Amylin is not an incretin, and cagrilintide is not a GLP-1 agonist

Adding glucagon receptor agonism to a GLP-1 backbone is the most interesting and most delicate design choice in the current pipeline. Glucagon receptor activation raises energy expenditure, which is the point. It also raises hepatic glucose output, which is emphatically not. Whether a given molecule’s balance of activities is therapeutic depends on the ratio, and the ratio is a property of the sequence.

Selectivity, potency and efficacy are three measurements

Three quantities are routinely conflated in discussions of this class. Affinity is how tightly a ligand binds, usually reported as a dissociation constant. Potency is the concentration producing half-maximal response, reported as an EC₅₀. Efficacy is the maximal response achievable, reported relative to a reference agonist. A molecule can be more potent and less efficacious than another, and a molecule can bind a second receptor with high affinity and produce almost no response there.

Selectivity is the ratio of activities across receptors, and it is where the current pipeline diverges most sharply. Reported GIP-to-GLP-1 activity ratios for dual agonists vary by more than an order of magnitude between molecules; glucagon receptor arms in triple agonists vary similarly. Those ratios are properties of the sequence and they are not adjustable by dose. Two molecules with different ratios are different drugs at every dose, which is the reason head-to-head trials cannot be replaced by cross-trial comparison.¹

What GIP receptor agonism appears to contribute

Three explanations are current for the additional effect of GIP receptor agonism, and they are not mutually exclusive. The first is that GIP receptor activation in adipose tissue improves lipid handling and insulin sensitivity, permitting greater fat mobilisation at a given level of energy deficit. The second is central: GIP receptors are expressed in hypothalamic and hindbrain regions, and GIP receptor agonism may reduce nausea signalling, allowing higher GLP-1 receptor engagement to be tolerated. The third is that chronic GIP receptor agonism produces functional desensitisation that resembles antagonism, which would reconcile the apparently contradictory finding that both GIP agonists and GIP antagonists reduce body weight in preclinical work.

The second explanation is the most consequential if true, because it would mean the dual agonist’s advantage is partly a tolerability advantage rather than a distinct metabolic one — a difference that matters for how the drugs should be compared.²

The glucagon arm and the balance problem

Glucagon receptor agonism increases resting energy expenditure and promotes hepatic fat oxidation. It also stimulates hepatic glucose production, which in a person with impaired glycaemic control is the opposite of what is wanted. A triple agonist therefore has to be balanced so that the GLP-1 arm’s insulinotropic and glucose-lowering effects exceed the glucagon arm’s glucose-raising effect at every therapeutic concentration.

That balance is set by the sequence, not the dose, which is why glucagon-containing agonists have historically failed in development for glycaemic reasons rather than efficacy ones, and why the ratio is the number to look for in any new molecule’s pharmacology package. Reported phase 2 glycaemic data for the current triple agonists suggests the balance has been achieved; the phase 3 programmes will establish whether it holds across a broader population.³

Nothing in this article is medical advice and nothing in this class of writing can be. Where a clinician is quoted here they say so themselves, and the distinction between describing a mechanism and recommending an action is the whole of the discipline.

Amylin analogues are a different class

Cagrilintide is not a GLP-1 receptor agonist and it is repeatedly described as one. It is a long-acting analogue of amylin, a 37-residue peptide co-secreted with insulin from the beta cell, acting at calcitonin and amylin receptor complexes. Its effects — slowed gastric emptying, reduced food intake, satiety signalling through the area postrema — overlap substantially with GLP-1 receptor agonism, which is why the confusion persists and why the co-formulation with semaglutide is pharmacologically interesting rather than redundant.

Two mechanisms converging on the same behavioural endpoint through different receptors is the argument for combining them: the ceiling of each is set by its own receptor-mediated adverse effects, and two half-doses at different receptors may sit below both ceilings. Whether that argument survives phase 3 is an empirical question.

The oral non-peptide agonists

An orally bioavailable small molecule that activates a class B GPCR was, for a long time, considered close to impossible. The current crop of non-peptide GLP-1 receptor agonists achieves it by binding a site that overlaps only partially with the peptide binding pocket, stabilising an active conformation without the two-domain capture mechanism.

Pharmacologically this matters for three reasons. Absorption does not depend on a permeation enhancer, so bioavailability is far less variable and far less dependent on fasting state than oral semaglutide’s. Elimination is hepatic rather than largely renal and proteolytic, which changes the interaction profile. And potency at the receptor is achieved without a fatty-acid albumin depot, so the concentration-time profile looks like a conventional small molecule rather than a peptide. None of this predicts efficacy; all of it predicts a different practical drug.

Four to five half-lives to approach steady state is the single most useful calculation in this area. For a molecule with a half-life of about a week it means more than a month, and every impression of a dose formed before then was formed on incomplete exposure.

A short glossary, because the words are used loosely

Agonist: a ligand that binds a receptor and produces a response. Full agonist: one producing the maximal response the system permits. Partial agonist: one producing less than maximal response even at full occupancy. Analogue: a molecule structurally derived from a natural ligand. Mimetic: a molecule reproducing a natural ligand’s effect without structural derivation.

Orthosteric site: the binding site the natural ligand occupies. Allosteric site: a distinct site whose occupancy modulates activity at the orthosteric one. Biased agonism: preferential activation of one downstream pathway over another. Tachyphylaxis: diminishing response to repeated administration. Steady state: the condition in which the rate of drug entering the body equals the rate leaving it.

Precision here is not pedantry. Several of the arguments this publication receives by post turn out, on inspection, to be disagreements about which of these words the writer meant.

None of this settles the question a reader most wants settled, which is what a given molecule will do to them. Receptor pharmacology is a description of average behaviour in a population of receptors, and a person is not a population. What it does provide is a way of telling a plausible claim from an implausible one — and in a market where the same four figures circulate for eighteen months attached to the wrong trials, that is not a small thing.