Why does glucagon co-agonism raise heart rate more than a pure GLP-1?

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

I suspect the usual explanation for this is wrong, or at least incomplete.

I am aware this may have a boring answer. I would still like the boring answer stated clearly.

So what is the mechanism, and how well established is it?

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

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.

In practice, 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.

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.

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.

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 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.

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

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

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.

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.

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.

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

The ratio between the limbs is the whole design problem.

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

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 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.

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

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

edited 15 Jan 2025 by laminar_bench — fixed an arithmetic slip in the third paragraph

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

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.

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.