What does the glucagon arm of a tri-agonist add, and what does it cost?

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

I have used one of these for a while and I am considering switching, which requires a reason.

What I care about is reproducibility, because a result I cannot repeat is not useful to me.

So which one, and on what grounds?

The honest position is that the balance is empirical: it has been found by dose-ranging rather than derived from first principles.

Hepatic fat reduction with glucagon-containing agonists in phase 2 has been substantial, which is why the MASH programmes in this class exist at all.

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.

Retatrutide phase 2 results reported substantial weight reduction over 48 weeks, and the ongoing phase 3 programme carries the TRIUMPH name.

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.

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

edited 3 Jun 2024 by siobhan_deasy — tightened the wording; no substantive change

Start with the apparent contradiction: glucagon raises blood glucose, so putting a glucagon agonist into a glucose-lowering drug looks perverse until you look at the energy-expenditure side.

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.

The underlying point is that the glycaemic penalty from the glucagon limb is dose-dependent and is the practical constraint on how far the limb can be pushed in a diabetic population.

Phase 2 results are not phase 3 results, and this class has a history of tolerability constraints appearing at scale.

The mechanism is not appetite-mediated, which makes it interesting and makes it harder to monitor.

Answering this needs the hepatic fat endpoint, because that is where the glucagon limb shows its clearest effect.

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.

In practice, 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.

Research-use material is not approved for human use, and a multi-agonist with a glycaemic penalty is the worst possible candidate for uncontrolled use.

Cite the hepatic-fat endpoints for this mechanism; they are where it shows most clearly.

On the detail: the safety question for this limb is glycaemic rather than gastrointestinal, which is a different monitoring problem.

Retatrutide is a triple agonist at the GIP, GLP-1 and glucagon receptors; survodutide is a dual glucagon and GLP-1 agonist. The compositions are different and so are the trial programmes.

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

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

Answer first: adding glucagon receptor agonism raises energy expenditure and hepatic fat oxidation, and the cost is a glycaemic penalty that the GLP-1 limb has to cover.

Reported increases in resting energy expenditure with glucagon receptor agonism are on the order of several per cent, which over months is a meaningful contribution to energy balance and is a genuinely different mechanism from eating less.

Survodutide phase 2 work in MASH reported histological improvement, which is the strongest evidence for the hepatic mechanism of the glucagon limb.

The ratio between the limbs is the whole design problem.