Owing to the therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists in the management of diabetes and obesity, the pharmacology of these drugs and their receptors has engendered considerable interest. GLP-1 and GIP are incretin hormones so named owing to their ability to increase insulin secretion. Currently FDA-approved GLP-1 peptide receptor agonists used for the management of diabetes include liraglutide, semaglutide, and injectable dulaglutide. Agonists approved for the management of obesity include liraglutide and semaglutide, which have injectable and oral formulations. Tirzepatide is a combined GLP-1 and GIP receptor peptide agonist given by injections that is FDA-approved for the management of type 2 diabetes, obesity, and obese patients with a weight-related comorbidity such as obstructive sleep apnea. Orforglipron is a small molecule orally bioavailable medicine that is approved for the treatment of obesity. Retatrutide is an injectable peptide agonist of GLP-1R, GIPR, and the glucagon receptor that is undergoing clinical trials for the management of obesity and diabetes. The peptides per se undergo rapid degradation in the body. To overcome the need for frequent injections, molecular engineering strategies were used to prolong circulating half-lives. Peptide fatty acid acylation represents one strategy for extending the half-life of peptides by co-opting the role of albumin as a fatty acid transporter thereby retaining peptides in the systemic circulation. A universal side effect of all GLP-1 receptor agonists includes nausea and vomiting. Consequently, the dosage is escalated sequentially over a period of weeks to mitigate these side effects.
