SGLT2 inhibitors like empagliflozin reduce the risk of hospitalization for heart failure independent of glycemic control. The most accepted mechanism for this cardioprotective effect involves:

• A Inhibition of RAAS activation in the kidney
• B Beta-1 adrenoceptor antagonism reducing sympathetic activation
• C Direct natriuresis and osmotic diuresis reducing cardiac preload and afterload ✓
• D Improvement in mitochondrial efficiency via ketone body utilization as preferred cardiac fuel

Explanation

SGLT2 inhibitors promote glucosuria with accompanying natriuresis and osmotic diuresis, leading to reduction in plasma volume, preload, and afterload. This diuretic-like effect reduces ventricular filling pressures, which is beneficial in heart failure. Additionally, mild ketosis may provide an energy substrate benefit. SGLT2 inhibitors do not directly block RAAS or beta-adrenoceptors. The cardiovascular benefits in heart failure have been demonstrated even in non-diabetic patients with HFrEF.

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

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