Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy

Jun 3, 2025Cell reports. Medicine

Targeting GLP-1 and GIP receptors with selective drugs improves blood sugar control and weight loss, with combined targeting working best

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Abstract

Biased activation of GLP-1R or GIPR individually leads to improved glycemic control and weight loss.

Biased signaling of GLP-1R or GIPR is associated with better regulation of blood sugar levels.
Greater suppression of food intake is observed with biased agonism of either receptor.
Weight loss is linked to the individual biased activation of GLP-1R and GIPR.
Using a combined approach with a dual agonist, CT-859, may enhance therapeutic efficacy compared to individual receptor activation.

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Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have recently been shown to play a significant role in the treatment of diabetes and obesity. Better understanding of their signaling and mechanism of action could further improve their therapeutic effects. In the current study, we investigate the impact of biased cyclic AMP (cAMP) signaling of GLP-1R and GIPR, individually, as well as the combined effects of a unimolecular dually biased GLP-1R/GIPR agonist, CT-859, on glucose, food consumption, and body weight regulation. Our data demonstrate that biased agonism of either GLP-1R or GIPR leads to better glycemic regulation, greater food intake suppression, and weight loss. In addition, concerted biased activation of both GLP-1R and GIPR results in substantially higher efficacy. Activation of GLP-1R and GIPR with a combination of individually biased agonists or via a dually biased unimolecular approach with CT-859 may provide significant therapeutic advantages for the treatment of diabetes and obesity.

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Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy

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