In view of the significant cardiovascular (CV) morbidity and mortality in patients with type 2 diabetes mellitus, and concerns raised about the CV safety of some glucose-lowering drugs, the US Food and Drug Administration (FDA) issued guidance for the industry in 2008 to demonstrate CV safety for the approval of all new antihyperglycemic drugs. Seven randomized controlled trials involving around 60,000 participants have been completed so far and have demonstrated the CV safety of dipeptidyl peptidase 4 inhibitors (saxagliptin, alogliptin and sitagliptin), glucagon-like peptide-1 receptor agonists (lixisenatide, liraglutide and semaglutide) and a sodium-glucose co-transporter 2 inhibitor (empagliflozin) in patients with type 2 diabetes. Three of these trials have in fact reported superiority of the study drug over placebo in terms of CV outcomes. However, all these trials were primarily designed as non-inferiority trials to exclude an unacceptable risk of CV events with these drugs in the shortest possible time period. The potential long-term benefit or risks were not assessed effectively as the median follow-up in these studies was limited to 1.5-3 years. Also, these trials included patients with relatively long duration of diabetes, advanced atherosclerosis and higher CV risk. Thus, these trials were not intended to assess CV benefit and are best interpreted as evidence for CV safety of these antihyperglycemic medications.