Background GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Scope of review To summarize current knowledge about GLP-1 receptor agonist. Major conclusions At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA 1c , both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA 1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal comp...

The incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) have their main physiological role in augmenting insulin secretion after their nutrient‐induced secretion from the gut. A functioning entero‐insular (gut‐endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to “isoglycaemic” intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP‐1 have additive effects on insulin secretion. Local production of GIP and/or GLP‐1 in islet α‐cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP‐1 suppresses, and GIP increases glucagon secretion, both in a glucose‐dependent manner. GIP plays a greater physiological role as an incretin. In type 2‐diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP‐1. While insulinotropic effects of GLP‐1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP‐1 have additional biological functions: GLP‐1 at pharmacological concentrations reduces appetite, food intake, and—in the long run—body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP‐1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP‐1, play a role in bone remodelling. GLP‐1, but not GIP slows gastric emptying, which reduces post‐meal glycaemic increments. For both GIP and GLP‐1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP‐1 receptor co‐agonists like tirzepatide have superior efficacy compared to selective GLP‐1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long‐term interaction of GIP and GLP‐1 receptor signalling. A GLP‐1 receptor antagonist (exendin [9‐39]) and, more recently, a GIP receptor agonist (GIP [3‐30] NH2) and, hopefully, longer‐acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin‐based diabetes drugs.