Revisiting: Hepatic effects of glucagon receptor agonism: the mechanistic worry

Revisiting: Hepatic effects of glucagon receptor agonism: the mechanistic worry Writing it up because I had to work it out twice and would rather nobody else did.

A methods question rather than a substantive one, about Hepatic effects of glucagon receptor.

Everyone quotes the same figure and I cannot find anyone who says how it was arrived at. That is not an accusation; it usually means the derivation is somewhere obvious and I have missed it.

Fine by me. I had wanted a stronger conclusion and there is not one available.

The arithmetic in the opening post is right; the assumption feeding it is the part to check.

If you are new and reading this thread for the answer to Hepatic effects of glucagon receptor: the answer is conditional, the conditions are in the third reply, and the rest of the thread is worth skipping.

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

Whether triple agonism is additive or synergistic is an open question and the published work does not answer it. A phase 2 trial without a dual-agonist comparator arm cannot distinguish the two.

Noting that the question and the thing people usually mean by it are different.

Building on post #5 rather than restating it.

Hepatic effects: glucagon receptor agonism promotes hepatic fat oxidation, which is mechanistically plausible for benefit in metabolic liver disease. Whether that translates to improved clinical outcomes is being tested in phase 2 work.

Two people can read the same figure differently here and both be reasonable.

Discontinuation for adverse effects in phase 2 was not negligible at the higher doses. That figure belongs next to the efficacy figure whenever the efficacy figure is quoted.

I have three months of notes on Hepatic effects of glucagon receptor and the honest summary is that the trend is real and the week-to-week numbers are noise. I nearly drew the opposite conclusion from the first fortnight.

Helpful, and short, which on this subject is harder than long.

Reporting rather than recommending, on Hepatic effects of glucagon receptor. What happened is above. Whether it should have is a different question and not one I am qualified to answer.

Taking post #10 at face value and following it one step further.

Triple agonism at GLP-1, GIP and glucagon receptors is the defining feature and the glucagon limb is the one people find counter-intuitive. It raises energy expenditure and promotes hepatic fat oxidation, and the incretin limbs offset the glycaemic consequence.

If someone has run Hepatic effects of glucagon receptor properly I would rather read that than my own reconstruction of it. Posting mine only because the thread has gone quiet.

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.

I am confident about the direction and much less about the magnitude.