Incretin-based therapies and the kidney: From physiology, to pharmacology and outcomes in type 2 diabetes

Despite improvements in the management of renal risk factors in type 2 diabetes mellitus patients, and the use of renin-angiotensin-system inhibitors, residual renal risk remains, and novel strategies or new therapeutic options are needed to reduce diabetic kidney disease-burden in this population. After more than a decade of clinical use of incretin-based drugs, the understanding and value of therapeutically engaging glucagon-like peptide (GLP)-1 receptor-mediated mechanisms for type 2 diabetes mellitus treatment are becoming increasingly clear. In addition to glucose-lowering, incretin-based therapies enable maintenance of or reductions in body weight, blood pressure and lipid levels. Such effects, which are not achieved by current standard diabetes care, might help to narrow the gap between recommended and established renal risk factor control in clinical practice. Furthermore, GLP-1 and associated drugs may temporarily increase the renal excretion of electrolytes (most notably sodium), although GLP-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitor treatment does not improve glomerular hyperfiltration in type 2 diabetes mellitus patients with normal renal function. Evidence of pooled analyses, as well as results of large-sized cardiovascular outcome trials indicate that use of some GLP-1 receptor agonists may reduce albuminuria and kidney function loss over time in high-risk patients with type 2 diabetes mellitus, independent of their glucose-lowering effect. DPP-4 inhibitors, in addition to standard care, may modestly improve albuminuria in type 2 diabetes mellitus, plausibly beyond the effects of glycemic control, though their renoprotective efficacy is likely limited and data are inconsistent. Although the renal benefits are far less pronounced than those of the sodium-glucose cotransporter (SGLT)2 inhibitors, the incretin-based therapies, particularly GLP-1 receptor agonists, may be of added value in alleviating the worldwide diabetic kidney disease-burden. However, specifically designed (renoprotection) trials in type 2 diabetes mellitus patients with high chronic kidney disease-risk, preferably using active comparators, would be needed to firmly establish their place in renoprotective management in this population.