Overview
What the Class Does Beyond Glucose
SGLT2 inhibitors act in the proximal convoluted tubule, where the sodium glucose cotransporter 2 normally reabsorbs most filtered glucose back into the bloodstream.
SGLT2 inhibitors act in the proximal convoluted tubule, where the sodium-glucose cotransporter 2 normally reabsorbs most filtered glucose back into the bloodstream. Blocking this transporter leaves glucose in the tubular fluid, so glucose is excreted in urine. Sodium follows as well, producing mild natriuresis and an osmotic diuresis. The glucose-lowering effect does not require pancreatic insulin secretion. This is why an SGLT2 inhibitor alone has little hypoglycemia risk. Hypoglycemia becomes more likely when the drug is added to insulin or an insulin secretagogue, such as a sulfonylurea. The kidney effect matters even more than the glucose effect. More sodium reaches the distal nephron, restoring tubuloglomerular feedback and increasing afferent arteriolar tone. In practical terms, the glomerulus is no longer filtering under excessive intraglomerular pressure. Serum creatinine may rise and eGFR may fall during the first weeks of therapy. In a stable, euvolemic patient, this initial dip is an expected hemodynamic response rather than acute kidney injury. Over time, reduced intraglomerular pressure slows kidney function loss. The class also reduces heart failure events, including in people without diabetes. Therefore, an SGLT2...