The gut–renal axis: do incretin-based agents confer renoprotection in diabetes?

Abstract

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, and is associated with a high risk of cardiovascular morbidity and mortality. Intensive control of glucose levels and blood pressure is currently the mainstay of both prevention and treatment of diabetic nephropathy. However, this strategy cannot fully prevent the development and progression of diabetic nephropathy, and an unmet need remains for additional novel therapies. The incretin-based agents--agonists of glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades glucagon-like peptide 1--are novel blood-glucose-lowering drugs used in the treatment of type 2 diabetes mellitus (T2DM). Therapeutic agents from these two drug classes improve pancreatic islet function and induce extrapancreatic effects that ameliorate various phenotypic defects of T2DM that are beyond glucose control. Agonists of GLP-1R and inhibitors of DPP-4 reduce blood pressure, dyslipidaemia and inflammation, although only GLP-1R agonists decrease body weight. Both types of incretin-based agents inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in rodents and humans. In rodents, incretin-based therapies also prevent onset of the morphological abnormalities of diabetic nephropathy.

The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial

“…In addition, DPP-4 has been elucidated to degrade many peptides such as glucagon-like peptide-2 (GLP-2), BNP, ANP, stromal cell-derived factor (SDF)-1α, substance P, neuropeptide Y, peptide YY, and so on. Activation and prolongation of their physiological activities by DPP-4 inhibition can lead to actions such as natriuresis, improvement of inflammation, suppression of the sympathetic nervous activity, suppression of the renin-angiotensin system, vasodilatation, and cytoprotection [33,34]. Natriuresis has been reported to occur by DPP-4 inhibitor independent of GLP-1 receptor [24] because DPP-4 inhibitors have directly reduced the expression of sodium-proton exchanger 3 (NHE3) protein [35], and promoted a distal tubular natriuresis through SDF-1α [36].…”

Efficacy of Saxagliptin versus Mitiglinid in patients with type 2 diabetes and end-stage renal disease

“…Several reports suggest that DPP-4 inhibitors have antiinflammatory effects and can improve bone marrow function [45,46]. The possibility of scission protection by DPP-4 with antiinflammatory agents such as BNP/ANP (brain natriuretic peptide/atrial natriuretic peptide) or NPY (neuropeptide), which are substrates of DPP-4, is suggested, and an intracorporeal inflammation condition is therefore thought to be ameliorated by DPP-4 inhibitor [47][48][49][50]. This may explain the improved iron bioavailability.…”

Novel approaches of glucose-lowering therapy in type 2 diabetes and chronic kidney disease

“…Определена эффективность и безопасность этих средств для лиц с нормальной функцией почек [17]. Применение препаратов инкретинового ряда при нарушении функции почек зависит от стадии ХБП [18]. В табли-це представлены рекомендации по назначению пре-паратов инкретинового ряда в зависимости от СКФ.…”