SGLT2 inhibitors

Mechanism: SGLT2 is responsible for ~90% of glucose reabsorption in the early proximal tubule (S1 segment). Inhibiting SGLT2 causes glucosuria, lowering blood glucose in an insulin-independent manner. This also causes mild osmotic diuresis and natriuresis, contributing to modest reductions in blood pressure and weight loss.

Clinical uses: Type 2 diabetes mellitus, heart failure with reduced or preserved ejection fraction (HFrEF/HFpEF), and chronic kidney disease (CKD) with or without diabetes—supported by major trials (EMPA-REG OUTCOME, DAPA-HF, EMPEROR-Reduced, DAPA-CKD, CREDENCE).

Cardiorenal benefits: Proposed mechanisms include reduced preload/afterload from diuresis, decreased intraglomerular pressure (afferent arteriolar vasoconstriction via tubuloglomerular feedback), reduced albuminuria, improved cardiac metabolism, and reduced epicardial fat/inflammation.

Adverse effects: Genital mycotic infections (due to glucosuria promoting fungal growth), urinary tract infections, euglycemic diabetic ketoacidosis (especially in stressed states, surgery, or low carbohydrate intake), volume depletion/hypotension, increased risk of Fournier gangrene (rare), and increased risk of lower limb amputation (notably with canagliflozin in CANVAS trial, though later data less conclusive). Contraindicated in type 1 diabetes due to DKA risk (though sometimes used off-label with caution) and in severe renal impairment (efficacy decreases as GFR falls, though renal protective effects persist even at lower eGFR).

Key boards points: Know the mechanism (proximal tubule SGLT2 blockade), the 'flozin' drug suffix, the paradox of benefit in HF and CKD independent of diabetes status, and the classic complication of euglycemic DKA (glucose may be only mildly elevated, but ketones and acidosis present).