The U.S. Sentinel System and the Canadian Network for Observational Drug Effect Studies (CNODES) are two medical product safety surveillance networks. Using Sentinel's pre-programmed, parameterizable analytic tools, we reproduced two protocol-based studies conducted by CNODES to assess the risks of acute pancreatitis and heart failure (HF) associated with the use of incretin-based drugs, compared with use of ≥2 oral hypoglycemic agents. Results from the replication new-user cohort analyses aligned with those from the CNODES nested case-control studies. The adjusted hazard ratios were 0.95 (0.81, 1.12) (versus 1.03 [0.87, 1.22] in CNODES) for acute pancreatitis and 0.91 (0.84, 1.00) (versus 0.82 [0.67, 1.00] in CNODES) for HF among patients without HF history. The CNODES's common protocol approach allows studies tailored to specific safety questions, while the Sentinel's common data model plus pre-tested program approach enables more rapid analysis. Despite these differences, it is possible to obtain comparable results using both approaches.