Saxagliptin improves glucose tolerance but not survival in a murine model of dilated cardiomyopathy

Objective: Glucagon-like peptide-1 (GLP-1) agonists improve myocardial function and insulin sensitivity in the setting of chronic heart failure. Endogenously produced GLP-1 peptide (7-36) is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) to 9-36 peptide, which lacks antihyperglycemic activity. The present study was designed to elucidate the effect of increased endogenous GLP-1 during heart failure progression. Methods: The DPP4 inhibitor saxagliptin or vehicle was administered by a daily oral gavage to female TG9 mice, a transgenic model of dilated cardiomyopathy, starting at 42 days of age, just before the development of detectable contractile dysfunction. Results: Saxagliptin treatment inhibited DPP4 activity by more than 90% and increased GLP-1 levels four-fold following a 2 g/kg glucose load, but did not affect fasting GLP-1 levels. There was no difference in food intake nor body weight between groups. At 56 days of age, oral glucose tolerance was improved in saxagliptin-treated versus vehicle-treated animals (AUC_0-120 1340±46 and 1501±43 min mmol/l, respectively, P < 0.015). In contrast to the effect of a GLP-1 agonist in TG9 mice, saxagliptin had no effect on survival (80.7±4.3 days) compared with the vehicle-treated mice (79.6±3.6 days, P = 0.46). Conclusions: Taken together, these data indicate that improvement in glucose tolerance is not sufficient to improve survival. Future efforts to confirm these findings in additional models of heart failure are warranted.