Introduction and Objective: T2DM is often driven by obesity, which leads to impaired glucose homeostasis and β-cell dysfunction. While oral small-molecule GLP-1RAs, such as orforglipron, promote weight reduction, dose-dependent gastrointestinal adverse effects can limit adherence. Dorzagliatin, a first-in-class glucokinase activator, enhances glucose sensing and early-phase insulin secretion. We evaluated whether combining these two oral agents could enhance glycemic control without compromising weight loss, potentially allowing for lower GLP-1RA dosing to improve tolerability.Methods: Male hGLP-1R transgenic DIO mice were randomized to receive vehicle, dorzagliatin, orforglipron, or combination therapy via oral gavage for 4 weeks. Body weight, body composition (fat and lean mass), fasting glucose, OGTT, and plasma C-peptide were measured to assess metabolic and weight-related outcomes.Results: Co-administration of dorzagliatin with orforglipron significantly improved glucose tolerance and disposal compared with orforglipron monotherapy (OGTT AUC reduction, p < 0.05). The combination therapy synergistically increased C-peptide secretion, compared with monotherapies, (p < 0.05), indicating enhanced beta-cell responsiveness during glucose challenge. Importantly, the addition of dorzagliatin did not diminish orforglipron’s weight-lowering efficacy, with the combination group achieving a 14-20% reduction in total body weight and significant fat mass loss among different dosage groups.Conclusion: Combined dorzagliatin and orforglipron enhanced glycemic control beyond either agent alone, improving both basal and glucose-stimulated disposal while maintaining potent weight reduction. This dual-mechanism oral strategy may allow for optimized GLP-1RA dosing, potentially reducing gastrointestinal side effects and improving treatment adherence in people with obesity-associated metabolic disorders. These findings warrant further investigation in clinical studies to confirm the benefit of this novel combination.
L. Feng: None. X. Gao: Employee; Current; Hua Medicine. J. Ni: Employee; Current; Hua Medicine. F. Tang: None. L. Chen: None.
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