The incretin class: single, dual and triple receptor agonists

The GLP-1 receptor agonist mechanism of action is the base case for an entire compound class: a peptide binds the glucagon-like peptide-1 receptor, a class B G protein-coupled receptor, drives Gs-coupled cAMP production through adenylate cyclase, and from that one signal produces glucose-dependent insulin secretion in the beta cell and reduced food intake via the central nervous system. Everything that followed — the dual and triple agonists — varies that theme by adding affinity for one or two further receptors in the same peptide family. Mapping the class means understanding three receptors (GLP-1R, GIPR and GCGR), where each is expressed, and what each arm was hypothesised to contribute.

The incretin effect and the three receptors that define the class

The incretin effect is the observation that oral glucose provokes a substantially larger insulin response than intravenous glucose infused to match the same blood-glucose curve. The difference is attributable to gut-derived hormones released in response to nutrients in the intestinal lumen — principally GLP-1 and GIP. Both are cleaved rapidly by dipeptidyl peptidase-4 and cleared within minutes, the central pharmacological problem the class had to solve (Drucker, Cell Metabolism 2018, PMID 29617641).

Glucagon is not an incretin — it comes from pancreatic alpha cells rather than the gut, and opposes insulin metabolically — but its receptor sits in the same class B GPCR family, shares Gs/cAMP coupling, and its ligand is close enough in sequence that one engineered peptide can address all three targets. That structural relatedness, not shared physiology, is why glucagon belongs here.

Receptor	Native ligand and source	Principal sites of expression	Canonical downstream effects
GLP-1R	GLP-1, from intestinal L-cells (distal small bowel, colon)	Pancreatic beta cells; hindbrain (area postrema, nucleus tractus solitarius) and hypothalamus; vagal afferents; stomach; heart	Glucose-dependent insulin secretion, suppression of glucagon release, slowed gastric emptying, reduced food intake
GIPR	GIP, from intestinal K-cells (duodenum, proximal jejunum)	Pancreatic beta and alpha cells; adipocytes; bone; central nervous system	Glucose-dependent insulin secretion, adipose nutrient handling and blood flow, central effects on intake and nausea signalling
GCGR	Glucagon, from pancreatic alpha cells	Hepatocytes predominantly; also kidney, heart and adipose tissue	Hepatic glycogenolysis and gluconeogenesis, lipolysis, hepatic fat oxidation, increased energy expenditure

Why the native hormones had to be re-engineered

Native GLP-1 has a circulating half-life of minutes. Two structural interventions made long-acting peptides possible. The first is substitution at the DPP-4 cleavage site near the N-terminus — commonly a non-natural residue such as alpha-aminoisobutyric acid — which blocks proteolysis without destroying receptor engagement. The second is acylation with a fatty diacid on a lysine side chain, which promotes reversible binding to serum albumin and slows renal clearance (reviewed in Nauck et al., Molecular Metabolism 2021, PMID 33068776).

One consequence is often skipped: these are not simply slower versions of the native hormones. Tirzepatide was characterised as an imbalanced and biased agonist — it mimics native GIP at GIPR, while at GLP-1R it favours cAMP generation over beta-arrestin recruitment and drives receptor internalisation more weakly than GLP-1 itself (Willard et al., JCI Insight 2020, PMID 32730231). Receptor occupancy alone is therefore a poor proxy for pharmacology here. Two compounds that both engage GLP-1R may signal quite differently at that same receptor.

Generation one: GLP-1 receptor mono-agonists

The first generation engaged GLP-1R alone, and the effect is dual-sited. Peripherally, cAMP-driven potentiation of glucose-stimulated insulin secretion in the beta cell — a signal that falls away as glucose falls, the mechanistic basis for the low hypoglycaemia rates reported in the trials cited below. Centrally, GLP-1R activation in the hindbrain and hypothalamus reduces food intake, with delayed gastric emptying contributing to short-term fullness. Semaglutide remains the reference compound for isolating GLP-1R effects, which is why models needing a clean single-receptor comparator reach for it; Merit lists semaglutide as a research compound alongside the dual and triple agonists for that purpose.

Adding the second arm: dual GIP/GLP-1 receptor agonism

GIP was for years the neglected incretin: its insulinotropic action is blunted in type 2 diabetes, which led much of the field to write it off. The dual-agonist hypothesis was that GIPR engagement would contribute through routes GLP-1R does not reach — adipose nutrient buffering, additive beta-cell signalling, and central effects that may moderate the nausea burden limiting GLP-1R agonists (reviewed in Liu, Frontiers in Endocrinology 2024, PMID 39114288).

The cleanest test of whether a second arm adds anything separable is a head-to-head trial. In SURPASS-2, which enrolled 1,879 adults with type 2 diabetes over 40 weeks, mean HbA1c change was −2.30 percentage points in the highest tirzepatide arm against −1.86 in the semaglutide comparator arm, and mean body-weight change was −11.2 kg against −5.7 kg (Frías et al., NEJM 2021, PMID 34170647). The full SURPASS-2 summary covers the caveat that matters most: the semaglutide comparator was studied at its diabetes indication, not the higher exposures later used in obesity trials. In the obesity setting, participants in the highest tirzepatide arm of SURMOUNT-1 had a mean body-weight change of −20.9% at 72 weeks against −3.1% with placebo (Jastreboff et al., NEJM 2022, PMID 35658024).

Adding the third arm: triple GIP/GLP-1/glucagon receptor agonism

The glucagon arm is the conceptually strange one, because glucagon raises hepatic glucose output — the opposite of what a metabolic compound is normally asked to do. The hypothesis was that with enough incretin signalling to contain the glycaemic consequence, GCGR activation contributes on the expenditure side of the energy-balance equation rather than the intake side: hepatic fat oxidation, lipolysis, and a rise in energy expenditure. No mono- or dual-agonist reaches that mechanism.

Retatrutide, developed under the code LY3437943, carries the most substantial published human data on the question. In a Phase 2 trial that enrolled 338 adults with obesity, mean body-weight change at 48 weeks was −24.2% in the highest-dose arm against −2.1% with placebo (Jastreboff et al., NEJM 2023, PMID 37366315). The trial summary in this library works through the design, including the dose-dependent rise in heart rate the investigators reported, which peaked at 24 weeks and declined thereafter. Merit's retatrutide research listing uses the current name; older literature and some suppliers still use the LY3437943 code for the same sequence — a frequent source of confusion when cross-referencing.

How the three generations compare

Generation	Receptors engaged	Representative compound	What the added arm was hypothesised to contribute
Mono-agonist	GLP-1R	Semaglutide	Baseline: glucose-dependent insulin secretion, central suppression of intake
Dual agonist	GIPR + GLP-1R	Tirzepatide	Adipose nutrient handling, additive beta-cell signalling, possible moderation of central nausea signalling
Triple agonist	GIPR + GLP-1R + GCGR	Retatrutide (LY3437943)	Energy expenditure and hepatic fat oxidation — not accessible to the earlier generations

The unresolved question the generational story hides

The tidy narrative — one receptor, then two, then three — implies that more receptor arms are monotonically better. The literature does not fully support that. The most interesting open problem is the direction of the GIP arm. Clinical programmes have pursued the opposite configuration, pairing GIPR antagonism with GLP-1R agonism, and have also reported substantial weight reduction: in a Phase 2 trial of maridebart cafraglutide, a peptide-antibody conjugate combining GLP-1R agonism with GIPR antagonism, mean body-weight change in the obesity cohort ranged to −16.2% at 52 weeks against −2.5% with placebo (Jastreboff et al., NEJM 2025, PMID 40549887). That is hard to reconcile with the tirzepatide data if GIPR agonism works by the mechanism originally assumed. Proposed explanations include sustained agonism producing functional receptor desensitisation that resembles antagonism at the tissue level, and central versus peripheral GIPR populations contributing in opposing directions. The question is unsettled, and a design treating "GIP arm present" as a binary variable will obscure more than it resolves.

Practical takeaway

Choosing within this class is a question about which receptor arms a model needs, not which generation is newest. Isolating GLP-1R signalling calls for a mono-agonist; examining the GIP contribution needs the dual agonist with a GLP-1R comparator alongside it; expenditure-side mechanisms need the triple agonist, and should expect the glucagon arm to complicate glycaemic readouts. Whichever compound a protocol calls for, identity and purity are prerequisites to interpreting anything downstream — every Merit lot ships with its HPLC and mass-spectrometry certificate, and each lot's published certificate is keyed to the lot number printed on the vial.

This is a summary of published clinical and preclinical literature. It is not a recommendation for any research protocol or design. For research use only. Not for human or veterinary use.

References

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2. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes — state-of-the-art. Mol Metab. 2021;46:101102. PMID: 33068776
3. Liu QK. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol. 2024;15:1431292. PMID: 39114288
4. Willard FS, Douros JD, Gabe MB, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532. PMID: 32730231
5. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503–515. PMID: 34170647
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8. Jastreboff AM, Ryan DH, Bays HE, et al. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial. N Engl J Med. 2025;393(9):843–857. PMID: 40549887