Why the study?
Although GLP-1RAs improve outcomes in obese HFpEF, it remains unclear whether their benefits reflect weight reduction alone or direct modification of HFpEF pathophysiology.
Does semaglutide improve cardiac and systemic features of HFpEF in a preclinical mouse model of obesity and volume overload?
Does semaglutide improve cardiac and systemic features of HFpEF in a preclinical mouse model of obesity and volume overload?
In a novel mouse model of cardiometabolic HFpEF, semaglutide attenuated hypertension, tended to reduce volume expansion, and reduced left atrial remodelling, supporting direct effects on systemic and cardiac drivers of HFpEF.
Supports mechanistic studies of GLP-1RAs in HFpEF; extends preclinical data complementing STEP-HFpEF and SUMMIT but leaves clinical translation open.
Background Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent cardiometabolic syndrome linked to obesity, type 2 diabetes, and hypertension. Recent trials, including STEP-HFpEF1 and SUMMIT2, demonstrate that glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve outcomes in obese HFpEF. However, as GLP-1RAs induce substantial weight loss, it remains unclear whether benefits reflect weight reduction alone or direct modification of HFpEF pathophysiology. Purpose To determine whether semaglutide improves cardiac and systemic features of HFpEF in a novel preclinical model of obesity and volume overload. Methods Male wild-type mice were fed a high-fat diet (HFD; 36% fat) for 16 weeks to induce obesity. Hypertension was induced at week 10 via uninephrectomy with deoxycorticosterone acetate (DOCA; 2.4 mg/day, s.c.) and 0.9% saline drinking water (1K/DOCA/salt). Semaglutide (0.04 mg/kg) or vehicle was administered every second day for 42 days. Blood pressure was measured by tail-cuff plethysmography, body composition by EchoMRI, and cardiac tissue analysed for histopathology and mRNA expression. Results 1K/DOCA/salt + HFD increased blood pressure within 14 days compared with controls; semaglutide attenuated this rise (141 ± 10 vs. 120 ± 17 and 112 ± 14 mmHg; P < 0.05; n = 7–10). Free water content was elevated in 1K/DOCA/salt + HFD mice versus controls (0.37 ± 0.17 vs. 0.13 ± 0.06; P < 0.001) and tended to decrease with semaglutide (P = 0.059). Left atrial weight was increased in 1K/DOCA/salt + HFD mice (6.03 ± 0.23 vs. 4.14 ± 1.17 mg; P < 0.05) and reduced by semaglutide (5.56 ± 0.30 mg; P < 0.05). Conclusion Semaglutide improved haemodynamic and structural features of cardiometabolic HFpEF, attenuating hypertension, volume expansion, and atrial remodelling. These findings support GLP-1 receptor agonism as a therapeutic strategy targeting systemic and cardiac drivers of HFpEF.
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Thomas et al. (2026) studied this question.
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