Abstract 13148: Dpp-4 Inhibition Improves Cardiac Function Following Experimental Myocardial Infarction: Potential Non-glp-1 Mediated Effects

Abstract

Background: Excessive myocyte apoptosis and impaired neoangiogenesis are implicated in the pathogenesis of heart failure following myocardial infarction (MI) in diabetic (DM) patients. Stromal derived factor-1 (SDF-1) is an anti-apoptotic/pro-angiogenic chemokine that is elaborated in response to ischemic injury but is degraded by di-peptidyl peptidase-4 (DPP-4). Because DPP-4 also degrades the glucose lowering incretin, GLP-1, inhibitors of DPP-4 are currently marketed for the treatment of type 2 diabetes. We speculated that DPP-4 inhibition may confer benefit following MI in the diabetic setting as a consequence of enhanced SDF-1 availability rather than potentiating GLP-1. To test this hypothesis we compared the DPP-4 inhibitor, saxagliptin with the GLP-1 agonist, liraglutide in a type 1 model of DM to avoid the confounding effects of GLP-1 on insulin.

Methods: Fischer F344 rats with streptozotocin (STZ)-diabetes were randomized to receive the DPP-4 inhibitor, saxaglitpin (10 mg/kg/d), liraglutide (0.2mg/kg/sc/d) or vehicle. Two weeks later animals underwent experimental MI. Cardiac function, assessed by conductance catheterisation and echocardiography were examined 4 weeks post-MI.

Results: All animals receiving STZ became diabetic (mean HbA1c >10%, P=NS between groups). MI size, 2 days post LAD ligation was similar in all MI groups as was systolic BP. When compared with untreated post-MI rats, those receiving saxagliptin had lower lung weight (indexed to body weight, p < 0.05), improved fractional shortening (p < 0.05) and better diastolic function in both early and late phases as measured by Tau and the slope of the end diastolic pressure volume relationship, respectively (p < 0.05 for both). By contrast, liraglutide-treated animals closely resembled those that had received vehicle (p=NS for all measures c/w sham or saxa treated animals).

Conclusion: Without affecting glycaemic control or blood pressure, saxagliptin-mediated DPP4 inhibition but not liraglutide-mediated GLP-1 agonism improved ventricular systolic and diastolic function post myocardial infarction in a model of type 1 diabetes. These findings suggest that non-GLP-1 effects such as SDF-1 potentiation may underlie the cardioprotective effects of DPP-4 inhibition.