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

Abstract

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 (AUC0–120 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.