GIP was a failed target for thirty years. Then it was not.

For most of thirty years, glucose-dependent insulinotropic polypeptide was the incretin that did not work. Its insulinotropic effect is blunted in type 2 diabetes; GIP receptor agonism was associated with weight gain in some preclinical models; and pharmaceutical interest drifted almost entirely to GLP-1. Tirzepatide’s clinical results forced a reconsideration that is still in progress, and the honest position is that the mechanism by which adding GIP activity improves outcomes is not settled.

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

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.²

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.

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.

Two things follow practically from the pharmacology above, and only two. Consistency of dosing interval matters more than consistency of hour. And an interruption long enough to clear the drug is an interruption long enough to reset tolerability, which means resumption is a fresh escalation and not a continuation. Everything else in this piece is background.