The LEADER study is a trial performed to demonstrate the cardiovascular safety of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. The study was performed on patients with type 2 diabetes and high cardiovascular risk, mostly with prior cardiovascular events. Although the primary goal was the demonstration of non-inferiority versus placebo, the LEADER study revealed a significant reduction of the overall incidence of major cardiovascular events, as well as a reduction of all-cause and cardiovascular mortality. A trend toward a reduction, although not statistically significant, was also observed for the incidence of myocardial infarction, stroke, and hospitalization for heart failure. Even though it was designed for safety purposes, the LEADER study provided a demonstration that liraglutide treatment is associated with a relevant reduction of cardiovascular risk. These results support the use of the drug as one of the treatments of choice in patients with diabetes and prior cardiovascular events. Recently, similar results have been observed with another GLP-1 receptor agonist, semaglutide, whereas another component of the class, lixisenatide, failed to show any differences in comparison with placebo. Overall, these results raise interesting questions on similarities and differences across GLP-1 receptor agonists, as well as on potential mechanisms responsible for cardiovascular protection during liraglutide treatment.