GCGR is intricately involved in numerous physiological processes in the body, not only related to blood glucose regulation but also to other normal bodily functions. Previous GCGR-targeted inhibitors designed for glycemic-related indications including diabetes were all halted in clinical development due to safety and toxicity issues. Although these molecules showed strong activity, they simultaneously inhibited both the cAMP and β-Arrestin pathways, leading to clinical toxicity (Figure 1).   To successfully develop drugs for this target, the challenge of biased inhibition must be addressed: how to suppress glucose-related pathways without inhibiting other normal physiological pathways? Currently, only one clinical-stage inhibitor, LGD6972, has demonstrated some degree of biased inhibitory effect.