Dual vs. Triple Incretin Agonism: Comparing Tirzepatide and Retatrutide Receptor Affinity

 

Tirzepatide and retatrutide represent two distinct stages in the evolution of multi-receptor incretin agonists. Tirzepatide is an approved dual GIP/GLP-1 receptor agonist, while retatrutide is an investigational triple agonist targeting GIP, GLP-1, and glucagon receptors. Their receptor affinity profiles, signalling bias, and resulting pharmacological characteristics differ substantially.

Tirzepatide: A GIPR-Biased Dual Agonist

Tirzepatide is a 39-amino acid linear peptide engineered from the native GIP sequence with a C20 fatty diacid moiety that enables albumin binding and extends its half-life to approximately five days.

At the receptor level, tirzepatide exhibits high affinity for GIPR, with a Ki of approximately 0.135 nM for the human GIP receptor, compared to a Ki of approximately 4.23 nM for the human GLP-1 receptor. This represents roughly a 30-fold higher affinity for GIPR over GLP-1R. The European Medicines Agency assessment confirms that tirzepatide binds both receptors in the nanomolar range but with a clear GIPR preference, maintaining affinity comparable to native GIP at GIPR while showing approximately five-fold lower affinity than native GLP-1 at GLP-1R.

Tirzepatide's most distinctive pharmacological feature is its signalling bias. At GLP-1R, tirzepatide acts as a biased agonist, effectively activating cAMP signalling while showing minimal β-arrestin recruitment and reduced receptor internalisation. This contrasts with native GLP-1, which promotes robust β-arrestin recruitment and receptor internalisation. At GIPR, tirzepatide behaves similarly to native GIP, with full agonism for both cAMP production and β-arrestin recruitment.

Retatrutide: Triple Agonism with GIPR "Super-Agonism"

Retatrutide (LY3437943) is a triple agonist peptide targeting GCGR, GIPR, and GLP-1R simultaneously. Its receptor affinity profile differs markedly from tirzepatide.

Retatrutide binds human GIPR with a Ki of 0.057 nM and an EC50 of 0.0643 nM. This affinity is notably superior to tirzepatide's GIPR binding. More critically, compared to native GIP, retatrutide is approximately 8.9-fold more potent at GIPR, thus classifying it as a GIPR "super-agonist". At GLP-1R, retatrutide shows a Ki of 7.2 nM and an EC50 of 0.775 nM, indicating weaker potency than native GLP-1. At GCGR, its Ki is 5.6 nM with an EC50 of 5.79 nM.

Retatrutide acts as a partial agonist at both GLP-1R and GCGR, while it displays super-potency at GIPR. This "GIPR-dominant, GLP-1R-partial, GCGR-moderate" profile stands in contrast to tirzepatide's "GIPR-full, GLP-1R-biased" pharmacology.

Functional Consequences of Affinity Differences

The distinct receptor affinity profiles translate into different functional characteristics. Tirzepatide achieves its effects through GIPR-driven mechanisms combined with GLP-1R biased agonism that minimises receptor desensitisation and internalisation. Retatrutide activates GCGR, which increases energy use. This is not the case with tirzepatide. This GCGR component complements the appetite suppression and glycaemic control mediated through GLP-1R and GIPR.

At the signalling level, GLP-1R is a highly efficient Gs/cAMP-coupled receptor, meaning even weak or partial GLP-1R agonism can produce meaningful cAMP accumulation. This helps explain why both tirzepatide and retatrutide, despite being weak or partial agonists at GLP-1R, achieve substantial metabolic efficacy.

In summary, tirzepatide is characterised by full GIPR efficacy with GLP-1R cAMP-biased signalling, while retatrutide combines GIPR super-agonism with GCGR activation and partial GLP-1R engagement, creating a more complex receptor pharmacology profile.