The requirement from several health authorities to demonstrate cardiovascular (CV) safety of new antidiabetes drugs represents both an opportunity and a challenge. In a few years, this requirement may avail to regulatory agencies and the medical community data from large, prospective clinical trials assessing the benefits and risks of such drugs in high–CV risk patients with diabetes. These studies may also provide an opportunity to assess safety signals beyond CV. However, these studies pose significant challenges, including study design, long-term retention of patients, the risk of missing data, and varying regulatory requirements among countries and regions. In addition, these trials cost hundreds of millions of dollars. This significant investment may potentially detract from the investigation of other drug-specific risks or benefits. In this article, we discuss considerations in the design and execution of CV outcome studies in diabetes. The goals of antidiabetes treatment are to avert the untoward metabolic effects of high glucose concentrations and prevent microvascular and macrovascular complications. Compelling data in type 2 diabetic patients support the conclusion that improved long-term glycemic control reduces the risk of microvascular complications (1–3). Based on several large outcome studies, including the seminal Diabetes Control and Complications Trial (DCCT) and UK Prospective Diabetes Study (UKPDS), HbA1c was established as a surrogate biomarker of glycemic control and therapeutic goals were set accordingly (4). Based on the proven correlation between HbA1c and microvascular complications and inconclusive data on CV benefits, most clinical development programs for antidiabetes drugs have focused on glucose lowering. While confirmatory studies in these clinical development programs were being conducted to establish the glucose-lowering properties of novel drugs, CV safety assessment has been limited. CV safety concerns have been raised with respect to several antidiabetes compounds approved or under development for the treatment of type 2 …