Figure 1. Tirzepatide (TZP) is an imbalanced agonist of the GIP and GLP-1 receptors and shows biased pharmacology at the GLP-1 receptor.

(A–F) Intracellular cAMP accumulation was measured in low-density human GIPR- and GLP-1R–expressing HEK293 cells. (A) The intrinsic potency of TZP (n = 23) in the presence of casein (CAS) is equivalent to GIP(1-42) (n = 49). In the presence of human serum albumin (HSA), the potency of TZP right shifts 26-fold (n = 5), while GIP(1-42) is unaltered (n = 15). (B) The intrinsic potency of TZP (n = 22) is approximately 18-fold lower than GLP-1(7-36) (n = 57). In the presence of HSA, TZP right-shifts 81-fold (n = 5), while the potency of GLP-1(7-36) is unaltered (n = 24). (C–F) Agonist induced generation of cAMP was measured kinetically using a luminescence biosensor. Data are representative of 3 experiments. At the GIPR, GIP(1-42) (C), and TZP (E) have identical kinetic profiles. On the GLP-1R, native GLP-1(7-36) (D) has a complex profile with a bi-phasic kinetic response at high ligand concentrations, while TZP (F) is monophasic even at the highest tested concentrations. (G and H) Agonist-stimulated GTPγS binding of Gα_s in GIPR and GLP-1R in HEK293 cell membranes are presented as the mean ± SEM of 3 independent experiments. (G) On the GIPR, TZP is fully efficacious with an EC₅₀ (SEM, n) of 0.379 nM (0.070, 3) versus GIP(1-42) of 1.43 nM (0.18, 27). (H) On the GLP-1R, TZP is a partial agonist 51% stimulation (5.2, 3) with an EC₅₀ of 0.617 nM (0.190, 3) versus GLP-1(7-36) of 1.63 nM (0.21, 26). (I and J) The recruitment of ARRB2 to GIPR and GLP-1R in CHO-K1 cells. Representative data are presented. (I) The potency of TZP to recruit ARRB2 to GIPR is 2.34 nM (0.60, 7) and is comparable with GIP(1-42) of 1.58 nM (0.52, 6). (J) The potency of TZP to recruit ARRB2 to GLP-1R is difficult to determine due to low efficacy (n = 5), while GLP-1(7-36) is a full agonist with an EC₅₀ of 3.26 nM (0.71, 14).