Triple-G therapy in rodent HFpEF models significantly reduced body weight and fat mass, and improved endurance exercise capacity and left ventricular diastolic function compared to vehicle.
Does a GLP-1/GIP/Glucagon triple agonist improve cardiac function, exercise capacity, and alter the cardiac proteomic signature in rodent HFpEF models?
A GLP-1/GIP/Glucagon triple agonist improves diastolic function, exercise capacity, and body composition in rodent HFpEF models, with proteomic changes suggesting metabolic, antioxidant, and anti-fibrotic benefits.
Heart failure with preserved ejection fraction (HFpEF) with a cardiometabolic etiology is driven by a constellation of comorbidities such as diabetes, obesity, and hypertension. Recent STEP-HFpEF and SUMMIT clinical trials have demonstrated the potential of GLP-1 receptor agonists as a novel treatment strategy, given their ability to manage glucose and induce weight loss. However, the mechanisms by which incretin agonists confer cardioprotective characteristics in the HFpEF population outside of weight loss remain unknown. In this study, we aim to explore the cardiac effects of the triple agonist (triple-G) in preclinical rodent HFpEF models and the molecular pathways underlying these effects. We hypothesize that animals treated with the triple-G will have better cardiac and exercise capacity outcomes due to reduced body weight and adiposity. The “two-hit” mouse and the ZSF1 obese rat models were utilized and treated with the triple-G agonist for 5 and 10 weeks, respectively after confirmation of HFpEF. Body weight, DEXA, echocardiography, and exercise tolerance test served as non-invasive physiological assessments. Untargeted cardiac proteomics was performed to examine the protein profile of the treated vs. vehicle HFpEF animals. Our data show that treated HFpEF animals exhibited significant reductions in body weight, water intake, and food consumption. The body composition analysis showed that treated animals had significantly less fat mass compared to control animals. These body compositional changes were accompanied by significant improvements in endurance exercise capacity and left ventricular diastolic function (E/e’) assessed by echocardiography. Proteomics of rat hearts indicated changes in several pathways involved in lipid and glucose metabolism, redox balance, and inflammation. CES1C, a carboxylesterase essential in lipid metabolism, the antioxidant, glutathione S-transferase were both upregulated in the treated group. Decorin, a known antagonist of TGF-beta, was upregulated in the treated rat, providing preliminary evidence of triple-G’s ability to inhibit fibrotic deposition and promote reverse remodeling. In summary, our study demonstrates the efficacy of triple-G therapy for treating HFpEF and begins to characterize the proteomic profile, uncovering potential pathways by which triple-G confers cardiac benefits, paving the way for novel therapeutic strategies and targets in HFpEF. Funding: R01 AA029984 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Van et al. (Fri,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). GLP-1/GIP/Glucagon Triple Agonist (triple-G) vs. Vehicle was evaluated on Body weight, adiposity, cardiac and exercise capacity outcomes, and cardiac proteomic profile. Triple-G therapy in rodent HFpEF models significantly reduced body weight and fat mass, and improved endurance exercise capacity and left ventricular diastolic function compared to vehicle.