Dipeptidyl peptidase-4 inhibition in chronic kidney disease and potential for protection against diabetes-related renal injury

Abstract

The improvement in albuminuria associated with DPP-4i suggests that these agents may provide renal benefits beyond their glucose-lowering effects, thus offering direct protection from DKD. These promising results must be interpreted with caution and need to be confirmed in forthcoming studies.

Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes

“…Several recent reviews have explored the effects of DPP-4is on surrogate renal outcomes [70][71][72]. Renal protection has been demonstrated in various animal models implicating different underlying mechanisms independent of glucose control, including: upregulation of GLP-1 and GLP-1 receptors; inhibition of renal DPP-4 activity; attenuation of inflammasome activation, reduction of oxidative stress; mitochondrial dysfunction and apoptosis; suppression of connective-tissue growth factor; limitation of TGFb-related fibrosis and nuclear factor (NF)-kB p65-mediated macrophage infiltration; reduction of renal tubulointerstitial fibronectin; upregulation of stromal cell-derived factor-1; suppression of advanced glycation end-products; regulation of proliferation of preglomerular vascular smooth muscle and mesangial cells; and attenuation of rises in blood pressure [70][71][72][73]. However, despite such promising results in animal models, data on surrogate biological markers of renal function (UACR, eGFR) and clinical renal outcomes (progression to ESRD) are still relatively scanty in patients with T2DM, and mostly demonstrate the safety rather than true efficacy of DPP-4is regarding renal protection [70].…”

The kidney and cardiovascular outcome trials

“…Interestingly, there was no relationship between improvement in albuminuria and improvement in HbA1c . The other DPP4i CVOTs have not reported effects of these agents on renal function or albuminuria, but studies of sitagliptin and linagliptin suggest that these agents may also reduce albuminuria.…”

Treatment of diabetic kidney disease: current and future targets

“…Recently, growing evidence suggests that two oral hyperglycemic agents, dipeptidyl peptidase 4 (DPP-4) inhibitors [17,18], and sodium-glucose cotransporter 2 (SGLT2) inhibitors, exert renoprotective effects [19,20]. …”