[An historical overview of GLP-1/GIP incretins. From hormone to "swiss-army knife" medications].

Incretins are hormones released from the gut that play a vital role in regulating postprandial metabolism. It has been 30 years since the first demonstration of the glucose-lowering effects of GLP-1 in people with type 2 diabetes. Here, we review the foundational science that led to an unparalleled development in the pharmacological treatment of diabetes. A first step was achieved with the discovery of inhibitors of the dipeptidyl peptidase-4 (DPP-4), which prevent the inactivation of GLP-1 and GIP, thereby prolonging their raised levels after meal ingestion. At the same time, several GLP-1 receptor agonists (GLP1-RAs) were engineered. The GLP1-RAs used clinically are based on exendin-4 and native GLP-1 and are now available as formulations for daily or weekly s.c. (exenatide, liraglutide, semaglutide) or oral administration (oral semaglutide). They mimic (better effectiveness) the action of native GLP-1 to reduce glucose levels through stimulation of insulin secretion and inhibition of glucagon secretion. They also demonstrated remarkable cardiovascular and weight-regulating benefits, including safety, leading to their prominent inclusion in current treatment recommendations for type 2 diabetes. Exciting advancements continue to emerge as the fundamental research efforts led to the development of monomeric multi-incretin receptor agonists: GLP-1/GIP (tirzepatide) dual receptor agonists and GLP-1/GIP/glucagon (retatrutide) triple receptor agonists which can achieve more than 20% weight loss in obesity as well as offering superior benefits in diabetes. This review also presents the promise of GLP1-RAs for more extensive application of this new class of drugs, in treating other metabolic disorders such as obesity, MASLD/NAFLD, cardio-vascular diseases and neurodegeneration.