title: Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy.
abstract: BACKGROUND
  Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).
  
  
  RESULTS
  In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.
  
  
  CONCLUSIONS
  DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.
authors: Charité-Universitätsmedizin Berlin, Center for Cardiovascular Research, Institute for Pharmacology and Toxicology, Berlin, Germany.
authors: Lyubov
authors: L
authors: Chaykovska
authors: Karoline
authors: K
authors: von Websky
authors: Jan
authors: J
authors: Rahnenführer
authors: Markus
authors: M
authors: Alter
authors: Susi
authors: S
authors: Heiden
authors: Holger
authors: H
authors: Fuchs
authors: Frank
authors: F
authors: Runge
authors: Thomas
authors: T
authors: Klein
authors: Berthold
authors: B
authors: Hocher
mesh_terms: D000818:Animals; D019540:Area Under Curve; D009202:Cardiomyopathies / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005919:Glomerular Filtration Rate; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control; D000069476:Linagliptin; D009206:Myocardium / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D009392:Nephrectomy; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D014511:Uremia / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D011687:Purines; D011719:Pyrazines; D011799:Quinazolines; D014230:Triazoles; D020097:Natriuretic Peptide, Brain; D000069476:Linagliptin; D014498:Uracil; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; C520853:alogliptin; D000068900:Sitagliptin Phosphate