Dapagliflozin mechanism of action
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Dapagliflozin Mechanism of Action: SGLT2 Inhibition and Beyond
SGLT2 Inhibition and Glucose Lowering
Dapagliflozin is primarily known as a sodium-glucose cotransporter 2 (SGLT2) inhibitor. By blocking SGLT2 in the kidneys, it reduces glucose reabsorption, leading to increased glucose excretion in urine and lower blood sugar levels in people with diabetes .
Vascular Effects: Vasodilation and Blood Pressure Reduction
Dapagliflozin directly relaxes small arteries by stimulating smooth muscle cell KV7 potassium channels, causing vasodilation. This effect is independent of SGLT2 inhibition and does not rely on nitric oxide or prostacyclin pathways, suggesting a direct action on vascular smooth muscle that may help lower systemic blood pressure . Additionally, dapagliflozin induces vasorelaxation in both endothelium-dependent and independent manners, which may contribute to its cardiovascular benefits .
Cardioprotective Mechanisms: Endothelial Function and Anti-Inflammatory Actions
Dapagliflozin improves endothelial function by reducing oxidative stress and inflammation. It activates sirtuin 1 (SIRT1), which restores endothelial nitric oxide synthase (eNOS) activity, increases nitric oxide (NO) bioavailability, and reduces reactive oxygen species (ROS) generation, protecting against endothelial dysfunction . Dapagliflozin also inhibits inflammatory pathways by reducing TLR-4 expression and NF-κB activation in endothelial cells and macrophages, shifting macrophage polarization toward an anti-inflammatory state 47.
Cardiac Effects: Antiarrhythmic and Anti-Hypertrophic Actions
Dapagliflozin exhibits antiarrhythmic effects by suppressing action potential formation in human atrial cardiomyocytes through inhibition of voltage-gated sodium currents, acting similarly to class I antiarrhythmic drugs . It also increases sodium and inward rectifier potassium current densities in human cardiomyocytes, which may help stabilize cardiac electrical activity and reduce arrhythmia risk . In models of heart failure and myocardial hypertrophy, dapagliflozin activates protective signaling pathways such as SIRT1/HIF-1α and upregulates erythropoietin, leading to reduced cardiac fibrosis, inflammation, and cell death 69.
Metabolic Effects: Lipid Metabolism and Autophagy
Beyond glucose lowering, dapagliflozin improves lipid metabolism by promoting fatty acid oxidation and reducing lipogenesis in the liver. It activates the AMPK-mTOR pathway, which enhances autophagy and reduces hepatic steatosis, suggesting benefits for non-alcoholic fatty liver disease (NAFLD) .
Summary
Dapagliflozin’s mechanism of action extends well beyond SGLT2 inhibition and glucose lowering. It directly affects vascular tone, improves endothelial and cardiac function, reduces inflammation, and positively influences lipid metabolism and autophagy. These diverse actions contribute to its cardiovascular and metabolic benefits in both diabetic and non-diabetic settings 12345678+2 MORE.
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