This presentation will be based on the work of the ASA Biopharmaceutical Section Working Group on Safety. In 2008 the US FDA released the Guidance for Industry, “Diabetes Mellitus – Evaluating Cardiovascular Risk in New Anti-diabetic Therapies to Treat Type 2 Diabetes”, that changed the way new non-insulin anti-diabetes drugs are evaluated and brought to market. With representatives from different institutions, the group reviewed treatments approved by the United States Food and Drug Administration (FDA) to treat type 2 diabetes mellitus during 2002-2014 with a focus on cardiovascular (CV) risk assessment. To meet guidance requirements on CV risk assessment, different strategies that include meta-analyses and stand-alone cardiovascular outcome trials (CVOTs) have been conducted. CVOTs provide an opportunity to evaluate safety signals beyond CV risk and better assess the benefit-risk profile in diabetic patients with a high risk for CV events, but they also present numerous challenges. The advantages and disadvantages of different CV assessment strategies will be summarized, and some emerging questions will be raised in the presentation.