Glucagon-like Peptide-1 Therapy in Obesity-Related Heart Failure with Preserved Ejection Fraction: Mechanisms, Clinical Evidence, and Implications.
This narrative review synthesizes current evidence on glucagon-like peptide-1 (GLP-1)-based therapies—primarily semaglutide and tirzepatide—for the management of obesity-related heart failure with preserved ejection fraction (HFpEF). Drawing on PubMed and Scopus literature published between January 2020 and March 2026, the authors incorporated randomized trials, pooled analyses, mechanistic studies, and observational data. The review describes how obesity-related HFpEF arises from a complex interplay of excess lipids, chronic inflammation, and metabolic dysregulation, which also interact with GLP-1 pathways. According to the authors, GLP-1-based therapies demonstrated meaningful improvements in symptoms, exercise capacity, and quality of life in this population, with benefits attributed to weight reduction, decreased systemic inflammation, and improved congestion indices. Tirzepatide was additionally associated with reductions in heart failure-related complications. Proposed mechanisms include coordinated effects on metabolism, inflammation, hemodynamics, and cardiac remodeling. The authors note that evidence for improvements in morbidity appears stronger than evidence for reductions in mortality. Key limitations include the narrative (non-systematic) review methodology, potential selection bias in study inclusion, and the absence of long-term mortality data. The authors conclude that further research is needed to clarify long-term outcomes, refine patient selection, and guide clinical integration.
Why this grade: This is a narrative review synthesizing existing studies rather than generating new primary human or experimental data, so it is graded as review-level evidence.
Background: Glucagon-like peptide-1 (GLP-1)-based therapies offer significant cardiometabolic benefits. Obesity-related heart failure with preserved ejection fraction (HFpEF) arises from a complex interplay of increased lipids, chronic inflammation, and metabolic disturbances. These factors not only exacerbate the disease but also affect GLP-1 pathways, supporting the potential role of GLP-1-based therapies in targeting this condition. Objective: This review aimed to synthesize the current evidence on GLP-1-based therapy in HFpEF, focusing on mechanisms of action, clinical outcomes, and practical significance. Methodology: A narrative review using PubMed and Scopus was conducted, including studies published between January 2020 and March 2026. Evidence from randomized trials, pooled analyses, mechanistic studies, and observational data was incorporated. Results: GLP-1-based therapies, including semaglutide and tirzepatide, demonstrated significant improvements in symptoms, exercise capacity, and quality of life. These benefits are closely linked to weight loss, reduced inflammation, and improved congestion indices. Tirzepatide use has also been associated with a reduction in heart failure-related complications. The underlying mechanisms likely involve coordinated effects on metabolism, inflammation, hemodynamics, and cardiac remodeling. Current evidence suggests that its efficacy in improving morbidity rates is stronger than its efficacy in reducing mortality rates. Conclusions: GLP-1-based therapies offer a promising, phenotypically targeted approach to managing obesity-associated HFpEF. However, their long-term effects on mortality remain unclear, highlighting the need for further research. Further studies should refine patient selection and define optimal clinical integration.
Educational summary of published research — not medical advice. License: cc by. Full text is shown only where licensing permits.