The incretin axis: a brief orientation
Before comparing individual compounds, it helps to establish what the incretin axis actually is. Incretins are gut hormones released in response to food intake that amplify insulin secretion in a glucose-dependent manner. The two principal incretins are GLP-1 (glucagon-like peptide-1, secreted by intestinal L-cells) and GIP (glucose-dependent insulinotropic polypeptide, secreted by intestinal K-cells). Both act via specific G protein-coupled receptors (GLP-1R and GIPR respectively) expressed on pancreatic beta cells and at multiple other sites including the brain, gut, bone, and adipose tissue.
The observation that incretin biology was impaired in type 2 diabetes drove pharmaceutical interest in GLP-1 receptor agonists from the early 2000s onwards. The more recent compounds — tirzepatide and retatrutide — extend the approach by co-activating additional receptors to capture additive or synergistic metabolic effects that GLP-1 agonism alone does not produce.
Semaglutide: the GLP-1 monoagonist
Semaglutide is a synthetic analogue of human GLP-1(7–36) amide, with a fatty acid chain and albumin-binding linker attached to enable once-weekly dosing. It binds and activates the GLP-1 receptor selectively, with high potency and a half-life of approximately one week in vivo due to the albumin-binding design.
| Property | Detail |
|---|---|
| Receptor target | GLP-1 receptor (GLP-1R) — monoagonist |
| Molecular weight | 4113.58 g/mol |
| Structure | 34-amino-acid GLP-1 analogue with C18 fatty di-acid albumin linker |
| Half-life (in vivo) | ~7 days (albumin binding) |
| Licensed medicines (UK) | Ozempic (diabetes), Wegovy (obesity), Rybelsus (oral) |
| Research use | GLP-1R pathway studies, metabolic research models |
In the research literature, semaglutide has the largest body of published data of any compound in this group, reflecting its earlier entry into clinical development. As a research reagent it is used in in-vitro GLP-1R binding and activation assays, in cell-based studies of insulin secretion, appetite signalling, and neurological GLP-1R expression, and as a reference standard in assays comparing newer incretin analogues.
Tirzepatide: dual GIP and GLP-1 agonism
Tirzepatide (LY3298176) is a 39-amino-acid synthetic peptide with a C20 fatty di-acid albumin-binding modification. It was designed as a “twincretin” — a single molecule that activates both GIPR and GLP-1R. The balance of activity is not 1:1: tirzepatide has higher relative potency at GIPR compared to GLP-1R, with approximately equal GIP potency to native GIP and lower-than-semaglutide potency at GLP-1R. The net pharmacological effect is distinct from either a pure GLP-1 agonist or a pure GIP agonist.
| Property | Detail |
|---|---|
| Receptor targets | GIP receptor (GIPR) + GLP-1 receptor (GLP-1R) — dual agonist |
| Molecular weight | 4813.48 g/mol |
| Structure | 39-amino-acid peptide, GIP-based backbone, C20 fatty di-acid albumin linker |
| Half-life (in vivo) | ~5 days |
| Licensed medicine (UK) | Mounjaro (diabetes and obesity) |
| Research use | Dual incretin receptor studies, GIPR/GLP-1R co-activation models |
The SURPASS and SURMOUNT clinical trial programmes produced the most comprehensive published body of comparative data for tirzepatide versus semaglutide. A 2024 NEJM study reported greater average weight reduction with tirzepatide compared to semaglutide in a head-to-head design, which led NICE to conclude in its obesity appraisal that tirzepatide 15 mg was statistically significantly more effective than semaglutide 2.4 mg for weight reduction over 72 weeks. For researchers, the key mechanistic question tirzepatide opens is what GIPR co-activation specifically contributes, which remains an active area of investigation.
Why GIPR activation matters as a research question
For many years GIP was considered a poor therapeutic target because early GIP agonist studies in humans showed little effect. Tirzepatide's clinical performance reignited the research question: does GIP receptor activity genuinely add metabolic benefit when combined with GLP-1R stimulation, or is it permissive? This remains unresolved in the mechanistic literature, making tirzepatide a particularly active research tool for GIPR pathway studies.
Retatrutide: triple agonist (GIP, GLP-1, glucagon)
Retatrutide (LY3437943) adds a third receptor to the mix: the glucagon receptor (GCGR). It is a 36-amino-acid peptide with a C20 fatty di-acid modification. The glucagon receptor co-agonism introduces a mechanism not present in either semaglutide or tirzepatide: glucagon drives hepatic glucose output and thermogenesis via brown adipose tissue, which in the context of a triple agonist is intended to increase energy expenditure without producing the hyperglycaemia that glucagon alone would cause (because GLP-1R and GIPR activation simultaneously enhance insulin secretion).
| Property | Detail |
|---|---|
| Receptor targets | GIP receptor + GLP-1 receptor + glucagon receptor (GCGR) — triple agonist |
| Molecular weight | ~4500 g/mol |
| Development status | Phase 3 clinical trials (Eli Lilly, as of 2026) |
| Licensed medicine | Not yet licensed in any market |
| Research use | Triple receptor agonism models, GCGR contribution to energy expenditure research |
Phase 2 data published in 2023 in the New England Journal of Medicine (Jastreboff et al.) reported weight reductions of up to 24.2% at 48 weeks in participants with obesity. The glucagon receptor component distinguishes retatrutide mechanistically from tirzepatide and makes it a distinct research tool for studying GCGR pathways in the context of incretin co-agonism. Phase 3 TRIUMPH trials are ongoing.
Cagrilintide: the amylin analogue
Cagrilintide is not a GLP-1 agonist. It is a long-acting synthetic analogue of amylin (islet amyloid polypeptide, IAPP), a peptide co-secreted with insulin from pancreatic beta cells. It primarily activates amylin receptors (AMY1–3, which are calcitonin receptor complexes) in the hypothalamus and brainstem, reducing gastric emptying and food intake via central pathways distinct from GLP-1R activation.
| Property | Detail |
|---|---|
| Receptor targets | Amylin receptors (AMY1–3) / calcitonin receptor complexes |
| Development status | Phase 3 (as CagriSema combination with semaglutide, Novo Nordisk) |
| Mechanism | Amylin analogue — not a GLP-1 agonist |
| Research use | Amylin receptor pathway studies; dual amylin/GLP-1 combination models |
Cagrilintide is studied primarily in combination with semaglutide (the CagriSema fixed-ratio combination). Phase 2 data reported additive weight-reduction effects compared to either agent alone, and phase 3 REDEFINE trials are investigating the combination further. For research purposes, cagrilintide is the reference compound for amylin receptor pathway studies in metabolic models, a pathway that is mechanistically independent of incretin receptor activation.
Side-by-side summary
| Compound | Receptor(s) | Class | Status (UK, 2026) |
|---|---|---|---|
| Semaglutide | GLP-1R | GLP-1 monoagonist | Licensed (Ozempic / Wegovy) |
| Tirzepatide | GLP-1R + GIPR | Dual incretin agonist (twincretin) | Licensed (Mounjaro) |
| Retatrutide | GLP-1R + GIPR + GCGR | Triple agonist | Investigational (Phase 3) |
| Cagrilintide | Amylin receptors (AMY1–3) | Amylin analogue | Investigational (Phase 3, with semaglutide) |
Choosing the right compound for your research
The choice between compounds depends entirely on which receptor pathway you are studying:
- GLP-1R pathway only: semaglutide is the established reference compound with the widest published literature base.
- GLP-1R + GIPR co-activation: tirzepatide is the appropriate tool. It is the only licensed compound that co-activates both receptors, giving it the most clinical-grade validation of the dual-agonist class.
- Triple pathway (GLP-1R + GIPR + GCGR): retatrutide is the current reference compound for this mechanism. Its development-stage status means the research literature is less extensive than semaglutide or tirzepatide, making in-vitro and preclinical work with retatrutide particularly valuable for the field.
- Amylin receptor pathway: cagrilintide is the appropriate tool. Studying the amylin component of metabolic control independently of incretin agonism requires an amylin-selective compound.