Endocrinology · USMLE Step 1 and Step 2

SGLT-2 Inhibitors song

SGLT-2 Inhibitors - Mechanism & Side Effects, as a song. Hear the short teaser here. The full song is on YouTube and Spotify.

SGLT-2 Inhibitors

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Key points in this song10

SGLT-2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) block sodium-glucose cotransporter-2 in the proximal convoluted tubule, reducing glucose reabsorption and lowering blood glucose independently of insulin.
Primary cardiovascular benefit: empagliflozin and canagliflozin reduce major adverse cardiovascular events (MACE) and heart failure hospitalizations, making them first-line in T2DM with established atherosclerotic cardiovascular disease.
Dapagliflozin and empagliflozin reduce progression of heart failure with reduced ejection fraction (HFrEF) regardless of diabetes status, earning an independent HFpEF/HFrEF indication.
SGLT-2 inhibitors slow progression of diabetic nephropathy by reducing intraglomerular pressure via afferent arteriolar constriction (tubuloglomerular feedback), making them renoprotective in CKD with albuminuria.
Classic adverse effect: euglycemic diabetic ketoacidosis — DKA with normal or near-normal blood glucose, caused by increased glucagon and ketogenesis; hold before surgery or prolonged fasting.
Canagliflozin carries the highest risk of lower-limb amputations and is associated with increased fracture risk due to phosphate retention and FGF-23 elevation.
Osmotic diuresis from glucosuria causes genital mycotic infections (especially Candida) and urinary tract infections — most common adverse effects seen on USMLE questions.
SGLT-2 inhibitors cause a modest blood pressure reduction through osmotic diuresis and natriuresis, and promote weight loss by urinary caloric wasting (~70 g glucose/day).
Contraindicated in eGFR below 20–30 mL/min (glucose-lowering effect lost) and in type 1 diabetes due to high euglycemic DKA risk.
Unique mechanism of action produces a mild hyperkalemia-sparing and uric acid-lowering effect, in contrast to thiazides which raise uric acid and can cause hypokalemia.