Introduction and Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects ~38% of the global population, with over 65% of patients exhibiting concomitant T2DM. Current therapies for MASLD are limited, particularly in patients with metabolic comorbidities. This study evaluated whether combining dorzagliatin (glucokinase activator) and chiglitazar (pan-PPAR agonist) provides synergistic benefits on glucose metabolism and hepatic outcomes in a mouse of MASLD. Methods: Male DIO mice with confirmed MASLD were randomized to receive dorzagliatin, chiglitazar, or combination therapy for 8 weeks. Metabolic outcomes were assessed by oral glucose tolerance test (OGTT) and related indices. Hepatic outcomes were evaluated by liver histopathology. Results: Chiglitazar monotherapy induced body weight increase up to 20%, which was partially mitigated by dorzagliatin co-administration. Combined treatment significantly improved glucose tolerance versus chiglitazar alone (AUCglucose reduction, p 0.05) and synergistically enhanced HOMA2 indices (p 0.05), indicating improved β-cell responsiveness and insulin resistance. Histopathology analysis revealed no significant changes in NAS score with any treatment. Conclusion: Combined dorzagliatin and chiglitazar enhanced glycemic control beyond either agent alone, improving both basal and glucose-stimulated disposal, while partially mitigating chiglitazar-induced body weight gain. Although hepatic histology was unchanged, these findings underscore the potential of this combination to address metabolic dysregulation in MASLD. Further preclinical and clinical studies are warranted to explore the metabolic and hepatic benefits of this dual-mechanism approach. Disclosure X. Gao: Employee; Current; Hua Medicine. L. Feng: None. F. Tang: None. L. Chen: None.
GAO et al. (Fri,) studied this question.