The DAPA-HF trial and EMPEROR-Reduced trial demonstrated benefit of SGLT2 inhibitors (dapagliflozin and empagliflozin respectively) in patients with HFrEF. Which of the following best describes their mechanism of benefit in heart failure, DISTINCT from their glucose-lowering effect?

• A Beta-1 receptor blockade reducing heart rate and myocardial oxygen demand
• B Inhibition of NHE-1 (sodium-hydrogen exchanger) in cardiomyocytes, reducing intracellular sodium and calcium overload, plus osmotic diuresis and reduction in preload/afterload ✓
• C Aldosterone receptor antagonism in the kidney and heart
• D Neprilysin inhibition increasing natriuretic peptide levels

Explanation

SGLT2 inhibitors' benefit in HFrEF (independent of diabetes status) is attributed to multiple non-glycaemic mechanisms: (1) NHE-1 inhibition in cardiomyocytes reduces intracellular Na+ and Ca2+ overload, improving mitochondrial function and contractility; (2) osmotic-diuretic and natriuretic effect reducing preload; (3) shift to ketone metabolism (more efficient cardiac fuel); (4) reduction in epicardial adipose tissue inflammation; (5) erythropoietin stimulation improving oxygen delivery. DAPA-HF and EMPEROR-Reduced showed ~25% reduction in CV death/HF hospitalisation regardless of diabetic status. Sacubitril/valsartan inhibits neprilysin. MRAs are aldosterone antagonists.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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