Contemporary Management of Heart Failure with Preserved and Mildly Reduced Ejection Fraction: Where Do SGLT2 Inhibitors and ARNi Fit in Routine Care?

Abstract

Heart failure with preserved and mildly reduced ejection fraction (HFpEF and HFmrEF) account for more than half of heart‑failure cases and are increasing as populations age. Historically, therapeutic options were limited and aimed primarily at symptom relief. In the last decade, sodium–glucose cotransporter‑2 (SGLT2) inhibitors and angiotensin receptor–neprilysin inhibitors (ARNi) have emerged as treatments capable of reducing cardiovascular events across the ejection‑fraction spectrum. This review synthesises contemporary evidence to appraise their role in routine care. We discuss the complex pathophysiology of HFpEF and HFmrEF, evolution of guideline recommendations, mechanisms of action of SGLT2 inhibitors and ARNi, results of pivotal randomised‑controlled trials and meta‑analyses, and safety considerations. We also compare these agents, explore integration with other therapies and non‑pharmacologic strategies, highlight patient phenotypes most likely to benefit, and outline unanswered questions. More than 30 unique studies are used to provide a balanced narrative and avoid reliance on single sources. The evidence supports early initiation of SGLT2 inhibitors in all stabilised patients and selective use of ARNi in HFmrEF or lower‑range HFpEF, while emphasising personalised care and ongoing research needs.