Cardiovascular Effects of Sodium-Glucose Cotransporter Inhibitors
Summary
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally developed for glycaemic control in type 2 diabetes, have demonstrated substantial cardiovascular benefits beyond glucose lowering. Large clinical trials have revealed reductions in heart failure hospitalisations and cardiovascular mortality in both diabetic and non-diabetic patients with heart failure with preserved or reduced ejection fraction. Conventional explanations—such as diuresis, natriuresis, blood pressure lowering and weight loss—do not fully account for the rapid onset and magnitude of benefit. Emerging evidence points to direct cardiac and vascular actions, including modulation of myocardial ion homeostasis through inhibition of the sodium–hydrogen exchanger (NHE1), leading to reduced intracellular sodium and calcium, improved mitochondrial function and enhanced myocardial energetics via a shift towards ketone body oxidation. Additional mechanisms include attenuation of oxidative stress and inflammation in endothelial and cardiac cells, improvement of endothelial function, and preservation of mitochondrial and metabolic integrity. Novel findings also suggest epigenetic regulation of inflammatory and antioxidant gene expression. Together, these pleiotropic effects underline the global significance of SGLT2 inhibitors as heart-failure therapies and highlight practical opportunities for broader cardiovascular application.
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Cardiovascular Effects of Sodium-Glucose Cotransporter Inhibitors publication trend
The graph below shows the total number of articles in cardiovascular effects of sodium-glucose cotransporter inhibitors across all publications each year (not limited to Nature Index journals).
Technical terms
Sodium–glucose cotransporter 2 (SGLT2): A membrane protein in renal proximal tubules that facilitates glucose reabsorption in exchange for sodium.
Ischaemia–reperfusion injury: Tissue damage occurring when blood flow is restored after a period of oxygen deprivation.
Ketone bodies: Alternative energy substrates (for example β-hydroxybutyrate) generated during fatty acid oxidation.
Sodium–hydrogen exchanger (NHE1): A membrane transporter exchanging intracellular H+ for extracellular Na+, regulating cellular pH and sodium loading.
Protein kinase C (PKC): An enzyme family that phosphorylates serine and threonine residues, modulating diverse signalling pathways.
NADPH oxidase (NOX): A multi-subunit enzyme complex that generates reactive oxygen species by transferring electrons from NADPH to molecular oxygen.
DNA methylation: An epigenetic modification involving addition of methyl groups to cytosine residues in DNA, often regulating gene expression.
References
- Empagliflozin improves cardiac energetics during ischaemia/reperfusion by directly increasing cardiac ketone utilization. Cardiovascular Research (2023).
- Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis. Redox Biology (2023).
- Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors. Cardiovascular Diabetology (2023).
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