Different Augmentation of Left Ventricular Contractility of Mice during Myocardial Infarction following Gliptin and Sulfonylurea Treatment

Abstract

DPP-4 inhibitors are a class of antidiabetic drugs which act by augmentation of the GLP-1 system and insulin secretion. Despite similar glucose lowering efficacy within the class, only saxagliptin increased heart failure hospitalization in diabetic patients. This unexpected effect might relate to the metabolism of saxagliptin (saxa). Here, we directly compare linagliptin (lina, 3 mg/kg, p.o.), saxa (10 mg/kg, p.o.), and its metabolite 5-hydroxy-saxagliptin (OH-saxa, 10 mg/kg, p.o.) to the sulfonylurea glimepiride (glim, 2 mg/kg, p.o.) and control during acute myocardial infarction in mice. Millar catheter analysis under dobutamin stress 6h post (permanent) LAD ligation were performed. Drugs were given 3 days prior infarction. Active GLP-1 was significantly increased by Lina (1,69 fold), saxa (1,49 fold) and OH-saxa (2,27 fold) vs. control (each p < 0.05), but not by glim. Despite similar GLP-1 levels, only lina and saxa but not OH-saxa or glim increased left ventricular contractility (Lina: 11.549 ± 795 dp/dt max; p < 0.0001; n=9. Saxa: 10.121 ± 200 dp/dt max; p < 0.05; n=12. OH-saxa: 8.201 ± 567 dp/dt max; n=7. Glim: 9.947 ± 813 dp/dt max; n=6 relative to control: 8.764 ± 284 dp/dt max; n=21). We further isolated mitochondria from non-infarcted myocardial tissue and found for lina 2.89 fold (p < 0.0001; n=3), saxa 1.78 fold (p < 0.05; n=8) and OH-saxa 2.2 fold (p < 0.01; n=4) increase in mitochondrial respiration by Clark electrode, but not for glim. In conclusion, only linagliptin and saxagliptin increased left ventricular contractility and myocardial mitochondrial respiration following LAD ligation; 5-hydroxy-saxagliptin had no effect on contractility despite increasing mitochondrial respiration. Glimepiride had no effect on contractility and mitochondrial function. Metabolism of saxagliptin might be linked to differences found in the DPP-4 class regarding heart failure. Disclosure E. Haj-Yehia: None. S. Diebold: None. J. Moellmann: None. F. Kahles: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. M. Mark: Employee; Self; Boehringer Ingelheim GmbH. N. Marx: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. M. Lehrke: Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi, Amgen Inc., Bayer AG, MSD K.K..