Why a glucagon receptor agonist in a weight-loss compound is not a contradiction — one year on

Why a glucagon receptor agonist in a weight-loss compound is not a contradiction — one year on — that is the question, and I have not found it answered plainly anywhere I have looked.

The question about glucagon receptor agonist that I actually want answered is the second one below. The first is context and I have kept it short.

Both are stated with units, and I have said what I already checked so that nobody repeats it.

The opening post put the caveat in the right place and I want to underline it.

Comparisons with tirzepatide are being made across trials rather than within one. Different populations, different durations, different endpoints; the effect sizes are not commensurable and nobody has run the head-to-head.

Taking post #4 at face value and following it one step further.

Glucagon receptor agonism seems paradoxical in a weight-loss compound because glucagon raises blood glucose. The paradox resolves because glucagon agonism also increases energy expenditure and promotes hepatic fat oxidation, and the incretin components offset the glycaemic effect. In diabetes trials, HbA1c improved rather than worsened.

Grateful for the specificity. Vague answers to this question are what sent me looking.

Glycaemic effects improved rather than worsened in the diabetes work despite the glucagon component, which is the observation that resolves the apparent paradox. It is worth understanding that mechanism before repeating either half of it.

That is the practical version. The rigorous version is longer and says the same thing.