Al Mashtoub E, Hteit A, Bedran A, Al Banna J, El Hachem C, Obeid N, Msheik M, Tlais M, Abdulaal R. Glucagon-like peptide-1-based incretin agonists in obesity-related heart failure with preserved ejection fraction: A systematic review and meta-analysis. World J Meta-Anal 2026; 14(2): 119849 [DOI: 10.13105/wjma.v14.i2.119849]
Corresponding Author of This Article
Mohamad Tlais, MD, Cardiology, University of Balamand, Hazmieh, Beirut 1100, Beyrouth, Lebanon. mmtlaiss22@gmail.com
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Cardiac & Cardiovascular Systems
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research-article
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Al Mashtoub E, Hteit A, Bedran A, Al Banna J, El Hachem C, Obeid N, Msheik M, Tlais M, Abdulaal R. Glucagon-like peptide-1-based incretin agonists in obesity-related heart failure with preserved ejection fraction: A systematic review and meta-analysis. World J Meta-Anal 2026; 14(2): 119849 [DOI: 10.13105/wjma.v14.i2.119849]
World J Meta-Anal. Jun 18, 2026; 14(2): 119849 Published online Jun 18, 2026. doi: 10.13105/wjma.v14.i2.119849
Glucagon-like peptide-1-based incretin agonists in obesity-related heart failure with preserved ejection fraction: A systematic review and meta-analysis
Ehab Al Mashtoub, Ali Hteit, Anthony Bedran, Janette Al Banna, Charbel El Hachem, Nazih Obeid, Mostafa Msheik, Mohamad Tlais, Razan Abdulaal
Ehab Al Mashtoub, Anthony Bedran, Janette Al Banna, Charbel El Hachem, Nazih Obeid, Mostafa Msheik, Mohamad Tlais, Razan Abdulaal, Cardiology, University of Balamand, Beirut 1100, Beyrouth, Lebanon
Ali Hteit, Department of Cardiology, Georgian American University, Tbilisi 1100, Georgia
Author contributions: Al Mashtoub E and Tlais M conceived and designed the review; Bedran A and Hteit A independently screened titles and abstracts, performed full-text eligibility assessment, and extracted data; Msheik M adjudicated discrepancies; Abdulaal R and Al Banna J performed risk of bias assessment; El Hachem C and Obeid N conducted the statistical analyses and generated the meta-analytic figures; Mashtoub EA drafted the manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version for submission.
Conflict-of-interest statement: All authors declare no conflict of interest related to this work. No funding was received for the design, conduct, or reporting of this systematic review and meta-analysis.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Mohamad Tlais, MD, Cardiology, University of Balamand, Hazmieh, Beirut 1100, Beyrouth, Lebanon. mmtlaiss22@gmail.com
Received: February 7, 2026 Revised: March 8, 2026 Accepted: March 19, 2026 Published online: June 18, 2026 Processing time: 125 Days and 8.7 Hours
Abstract
BACKGROUND
Obesity-related heart failure with preserved ejection fraction (HFpEF) is highly prevalent, symptomatically disabling, and lacks clearly disease-modifying pharmacotherapy. Glucagon-like peptide (GLP)-1-based incretin agonists-including GLP-1 receptor agonists (GLP-1 RAs; e.g., semaglutide) and the dual GIP/GLP-1 RA tirzepatide-induce substantial weight loss and favorable cardiometabolic effects and have recently been evaluated in obese HFpEF populations.
AIM
To systematically evaluate the efficacy and safety of GLP-1–based incretin agonists (including GLP-1 RAs and the dual GIP/GLP-1 RA tirzepatide) in patients with obesity-related HFpEF and to quantify their effects through meta-analysis.
METHODS
PubMed/MEDLINE, EMBASE, Cochrane CENTRAL, and Web of Science were searched from inception to October 2025 for randomized controlled trials (RCT) evaluating GLP-1–based incretin agonist therapy in adults with HFpEF and obesity. Outcomes included health status [Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS)], body weight, exercise capacity, heart failure events, and safety. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analyses were performed for KCCQ-CSS and percentage body weight change.
RESULTS
Three RCTs (n = 1876) were included in quantitative synthesis: STEP-HFpEF (n = 529), STEP-HFpEF DM (n = 616), and SUMMIT (n = 731). GLP-1-based incretin agonist therapy significantly improved health status, with a pooled increase in KCCQ-CSS of +7.33 points [95% confidence interval (CI): 5.84 to 8.82; I² = 0%]. Substantial weight loss was observed, with a pooled reduction of -9.56 percentage points (95%CI: -12.15 to -6.97; I² = 58%). Tirzepatide significantly reduced the composite of cardiovascular (CV) death or worsening heart failure event (hazard ratio 0.62, 95%CI: 0.41-0.95; P = 0.026), while semaglutide trials demonstrated consistent favorable trends. Across trials, GLP-1-based therapies improved exercise capacity and were associated with fewer serious adverse events, with gastrointestinal symptoms being the most common side effect.
CONCLUSION
GLP-1-based incretin agonists produce clinically meaningful improvements in symptoms, functional capacity, and body weight in patients with obesity-related HFpEF, with consistent benefit across trials and acceptable safety. Meta-analysis confirms robust improvement in health status and substantial weight reduction, supporting this therapeutic class as a promising disease-modifying strategy for this high-risk HFpEF phenotype. Tirzepatide additionally reduced hard CV outcomes, providing proof of concept that targeting obesity can favorably alter HFpEF disease course.
Core Tip: Glucagon-like peptide-1 (GLP)-1-based incretin agonists, including semaglutide and the dual GIP/GLP-1 receptor agonist tirzepatide, produce consistent and clinically meaningful improvements in symptoms, functional capacity, and body weight in patients with obesity-related heart failure with preserved ejection fraction. Tirzepatide additionally reduced the composite of cardiovascular death or worsening heart failure events, establishing weight-centric pharmacotherapy as a promising disease-modifying strategy for this high-risk and previously treatment-resistant phenotype.
