OBJECTIVES: The increase in the prevalence of type-2 diabetes has resulted in a substantial increase in the utilization of oral diabetes drugs in the US. This study assessed changes in the safety profile of the oral diabetes medications approved by the US Food and Drug Administration (FDA) as of December 31, 2014. METHODS: Regulatory information for oral diabetes medications as of December 31 was derived from the FDA webpage. Label information was extracted from the FDA webpage and paper copies of the PDR Book. Drugs were classified according to the WHO anatomical therapeutic chemical classification. Descriptive statistics and chi-square tests were used for the analysis. RESULTS: The FDA listed a total of 44 oral diabetes medications as of December 31, 2014, including 30 single active ingredients and 14 fixed-dose combinations. Three of the single active ingredients and 1 of the combinations were discontinued from the market as of December 31, 2014.  In total, 15.9% of the drugs were approved before 1990, 22.7% in the 1990s, 36.4% in the 2000s, and 25.0% in 2010-2014. The main changes in safety profile of the drugs included in the study occurred in contraindications (changes in 50.0% of the drugs), limitations (38.6%), warning and precautions (36.4%), and black box warnings (20.5%). Additionally, changes also occurred in the indications approved by the FDA for 31.8% of the drugs. Changes in safety profile did not significantly varied according to the year of approval of a drug; however, drugs approved in the period 2010-2014 had a lower number of safety changes due to the limited time these drugs have been in the market. CONCLUSIONS: This study found substantial changes over time in the safety profile of oral diabetes drugs. Future research should evaluate the effect of changes in the safety profile of oral diabetes medication on patient outcomes.