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

Coenraad Withaar, Laura M.G. Meems, Edgar E. Nollet, E. Marloes Schouten, Marie A. Schroeder, Lotte B. Knudsen, Kristoffer Niss, Christian T. Madsen, Annabelle Hoegl, Gianluca Mazzoni, Jolanda van der Velden, Carolyn S.P. Lam, Herman H.W. Silljé, Rudolf A. de Boer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
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Abstract

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes. In a mouse model of HFpEF that was caused by advanced aging, female sex, obesity, and type 2 diabetes mellitus, semaglutide, compared with weight loss induced by pair feeding, improved the cardiometabolic profile, cardiac structure, and cardiac function. Mechanistically, transcriptomic, and proteomic analyses revealed that semaglutide improved left ventricular cytoskeleton function and endothelial function and restores protective immune responses in visceral adipose tissue. Strikingly, treatment with semaglutide induced a wide array of favorable cardiometabolic effects beyond the effect of weight loss by pair feeding. Glucagon-like peptide-1 receptor agonists may therefore represent an important novel therapeutic option for treatment of HFpEF, especially when obesity-related.

Original languageEnglish
Pages (from-to)1298-1314
Number of pages17
JournalJACC: Basic to Translational Science
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 2023

Bibliographical note

Funding Information:
The authors acknowledge Martin Dokter for his excellent technical assistance and Jose M. G. Izarzugaza and Lene Petersen for providing sequence data science support.

Publisher Copyright:
© 2023 The Authors

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