Background Evidence is limited in comparing treatment modification by substitution or add-on of glucose-lowering medications in patients with type 2 diabetes. This observational study aims to compare switching versus add-on of incretin-based drugs among patients with type 2 diabetes on background sodium-glucose cotransporter-2 inhibitors (SGLT2i). Methods and Results This population-based, retrospective cohort study was conducted using the IQVIA Medical Research Data, including adults with type 2 diabetes on background SGLT2i from 2005 to 2020. New users of incretin-based drugs were allocated into the "Switch" group if they had discontinued SGLT2i treatment, or the "Add-on" group if their background SGLT2i was continued. Baseline characteristics of patients were balanced between groups. Study outcomes were all-cause mortality, cardiovascular diseases, kidney diseases, hypoglycemia, and ketoacidosis. Patients were observed from the index date of initiating incretin-based drugs until the earliest of an outcome event, death, or data cut-off date. Changes in anthropometric and metabolic parameters were also compared between groups from baseline to 12-month follow-up. A total of 2888 patients were included, classified into "Switch" (n=1461) or "Add-on" group (n=1427). Median follow-up was 18 months with 5183 person-years. Overall, no significant differences in the risks of study outcomes were observed between groups; however, patients in the "Add-on" group achieved significantly greater reductions in glycated hemoglobin, weight, percentage weight loss, and systolic blood pressure than their "Switch" counterparts. Conclusions Initiating incretin-based drugs as add-on among patients with type 2 diabetes on background SGLT2i was associated with risks of clinical end points comparable to switching treatments, in addition to better glycemic and weight control observed with the combination approach.