Semaglutide and Tirzepatide Consistently Improve Obesity-Related HFpEF Symptoms, Exercise Capacity, and Cardiac Remodeling

Heart failure with preserved ejection fraction (HFpEF), particularly in patients with obesity-related cardiometabolic dysfunction, remains a complex syndrome with limited disease-modifying therapies. This phenotype is characterized by significant visceral adiposity, endothelial dysfunction, and adverse cardiac remodeling, leading to impaired exercise capacity. Traditional treatments often fall short in addressing the underlying inflammatory and metabolic drivers. Incretin-based therapies, targeting GLP-1R and GIPR, have emerged as promising interventions due to their broad cardiometabolic benefits beyond glycemic control, offering a potential solution for this challenging patient population.

This systematic review evaluated contemporary randomized clinical evidence on semaglutide and tirzepatide in obesity-related HFpEF. Researchers conducted a comprehensive literature search across PubMed/MEDLINE, Scopus, and Web of Science for studies published between January 2020 and July 2025. A total of nine studies met the predefined eligibility criteria, encompassing landmark randomized controlled trials, pooled analyses, and detailed mechanistic imaging and biomarker substudies. The review focused on assessing the effects of these incretin-based therapies on heart failure-related symptoms, exercise capacity, quality of life, and various cardiometabolic biomarkers.

Across the nine studies included in this systematic review, incretin-based therapies consistently demonstrated significant improvements in key HFpEF outcomes. Patients experienced improved heart failure-related symptoms, enhanced exercise capacity, and better quality of life. The therapies also showed favorable effects on structural remodeling, congestion-related physiology, and crucial cardiovascular-kidney interactions. Mechanistic analyses further suggested substantial benefits, including reductions in left ventricular mass, paracardiac adipose tissue, and overall inflammatory burden.

Incretin-based therapies led to reductions in plasma volume expansion and markers of myocardial and renal injury, underscoring their broad therapeutic impact. These findings collectively support the growing role of semaglutide and tirzepatide as promising phenotype-oriented interventions in managing obesity-related HFpEF, extending their utility beyond traditional glycemic control to comprehensive cardiometabolic disease modification.