Dipeptidyl peptidase-4 inhibitor use in patients with type 2 diabetes and cardiovascular disease or risk factors

Objectives: Management of cardiovascular (CV) risk is an essential aspect of diabetes care, and acceptable CV risk is a requirement for antidiabetes medications. Dipeptidyl peptidase-4 (DPP-4) inhibitors effectively reduce glycated hemoglobin, with a low risk of hypoglycemia and weight gain. The purpose of this review is to discuss the use of DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) and CV disease or risk factors. Methods: A PubMed search (January 2013-June 2015) was conducted to identify prospective trials, meta-analyses, pooled analyses and cohort studies evaluating CV outcomes with DPP-4 inhibitors. Results: Meta-analyses, pooled analyses and retrospective cohort studies in patients with T2DM suggest no increased CV risk and possible CV benefit compared with some antidiabetes medications. The three published, long-term, prospective, randomized, double-blind CV outcomes trials in patients with CV disease or risk factors found no increased rate of major CV events in patients treated with alogliptin, saxagliptin or sitagliptin versus placebo as add-on to standard-of-care. However, the analysis of the components of the secondary end point of the saxagliptin study showed an increased number of hospitalizations for heart failure (HF) in treated patients versus placebo. A post hoc analysis of the alogliptin study showed no increase in HF hospitalization in treated patients with a history of HF versus placebo, but did show an increase in alogliptin-treated patients with no baseline HF history. Sitagliptin showed no increased risk for HF hospitalization versus placebo in the overall cohort. Two CV outcomes trials for linagliptin are ongoing. Conclusion: The majority of available data from CV outcomes trials suggest a neutral effect of DPP-4 inhibitors on major CV events.