Impact of the novel DPP-IV-inhibitor Dutogliptin in combination with G-CSF on survival rates and cardiac remodelling after acute myocardial infarction

BACKGROUND This study analysed the effects of different treatment regimens involving administration of the novel new DPP-IV (dipeptidylpeptidase IV)-inhibitor Dutogliptin alone and in combination with G-CSF on myocardial regeneration and survival after myocardial infarction in a mouse model. The SDF-1-CXCR4 axis is a key mechanism of cardiac homing of stem cells. G-CSF is known to mobilize bone-marrow-derived stem cells into peripheral blood. Dutogliptin has an excellent clinical safety profile that prevents the cleavage of the essential stem cell homing factor SDF-1. METHODS After myocardial infarction by surgical occlusion of the left descending artery in CD1 mice, Dutogliptin was administered from day 1 to 28 by gavage alone in high/low dose and in combination with standard G-CSF application. Infarct size in the different study arms was assessed by histology and on cardiac survival using the Kaplan-Maier-method. RESULTS High dose Dutogliptin administered in combination with GCSF significantly improved survival and reduced infarct size compared to Dutogliptin, G-CSF and saline administered alone. CONCLUSION Dutogliptin is a novel, clinically proven DPP-IV-inhibitor with a unique safety and compound profile, initially developed for diabetes and repurposed for the parenteral use in cardiovascular diseases. This is the first study in a myocardial infarction mouse model showing that administration of high dose Dutogliptin in combination with G-CSF improves cardiac remodelling and significantly prolongs survival after acute myocardial infarction. Based on the already completed pre-clinical program, a global phase 2 study to evaluate the effects of Dutogliptin in co-administration with G-CSF in patients with myocardial infarction will start shortly.