To compare SGLT2 inhibitors and GLP-1 agonists on cardiovascular (CV) outcomes, treatment persistence/discontinuation, healthcare utilization and costs. This retrospective cohort study utilized medical and pharmacy claims to identify new SGLT2 inhibitor or GLP-1 agonist users from January 2015 to June 2017. A total of 5,507 patients were included in each treatment group after 1:1 propensity score matching. Cox proportional hazards models were used to compare CV outcomes and treatment discontinuation. Healthcare utilization and costs were compared using Wilcoxon signed rank test. No differences in the primary composite CV outcome or secondary CV outcome were observed. Patients using GLP-1 agonists were more likely to discontinue treatment (hazard ratio 1.15, 95% confidence interval 1.10–1.21) and more likely to have an inpatient hospitalization (14.4% vs. 11.9%, P < 0.001) or emergency department visit (27.4% vs. 23.5%, P < 0.001) compared to patients on SGLT2 inhibitors. The average per-person per-month cost difference was +$179 for total cost (P < 0.001), +$70 for medical cost (P < 0.001) and +$108 for pharmacy cost (P < 0.001) for GLP-1 agonists compared to SGLT2 inhibitors. Differences in composite CV outcomes were not established. However, other findings that favored SGLT2 inhibitors should be weighed against the known risks associated with this therapeutic class.