A Dicyanocobinamide Conjugate of the GLP-1R Agonist Exendin-4 Improves Glucose Homeostasis in Tumor-Bearing Rats without Exacerbating Anorexia and Weight Loss.

Cancer anorexia-cachexia syndrome (CACS) is a prevalent and debilitating complication of malignancy, characterized by reduced food intake, loss of skeletal muscle mass, and severe metabolic dysfunction. Insulin resistance and impaired glucose tolerance are prominent features of CACS and contribute to worsened prognosis, yet treatment options that improve metabolic regulation without exacerbating anorexia are limited. Although GLP-1 receptor (GLP-1R) agonists effectively enhance glucose control, their centrally mediated anorectic and aversive effects limit their use in cancer patients. To address this limitation, we developed a peripherally restricted GLP-1R agonist by conjugating exendin-4 (Ex4) to dicyanocobinamide (Cbi), a vitamin B12-derived corrin ring with minimal blood-brain barrier penetration. Here, we evaluate Cbi-Ex4 in vitro and across healthy and tumor-bearing rodent models. Cbi-Ex4 retained GLP-1R agonism and improved glucose tolerance without inducing anorexia, weight loss, or malaise, in contrast to native Ex4. These findings support peripheralized GLP-1R agonism as a promising strategy to improve metabolic dysfunction in cancer without worsening malaise and cachexia.