SGLT2 inhibitors like empagliflozin reduce cardiovascular mortality in patients with type 2 diabetes and established CVD. A key non-glycaemic mechanism contributing to this cardiac benefit is:

• A Inhibition of cardiac angiotensin-converting enzyme, reducing cardiac fibrosis
• B Direct activation of cardiac AMPK pathways through SGLT2 receptor-mediated signalling
• C Antagonism of mineralocorticoid receptors in the heart, preventing aldosterone-mediated fibrosis
• D Shifting myocardial substrate utilisation toward ketone bodies (a 'super fuel'), reducing oxygen demand and improving cardiac efficiency ✓

Explanation

SGLT2 inhibitors induce mild ketogenesis by lowering insulin and promoting fat oxidation, increasing circulating ketone bodies (β-hydroxybutyrate). Ketones are a more oxygen-efficient fuel than glucose or fatty acids for the failing myocardium, and this metabolic shift may improve cardiac energetics and reduce cardiac oxygen consumption. Additional mechanisms include volume reduction (osmotic diuresis), afterload reduction, and reduced cardiac fibrosis via haemodynamic effects. The SGLT2 receptor is predominantly renal; direct cardiac SGLT2 signalling is not the established mechanism. Mineralocorticoid antagonism is the mechanism of spironolactone/eplerenone.

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

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Written and medically reviewed by the StethoPrep medical team.