The study of incretins spans more than a century and has revealed their essential role in glucose homeostasis and metabolic regulation. This understanding has led to the development of incretin receptor agonists as highly effective pharmacological agents for the treatment of such cardiometabolic diseases as type 2 diabetes and obesity, showing substantial benefits in glycemic control, body weight reduction, and cardiometabolic outcomes. However, their use is limited by adverse events, most commonly gastrointestinal intolerance, along with ongoing safety concerns regarding pancreatic, renal, and ophthalmologic effects. Although incretin-based therapies have fundamentally reshaped the management of diabetes and obesity, continued innovation in drug design and delivery holds promise for expanding their applicability, improving patient adherence, and reinforcing their role as a cornerstone of metabolic disease management and beyond. This review summarizes the historical development, molecular design, and clinical relevance of incretin-based therapies, with particular emphasis on approved agents used in current clinical practice.
Incretins are gut-derived peptide hormones that are secreted in response to nutrient intake and play a pivotal role in glucose homeostasis. The two principal incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance insulin secretion from pancreatic β-cells in a glucose-dependent manner. Beyond their classic pancreatic effects, incretins exert multiple systemic actions that influence appetite regulation, gastric motility, cardiovascular function, renal physiology, and even neuroprotection.
Agonists of GLP-1 and GIP receptors have rightfully attracted significant scientific and clinical attention and have already secured their place in the treatment of severe cardiometabolic diseases, such as type 2 diabetes mellitus (T2DM) and obesity. Cardiometabolic diseases also include cardiovascular diseases (CVDs) such as coronary artery disease and arterial hypertension, as well as dyslipidemia, insulin resistance, liver and kidney damage, which often accompany T2DM and reflect the systemic nature of metabolic disorders. These diseases remain a leading cause of morbidity and mortality worldwide. According to the International Diabetes Federation (IDF) Diabetes Atlas (2025), approximately 600 million adults aged 20–79 are currently living with diabetes. Projections indicate a dramatic rise, with this number expected to reach 853 million by 2045. Cardiovascular mortality is also expected to rise sharply by 73% between 2025 and 2050, reaching approximately 35.6 million deaths per year, with coronary artery disease remaining the leading cause.
The invention of GLP-1 receptor agonists (GLP-1RAs) was a major milestone in the treatment of T2DM. These pharmaceutical drugs provide significant glycemic control by stimulating insulin secretion, suppressing glucagon secretion. It also reduces body weight. Over time, the understanding of the role of incretins has expanded significantly: their systemic effects on the central nervous system (CNS), cardiovascular function, cognitive processes, and immune response have been identified. GLP-1 agonists and combination drugs demonstrate not only glucose-lowering and anorexigenic properties but also nephro- and cardioprotective effects, including blood pressure reduction, improved lipid profile, and reduced albuminuria, effects that are partially independent of glycemic reduction. Furthermore, accumulating evidence supports their neuroprotective potential, as GLP-1RAs have been shown to improve cerebral glucose hypometabolism, reduce neuroinflammation, and attenuate neuronal death in models of neurodegenerative diseases, suggesting possible therapeutic relevance beyond metabolic disorders.
Despite impressive progress, the widespread implementation of incretin therapy is limited by the high cost of treatment, limited availability in some regions, the need for injectable administration, and gastrointestinal side effects that impact treatment adherence. These barriers underscore the need for further drug optimization, including the development of more affordable oral formulations, improved delivery systems, and multi-agonists with an enhanced safety profile.
In the context of the global epidemic of obesity and metabolic diseases, incretin-based therapy has become a cornerstone of modern treatment. However, its potential can only be fully realized when integrated with lifestyle modifications, social and digital patient support programs, and an interdisciplinary approach aimed at achieving long-term clinical outcomes. This review is dedicated to the historical development, molecular design, and clinical significance of incretin-based drugs, with special attention to approved agents used in current practice and prospects for their further improvement. It also focuses on clinical studies in the context of cardiometabolic health.
The history of the discovery of incretins reflects the evolution of scientific understanding of the neuroendocrine regulation of digestion and carbohydrate metabolism. The complex relationship between the intestine and pancreatic function had long attracted the interest of researchers. The prevailing theory, championed by I. Pavlov, was that pancreatic secretion was regulated exclusively by the nervous system through vagal reflexes. However, an experiment in 1902 provided the first evidence for endocrine regulation of digestion, when W. Bayliss and E. Starling managed to demonstrate that a substance secreted by the intestinal mucosa, upon entering the bloodstream, stimulates pancreatic secretion. In 1906 B. Moore was the first to successfully use a duodenal mucosal extract in the treatment of diabetes mellitus. And in 1929, Belgian researchers J. La Barre and E. Zunz proposed the existence of an intestinal factor that could enhance pancreatic insulin secretion.
And in 1932, La Barre first coined the term “incretin” (from INtestine seCRETion INsulin) to describe an intestinal hormone that stimulates the endocrine function of the pancreas, including insulin release. Although a duodenal extract presumed to stimulate insulin secretion and lower blood glucose levels was also described by H. Heller in 1934, the incretin hypothesis remained controversial for many years due to the lack of reliable methods for accurately measuring insulin levels. The situation changed in the late 1950s with the invention of radioimmunoassay by S. Berson and Rosalyn Yalow—a method that enabled accurate measurement of plasma insulin levels. This technological breakthrough allowed researchers to explore incretins and their physiological effects in greater depth. With this new tool H. Elrick and colleagues conducted a 1964 study that provided the first quantitative evidence for gut-mediated regulation of glycemia, paving the way for the identification of incretin hormones. Using plasma insulin assays, they directly demonstrated enhanced insulin secretion after oral glucose administration compared with intravenous glucose—despite identical glucose concentrations—an observation now known as the “incretin effect”. In subsequent work published in 1967, M. Perley and D. Kipnis showed that this effect was mediated by endocrine factors of gastrointestinal origin. They found that obese individuals, both with and without diabetes, exhibited increased insulin secretion (hypersecretion), whereas in diabetic patients, regardless of weight, insulin secretion was significantly impaired.
The search for intestinal hormones responsible for the incretin effect continued for decades and concluded in 1969 when a peptide was successfully isolated in the laboratory of professor V. Mutt. It was later named “gastric inhibitory polypeptide” or “GIP” in 1972 in studies conducted by R. Pederson and J. Brown. Animal experiments confirmed the role of GIP as an incretin hormone—immunoneutralization with specific antibodies suppressed glucose-dependent insulin secretion. Human studies also demonstrated its strong insulinotropic activity. In healthy volunteers, intravenous infusion of physiological doses of GIP together with glucose led to a greater rise in plasma immunoreactive insulin and improved glucose tolerance. Studies in the 1980s using GIP immunoneutralization in rats and small-intestinal resection in humans did not completely abolish the incretin effect, indicating that another incretin hormone must exist.
After its discovery, it was established that the primary physiological role of GIP is to stimulate insulin secretion in response to the intake of glucose and fats in the duodenum. Accordingly, the peptide was renamed “glucose-dependent insulinotropic polypeptide” while retaining the abbreviation GIP. Although the molecular mechanisms of incretin signaling have been comprehensively described, a concise overview of the physiological actions of GIP is outlined below to provide context for its therapeutic relevance.
GIP is secreted by K-cells located in the proximal small intestine, predominantly in the duodenum and jejunum. GIP secretion peaks within 30–60 min after glucose administration or ingestion of mixed meals. The biologically active form, GIP(1–42), is generated from its 153-amino-acid precursor, a proprotein encoded by the GIP gene, through proteolytic processing. GIP acts through the GIP receptor (GIPR), which belongs to the GPCR (G-protein-coupled receptor) family. GIPR is expressed in pancreatic β-cells, adipose tissue, and the CNS. Upon binding to GIPR on the surface of β-cells, GIP activates the Gαs subunit, leading to stimulation of adenylate cyclase (AC) and a subsequent increase in intracellular cyclic AMP (cAMP) levels. Elevated cAMP activates protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), thereby enhancing calcium influx through voltage-gated calcium channels (VGCCs) and priming insulin granules for calcium-dependent exocytosis. Through these mechanisms, GIP directly augments insulin secretion in a glucose-dependent manner, potentiating insulin release only when plasma glucose concentrations are elevated.
