Overview
Clinical Meaning
Sodium glucose cotransporter 2 (SGLT2) inhibitors (empagliflozin, dapagliflozin, canagliflozin) block the SGLT2 protein in the proximal convoluted tubule of the kidney, which no...
Sodium-glucose cotransporter-2 (SGLT2) inhibitors (empagliflozin, dapagliflozin, canagliflozin) block the SGLT2 protein in the proximal convoluted tubule of the kidney, which normally reabsorbs ~90% of filtered glucose. By inhibiting SGLT2, these drugs cause glucosuria (urinary glucose excretion of 60-80 g/day), lowering blood glucose independently of insulin. However, their cardiovascular and renal benefits far exceed what glycemic control alone would explain. Proposed mechanisms: (1) Hemodynamic effects — osmotic diuresis reduces preload and plasma volume, lowering blood pressure by 3-5 mmHg systolic; natriuresis reduces cardiac filling pressures; (2) Cardiac metabolism — shift myocardial fuel substrate from glucose/fatty acids toward ketone bodies (more efficient fuel for failing myocardium); (3) Renal protection — restore tubuloglomerular feedback by increasing sodium delivery to the macula densa, constricting the afferent arteriole, reducing intraglomerular pressure and hyperfiltration (similar mechanism to ACEi/ARBs but complementary); (4) Anti-inflammatory and anti-fibrotic effects — reduce oxidative stress, decrease inflammatory cytokines, and inhibit renal fibrosis; (5) Uricosuria — reduce serum uric acid levels. Landmark trials: EMPA-REG OUTCOME (empagliflozin reduced CV death 38% in T2D with CVD), DAPA-HF and EMPEROR-Reduced (dapagliflozin and empagliflozin reduced HF hospitalizations...