Beat it early: putative renoprotective haemodynamic effects of oral hypoglycaemic agents

Diabetic kidney disease represents a considerable burden; around one-third of patients with type 2 diabetes develop chronic kidney disease. In health, the kidneys play an important role in the regulation of glucose homeostasis via glucose utilization, gluconeogenesis and glucose reabsorption. In patients with diabetes, renal glucose homeostasis is significantly altered with an increase in both gluconeogenesis and renal tubular reabsorption of glucose. Environmental factors, both metabolic (hyperglycaemia, obesity and dyslipidaemia) and haemodynamic, together with a genetic susceptibility, lead to the activation of pro-oxidative, pro-inflammatory and pro-fibrotic pathways resulting in kidney damage. Hyperfiltration and its haemodynamic-driven insult to the kidney glomeruli is an important player in proteinuria and progression of kidney disease towards end-stage renal failure. Control of glycaemia and blood pressure are the mainstays to prevent kidney damage and slow its progression. There is emerging evidence that some hypoglycaemic agents may have renoprotective effects which are independent of their glucose-lowering effects. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors may exert a renoprotective effect by a number of mechanisms including restoring the tubuloglomerular feedback mechanism and lowering glomerular hyperfiltration, reducing inflammatory and fibrotic markers induced by hyperglycaemia thus limiting renal damage. Simultaneous use of an SGLT-2 inhibitor and blockade of the renin-angiotensin-aldosterone system may be a strategy to slow progression of diabetic nephropathy more than either drug alone. The use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists may exert a renoprotective effect by reducing inflammation, fibrosis and blood pressure. Given the burden of diabetic kidney disease, any additional renoprotective benefit with hypoglycaemic therapy is to be welcomed. Large randomized controlled trials are currently underway investigating if these new anti-diabetic agents can provide renoprotection in diabetes.