Heart failure with mildly reduced ejection fraction (HFmrEF) has been classified using various definitions since its first mention in the literature in 2014. This group was most recently defined in the Universal Definition and Classification of Heart Failure (HF) as HF with a left ventricular ejection fraction of 41% to 49%. An increasing emphasis has been placed on HFmrEF over the past several years, with many recent publications suggesting that common therapies used in HF with reduced ejection fraction provide benefit in this population as well. Patients with HFmrEF comprise approximately one-quarter of all patients with HF. The lack of authoritative guidance concerning pharmacotherapeutic approaches in these patients leaves a significant portion of HF patients without an evidence-based approach. Although it remains unclear if HFmrEF is simply a transitional state from preserved to reduced ejection fraction, or a distinct phenotype requiring medical optimization, there are clear cardiovascular benefits to managing this subset appropriately. This publication was created to help serve as a resource for clinicians on this evolving subset of HF and aid in preventing the progression of this disease state through improved therapy optimization. The objective of this article is to briefly discuss the epidemiology and pathophysiology of HFmrEF and review the pharmacology and clinical application of therapies for the management of HFmrEF.

Following the results observed in the DAPA‐HF trial and subsequent FDA approval of dapagliflozin in patients living with heart failure with reduced ejection fraction (HFrEF), numerous trials quickly began to assess the effects of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) in a wide range of cardiovascular (CV) conditions. Since the publication of those findings, multiple SGLT2i have demonstrated benefit in patients regardless of left ventricular ejection fraction (LVEF)—allowing the drug class to establish itself within the first line of guideline‐directed medication therapy. Although the full mechanistic properties of SGLT2i in heart failure (HF) have yet to be fully understood, benefits in other disease states have continued to emerge over the past decade. This review summarizes the findings of 14 clinical trials investigating the use of SGLT2i in various CV disease states, with a special focus on HF with preserved ejection fraction (HFpEF) and acute decompensated HF (ADHF). Additionally, studies assessing the CV‐related mechanisms, cost‐effectiveness, and exploratory effects of dual SGLT1/2 blockade are described. A review of select ongoing trials has also been incorporated to further characterize the research landscape with this medication class. The aim of this review is to serve as a comprehensive tool for healthcare providers to better understand how this class of diabetes medications established its place in the treatment of HF.