PHARMACOVIGILANCE SIGNALS OF SEMAGLUTIDE AND OTHER GLP-1 RECEPTOR AGONISTS: AN ANALYSIS OF THE FOOD AND DRUG ADMINISTRATION (FDA) ADVERSE EVENTS REPORTING SYSTEM (FAERS) DATASET

Abstract Background Semaglutide is a medication used to treat type 2 diabetes and obesity, belonging to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists [1]. GLP-1 is a hormone released in the intestine during the digestion of food helping to regulate blood sugar levels by stimulating the release of insulin. Semaglutide mimics the actions of GLP-1, leading to increased insulin release and decreased glucagon release, which in turn helps lower blood sugar levels, reducing appetite and food intake, leading to weight loss [2]. Moreover, recent media reports commented about a possible issue of the misuse of antidiabetics related to molecules promoted as a weight-loss treatment in non-obese people [3-5], issue facilitated by the putative acquisition of medications from rogue websites. Aims & Objectives to determine the available pharmacovigilance misuse/abuse signals relating to semaglutide versus other GLP-1-receptor agonists, e.g. albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and tirzepatide, by analyzing the Food and Drug Administration’ s FDA Adverse Events Reporting System (FAERS) pharmacovigilance dataset. Method A descriptive analysis of the characteristics of Adverse Event Reports (AER), including sociodemographic data, country of origin, and concomitant licit/illicit substances, was performed here. Pharmacovigilance measures, including reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and Bayesian empirical geometric mean (EBGM), were calculated, using the R package PhViD. Results From January 2018 to December 2022, a total of 31,439 AERs involving the selected molecules were submitted to FAERS, being the most represented: dulaglutide (37.6%), semaglutide (26.1%), and liraglutide (25.0%). Regarding Semaglutide an increase in the number of reported AERs compared to remaining molecules was observed; overall, most reports came from the US and involved female adults. Drug misuse-, abuse-, and withdrawal-related AERs were most typically reported for semaglutide compared with the other selected GLP-1 analogues. Specifically, ‘drug abuse’, ‘drug withdrawal syndrome’, and ‘prescription drug used without a prescription’ were reported >3.50 times as frequently (e.g., PRR values were 4.05, 4.05, and 3.60, respectively; FDR <0.01), and ‘intentional product use issue’ was reported almost two times as frequently (PRR = 1.80; FDR <0.01). Discussion & Conclusion To the best of our knowledge, this is the first study documenting the misuse and abuse potential of semaglutide in comparison with both remaining GLP-1 analogues. Results here suggested a potential misuse of semaglutide, warranting additional in-depth research. Further studies are essential to understand the central pharmacodynamics of GLP-1 receptor agonists and their interactions with various receptors. Moreover, it's crucial to examine the accessibility of GLP-1R agonists from untrustworthy online sources. Well-structured epidemiological research will also be beneficial in determining the extent and nature of any misuse or abuse among both the general public and susceptible groups of patients. References [1]Scheen A.J. Dual GIP/GLP-1 receptor agonists: New advances for treating type-2 diabetes. Ann. Endocrinol. 2023;10:316–321. doi: 10.1016/j.ando.2022.12.423. [2]Neuville M.F., Paquot N., Scheen A.J. A new era for glucagon-like peptide-1 receptor agonists. Rev. Med. Liege. 2023;78:40–45. [3]Alvarez-Mon M.A., Llavero-Valero M., Asunsolo del Barco A., Zaragozá C., Ortega M.A., Lahera G., Quintero J., Alvarez-Mon M. Areas of Interest and Attitudes Toward Antiobesity Drugs: Thematic and Quantitative Analysis Using Twitter. J. Med. Internet Res. 2021;23:e24336. doi: 10.2196/24336 [4]The Guardian. 2023. [(accessed on 3 October 2023)]. Available online: https://www.theguardian.com/australia-news/2023/jan/06/tga-investigates-influencers-after- diabetes-drug-ozempic-promoted-as-weight-loss-treatment [5]Valdesolo F. What You Need to Know About Ozempic: The Diabetes Drug Fuelling Hollywood’ s Harmful Weight-Loss Obsession. 10 February 2023. [(accessed on 3 October 2023]]. Available online: https://www.vogue.co.uk/beauty/article/what-is-ozempic