A 58-year-old with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes started on empagliflozin shows symptomatic improvement. The mechanism responsible for HFpEF benefit beyond glycemic control is BEST explained by:
- A SGLT2 inhibition causing osmotic diuresis and plasma volume reduction, decreasing left ventricular preload and filling pressures
- B Direct myocardial NHE-1 inhibition by SGLT2 inhibitors, reducing intracellular Na+ and Ca2+ overload in cardiomyocytes
- C Ketone body utilization as an alternative cardiac fuel ('thrifty substrate hypothesis')
- D All of the above mechanisms contribute independently and synergistically ✓
Explanation
SGLT2 inhibitors exert cardiac benefits through multiple concurrent mechanisms: (1) Natriuresis/diuresis reduces preload and afterload without activating neurohormonal compensatory responses; (2) NHE-1 inhibition in cardiomyocytes (an off-target cardiac SGLT2i effect) reduces Na+ and therefore Ca2+ overload via NCX, improving diastolic function; (3) Increased beta-hydroxybutyrate serves as a more oxygen-efficient ('super fuel') cardiac substrate, improving myocardial energetics. In HFpEF, diastolic dysfunction and ventricular stiffness are primary, and volume reduction plus improved myocardial energetics are both critical. EMPEROR-Preserved and DELIVER trials validated empagliflozin and dapagliflozin in HFpEF.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.