Renoprotective Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin: A Review in Type 2 Diabetes

Abstract

Diabetic nephropathy (DN) is now the single commonest cause of end-stage renal disease (ESRD) worldwide and one of the main causes of death in diabetic patients. It is also acknowledged as an independent risk factor for cardiovascular disease (CVD). Since sitagliptin was approved, many studies have been carried out revealing its ability to not only improve metabolic control but also ameliorate dysfunction in various diabetes-targeted organs, especially the kidney, due to putative underlying cytoprotective properties, namely, its antiapoptotic, antioxidant, anti-inflammatory, and antifibrotic properties. Despite overall recommendations, many patients spend a long time well outside the recommended glycaemic range and, therefore, have an increased risk for developing micro- and macrovascular complications. Currently, it is becoming clearer that type 2 diabetes mellitus (T2DM) management must envision not only the improvement in glycaemic control but also, and particularly, the prevention of pancreatic deterioration and the evolution of complications, such as DN. This review aims to provide an overview of the current knowledge in the field of renoprotective actions of sitagliptin, namely, improvement in diabetic dysmetabolism, hemodynamic factors, renal function, diabetic kidney lesions, and cytoprotective properties.

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

“…Among a variety of potential mechanisms by which DPP4 inhibitors exert this renoprotective effect on damaged kidneys, we focused on the regulation of NLRP3 inflammasome activity. Similarly to previous studies [29,33], we found no improvement in serum creatinine levels by DPP4 inhibition. Proteinuria contributes to tubulointerstitial inflammation, leading to renal fibrosis.…”

“…Finally, we showed that these inflammatory processes were effectively blocked by sitagliptin treatment. Previous studies have shown that sitagliptin treatment reduces renal inflammation and oxidative stress in animal models of type 2 diabetes [29,35].…”

“…DPP4 inhibition has been a plausible treatment strategy for management of diabetic nephropathy [29]. However, only a few previous studies have shown that DPP4 inhibitors play a role in preventing the progression of non-diabetic kidney disease.…”

“…Although we failed in reversing heavy proteinuria by using sitagliptin or linagliptin in our rat model of doxorubicin nephropathy, both DPP4 inhibitors were successful in ameliorating tubulointerstitial injury and interstitial fibrosis, most likely via anti-inflammatory action. Previous studies have shown that DPP4 inhibition can improve renal histopathology in animal models of diabetic nephropathy [29,32]. Among a variety of potential mechanisms by which DPP4 inhibitors exert this renoprotective effect on damaged kidneys, we focused on the regulation of NLRP3 inflammasome activity.…”

Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas and Other Glucose-lowering Therapies for Three Acute Outcomes

“…Given that the DPP4 enzyme is present in various components of the endothelial and epithelial kidney tissues (including renal proximal tubular epithelia, podocytes, mesangial cells, and pre-glomerular vascular smooth muscle cells), it has been hypothesized that DPP4 inhibitors will have a protective effect on the kidney by reducing inflammation and fibrosis and improving overall function 6,7 . However, other mechanisms may be responsible for acute changes in renal function including fluid depletion and volume contraction via vomiting and diarrhea, although evidence exists suggesting a beneficial effect of natriuretic and diuretic properties of DPP4 inhibitors 8,9 . Findings from observational studies have been inconsistent.…”