Results from recent cardiovascular outcome trials have ushered in a new era in the management of type 2 diabetes mellitus, moving from a focus on glycemic control to the cardiovascular safety of antihyperglycemic agents. Several new antihyperglycemic drugs have been shown to exert either neutral or cardioprotective effects in patients with diabetes. Among them, the sodium-glucose co-transporter-2 (SGLT-2) inhibitors (gliflozins) and selected agents from the incretin mimetics or enhancers, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins), appear to confer cardiovascular safety and/or protection in patients with underlying, or at high risk for, cardiovascular disease. Metformin remains the standard first-line drug treatment for patients with diabetes because of its established effectiveness and cardiovascular safety. However, this initial drug therapy may not prove adequate as this disease appears to be progressive with a decline in function of the pancreatic beta cells, necessitating the addition of other agents to better control rising glucose levels. With the advent of several new classes of antihyperglycemic drugs and the completion of their respective cardiovascular outcome trials, the therapeutic armamentarium against this disease pandemic appears to be greatly expanding and moving closer to the direction of the Hippocratic aphorism "Do Good or Do No Harm". In this review, we discuss all these issues and summarize the contemporary literature on cardiovascular safety and outcomes of the available glucose-lowering agents.