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DPP-4 (dipeptidyl peptidase-4) inhibitors have increased the risk of heart failure events in both randomized clinical trials and observational studies, but the mechanisms that underlie their deleterious effect remain to be elucidated. Previous work has implicated a role of these drugs to promote cardiac fibrosis.This article postulates that DPP-4 inhibitors increase the risk of heart failure events by activating the sympathetic nervous system to stimulate cardiomyocyte cell death, and it crystallizes the findings from both experimental studies and clinical trials that support the hypothesis.Inhibition of DPP-4 not only potentiates the actions of GLP-1 (glucagon-like peptide-1; which can increase myocardial cAMP) but also potentiates the actions of SDF-1 (stromal cell-derived factor 1), NPY (neuropeptide Y), and substance P to activate the sympathetic nervous system and stimulate β-adrenergic receptors to cause cardiomyocyte apoptosis, presumably through a CaMKII (Ca++/calmodulin-dependent protein kinase II) pathway. An action of SDF-1 to interfere with cAMP and protein kinase A signaling may account for the absence of a clinically overt positive chronotropic effect. This conceptual framework is supported by the apparent ability of β-blocking drugs to attenuate the increased risk of DPP-4 inhibitors in a large-scale clinical trial.Sympathetic activation may explain the increased risk of heart failure produced by DPP-4 inhibitors. The proposed mechanism has major implications for clinical care because in the treatment of patients with type 2 diabetes mellitus, DPP-4 inhibitors are widely prescribed, but β-blockers are underutilized because of fears that they might mask hypoglycemia.