Glucagon-like peptide-1 (GLP-1) is an incretin, a gastrointestinal polypeptide hormone that binds to specific receptors on pancreatic beta cells and increases insulin release. The incretins – GLP-1 and gastric inhibitory peptide (GIP) – are secreted from the upper gastrointestinal tract in response to feeding and act on the pancreas, increasing insulin release even before blood glucose levels are elevated. The incretins also delay gastric emptying and suppress glucagon secretion, features that may increase their beneficial effects in type 2 diabetes. Both hormones are polypeptides that are rapidly cleared from the serum by the peptide cleaving enzyme, dipeptidyl peptidase-4 (DPP-4). The incretin pathway provides several potential targets for therapy of type 2 diabetes, the main ones being DPP-4 (inhibition) and GLP-1 receptors (agonist activity). Several GLP-1 analogues (also called GLP-1 receptor agonists) have been developed and approved for use in the United States for type 2 diabetes: exenatide (also known as exendin-4, Byetta) in 2005, liraglutide (Victoza) in 2010, albiglutide (Tanzeum) and dulaglutide (Trulicity) in 2014, lixisenatide (Adlyxin) in 2016 and semaglutide (Ozempic) in 2018. All are given parenterally and are approved for use in type 2 diabetes only. The GLP-1 analogues are recombinant polypeptides, have little or no hepatic metabolism and have not been convincingly implicated in causing clinically apparent liver injury.
Selected references to the safety and potential hepatic injury associated with these agents are given after this introductory section.
Drug Class: Antidiabetic Agents