Poster Session 2 - C8
1Dorrin Zarrin Khat, 4Abdul Momen, 4Muhammad A. Siraj, 2Sina Hadipour-Lakmehsari, 4Mark J. Chandy, 1-5.Mansoor Husain
1 Departments of Laboratory Medicine & Pathobiology, 2 Physiology, 3 Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto; 4 Toronto General Hospital Research Institute,5 Ted Rogers Centre for Heart Research, Toronto, ON, Canada
Introduction: In addition to glucose-lowering effects, anti-diabetic drugs such as sodium glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) independently reduce major adverse cardiovascular events (MACE) in subjects with type-2 diabetes (T2D). It is not known if this is through shared or distinct mechanisms, or whether combining both agents would have additive effects. Hypothesis: Combined treatment with SGLT2i dapagliflozin [Dapa] and GLP-1RA exenatide [Ex4] will be more cardioprotective against ischemia-reperfusion injury (IRI) than either agent alone. Methods/Results: Non-diabetic male C57BL/6-J mice were randomized to treatment with Dapa, Ex4, both, or vehicle for 7-days (d), followed by in vivo IRI via transient coronary artery ligation. Functional recovery from IRI was assessed on d2 by echocardiography, and area at risk (AAR) and infarct size were demarcated by Evan’s blue and TTC-staining, respectively. Mice treated with Dapa, Ex4, and both, suggest improved ejection fraction [EF] (50%, 53%, 48%, respectively) vs. controls (41%) [sham 63%]. Treatment with Dapa and Ex-4 did not reduce infarct size/AAR vs. controls. Analysis of cardiac remodeling at d28 post-IRI mice treated with Dapa, Ex4, and combination showed improved EF (41%, 43%, 50%, respectively) vs. controls (36%). These improvements in cardiac function were associated with reduced infarct size (%) in mice treated with combination (17%) vs. Dapa (39%), Ex4 (29%), and controls (44%). GLP-1RA and SGLT2i appeared to modulate basal respiration of cardiomyocytes isolated after in vivo treatment. Conclusions: Non-diabetic mice treated with both SGLT2i and GLP-1RA demonstrate better protection from IRI than either agent alone, or controls. These findings suggest further studies of combined use of these agents are needed in a condition (IRI) for which there is no approved therapy.