GLP-1 receptor agonists and next-generation metabolic hormone therapies in chronic kidney disease

Chronic kidney disease (CKD) remains a major public health problem, with type 2 diabetes and obesity representing key risk factors worldwide. The complex pathophysiology and the metabolic risk factors shared between type 2 diabetes, obesity, CKD and cardiovascular disease have led to the concept of a cardiovascular-kidney-metabolic (CKM) syndrome. The treatment landscape for CKM changed dramatically when agents from several medication classes, originally developed as glucose-lowering therapies, were recognized to reduce the risk of multiple components of CKM syndrome. Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic-GLP-1RAs, have evolved from metabolic therapies to agents with either proven or potential protective effects on the kidney and heart. In addition to their potent metabolic actions that reduce hyperglycaemia and body weight, GLP-1RAs also lower the risk of major kidney, cardiovascular and mortality outcomes across broad populations with cardiovascular disease or CKD, with and without diabetes or obesity. GLP-1RAs have been combined with glucose-dependent insulinotropic agonism, as well as glucagon agonism or amylin analogues to further enhance their metabolic benefits. However, kidney and heart protection are not fully explainable by the metabolic actions of these agents. Rather, a growing body of evidence suggests that the systemic and local actions of incretins and metabolic hormones modulate multiple pathways that can promote inflammatory and fibrotic injury.