The potential and pitfalls of GLP-1 receptor agonists for renal protection in type 2 diabetes.

Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) offer substantial benefits for the management of glucose levels in type 2 diabetes. In addition, recent data from clinical trials have demonstrated that treatment with Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) are also able to reduce new onset macroalbuminuria. These benefits may be consistent with the known effects of GLP-1 RA on traditional risk factors for progressive kidney disease including glucose lowering, blood pressure lowering, reduced insulin levels and weight reduction. However, emerging evidence suggests that GLP-1 RA can also have direct effects in the kidney, including inhibiting NHE3-dependent sodium reabsorption in the proximal tubule. Additional effects on the intrarenal renin angiotensin system, ischaemia/hypoxia, inflammation, apoptosis and neural signalling may also contribute to renal benefits. The extent to which these effects are mediated by the GLP-1R remains to be established. Recent studies confirm that the metabolic products of GLP-1 retain important antioxidant and anti-apoptotic activities that are GLP-1 R independent. Moreover the divergent peptide sequences of the currently available GLP-1 RA may mean that divergent reno-protective efficacy could be anticipated from different GLP-1 RA on this basis. Kidney disease is an important and deadly clinical outcome, and one worth preventing. Although both experimental and clinical data now support the possibility of renoprotective effects arising from treatment with GLP-1 RA, further work is needed to optimise these effects. A logical synergism with SGLT2 inhibition also exists, and at least in the short term, this combination approach may become the most useful way to protect the kidney in type 2 diabetes.