Potential cardiovascular effects of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: current evidence and ongoing trials

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Cardiologists, who often treat patients with CVD and T2DM, are faced with the unmet need for an agent that provides glycaemic control yet does not pose CV risk. No antidiabetic therapy is currently indicated to improve macrovascular outcomes. Results of studies assessing the association between intensive antidiabetic therapy and a reduction in the risk of major CV events in patients with T2DM have been inconsistent, and independent reports have linked certain T2DM therapies (e.g. rosiglitazone, sulphonylureas) with negative CV outcomes. These findings prompted the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to develop guidelines for assessing CV risk in investigational antidiabetic therapies. The FDA guidelines specifically call for meta-analyses of completed phase 2 and 3 trials; long-term, prospective, CV safety studies; or both. Results from meta-analyses involving dipeptidyl peptidase-4 (DPP-4) inhibitors, including those approved before the issuance of the FDA guidelines, suggest that these agents are not associated with an increase in CV risk and may potentially provide CV benefits. Prospective, large-scale, long-term trials designed in accordance with the FDA guidelines examining the CV risks and potential benefits of DPP-4 inhibitors are under way. This review discusses the current evidence and ongoing trials that may support the potential CV benefit of DPP-4 inhibitors in T2DM.