More than 30 million people living in the US have diabetes. Over time, increased concentrations of glucose in the blood lead to cellular damage and cause a variety of serious complications in these individuals. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2i) are the latest class of oral antidiabetic medications approved for use in the US. They work by blocking the resorption of glucose in the kidney thereby increasing urinary glucose excretion. Due to their distinct mechanism of action, these drugs demonstrate cardio- and reno-protective effects in addition to their antihyperglycemic effect. However, clinical trials report an increased risk for adverse events such as amputations, fractures, and mycotic infections raising concerns about their safety. The objective of this dissertation was to evaluate the comparative safety of these drugs in a real-world setting outside of clinical trials. Three observational studies were conducted using prescription and medical insurance data from Truven Health MarketScan Databases (2009-2015). The first study investigated the association between SGLT2i and amputations and concluded that the potential for harm cannot be ruled out. While there was a 38% increase in risk for amputations following initiation of treatment with SGLT2i, the 95% confidence interval included the null. The second study investigated the association between SGLT2i and fractures. There was an 82% increase in risk for fractures early in treatment with SGLT2i. Beyond the initial 2-week treatment period, there was no apparent effect on fracture risk. The third study investigated the association between SGLT2i and mycotic infections. There was a 53% increase in risk for mycotic infections within the first 90 days of treatment with SGLT2i. This dissertation evaluated the post-marketing safety of this new class of antidiabetic medications in a real-world setting. Evidence from such observational studies can supplement that from clinical trials to more thoroughly inform decision-making. Findings from this research can help clinicians understand patients at high-risk for experiencing these events and devise remedial measures in anticipation. Advisors/Committee Members: Schumock, Glen T (advisor), Lee, Todd A (committee member), Calip, Gregory S (committee member), Smith Marsh, Daphne E (committee member), Layden, Brian T (committee member), Schumock, Glen T (chair).