In 2008, the US Food and Drug Administration (FDA) issued guidance requiring robust assessment of cardiovascular safety for all antidiabetic drugs to be licensed in the future. Here, we review the circumstances giving rise to the FDA guidance and describe the characteristics of clinical trials registered on ClinicalTrials.gov in the 36 months before and after the guidance was issued. We noted a doubling in the number of cardiovascular outcome trials registered and a sixfold increase in the median number of patients included in cardiovascular outcome trials in the latter 36 months. As the size and duration of follow-up for these trials increases, the clinical trials industry will need to adapt. The present review summarizes current attempts to streamline trial design and management to meet the requirements efficiently while adhering to the highest scientific standards.