Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure

Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca²⁺/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca²⁺-ATPase 2a axis and Na⁺-Ca²⁺ exchanger function in Ca²⁺ extrusion. This resulted in reduced sarcoplasmic reticulum Ca²⁺ content, diastolic Ca²⁺ overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C-mediated delayed rectifier K⁺ current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure.