Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Abstract

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signaling at glucagon family receptors

“…Although GLP-1R agonists developed specifically to G protein–directed signaling are yet to be tested in humans, the potential utility of this approach is supported by the recent observation that Tirzepatide, a dual GLP-1R/GIPR agonist peptide currently in late-stage clinical trials ( 18 ), and its nonacylated precursor show a significant degree of bias at the GLP-1R in favor of cAMP over β-arrestin recruitment ( 19 , 73 ). Conflicting reports exist for bias between cAMP and β-arrestin recruitment to the GIPR for Tirzepatide, with one study showing bias in favor of cAMP and another showing no difference ( 19 , 74 ). Biased agonism at the GCGR is relatively unexplored, except for a recent study of a series of dual GLP-1R/GCGR agonists in which a small response amplitude for β-arrestin-2 recruitment to GCGR hampered bias assessments ( 75 ), but should be further explored in the future.…”

“…Importantly, G protein-biased GLP-1R agonists derived from exendin-4 lead to increases in sustained insulin secretion through avoidance of GLP-1R desensitization, reduction of GLP-1R endocytosis, and resultant attenuation of GLP-1R downregulation over pharmacologically relevant time periods ( 16 , 17 ). Moreover, a GLP-1R/GIPR dual agonist (Tirzepatide) with promising results for the treatment of T2D in clinical trials ( 18 ) has recently been reported to show pronounced G protein bias at the GLP-1R, although not at the GIPR ( 19 ). In view of the current drive to develop incretin analogs jointly targeting GLP-1R, GCGR, and GIPR ( 1 ), we sought to establish whether biased agonism could similarly be achieved at the latter two receptors and to determine if this is associated with prolonged signaling responses, as seen with the GLP-1R.…”

Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases

“…The clinical phase III data, communicated in a press release in December 2020, indicated that 51.7% of the participants can reach normal HbA1c levels with the highest dose of tirzepatide [ 98 ]. Tirzepatide was engineered from the native GIP sequence [ 95 ] and has a five-fold higher affinity to GIP-R than GLP-1R [ 99 ]. A recent publication has suggested that tirzepatide activates GIP and GLP-1 receptors differently.…”

“…By investigating the downstream signaling molecules, the authors show that tirzepatide resembles GIP at GIP-R but has a biased agonism against GLP-1R in favor of cAMP generation over β-arrestin recruitment. In fact, the observed pharmacology of tirzepatide, such as enhanced insulin secretion, was linked to its imbalanced activity against GIP-R and biased activity towards GLP-1R [ 99 ]. Tirzepatide is associated with fewer gastrointestinal adverse effects that are commonly occurring during GLP-1R agonism but has never been reported with GIP-R activity [ 100 ].…”

“…GIP-R activation may provide additional benefits, including the increased lipid buffering ability governed by the adipocytes in white adipose tissue and the suppressed appetite for bodyweight reduction [ 101 ]. Tirzepatide is linked to a C20 unsaturated di-acid acyl chain achieving a weekly injection dosing regimen [ 99 ].…”