Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) are prevalent clinical syndromes associated with significant morbidity and mortality. Although both diagnoses are part of the same spectrum, the underlying pathophysiology and responsiveness to medical therapies differ. HFrEF is characterized by a maladaptive neurohormonal response that results in ventricular remodeling, forming the basis of guideline-directed medical therapy (GDMT) centered traditionally on the four pillars: renin–angiotensin–aldosterone system inhibition, β-blockade, mineralocorticoid receptor antagonism (MRA), and sodium-glucose transporter 2 (SGLT2) inhibition. GDMTs confer robust mortality benefit and heart failure hospitalizations and should be initiated early and in combination, when hemodynamics and end organ function permits. In contrast, HFpEF is driven largely by comorbid associated inflammation, diastolic dysfunction, and elevated ventricular filling pressures, with fewer therapies demonstrating clear mortality benefits. Recent research has established SGLT2 inhibitors as the most consistently effective therapy for HFpEF, with some emerging research on selective use of MRAs and glucagon-like peptide-1 receptor agonists. This literature review summarizes the current evidence-based pharmacological management strategies for both HFrEF and HFpEF, highlighting differences in guideline recommendations, exploring the therapeutic overlap and ongoing uncertainty. As newer clinical trial data emerge, future guidelines may further refine optimal treatment strategies for the heterogeneity of the heart failure population.

Received: 26 January 2026

Accepted after revision: 11 May 2026

Article published online:
20 May 2026

© 2026. International College of Angiology. This article is published by Thieme.

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