Novel Dual Incretin Receptor Agonists Reduce Body Weight and Improve Metabolic Profile in DIO Mice

Background: The beneficial effects of glucagon-like peptide-1 (GLP-1) receptor activation may be impaired in obese subjects, even those with normal glucose tolerance. Concomitant activation of glucose-dependent insulinotropic polypeptide (GIP) receptors may potentiate the satiety-promoting effect of GLP-1 receptor activation leading to enhanced clinical benefits. We developed a series of novel agonists to assess the effect of dual GLP-1/GIP receptor activation on body weight (BW) and other metabolic parameters. We report herein the results from an evaluation of these compounds in a rodent model of obesity.Methods: Male diet-i nduced obese (DIO) mice were treated with daily subcutaneous injections of vehicle or one of a series of novel dual GLP-1/GIP receptor agonists, VK2742-VK2747 (10 nmol/kg), for 2 weeks. Tirzepatide and novel dual agonist VK2735 (10 nmol/ kg) were used as positive controls. Cohorts were then assessed for changes in BW, glucose and lipids.Results: Treatment with novel dual GLP-1/GIP receptor agonists resulted in reductions to BW (up to 28%, p < 0.0001), plasma glucose (up to 26%, p = 0.0001), and insulin (up to 61%, p = 0.0003), compared to vehicle treatment. Weight loss effects were comparable to those observed in tirzepatide-treated animals, while liver lipid reductions were greater among animals treated with the new series of compounds. Reductions in plasma triglycerides and cholesterol were observed in all treatment groups.Conclusions: A novel series of dual agonists of the GLP-1 and GIP receptors produced significant reductions in BW in DIO mice. Effect sizes were comparable to those observed in the tirzepatide control group. Dual incretin receptor activation also produced desirable changes to lipid profile, suggesting global cardiometabolic benefit. Dual agonism of GLP-1 and GIP receptors represents a promising therapeutic approach to metabolic disorders such as obesity, type 2 diabetes, and non-alcoholic steatohepatitis. Further evaluation of these compounds is ongoing.