(039) Comparative Analysis of Potential Misuse between Tirzepatide and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs): Insights from FDA Adverse Event Reporting System (FAERS) Data

Background: Recent studies and media coverage have highlighted the increasing potential misuse of GLP-1 RAs for unapproved indications, especially for cosmetic weight loss in non-diabetic individuals. Tirzepatide, as the first combination of a GLP-1 RA and a gastric inhibitory polypeptide receptor agonist (GIP-RA), has consistently been pointed out for its heightened potential for misuse and abuse due to its dual mechanism, which confers superior efficacy in managing glycemic levels, lipid profiles, and weight reduction.

Objectives: This study aims to compare the safety signal of potential misuse and abuse related adverse drug events (ADEs) between tirzepatide and other GLP-1 RAs (dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide) using data from the FDA Adverse Event Reporting System (FAERS).

Methods: Data from the FAERS Quarterly Data Extract database spanning from 2022 Q2 to 2024 Q1 were analyzed. Reactions related to potential misuse and abuse were determined based on Preferred Terms (PTs) from the Medical Dictionary for Regulatory Activities (version 27.0), especially using Standardised MedDRA Queries (SMQs) for ‘Drug Abuse, Dependence and Drug Withdrawal’. Misuse and abuse-related PTs were defined as (i) terms indicative of drug abuse and dependence, (ii) terms related to withdrawal, and (iii) terms related to ‘Product quality issue’ in System Organ Classes (SOCs), implying potential drug misuse and abuse. The extent of potential misuse and abuse was assessed using descriptive statistics from the FAERS database ‘DRUG’, ‘INDI’ and ‘REAC’ files. For disproportionality analysis, proportional reporting ratio (PRR) and reporting odds ratio (ROR) were calculated and compared between tirzepatide and other GLP-1 RAs.

Results: The number of ‘Product used for unknown indication’ for tirzepatide and GLP-1 RAs was 21,855 (57.46%) and 17,959 (49.67%), respectively. Among 79,142 adverse drug events (ADEs) reported for tirzepatide, 5,346 (6.75%) were attributed to ‘Off-label use’, which can be considered as a potential misuse. For GLP-1 RAs, 105,798 ADEs were reported, and 1,981 (1.87%) of ADEs were counted as ‘Off label use’. Tirzepatide exhibited a significantly higher likelihood of ADE reports for ‘Off label use’ compared to other GLP-1 RAs, with PRR and ROR values of 3.61 and 3.80, respectively. In comparison to GLP-1 RAs, tirzepatide was found to have a higher probability of ‘Product tampering’, with PRR and ROR values of 37.43 and 37.46, respectively, indicating intentional manipulation or alteration of the drug, often for the purpose of misuse or abuse.

Conclusions: Analysis of FAERS drug safety reports suggests that tirzepatide has a higher potential for certain signals of adverse drug reactions associated with misuse and abuse compared to other GLP-1 RAs. Continuous monitoring of tirzepatide's safety profile is warranted to address potential misuse and abuse concerns.