Pathophysiology
Clinical meaning
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have revolutionized heart failure management. SGLT2, located in the S1 segment of the proximal convoluted tubule, normally reabsorbs ~90% of filtered glucose along with sodium. SGLT2 inhibitors (empagliflozin, dapagliflozin) block this transporter, causing glucosuria (~70 g glucose/day excreted), osmotic diuresis, and natriuresis. The cardiovascular benefits are independent of glucose lowering and work in non-diabetic patients. Mechanisms include: (1) Hemodynamic effects โ osmotic diuresis reduces preload preferentially from the interstitial compartment (rather than intravascular depletion), reducing congestion without reflexive neurohormonal activation; (2) Metabolic effects โ promote ketogenesis, shifting myocardial fuel from glucose to ketone bodies (more energy-efficient substrate, producing more ATP per oxygen consumed); (3) Direct cardiac effects โ reduce myocardial inflammation, fibrosis, and oxidative stress; improve calcium handling; promote autophagy; (4) Renal effects โ restore tubuloglomerular feedback by increasing sodium delivery to macula densa, constricting afferent arteriole, reducing intraglomerular pressure and hyperfiltration (renal protective). Landmark trials: DAPA-HF and EMPEROR-Reduced showed ~25% reduction in CV death/HF hospitalization in HFrEF; EMPEROR-Preserved and DELIVER showed benefit in HFpEF โ making SGLT2i the only class beneficial across the entire...