SGLT2 inhibitors (empagliflozin, dapagliflozin) reduce major adverse cardiovascular events in patients with established CVD or HFrEF. Their cardiovascular benefit is largely attributed to which mechanism BEYOND glucose lowering?

• A Increased GLP-1 secretion stimulating myocardial beta-cell-like proliferation
• B Osmotic diuresis reducing cardiac preload, inhibition of myocardial Na+/H+ exchanger (NHE-1) reducing cardiac hypertrophy ✓
• C Direct blockade of L-type calcium channels in vascular smooth muscle
• D Inhibition of DPP-4 increasing endogenous GLP-1 levels

Explanation

The cardioprotective effects of SGLT2 inhibitors beyond glycemia include: (1) natriuresis/osmotic diuresis reducing preload and afterload; (2) inhibition of the myocardial Na+/H+ exchanger (NHE-1), which reduces intracellular sodium and calcium overload in cardiomyocytes — a direct cardioprotective mechanism independent of glycemic control; (3) reduction of sympathetic tone; and (4) potential ketone body utilization as an alternative fuel source improving cardiac efficiency. SGLT2 inhibitors do not increase GLP-1 secretion; that is the mechanism of GLP-1 receptor agonists. They do not block calcium channels. DPP-4 inhibition is the mechanism of gliptins.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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