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doi: 10.1210/en.2018-00336 [DOI] [PubMed] [Google Scholar] 53.Hiromura M, Mori Y, Kohashi K, et al

Keywords: GLP-1, GIP, pharmacokinetics, drugdrug interactions, physiologically based pharmacokinetic model Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide hormone-derived analogs classified as incretin mimetic drugs (Figure 1).15 Incretins are gut hormones released into the bloodstream following food consumption that enhances insulin secretion in pancreatic -cells and help decrease high blood glucose levels.6 Therefore, GLP-1 RAs were first investigated as treatments for type 2 diabetes.7 Compared to other antidiabetic drugs, GLP-1 RAs have the advantage of only being pharmacologically active when blood glucose levels are high.8 This significantly reduces the incidence of hypoglycemiaa frequently reported adverse drug reaction associated with other antidiabetic drugs like sulfonylureas or insulin.9,10 Additionally, GLP-1 RAs suppress glucagon secretion from the -cells in the pancreas, leading to decreased blood glucose levels.11 However, a drawback of the native human GLP-1 (Figure 1A) is its extremely short in vivo half-life (2 min) due to fast clearance by dipeptidyl peptidase-4 (DPP-4).1 Thus, numerous studies have used biotechnology to extend the half-life of GLP-1 RAs, with strategies including amino acid sequence substitution, fatty acid conjugation with a linker, fusion of albumin or the IgG fragment crystallizable (Fc) region (Figure 1).5,12,13 These efforts have yielded six GLP-1 RAsstarting with the development of exendin-4 (Figure 1B)-based exenatide (Figure 1C), followed by liraglutide (Figure 1D), albiglutide, dulaglutide (Figure 1E), lixisenatide, and semaglutide (Figure 1F)that have been approved by the United States Food and Drug Administration (US FDA) to treat type 2 diabetes.14 Among these, albiglutide was pulled from the market in 2017 because of declining sales;15 likewise, lixisenatide was withdrawn from the US market as of January 1, 2023, for commercial reasons, rather than because of any safety or efficacy issues.14 Furthermore, GLP-1 RAs reportedly induce weight loss by reducing appetite and this satiety-promoting effect has recently attracted significant interest.16,17 The appetite-regulating effects of GLP-1 RAs are primarily mediated by both peripheral (vagal) and central nervous system pathways.1,18 Food intake causes the stomach to stretch, activating gastro-mechanoreceptors in the intestinal wall, which then transmit satiety signals via the vagus nerve.19,20 GLP-1 RAs delay gastric emptying and reduce stomach motility in obese patients, contributing to their satiating effect.21 In addition, intracerebro ventricular administration of GLP-1 decreased food intake in rats, suggesting GLP-1 RAs are involved in a central nervous system pathway.22 Eight obese women reported reduced hunger following subcutaneous injections of exenatide and it was related with an enhanced functional connectivity of the nucleus tractus solitarius with the thalamus and hypothalamus.23 Clinical trials also indicated that GLP-1 RA treatment for obese patients presented superior weight loss efficacy compared to other anti-obesity medications.24 Based on these findings, two GLP-1 RAs were approved by the US FDA to treat obesity so far: liraglutide and semaglutide

"If someone is experiencing any side effects while taking any Lilly medication, we encourage them to speak with their healthcare provider." Users can also call the The Lilly Answers Center at 1-800-LillyRx

This risk is heightened during menopause when muscle preservation is already challenged by hormonal changes

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