Abstract
BackgroundUremic 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).Methodology/Principal FindingsIn 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/SignificanceDPP-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.
Highlights
Chronic kidney disease (CKD) and end-stage renal disease (ESRD), have been shown to increase cardiovascular disease and risk of death [1,2]
We studied the pharmacokinetics and pharmacodynamics of different dipeptidyl peptidase-4 (DPP-4) inhibitors, in the settings of chronic renal failure (CRF), in order to determine the properties of DPP-4 inhibitors to be used in patients with impaired renal function, and investigated the effects of linagliptin on biomarkers of cardiac and renal fibrosis
The results showed that DPP-4 inhibition increases plasma Glucagon-like peptide-1 (GLP-1) levels, in uremia, suggesting that linagliptin may offer a unique approach for treating uremic cardiomyopathy in chronic kidney disease (CKD) patients
Summary
Chronic kidney disease (CKD) and end-stage renal disease (ESRD), have been shown to increase cardiovascular disease and risk of death [1,2]. This has been substantiated in a systematic review on mortality risk, which concluded that increased risk for all-cause mortality in CKD patients was largely driven by cardiovascular deaths (58% deaths from 13 studies reporting both cardiovascular and all-cause deaths) [3]. Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4)
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