SGLT2 inhibitors: mechanisms, physiology and pharmacology, and clinical applications

Abstract Sodium-glucose cotransporter 2 (SGLT2) is a low-affinity, high-capacity transporter expressed predominantly in the renal proximal tubule, where it mediates the sodium-coupled reabsorption of most filtered glucose. SGLT2 inhibitors have evolved from glucose-lowering agents into disease-modifying therapies across the cardio-renal-metabolic continuum. Blockade of proximal tubular transport induces glycosuria, osmotic diuresis, restoration of tubuloglomerular feedback, resetting of renal haemodynamics, and altered fluid compartmentalisation. These early renal and circulatory effects interact with systemic metabolic adaptations, including pseudo-starvation signalling, erythropoiesis, altered uric acid handling, and changes in substrate availability. At the cellular level, SGLT2 inhibition has been linked to improved ionic homeostasis and mitochondrial quality control, reduced oxidative stress, modulation of inflammation, and attenuation of maladaptive tissue remodelling. Endothelial injury may connect these cellular effects with microvascular dysfunction and fibrosis. Endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT) offer a mechanistic framework for understanding the relationship between microvascular injury and fibrosis. However, EndMT is best viewed as one component of a broader endothelial–stromal stress response rather than as a single proven mediator of clinical benefit. These pharmacodynamic and cellular effects help explain the consistent clinical efficacy of SGLT2 inhibitors across type 2 diabetes, chronic kidney disease, and heart failure (HF), while also informing emerging applications in acute HF, after myocardial infarction, and in patients with arrhythmia or metabolic dysfunction-associated steatohepatitis. This Review integrates mechanistic, pharmacological, and clinical evidence to identify unresolved translational gaps and future directions, including mechanism-informed biomarkers, imaging, spatial multi-omics, phenotype-guided patient stratification, dual sodium-glucose cotransporter 1/2 inhibition, and rational combination therapy.