SGLT2 inhibitor

**Mechanism:** SGLT2 is located on the apical membrane of the early proximal convoluted tubule (S1/S2 segments) and reabsorbs ~90% of filtered glucose (coupled with Na+). Inhibition lowers the renal threshold for glucose, producing glucosuria (~60-80 g/day), osmotic diuresis, and mild natriuresis. Action is insulin-independent, so hypoglycemia risk is low as monotherapy. SGLT1 (in the distal PCT/S3 segment and intestine) reabsorbs the remaining ~10%.

**Drugs:** Empagliflozin, dapagliflozin, canagliflozin, ertugliflozin (sotagliflozin is a dual SGLT1/2 inhibitor).

**Indications:** - Type 2 diabetes mellitus: lowers HbA1c ~0.5-1%. Efficacy falls with reduced eGFR. - Heart failure (HFrEF and HFpEF), regardless of diabetes status: reduces HF hospitalization and CV death (EMPA-REG, DAPA-HF, EMPEROR-Reduced/Preserved). - Chronic kidney disease (with or without diabetes): slows eGFR decline and progression to ESKD (CREDENCE, DAPA-CKD, EMPA-KIDNEY). Mechanism: restores tubuloglomerular feedback, causing afferent arteriolar vasoconstriction and lowering intraglomerular pressure. - ASCVD benefit in T2DM (reduced MACE).

**Adverse effects (high-yield):** - Genital mycotic infections (vulvovaginal candidiasis, balanitis) from glucosuria. This is the most common adverse effect. - UTIs and, rarely, urosepsis. Fournier gangrene (necrotizing fasciitis of the perineum) is rare but a classic FDA warning. - Euglycemic diabetic ketoacidosis: more likely with insulin deficiency, acute illness, surgery, fasting, or alcohol use. Hold the drug before surgery (~3-4 days). - Volume depletion, orthostatic hypotension, and acute kidney injury (especially with loop diuretics, ACEi/ARB). - Transient initial eGFR dip (hemodynamic, expected). - Canagliflozin: increased lower-limb amputation and fracture risk (CANVAS). - Mild increase in LDL and hematocrit. Weight loss of 2-3 kg and a 3-5 mmHg drop in systolic BP are beneficial effects.

**Contraindications/cautions:** Type 1 DM (DKA risk), history of DKA, recurrent genitourinary infections, severe volume depletion, and dialysis. Glycemic efficacy is minimal at eGFR <30-45, but cardiorenal benefits persist.

**Board pearls:** - Suffix "-gliflozin" = SGLT2 inhibitor. - Clinical vignette: a diabetic woman with recurrent vulvovaginal candidiasis, or a diabetic patient who is nauseated and tachypneic with a high anion gap acidosis and near-normal glucose, points to an SGLT2 inhibitor. - Urinalysis shows glucosuria despite normal serum glucose. - Familial renal glucosuria (an SGLT2 mutation) is a benign analog of the drug effect. - Compare other agents: metformin (↓ hepatic gluconeogenesis, lactic acidosis), GLP-1 agonists (pancreatitis, weight loss, CV benefit), DPP-4 inhibitors (-gliptins), sulfonylureas (hypoglycemia), and thiazolidinediones (fluid retention, HF).