The U.S. Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 defining preapproval and postapproval requirements for the demonstration of cardiovascular safety for all new medications developed for glycemic management in type 2 diabetes. Seventeen large, prospective, randomized, controlled clinical trials involving more than 140,000 subjects thus far have been completed or are ongoing in accordance with this guidance. All five of the completed trials, involving three different drug classes, have met their primary objective to exclude an unacceptable level of ischemic cardiovascular risk as defined in the FDA guidance. Additionally, one trial found an increased risk of hospitalization for heart failure, and another demonstrated decreases in cardiovascular mortality and hospitalization for heart failure. Given that a heightened risk of cardiovascular ischemic events has not been demonstrated across several classes of new diabetes drugs, we believe it is time for the scientific community and the FDA to consider a more targeted approach to what is, in effect, a global cardiovascular safety trial requirement for all new type 2 diabetes medications in development.