Connelly_2016_J.Diabetes_8_63

BACKGROUND: In addition to degrading glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4) inactivates several chemokines, including stromal cell-derived factor-1alpha (SDF-1alpha), a pro-angiogenic and cardiomyocyte protective protein. We hypothesized that DPP-4 inhibition may confer benefit following myocardial infarction (MI) in the diabetic setting as a consequence of enhanced SDF-1alpha availability rather than potentiating GLP-1. To test this we compared the effects of saxagliptin with those of liraglutide and used the SDF-1alpha receptor (CXCR4) antagonist plerixafor.
METHODS: Studies were conducted in streptozotocin-diabetic rats. Rats were randomized to receive saxagliptin (10 mg/kg per day), liraglutide (0.2 mg/kg, s.c., b.i.d.), plerixafor (1 mg/kg per day, s.c.), saxagliptin plus plerixafor or vehicle (1% phosphate-buffered saline). Two weeks later, rats underwent experimental MI, with cardiac function examined 4 weeks after MI.
RESULTS: Glycemic control and MI size were similar in all groups. Four weeks after MI, mortality was reduced in saxagliptin-treated rats compared with vehicle treatment (P < 0.05). Furthermore, rats receiving saxagliptin had improved cardiac function compared with vehicle-treated rats (P < 0.05). Antagonism of CXCR4 prevented the improvement in cardiac function in saxagliptin-treated rats and was associated with increased mortality (P < 0.05). CONCLUSION: Saxagliptin-mediated DPP-4 inhibition, but not liraglutide-mediated GLP-1R agonism, improved cardiac function after MI independent of glucose lowering. These findings suggest that non-GLP-1 actions of DPP-4 inhibition, such as SDF-1alpha potentiation, mediate biological effects.