Semaglutide Shows Potential in Obesity-Associated HFpEF, suggests study
A preclinical study published in the European Heart Journal suggests that semaglutide (Ozempic, Wegovy) may have potential to reverse obesity-associated heart failure with preserved ejection fraction (HFpEF). The findings provide a rationale for further clinical investigation of semaglutide as a treatment for obesity-related HFpEF. The study was conducted by Mahmoud H. and colleagues.
To identify mechanisms that operate independently of weight loss, the effects of semaglutide at doses not inducing weight loss were assessed in two translational models: male ZSF1 Obese rats (n = 12/group) and female Göttingen minipigs with "two-hit" induced cardiometabolic HFpEF (early intervention: n = 5/group; late intervention: n = 4/group). The comprehensive diagnostic assessment included invasive measurement of left ventricular end-diastolic pressure (LVEDP) and pulmonary capillary wedge pressure (PCWP), echocardiography, and histological quantification of myocardial interstitial fibrosis and lipid deposition.
In pre-existing HFpEF in swine, cardiac MRI was used for prospective quantification of fat depots (subcutaneous and ectopic). In rodents, advanced multi-omics analysis using NULISA plasma proteomics, single cell RNA sequencing, and tissue proteomics was conducted to define cardiomyocyte-specific signaling.
Key findings:
- The evaluation of rodent and swine HFpEF models has shown very impressive results in terms of functional improvement and histology regardless of the body weight loss.
- Sub-weight-loss therapy with semaglutide in ZSF1 Obese rats resulted in a considerable improvement in the left ventricle diastolic function associated with a reduction in invasively measured LVEDP by almost 60% and decreased cardiac hypertrophy by about 30%.
- Cardiac lipidosis and interstitial fibrosis were also significantly decreased.
- In the early-intervention HFpEF minipig model, treatment with semaglutide stopped the development of LV hypertrophy, significantly improved the echocardiographically determined E/e' ratio, and normalized PCWP without body weight loss, as well as normalized the advanced hepatic bridging fibrosis.
To conclude, preclinical data obtained in rodent and swine models reveal strong cardioprotective and hepatoprotective actions of semaglutide in cardiometabolic HFpEF that are not mediated by weight loss. It is important to stress that conclusions drawn from this study highlight the role of direct inhibition of pro-fibrotic signaling and restoration of cardiomyocytes' metabolism in these beneficial effects.
Reference:
Mahmoud H Elbatreek, Zhen Li, Xiaoman Yu, Natalie D Gehred, Tatiana Gromova, Jingshu Chen, Miguel Huerta, Naoto Muraoka, Martin Borch Jensen, Vinay Kartha, Chris Carrico, Timothy D Allerton, Xinheng Zhang, Hsin-Jung R Yang, Michael E Bowdish, Sanjiv J Shah, Kathleen C Woulfe, Timothy A McKinsey, Edwin Yoo, David J Polhemus, Thomas M Vondriska, David J Lefer, Traci T Goodchild, Semaglutide, independent of weight loss, attenuates cardiac and hepatic remodelling in experimental heart failure with preserved ejection fraction, European Heart Journal, 2026;, ehag732, https://doi.org/10.1093/eurheartj/ehag732
