Benefits of Semaglutide in Heart Failure are not Just Due to Weight Loss, in Mice at Least

GLP-1 receptor agonists such as semaglutide are suddenly a popular topic in the pharmaceutical industry. They alter metabolism to produce weight loss and improve the dysregulation that is characteristic of type 2 diabetes. Like any newly popular drug category, GLP-1 receptor agonists will now be assessed for their ability to produce marginal benefits in all sorts of conditions, from cancer to heart failure. Given that excess visceral fat is harmful, it is plausible that any marginal benefits will emerge largely or entirely due to weight loss in initially overweight patients. With that in mind, researchers here produce data in mice to argue that, at least in the case of heart failure, there are other mechanisms involved.

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.