Clinical meaning
Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a paradigm shift in diabetes and cardiorenal medicine. By blocking SGLT2 in the proximal convoluted tubule, these agents prevent reabsorption of approximately 70 g/day of filtered glucose, producing glycosuria (reducing A1C by 0.5-1.0%), osmotic diuresis (reducing blood pressure by 3-5/2-3 mmHg), and modest weight loss (2-3 kg). However, their most transformative benefits are cardiorenal, mediated through mechanisms independent of glucose lowering: (1) Tubuloglomerular feedback restoration — increased sodium delivery to the macula densa activates TGF, constricting the afferent arteriole, reducing intraglomerular pressure and hyperfiltration (renoprotective, analogous to ACEi/ARB effect on the efferent arteriole); (2) Natriuresis and osmotic diuresis reduce preload and afterload without neurohormonal activation (unlike loop diuretics); (3) Metabolic shift from glucose to ketone body oxidation improves cardiac energetics (ketone bodies are more oxygen-efficient myocardial fuel); (4) Anti-inflammatory and anti-fibrotic effects reduce cardiac and renal fibrosis. Landmark trials: EMPA-REG OUTCOME (empagliflozin: 38% reduction in CV death in T2DM with ASCVD), DAPA-HF (dapagliflozin: 26% reduction in HF hospitalization/CV death in HFrEF regardless of diabetes), DAPA-CKD (dapagliflozin: 39% reduction in CKD progression regardless of diabetes). Current indications: T2DM, HFrEF, HFpEF, and CKD with proteinuria — the first drug class with evidence across all three conditions.