The Glucagon Arm: Why GLP-1/Glucagon Differs from GLP-1/GIP

Two Ways to Build a Dual Agonist

Adding a second receptor to a GLP-1 agonist is now a standard move, but there are two different second receptors on offer. Tirzepatide pairs GLP-1 with GIP. Mazdutide pairs it with glucagon. Both are called dual agonists; they are not variations on the same idea.

GIP and glucagon do close to opposite things. GIP is an incretin — it promotes insulin secretion. Glucagon is the counter-regulatory hormone that raises blood glucose. A molecule that activates the glucagon receptor on purpose is doing something that needs explaining, and that explanation is the subject of this article.

A Different Starting Hormone

Most GLP-1 analogues are built on GLP-1(7–37) and modified from there. Mazdutide is not. It is an analogue of oxyntomodulin, an endogenous product of proglucagon processing that natively engages both the GLP-1 and glucagon receptors.

That is a meaningful distinction. Tirzepatide's dual activity was engineered onto a GIP backbone. Mazdutide's dual activity is inherited — oxyntomodulin already does both jobs, and the engineering work went into making it last. An Aib substitution at position 2 blocks DPP-4 cleavage at the N-terminus, and a fatty-acyl chain on Lys20, attached through two AEEA spacers and a γGlu linker, provides albumin binding and once-weekly kinetics.

Mazdutide carries CAS 2259884-03-0 and is also catalogued as IBI362, LY3305677 and OXM-3 — that last code being a direct reference to the oxyntomodulin origin.

Why Activate the Glucagon Receptor at All

The stated rationale is energy expenditure. Glucagon-receptor engagement has been associated in animal work with increased metabolic rate, which is a different lever from the appetite and insulin effects that GLP-1 and GIP act on. A molecule that both reduces intake and raises expenditure is, in principle, working on both sides of the equation.

The counter-argument is that unopposed glucagon-receptor activity raises glucose. The design answer is that the GLP-1 arm is meant to offset it — which makes the ratio of the two activities, not the presence of either, the thing that matters. That ratio is a genuine point of difference between molecules in this class and a reasonable thing to measure.

The same logic scales to three receptors. Retatrutide adds glucagon to a GIP/GLP-1 pair rather than substituting it, and commentary attributes the additional effect seen with triple agonism to that glucagon component.

What Has Been Published

A phase 1b multiple-ascending-dose trial in Chinese adults with overweight or obesity reported body-weight reduction of up to about 6.4% over 12 weeks at doses up to 6 mg. A separate phase 1b cohort in type 2 diabetes reported reductions in HbA1c, fasting plasma glucose and post-meal-tolerance-test glucose from baseline to week 12.

Gastrointestinal events dominated the adverse-event profile, with diarrhoea in roughly 29% of recipients against 33% for dulaglutide and 0% for placebo. The absence of a GIP arm has been discussed as a possible contributor to tolerability differences within this class, since GIP-receptor signalling has been proposed to modulate the nausea response.

Phase 3 figures from the GLORY-1 trial circulate widely online, but largely through secondary sources. Regulatory-status reporting also conflicts between sources. Check both against the primary publications before relying on either.

An Identity Caveat Worth Knowing

Vendor catalogs disagree about mazdutide's molecular formula, and the disagreement is not trivial. The certificate we ship reports C207H317N45O65 at 4476.08 g/mol. Several supplier listings instead give C210H322N46O67 at 4563.06, a difference of roughly 87 Da.

They also disagree on the acyl group: most describe nonadecanoic acid (C19), while at least one lists an eicosanedioic (C20) diacid. Since the lipid is part of the formula, these two disagreements are probably the same disagreement.

The practical consequence is that a mass-spec identity check against the wrong theoretical mass will look like a failure when the material is fine, or pass when it is not. Take the theoretical value from the batch certificate, not from a catalog. Our guide on how to read a peptide COA covers how to read that comparison.

Designing a Comparison

To isolate the glucagon arm specifically, the cleanest contrast is mazdutide against a selective GLP-1 agonist: one variable, one added receptor. Comparing mazdutide to tirzepatide changes two things at once — glucagon in, GIP out — and will not tell you which change produced the effect.

Glucagon-receptor assays need their own expression system. A GLP-1R line will show mazdutide and semaglutide as broadly similar, because the arm that distinguishes them is invisible in that readout.

For the three-receptor case, retatrutide against tirzepatide isolates glucagon while holding GIP and GLP-1 constant — a cleaner single-variable comparison than mazdutide offers.

Handling is unremarkable: mazdutide dissolves in water and bacteriostatic water, with reduced solubility under acidic conditions, and follows the usual lyophilised-peptide storage rules in our peptide storage guide.

Frequently Asked Questions

References & Further Reading

Ji L et al., Nat Commun 2022 (PMC9561728); phase 1b obesity trial, PubMed 35750681; type 2 diabetes cohort, PubMed 36247927; Coskun T et al., Cell Metab 2022 (retatrutide).