Sodium-Glucose Cotransporter 2 Inhibition in Cardiometabolic Health

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were originally developed to lower blood glucose by blocking renal glucose reabsorption, but large outcome trials have revealed a broad spectrum of cardiometabolic benefits. By promoting glycosuria and natriuresis, these agents reduce plasma volume, lower blood pressure and induce weight loss. Emerging evidence highlights direct effects on cardiac and vascular tissues, including improvement of endothelial function, attenuation of arterial stiffness and modulation of inflammatory and fibrotic pathways. In heart failure, SGLT2 inhibition appears to favourably shift myocardial substrate utilisation towards ketone bodies, enhance myocardial energetics and reduce interstitial fluid. In the kidney, these drugs alleviate glomerular hyperfiltration and slow progression of diabetic nephropathy. Collectively, the pleiotropic actions of SGLT2 inhibitors translate into reduced hospital admissions for heart failure, diminished cardiovascular mortality and slower decline in renal function across diabetic and non-diabetic populations. The integration of these agents into international guidelines underscores their global significance as cornerstone therapies in modern cardiometabolic medicine.

Research from Nature Portfolio

Recent studies have demonstrated that one SGLT2 inhibitor can directly inhibit pro-inflammatory cytokine secretion in vascular endothelial cells by activating AMP-activated protein kinase (AMPK) and through AMPK-independent mechanisms. At clinically relevant concentrations, the drug reduced interleukin-6 and monocyte chemoattractant protein-1 release in response to inflammatory stimuli without altering early nuclear factor-κB signalling or adhesion molecule expression. These findings point to a direct vascular anti-inflammatory action, offering mechanistic insight into the cardiovascular protection observed in clinical trials.

Sodium-Glucose Cotransporter 2 Inhibition in Cardiometabolic Health publication trend

The graph below shows the total number of articles in sodium-glucose cotransporter 2 inhibition in cardiometabolic health across all publications each year (not limited to Nature Index journals).

Technical terms

Sodium-glucose cotransporter 2 (SGLT2): A membrane protein in the renal proximal tubule responsible for reabsorbing filtered glucose and sodium.

Endothelial–mesenchymal transition (EndMT): A phenotypic conversion of endothelial cells into mesenchymal, pro-fibrotic cells contributing to tissue fibrosis.

AMP-activated protein kinase (AMPK): A cellular energy sensor that, when activated, regulates metabolic and anti-inflammatory pathways.

Flow-mediated dilation: A non-invasive ultrasound measure of endothelium-dependent arterial vasodilatation in response to increased shear stress.

Arterial stiffness (pulse wave velocity): A measure of the speed at which blood pressure waves travel along the arterial tree, reflecting vascular elasticity.

Glycosuria: The excretion of glucose in the urine, a direct pharmacodynamic effect of SGLT2 inhibition.

References

1. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Scientific Reports (2018).
2. SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1. Cardiovascular Diabetology (2023).
3. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovascular Diabetology (2017).
4. SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. Cardiovascular Diabetology (2018).