Objectives: In this study, we aimed to check to what extent findings from existing RCTs can be replicated in the RWD study by analyzing in the transparent and reproducible processes those would be acceptable to regulators. Methods: This study used a cohort study design to assess the effect of empagliflozin versus placebo on cardiovascular safety outcomes. EMPA-REG OUTCOME trial (NCT01131676) was selected to target for replication. The inclusion/exclusion criteria and follow up method were applied as same with RCT. Major adverse cardiovascular events (MACEs) (all-cause death, myocardial infarction, and stroke) were used as primary outcomes. Results: We followed-up (median, 2.7 years) 23,126 matched patients with type 2 diabetes mellitus (11,563 empagliflozin users and 11,563 sitagliptin users). Empagliflozin was related with a significantly decreased risk of MACEs [adjusted HR 0.87, 95% confidence interval (CI) 0.79–0.96]. The predefined estimate agreement, regulatory agreement, and standardized difference for RCT duplication were achieved [EMPA-REG OUTCOME: adjusted HR 0.86, 95% (CI) 0.74–0.99]. Conclusions: Our study results suggest that RWD results can replicate RCT results satisfactorily and have the potential for providing evidence for future regulatory decision-making.