Semaglutide, independent of weight loss, attenuates cardiac and hepatic remodelling in experimental heart failure with preserved ejection fraction.

BACKGROUND AND AIMS: Heart failure with preserved ejection fraction (HFpEF) remains a significant therapeutic challenge. While GLP-1 receptor agonists (GLP-1RAs) show clinical promise, it remains unknown if their benefits are driven solely by weight loss or involve weight loss-independent mechanisms. We investigated the weight loss-independent effects of semaglutide in two preclinical models of cardiometabolic HFpEF: the ZSF1 Obese rat and the Göttingen HFpEF minipig. METHODS: Male ZSF1 Obese rats (n = 12/group) and female Göttingen minipigs with 'two-hit' induced HFpEF (early intervention: n = 5/group; delayed intervention: n = 4/group) were treated with semaglutide at doses empirically determined to be non-weight-loss inducing. Comprehensive assessments included invasive hemodynamic (LVEDP, PCWP), echocardiography, and histological quantification of fibrosis and lipid burden. Delayed intervention utilized Cardiac MRI to quantify subcutaneous and ectopic fat depots. In rats, advanced multi-omics (NULISA plasma proteomics, single-cell RNA sequencing and tissue proteomics) were utilized to explore molecular mechanisms. RESULTS: In ZSF1 Obese rats, semaglutide significantly improved diastolic function (reducing LVEDP by ∼60%) and attenuated cardiac hypertrophy (by ∼30%), interstitial fibrosis, and cardiac lipid deposition in the absence of a significant weight loss. These functional benefits were conserved in the minipig HFpEF model, where treatment attenuated cardiac hypertrophy, left ventricular E/e', normalized pulmonary capillary wedge pressure (PCWP) and reversed advanced hepatic bridging fibrosis. Delayed intervention in established HFpEF minipigs reversed diastolic dysfunction and significantly reduced ectopic lipid depots (intramyocardial, epicardial, and hepatic fat) without affecting subcutaneous fat or total body weight. Mechanistically, multi-omics analyses in the rat heart revealed that these benefits were driven by suppression of pro-fibrotic and hypertrophic signals and up-regulation of branched-chain amino acid (BCAA) catabolism and fatty acid oxidation pathways in cardiomyocytes. CONCLUSIONS: Semaglutide attenuates cardiac and hepatic remodelling in preclinical models of obesity-associated cardiometabolic HFpEF in the absence of profound weight loss. The conservation of these effects across male rodents and female swine supports their translational relevance, while future studies are needed to define dose equivalence and confirm GLP-1 receptor engagement in cardiac and hepatic tissues. These findings support further mechanistic investigation of weight loss-independent GLP-1 receptor agonist signalling in this HFpEF phenotype.