Introduction of guideline-directed medical therapy (GDMT) has transformed the care of heart failure (HF) with reduced ejection fraction, establishing four foundational drug classes. Yet, in clinical practice, many patients cannot initiate or maintain all four, and clinicians must pragmatically prioritise agents such as angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 inhibitor, whose comparative impacts are still explored. Moreover, the optimal loop diuretic to pair with modern GDMT, which enhances natriuresis, remains uncertain.