The 2021 ESC guidelines [29] and the most recent 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guidelines [30] for the management of heart failure recommend a paradigm shift in the treatment of heart failure with reduced ejection fraction patients by introducing SGLT2i as the fourth therapeutic pillar, in addition to optimal medical therapy with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker or angiotensin receptor–neprilysin inhibitor, beta-blockers, and mineralocorticoid receptor antagonists. This evidence concerns the gene ACE and heart failure.