DPP-4 inhibitors, heart failure and type 2 diabetes: all eyes on safety

Epidemiological analyses have clearly outlined the association between heart failure (HF) and diabetes (DM). HF patients with concomitant DM show a further increase in morbidity and mortality due to coexistence of several mechanisms including disturbed neurohormonal axis as well as structural and functional abnormalities occurring in the diabetic myocardium. Although several studies have shown that poor glycemic control—as indicated by HbA_1c levels—may be associated with an increased risk of HF, this issue remains poorly understood and further evidence is required to show unequivocal benefits of this approach. In the attempt to explore the effects of new anti-hyperglycemic therapies, randomized trials have shown that some glucose-lowering drugs—thought not affecting cardiovascular (CV) death or ischemic complications—might significantly increase the risk of HF-hospitalizations in DM patients. Specifically, the use of dipeptidyl-peptidase-4 (DDP-4) inhibitors (DPP-4i) has recently raised a major safety concern owing to an increase of HF hospitalizations in SAVOR-TIMI 53 trial. In contrast with these findings, the more recent TECOS study as well as new TECOS sub-analyses presented at the last ESC Congress—have yielded to the conclusion that the DPP-4i sitagliptin is not associated with any sort of HF risk. Therefore, increased risk of HF hospitalizations does not seem to be a class effect of DPP-4i. The present article critically discusses available evidence concerning DPP-4i and risk of HF in patients with type 2 diabetes (T2D). The use of DPP-4i in combination therapy is also discussed, in light of the recent EMPA-REG trial.