Review of the cardiovascular safety of dipeptidyl peptidase-4 inhibitors and the clinical relevance of the CAROLINA trial

BACKGROUND: Cardiovascular (CV) disease (CVD) is a well-recognized complication of type 2 diabetes mellitus (T2DM) and there is a clinical need for glucose-lowering therapies that do not further increase CV risk in this population. Although sulfonylureas (SUs) may be used as second-line therapy for patients requiring additional therapy after first-line metformin to improve glycemic control, their long-term effects on CV outcomes remain uncertain, and a wide range of alternative agents exist including dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: Literature searches in PubMed (2013–2018) were conducted with terms for DPP-4 inhibitors combined with CV terms, with preference given to cardiovascular outcomes trials (CVOTs). Reference lists from retrieved articles and diabetes guidelines were also considered. RESULTS: This narrative review discusses current evidence for the CV safety of these agents, describes the long-term CV effects of DPP-4 inhibitors, including effects on CV events, mortality, the risk for heart failure hospitalization, and highlights the need for further research into the CV effects of SU therapy. Although SUs remain a treatment option for T2DM, the long-term effects of these agents on CV outcomes are unclear, and further long-term studies are required. For DPP-4 inhibitors, uncertainties have been raised about their long-term effect on hospitalization for heart failure in light of the results of SAVOR-TIMI 53, although the findings of other DPP-4 inhibitor CVOTs in T2DM and data analyses have suggested these agents do not increase the occurrence of adverse CV outcomes. CONCLUSIONS: Based on recent CVOTs and guideline updates, the choice of add-on to metformin therapy for patients with T2DM and established CV disease should be a sodium-glucose co-transporter-2 inhibitor or a glucagon-like peptide-1 agonist with proven CV benefit. Additional treatment options for those individuals who require therapy intensification, as well as in patients with T2DM and without established CVD include DPP-4 inhibitors and SUs. Since few head-to-head trials have compared the effects of different oral glucose-lowering agents on CV outcomes in T2DM, with most CVOTs using placebo as a comparator, the CAROLINA trial will provide important information on the comparative CV safety of a commonly prescribed SU and a DPP-4 inhibitor.