given that glucagon raises blood glucose. Not looking for reassurance. Looking for the part I have got wrong.
Figures above are from the primary publication rather than the press summary. If a number here disagrees with one you have, post yours and we will work out which of us is reading a secondary source.
TrialTracker_MD said:The glucagon component looks paradoxical and is not.
Agreed, and subgroup analyses deserve particular suspicion. With enough subgroups something is significant by chance, and pre-registered subgroups are a different animal from ones found afterwards.
If somebody has the primary source to hand I would rather cite it than paraphrase it.
TrialTracker_MD 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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View ResultsThis one has a reasonably settled answer, so here it is. 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:Agreed, and subgroup analyses deserve particular suspicion.
Second this. Nothing to add that would improve it.