OBJECTIVES: The Food and Drug Administration (FDA) approved formal indication for an antidiabetic drug for preventing cardiovascular deaths compared to placebo. It is not clear if cardiovascular hospitalizations are lower for sodium glucose transporter 2 inhibitors (SGLT2) compared to dipeptidyl peptidase 4 inhibitors (DPP4). Second, it is uncertain if any benefit occurs in heart failure. Recognizing both needs, we assessed the association between initial dispensing of either class with cardiovascular hospitalizations in general and heart failure in particular. METHODS: The new user study design was applied to type 2 diabetic patients initiating SGLT2 versus DPP4 medications from April 2013 to December 2014 and followed through June 2015. We analyzed time to first cardiovascular (myocardial infraction, stroke or angina) and heart failure admissions after initiating therapy (index date). We adjusted for post-index time-varying covariates and baseline characteristics. Continuous enrollment for 6 months pre-index was required to assess baseline factors. We conducted a marginal structural model (MSM) analyses to estimate Cox proportional hazards. RESULTS: Patients initiating SGLT2 (N=5,484) were younger (mean 55 years) compared to 59 years for DPP4 (N=32,113). Overall, 2.6% and 6.0% patients had cardiovascular admissions after initiating therapy for SGLT2 (n=142) and DPP4 (n=1,928) cohorts respectively. About 0.9% and 3.6% patients had heart failure admissions after initiating therapy for SGLT2 (n=50) and DPP4 (n=1,151) cohorts respectively. Using DPP4 as a reference, the Cox MSM adjusted risk for heart failure admissions was significantly lower for patients on SGLT2 (HR = 0.64, 95% CI 0.48 – 0.85, p = 0.002). There was no difference in cardiovascular admissions (HR=0.86, 95% CI 0.72 – 1.03, p = 0.10). CONCLUSIONS: This study found a significantly lower risk in heart failure but not cardiovascular admissions for SGLT2 users. Clinical studies are needed to provide evidence on each SGLT2 agent's impact on heart failure exacerbations.