SGLT2 inhibitors reduce cardiovascular mortality in heart failure independent of glycaemic control. The proposed mechanism responsible for cardiac benefit is:

• A Reduction in blood pressure by natriuresis and plasma volume contraction
• B Shift of myocardial energy substrate utilisation from fatty acids to ketone bodies
• C Direct inhibition of sodium-hydrogen exchanger 1 (NHE-1) in cardiomyocytes ✓
• D Attenuation of RAAS activation by reducing afferent arteriolar vasoconstriction

Explanation

Emerging evidence suggests SGLT2 inhibitors (e.g., empagliflozin) directly inhibit NHE-1 in cardiomyocytes, reducing intracellular sodium and calcium overload that contributes to adverse cardiac remodelling. While ketone body utilisation and volume reduction are also beneficial mechanisms, NHE-1 inhibition is considered a key direct cardiac effect independent of glycaemic or diuretic actions, explaining efficacy even in non-diabetic HFrEF patients.

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

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Written and medically reviewed by the StethoPrep medical team.