Heart failure with preserved ejection fraction (HFpEF) remains a clinically heterogeneous syndrome with limited disease-modifying therapeutic options, particularly among patients with obesity-related cardiometabolic dysfunction. Increasing evidence suggests that obesity-associated HFpEF represents a distinct inflammatory and metabolically active phenotype characterized by visceral adiposity, endothelial dysfunction, congestion physiology, impaired exercise capacity, and adverse cardiac remodeling. Incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, have recently emerged as promising interventions within this evolving therapeutic landscape. This systematic review evaluated contemporary randomized clinical evidence examining the effects of semaglutide and tirzepatide in obesity-related HFpEF. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, and Web of Science for studies published between January 2020 and July 2025. Nine studies met the predefined eligibility criteria, including landmark randomized controlled trials, pooled analyses, and mechanistic imaging and biomarker substudies. Across the included studies, incretin-based therapies consistently improved heart failure-related symptoms, exercise capacity, quality of life, inflammatory biomarkers, and body weight, while also demonstrating favorable effects on structural remodeling, congestion-related physiology, and cardiovascular-kidney interactions. Mechanistic analyses suggested potential benefits involving reductions in left ventricular mass, paracardiac adipose tissue, inflammatory burden, plasma volume expansion, and markers of myocardial and renal injury. Collectively, the current evidence supports the growing role of incretin-based therapies as promising phenotype-oriented interventions in obesity-related HFpEF and raises the possibility that targeted cardiometabolic modulation may influence multiple domains of disease pathophysiology beyond glycemic control alone. However, further long-term studies are needed to clarify their effects on remodeling reversal, arrhythmia burden, and cardiovascular mortality.
