While intensive control of glucose levels and blood pressure is currently the mainstay of treatment of diabetic nephropathy, this strategy cannot fully prevent the development and progression of diabetic kidney disease, and thus an unmet need remains for additional therapies. In this regard, incretin-based agents, namely agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), improve pancreatic islet function and induce extrapancreatic effects that ameliorate various defects of type 2 diabetes that go beyond glucose control.
Both GLP-1R agonists and DPP-4 inhibitors reduce blood pressure, dyslipidaemia and inflammation, while GLP-1R agonists also decrease body weight. Of interest in renal protection, both types of incretin-based agents have been shown to inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in both rodents and humans6. The renal effects of incretin-based agents have been reported in several clinical studies, although the effects across trials are not entirely consistent.
Trials with DPP-4 inhibitors were mostly cardiovascular safety studies and have shown mostly neutral results; considering renal function, these agents have had no effects or only slightly reduced albuminuria, with no effect on eGFR. However, in these studies, the cohorts examined were not those with diabetic kidney disease. In animal studies with diabetic mice, DPP-4 inhibition, independent of GLP-1R signaling, has been shown to contribute to protection of the diabetic kidney through antioxidative and antifibrotic effects and amelioration of adverse renal haemodynamics.7 DPP-4 inhibition further increases distal natriuresis.