Key result
Saxagliptin impaired cardiac contractility and prolonged QTc interval in cardiomyocytes and guinea pig hearts via a dipeptidyl peptidase-4 independent mechanism, aggravating pre-existing dysfunction.
Why the study?
Does saxagliptin impair cardiac contractility and electrophysiology in preclinical models?
Does saxagliptin impair cardiac contractility and electrophysiology in preclinical models?
Saxagliptin exerts direct, DPP-4-independent deleterious effects on cardiomyocyte contractility and electrophysiology, providing a mechanistic explanation for the increased heart failure risk observed in clinical trials.
Raises concern for saxagliptin in patients with cardiac dysfunction; leaves open translation of DPP-4-independent effects to clinical HF risk.
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.
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Koyani et al. (2017) studied Heart failure. Saxagliptin was evaluated on Cardiac contractility and Ca2+ handling. Saxagliptin impaired cardiac contractility and prolonged QTc interval in cardiomyocytes and guinea pig hearts via a dipeptidyl peptidase-4 independent mechanism, aggravating pre-existing dysfunction.
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