SGLT2 inhibitors reduce cardiovascular mortality in HFrEF independent of their glucose-lowering effect. The mechanism most directly responsible for their cardiac benefit is:

• A Reduction of systemic blood pressure via osmotic diuresis
• B Upregulation of erythropoietin synthesis, improving tissue oxygen delivery
• C Inhibition of the cardiac sodium-hydrogen exchanger (NHE1), reducing intracellular sodium and calcium overload ✓
• D Activation of PPARalpha in cardiomyocytes, improving fatty acid oxidation efficiency

Explanation

Beyond glycosuria and diuresis, SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin) directly inhibit the cardiac NHE1 isoform, which is overactive in heart failure. NHE1 inhibition reduces intracellular sodium accumulation, which in turn reduces calcium overload via reverse-mode Na-Ca exchange (NCX). Lower intracellular calcium reduces diastolic dysfunction and myocardial energy demand. This mechanism, along with anti-fibrotic and anti-inflammatory effects, underlies their heart failure benefit independent of HbA1c reduction.

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

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