Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence

As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents — sodium–glucose cotransporter 2 inhibitors and incretin therapies — has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney. Clinical trials have demonstrated that glucagon-like peptide 1 receptor (GLP1R) agonists have therapeutic benefits beyond glycaemic control. Here, the authors examine the protective effects of incretin-based therapies in patients with diabetic kidney disease and how the immunomodulatory and anti-inflammatory effects of GLP1 might underlie this protection. Key points Glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors reduce the onset and progression of albuminuria in patients with type 2 diabetes mellitus (T2DM). GLP1R agonists have been shown to delay the decline of estimated glomerular filtration rate in patients with T2DM, including those with or without moderate-to-severe chronic kidney disease. DPP4 inhibitors demonstrate only modest improvement in albuminuria, with no effect on glomerular filtration rate. The kidney-protective effects of GLP1R agonists might be at least partly independent of their effects on glycaemic control. In addition to