Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were originally characterised as incretin hormones mediating post-prandial insulin secretion and glucose homeostasis. Over the past two decades, however, experimental biology, human genetics, and large cardiovascular and renal outcome trials have fundamentally expanded this view. GLP-1 and GIP are now recognised as pleiotropic, multi-system hormones exerting profound effects on the cardiovascular, renal, hepatic, adipose, and central nervous systems—many of which are independent of glycaemic control.

This Journal Watch review synthesises contemporary evidence on the non-glycaemic roles of GLP-1 and GIP in current clinical practice. It examines cardiovascular and renal protection observed in outcome trials, mechanisms of vascular and myocardial benefit, effects on adipose biology, ectopic fat, inflammation, and neuroendocrine regulation, and the emerging paradigm of dual GIP/GLP-1 receptor agonism. Special emphasis is placed on how these actions reposition incretin-based therapies from glucose-lowering agents to disease-modifying, organ-protective treatments within modern cardio-renal-metabolic medicine.