Twelve drug categories are marketed in the United States to lower blood glucose concentrations in type 2 diabetes mellitus (T2DM). After metformin, there is disagreement about the optimal next choice for combination therapy. Guidelines advise balancing potency, risks, benefits, and costs. For T2DM and cardiovascular disease (CVD), emerging evidence suggests that certain options may have specific advantages. Specific members of the thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, and glucagon-like peptide-1 receptor agonist classes have been associated with significant reductions in major adverse cardiovascular events, generally in those with established CVD. A personalized approach should consider these evidence-based therapies to optimize clinical outcomes.