Objective: To analyze the clinical effect of metformin and empagliflozin combined with degulliraglutide injection in the treatment of refractory diabetes. Methods: The clinical data of 60 patients with refractory diabetes admitted to our hospital from May 2023 to February 2025 were retrospectively collected. The research subjects were divided into the control group (treated with metformin hydrochloride combined with degulliraglutide injection, 30 cases) and the observation group (treated with metformin empagliflozin tablets combined with degulliraglutide injection, 30 cases) according to different treatment plans. The blood glucose indicators (fasting blood glucose, 2-hour postprandial blood glucose, HbAlc), blood glucose fluctuation levels [mean amplitude of glycemia (MAGE), maximum amplitude of glycemia (LAGE)], and insulin resistance conditions [insulin resistance index (HOMA-IR)], Lipid indicators [Triglyceride (TG), High density liPoProtein cholesterol (HDL-C), Total cholesterol (TC), Low density liPoProtein cholesterol (LDL-C) ] and the level of adverse drug reactions of the two groups were statistically compared. Result: At 6 weeks and 3 days of treatment, the fasting blood glucose, 2-hour postprandial blood glucose and HbAlc in both groups decreased significantly compared with those before treatment (P < 0.05). Compared with the treatment for 6 weeks, the fasting blood glucose, 2-hour postprandial blood glucose and HbAlc at 3 days of treatment in both groups decreased significantly (P < 0.05). Moreover, the fasting blood glucose, 2-hour postprandial blood glucose and HbAlc of the observation group at 6 weeks and 3 days of treatment were significantly lower than those of the control group (P < 0.05). When treated for 6 weeks and 3 meters, the MAGE and LAGE of both groups decreased significantly compared with those before treatment (P < 0.05). Compared with the treatment of 6w, the MAGE and LAGE of both groups decreased significantly at 3m (P < 0.05). Moreover, the MAGE and LAGE of the observation group at 6 weeks and 3 meters of treatment were significantly lower than those of the control group (P < 0.05). At 6 weeks and 3 meters of treatment, the HOMA-IR of both groups was significantly lower than that before treatment (P < 0.05). Compared with treatment for 6w, HOMA-IR in both groups decreased significantly when treated for 3m (P < 0.05). Moreover, the HOMA-IR of the observation group at 6 weeks and 3 meters of treatment was significantly lower than that of the control group (P < 0.05). At 6 weeks and 3 meters of treatment, TC, LDL-C and TG in both groups decreased significantly compared with those before treatment, and HDL-C increased significantly compared with that before treatment (P < 0.05). Compared with treatment for 6w, TC, LDL-C and TG in both groups decreased significantly at 3m treatment, and HDL-C increased significantly (P < 0.05). Furthermore, the TC, LDL-C and TG in the observation group at 6 weeks and 3 meters of treatment were significantly lower than those in the control group, and the HDL-C was significantly higher than that in the control group (P < 0.05). There was no significant difference in the incidence of adverse drug reactions between the two groups (P > 0.05). Conclusion: Metformin and empagliflozin combined with degulliraglutide injection in the treatment of refractory diabetes can improve the blood glucose and lipid levels of patients, reduce blood glucose fluctuations and insulin resistance.