Although the causal mechanism for the increased risk of heart failure observed with DPP-4 inhibitor therapy in SAVOR-TIMI 53 and EXAMINE is currently unknown, sympathetic nervous system activation resulting in cardiomyocyte injury and death has been proposed as a possible explanation, as the actions of stromal derived factor-1, neuropeptide Y, and substance P to stimulate β-adrenergic receptors and cause cardiomyocyte apoptosis may be potentiated by DPP-4 inhibition [68]. This evidence concerns the gene TAC1 and heart failure.