Aims Recent trials (EMPA-REG OUTCOME and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LEADER) have shown improved cardiovascular (CV) mortality with specific currently available glucose-lowering medications (empagliflozin and liraglutide, respectively), but were limited to selected patient populations. We sought to evaluate the current use and potential real-world impact of empagliflozin (and other sodium-glucose co-transporter 2 inhibitors SGLT2is) and liraglutide (and other glucagonlike peptide-1 receptor agonist GLP-1 RAs) among patients in the Diabetes Collaborative Registry (DCR). Methods and results We evaluated 182,525 patients from the DCR - a large, US-based outpatient registry of individuals with type 2 diabetes from 313 sites that included cardiology, endocrinology and primary care practices. Among these patients, 26.2% met major eligibility criteria for EMPA-REG OUTCOME and 48.0% met major eligibility criteria for LEADER. Of these potentially eligible patients, only a small minority were actually prescribed these agents: 5.2% on an SGLT2i and 6.0% on a GLP-1 RA, respectively. Patients receiving these studied medications or medication classes, in general, had lower CV disease burden compared with those not on these agents. Assuming similar risk reductions as in the clinical trials, if all potentially trial-eligible patients in the DCR were treated for 1 year with empagliflozin (or other SGLT2is, assuming a class effect) or liraglutide (or other GLP-1 RAs, assuming a class effect), this may have prevented 354 CV deaths, 231 heart failure hospitalizations, 329 CV deaths and 247 myocardial infarctions, respectively. Conclusion In a large, US-based outpatient registry, we found a significant number of patients would have been potentially eligible for glucose-lowering agents that demonstrated CV benefit in recent clinical trials. In view of these findings, a broader and better-targeted use of these medications in evidence-based patient populations should be considered.