Background: Type 2 diabetes mellitus (T2DM) and obesity are metabolic diseases characterized by high economic and health burdens. A combination of sodium glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (DAPA) and glucagon-like peptide-1 receptor agonist (GLP1-RA) exenatide (ExQW) has not been explored as a treat-ment strategy for T2DM patients with obesity. Therefore, this retrospective analysis compared the efficacy and safety of dapagliflozin (DAPA) combined with GLP1-RAs Exenatide (ExQW) and dapagliflozin alone in the treatment of 125 T2DM patients with obesity. Methods: This study is a retrospective study. From May 2018 to December 2019, 62 T2DM patients with obesity were treated with DAPA + ExQW, labeled DAPA + ExQW group. From Decem-ber 2019 to December 2020, 63 patients with T2DM and obesity were treated with DAPA + placebo, labeled the DAPA + placebo group. DAPA + ExQW group received DAPA at a dose of 10 mg/day plus ExQW at 2 mg/week and DAPA + placebo group was administered with DAPA at a dose of 10 mg/day plus a placebo. The primary outcome for the present study was change in HbA1c (%) at different treatment points relative to the baseline. The second-ary outcomes included changes in fasting plasma glucose (FPG, mmol/L), systolic blood pressure (SBP, mm/Hg) and body weight (BW, kg). Study outcomes were evaluated at 0, 4, 8, 12, 24, and 52 weeks after initial treatment. All P values were two-sided, with a P value less than 0.05 indicating statistical significance. Results: A total of 125 patients completed the present study (62 in the DAPA + ExQW group and 63 in the DAPA group). Patients in the DAPA group showed a significant decrease in the level of HbA1c during the first 4 weeks, but the HbA1c level in this group remained stable for the remaining 48 weeks. Similar results were observed for other variables such as FPG, SBP, and BW. Patients who received a combination of DAPA and ExQW exhibited a continuous decline in the evalu-ated variables. The decrease in all the variables was greater in the DAPA + ExQW group than that in the DAPA group. Conclusions: A combination of DAPA and ExQW exerts a synergistic effect in the treatment of T2DM patients with obesity. However, the potential synergistic mechanism of this combination should be studied further.