“Next Generation GLP-1/GIP/glucagon Triple Agonists Normalize Body Weight in Obese Mice”, Patrick J. Knerr, Stephanie A. Mowery, Jonathan D. Douros, Bhavesh Premdjee, Karina Rahr Hjøllund, Yantao He, Ann Maria Kruse Hansen, Anette Kristensen Olsen, Diego Perez-Tilve, Richard D. DiMarchi, Brian Finan2022-07-07 ()⁠:

Objective: Pharmacological strategies that engage multiple mechanisms-of-action have demonstrated synergistic benefits for metabolic disease in preclinical models. One approach, concurrent glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor activation (ie. tri-agonism), combines the anorectic [appetite suppressant] and insulinotropic [insulin-level increasing] activities of GLP-1 and GIP with the energy expenditure effect [glycogenolysis] of glucagon. While the efficacy of tri-agonism in preclinical models is known, the relative contribution of GcgR activation remains unassessed. This work aims to addresses that central question.

Method: Herein, we detail the design of unimolecular peptide agonists with an empirically optimized receptor potency ratio potency. These optimized peptide agonists employ a protraction strategy permitting once-weekly human dosing. Additionally, we assess the effects of these peptides on weight-reduction, food intake, glucose control, and energy expenditure in an established DIO mouse model compared to clinically relevant GLP-1R agonists (eg. semaglutide), dual GLP-1R/GcgR agonists, and dual GLP-1R/GIPR agonists (eg. tirzepatide).

Results: Optimized triagonists normalize body weight in DIO mice and enhance energy expenditure in a manner superior to that of GLP-1R mono-agonists and GLP-1R/GIPR co-agonists.

Conclusion: These pre-clinical data suggest unimolecular poly-pharmacology as an effective means to target multiple mechanisms contributing to obesity and further implicate GcgR activation as the differentiating factor between mono or dual incretin receptor agonists and triagonists.

Figure 2: GcgR agonism provides additional body weight lowering efficacy over GLP-1R agonism and GLP-1R/GIPR co-agonism in DIO mice. Body weight (A) and food intake (B) for DIO mice given subcutaneous injections once per day with semaglutide1, an acyl-GLP-1R/GIPR co-agonist17, an acyl-GLP-1R/GcgR co-agonist18, an imbalanced GLP-1R/GIPR/GcgR triple agonist19, and a balanced GLP-1R/GIPR/GcgR triple agonist16…✱ indicate a p-value < 0.05 compared to vehicle control; ^ indicate a p-value < 0.05 relative to a treatment group as indicated.

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