The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

•Asks how the effects of semaglutide compare with the effects of weight loss by Pair Feeding (PF) in a mouse model of HFpEF and which cardioprotective effects of semaglutide are achieved in HFpEF.•PF and semaglutide reduce bodyweight and adipose tissue to a similar degree.•Semaglutide improves cardiometabolic profile, cardiac structure, and cardiac function.•Semaglutide improves LV cytoskeleton function and endothelial function and restores protective immune responses in VAT.•Semaglutide prompts a wide array of favorable cardiometabolic effects beyond that of weight loss by PF. Semaglutide may therefore represent an important novel therapeutic option for obesity-related HFpEF.