Objective To investigate the effect of Sitagliptin combined with Insulin Glargine on blood glucose, serum leptin and insulin resistance in patients with type 2 diabetes mellitus. Methods A total of 72 patients with type 2 diabetes mellitus who were admitted to the Third Affiliated Hospital of Nanchang University from March 2018 to December 2019 were selected as the research objects and divided into the control group and the observation group according to the random number table method, with 36 cases in each group. The control group was given subcutaneous injection of Insulin Glargine, and the observation group was treated with Sitagliptin based on the control group, with 2 months of treatment in two groups. The blood glucose, serum leptin levels, pancreatic function before and after treatment and incidence of adverse reactions in the two groups were observed. Results After treatment for 2 months, the levels of glucose metabolism indexes, serum leptin, fasting insulin (FINS) and homeostasis model assessment of insulin resistance(HOMA-IR) in the two groups were lower than those before treatment, and those in the observation group were lower than those in the control group, and the differences were statistically significant (P<0.05). The total incidence rate of adverse reactions in the observation group was lower than that in the control group, and the difference was statistically significant (P<0.05). Conclusion Sitagliptin combined with Insulin Glargine in the treatment of patients with type 2 diabetes mellitus can decrease the levels of blood glucose and serum leptin, improve insulin resistance,and reduce the incidence of adverse reactions, which has better curative effect.