Clinical Advances in Heart Failure with Preserved Ejection Fraction: A Systematic Review of Therapeutic and Mechanistic Evidence

Background: Heart failure with preserved ejection fraction (HFpEF) has emerged as the predominant of heart failure (HF), particularly among aging populations and individuals with a high burden of comorbidities. Its underlying pathophysiological mechanisms are complex, multifactorial and, heterogeneous. Objective: This systematic review aims to synthesize contemporary evidence on the epidemiology, pathophysiology, diagnostic challenges, and therapeutic strategies for HFpEF, with especially emphasis on emerging clinical approaches and future research directions. Methods: A comprehensive systematic literature search was conducted using PubMed, Scopus, Web of Science, and the Cochrane Library, covering publications from January 2015 through June 2025. Eligible studies included randomized controlled trials (RCTs), observational cohort studies, systematic reviews, meta-analyses, and current clinical guidelines talking key aspects of HFpEF. Results: HFpEF now accounts for more than 50% of all HF diagnoses worldwide. Although it shares overlapping clinical features with other cardiovascular (CV) and systemic disorders, recent advances in echocardiographic techniques and the use of circulating biomarkers have substantially improved diagnostic accuracy. Current management strategies primarily focus on comorbidity control, optimization of volume status, structured exercise and rehabilitation programs, and the adoption of novel pharmacological therapies, most notably sodium glucose cotransporter 2 (SGLT2) inhibitors. Notable recent advances include the nonsteroidal mineralocorticoid receptor antagonist finerenone, which demonstrated reductions in worsening HF events and CV mortality in patients with heart failure with mildly reduced ejection fraction (HFmrEF) and HFpEF in the FINEARTS-HF trial. In addition, incretin-based therapies such as semaglutide (STEP-HFpEF program) and tirzepatide (SUMMIT trial) have shown clinically meaningful improvements in symptoms, exercise capacity, weight reduction, and composite CV or HF outcomes, notably in obesity-associated HFpEF phenotypes. Conclusion: HFpEF continues to pose substantial diagnostic and therapeutic challenges owing to its marked heterogeneity and historically limited treatment options. Advances in phenotypic classification, personalized therapeutic strategies, and integrated multidisciplinary care models are critical for improving long-term outcomes in this expanding patient population. The emergence of finerenone and glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GLP-1/GIP) receptor agonists, including semaglutide and tirzepatide, represents a promising extension beyond SGLT2 inhibitors, particularly in cardiometabolic and obesity-driven HFpEF. However, further incorporation into clinical guidelines and validation through real-world evidence remain necessary. Plain Language Summary: Heart failure with preserved ejection fraction (HFpEF) is currently the most common form of heart failure (HF), especially among older adults and individuals with multiple chronic conditions such as diabetes mellitus (DM), hypertension (HTN), and obesity. Unlike traditional heart failure with reduced ejection fraction (HFrEF), in which the heart’s pumping ability is impaired, HFpEF occurs when the heart muscle becomes stiff and does not relax properly. This leads to symptoms such as shortness of breath, fatigue, and fluid retention. This systematic review examined global research between 2015and 2025 to better understand how HFpEF develops, how it is diagnosed, and which treatments are most effective. The findings indicate that HFpEF accounts for more than half of all HF cases worldwide. Although diagnosis remains challenging, recent improvements in cardiac imaging and blood-based biomarkers have enhanced diagnostic accuracy. Current treatment approaches focus on managing related conditions, maintaining appropriate fluid balance, and encouraging exercise-based rehabilitation. Promisingly, newer medications, particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors, have demonstrated meaningful benefits in this patient population. Overall, HFpEF is not a single disease but a complex clinical syndrome that requires individualized and multidisciplinary care. Continued research into its biological mechanisms and targeted therapies is essential to improving quality of life (QoL) and long-term outcomes for this rapidly growing group of patients. Keywords: heart failure with preserved ejection fraction, epidemiology, pathophysiology, sodium glucose co-transport inhibitors, therapeutic challenge