Objective: To analyze the effect of semaglutide combined with Degu insulin in the treatment of type 2 diabetes mellitus (T2DM) poorly controlled by oral hypoglycemic drugs. Method: 91 patients with type 2 diabetes mellitus (T2DM) who were diagnosed and treated in our hospital from October 2022 to July 2024 and had poor control with oral hypoglycemic drugs were selected as the research subjects. The patients were randomly divided into the control group (45 cases) and the observation group (46 cases). The control group was treated with metformin combined with Degu insulin; The observation group was treated with metformin combined with semaglutide and Deguinsulin. The blood glucose levels [fasting blood glucose (FBG), 2-hour postprandial blood glucose (2hPBG), HbA1c], islet function [HOMA-IR, HOMA-β value], blood lipid levels [total cholesterol (TC), triglycerides (TG)] and adverse reactions of the two groups were analyzed and compared. Result: After treatment, the FBG, 2hPBG and HbA1c in both groups were significantly lower than those before treatment, and the blood glucose indicators of FBG, 2hPBG and HbA1c in the observation group were significantly lower than those in the control group (P < 0.05). After treatment, HOMA-β in both groups was significantly increased compared with that before treatment, and HOMA-IR was significantly decreased compared with that before treatment. Moreover, the change amplitudes of HOMA-β and HOMA-IR in the observation group were significantly greater than those in the control group (P < 0.05). After the treatment, the TG and TC in both groups were significantly lower than those before the treatment, and the TG and TC in the observation group were significantly lower than those in the control group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Conclusion: For T2DM patients with poor control of oral hypoglycemic drugs, the combined use of semaglutide and deguinsulin for treatment can improve the hypoglycemic effect, improve the pancreatic islet function and blood lipid levels of patients, and has a relatively high safety of medication.