Mechanisms of GLP-1 Receptor Agonists in HFpEF: Exploring Weight-Dependent and Independent Drivers of Therapeutic Benefit

Figures

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  Figure 1.. Organ-specific effects of GLP-1 (glucagon-like peptide-1) signaling. Endogenous GLP-1 or exogenous GLP-1RAs (GLP-1 receptor agonists) act via widely distributed GLP-1 receptors to modulate key physiological processes. In the brain, GLP-1 reduces food intake and regulates blood pressure (BP) via sympathetic nerve activity. In the heart, it influences heart rate and inflammation, reducing hypertrophy and promoting anti-inflammatory signaling. In the lung, it reduces inflammation and contributes to vasodilatation. In the pancreas, it enhances insulin secretion and glucose control. In the kidney, GLP-1 improves renal blood flow and promotes natriuresis by modulating Ang II (angiotensin II) and NHE3 (sodium-hydrogen exchanger 3). In the vasculature, it supports vasodilation and reduces endothelial inflammation and leukocyte infiltration. ICAM indicates intercellular adhesion molecule; IL, interleukin; NTS, nucleus tractus solitarius; PKA, protein kinase A; ROS, reactive oxygen species; RVLM, rostral ventrolateral medulla; SNA, sympathetic nerve activity; and VCAM, vascular cell adhesion molecule. Created with BioRender.com. Thomas, J. and Dagan, M. (2026) https://BioRender.com/gy6cdbq.

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  Figure 2.. Summary of GLP-1RA (glucagon-like peptide-1 receptor agonist) effects in heart failure with preserved ejection fraction (HFpEF). GLP-1RAs impact autonomic signaling, cardiovascular function, inflammation, metabolism, vasculature, central control, gastric emptying, renal function, and adiposity—factors linked to reduced morbidity and hospitalizations, as shown in the SUMMIT and STEP-HFpEF trials. BMI indicates body mass index; BP, blood pressure; CRP, C-reactive protein; FFA, free fatty acid; HbA1c, hemoglobin A1c; hs, high sensitivity; IL, interleukin; NF-κB, nuclear factor-κB; NT-proBNP, N-terminal pro-B-type natriuretic peptide; RAAS, renin angiotensin aldosterone system; STEP-HFpEF, Semaglutide Treatment Effect in People With Obesity and HFpEF; SUMMIT, Study of Tirzepatide in Participants With HFpEF and Obesity; and TNFα, tumor necrosis factor α. Created with BioRender.com. Thomas, J, and Dagan, M. (2026) https://BioRender.com/gy6cdbq.

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  Figure 3.. Cardiac effects of GLP-1RAs (glucagon-like peptide-1 receptor agonists) in heart failure with preserved ejection fraction (HFpEF). GLP-1RAs improve diastolic function (lower E/e’ and left atrial [LA] area), reduce atrial fibrillation, peri- and para-cardiac fat, right ventricular (RV) area, left ventricular (LV) pressure/volume curves, and ventricular mass. Preclinical data show reduced fibrosis and myocardial hypertrophy. Effects on contractility are variable, and impacts on RV mass and systolic pressure are unclear. *Data from 1 study only. †Observed with GLP-1RA but not with dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1RA therapy. RVSP indicates right ventricular systolic pressure. Created with BioRender.com. Thomas, J. and Dagan, M. (2026) https://BioRender.com/gy6cdbq.

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  Figure 4.. Overlapping effects of weight loss and GLP-1RA (glucagon-like peptide-1 receptor agonist) therapy. GLP-1RAs contribute to improvements in left atrial (LA) function, atrial fibrillation (AF), blood pressure, blood volume, diastolic function, and cardiac metabolism, while also reducing systemic inflammation, left ventricular (LV) mass, right ventricular (RV) remodeling, and cardiac adiposity. The reductions in LV mass, blood pressure, and blood volume are likely directly related to GLP-1RA therapy, while other effects may also stem from the concomitant impact of weight loss. Created with BioRender.com. Thomas, J. and Dagan, M. (2026) https://BioRender.com/gy6cdbq.