What GLP-1 to glucagon potency ratio do the published dual agonists use?

I would like to know how much of this is established and how much is a reasonable story.

I have the document in front of me and I can read the numbers. What I cannot do is interpret them.

I am reasonably comfortable with statistics and completely uncomfortable with chromatography, or vice versa.

What is the correct interpretation, and what is the common misreading?

The safety question for this limb is glycaemic rather than gastrointestinal, which is a different monitoring problem.

Amino-acid handling changes too: glucagon drives hepatic ureagenesis, so the liver–alpha-cell axis is part of the picture and shows up as changes in circulating amino acids.

Because the mechanism is partly independent of appetite, the weight loss is less strongly coupled to reported food intake, which makes the trial data harder to interpret rather than easier.

The liver–alpha-cell axis linking glucagon signalling to hepatic amino-acid metabolism is well described and predicts the amino-acid changes seen with these agents.

The caveat is that the glycaemic penalty is real and the balance between limbs is not something anyone can reason about from outside a dose-ranging trial.

Expect a slightly larger heart-rate effect than with a pure GLP-1 agonist.

The relevant design parameter is the ratio between the limbs. Too much glucagon and glycaemia deteriorates; too little and the metabolic-rate benefit disappears.

Glucagon acts primarily on hepatocytes to promote glycogenolysis, gluconeogenesis and fatty-acid oxidation. The last of those is the therapeutic target; the first two are the reason a counterbalancing incretin limb is required.

On the detail: heart-rate elevation appears somewhat larger with glucagon-containing agonists than with pure GLP-1 agonists, which is consistent with a catecholaminergic or direct cardiac contribution.

The energy-expenditure effect of glucagon receptor agonism is established from human infusion studies and from indirect calorimetry within trials.

Energy expenditure up, hepatic fat down, glycaemia under pressure. That is the glucagon limb in one line.