Dipeptidyl peptidase-4 inhibition improves left ventricular function in chronic kidney disease

Abstract

Purpose: Heart failure with preserved ejection fraction (HFpEF) is a common comorbidity in people with chronic kidney disease (CKD) for which no evidence-based treatment currently exists. Recently, a group of anti-hyperglycemic agents used in the treatment of Type 2 diabetes, termed incretin-based therapies, have come under scrutiny for their putative glucose-independent effects on cardiac function. In the present study, the actions of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of incretin-based therapy in preventing HFpEF induced by chronic renal impairment were investigated. Methods: Sham-operated and subtotally-nephrectomized rats were randomized to receive the DPP-4 inhibitors, linagliptin or sitagliptin for seven weeks before assessment of cardiac and renal structure and function. Results: Analysis of pressure-volume loops revealed that both linagliptin and sitagliptin prevented the development of cardiac diastolic dysfunction, with cardiac collagen I synthesis also being reduced by DPP-4 inhibition. These attenuating cardiac effects occurred without change in renal function or structure where, in the doses administered, neither linagliptin nor sitagliptin affected GFR decline, proteinuria, renal fibrosis or the increased urinary excretion of biomarkers of renal toxicity. Conclusion: The beneficial cardiac effects of DPP-4 inhibition, in the absence of a concurrent improvement in renal dysfunction, raise the possibility that these agents may confer cardiovascular advantages in the CKD population.

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

“…Furthermore, linagliptin normalized the expression of the following key molecular markers of uremic cardiomyopathy in this model: TGF-β, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and procollagen type 3 α1 (Col3α1) [131]. Similarly, in a separate study utilizing a rat model of uremic cardiomyopathy, linagliptin prevented the development of cardiac diastolic dysfunction without affecting renal function [132]. Theoretically, other DPP-4 inhibitors that are excreted in the urine may modify the proteolytic activity of apical membrane-bound DPP-4 in the proximal tubule [133].…”

Potential Role of Dipeptidyl Peptidase IV in the Pathophysiology of Heart Failure

“…HF is characterized by cardiac dysfunction, increased renal vascular resistance and sodium retention. The findings that DPPIV catalytic activity, as well as its binding properties, are associated with increased sodium reabsorption [ 26 , 39 , 40 ], inflammation [ 41 , 42 , 43 ] and cardiac fibrosis [ 32 , 33 , 36 , 37 , 38 ] are consistent with the hypothesis that increased DPPIV activity plays a role in the pathophysiology of HF. In this review, we discuss how DPPIV might be involved in the cardio-renal axis of HF.…”

“…In fact, together with seprase, DPPIV forms a protease complex that contributes to cell migration and repair of connective tissue [ 31 ]. Interestingly, DPPIV inhibition has been shown to attenuate cardiac fibrosis in HF rats [ 32 , 33 , 34 ] as well as in other models of cardiac disease [ 35 , 36 , 37 , 38 ]. It is therefore tempting to speculate that an association of DPPIV with collagen and/or fibronectin may be involved in cardiac tissue remodeling, but this assumption requires further investigation.…”

DPP4 in Cardiometabolic Disease

“…DPP4 levels correlate with heart failure with plasma DPP4 activity being significantly higher in patients with more advanced 127,128 Pharmacological DPP4 inhibition in models of diabetic cardiomyopathy, pressure overload model of heart failure has been consistently shown to improve ventricular remodeling and survival as well as ameliorating severity of heart failure. [120][121][122][123][124][125][126] Similarly, both pharmacological and genetic DPP4 inhibition reversed diabetic diastolic left ventricular dysfunction and pressure-overload-induced left ventricular dysfunction. 120 Diabetes mellitus is well known to impair angiogenic ability through SDF-1α-dependent pathways in cardiac tissue.…”