Safety of Glucagon-Like Peptide-1 Receptor Agonists: A Real-World Study Based on the US FDA Adverse Event Reporting System Database

Background and objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as adjunctive therapy to lifestyle intervention and metformin treatment in type 2 diabetes mellitus patients, as most GLP-1RAs have cardiovascular benefits; however, a number of adverse events (AEs) have been reported in postmarketing surveillance.

Objective: The aim of this study was to describe the AEs associated with GLP-1RA monotherapy and identify important medical event (IME) signals for GLP-1RAs.

Methods: Data from 1 April 2005 to 31 December 2021 from the US FDA Adverse Event Reporting System (FAERS) database were extracted to conduct disproportionality analysis and Bayesian analysis. AEs and IMEs were classified by system organ classes (SOCs) and preferred terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA^®). The reporting odds ratio (ROR) and information component (IC) were used to indicate the disproportionality.

Results: A total of 71,515 records involving GLP-1RA monotherapy were submitted to the database, of which 16,350 records were GLP-1RA/IME pairs. Significant disproportionality emerged in five SOCs: 'gastrointestinal disorders' (n = 13,104; lower end of the 95% confidence interval (CI) of the IC [IC₀₂₅] = 1.34), 'investigations' (n = 6889; IC₀₂₅ = 0.64), 'metabolism and nutrition disorders' (n = 2943; IC₀₂₅ = 0.44), 'neoplasms benign/malignant' (n = 1989; IC₀₂₅ = 0.01), and 'hepatobiliary disorders' (n = 1497; IC₀₂₅ = 0.38). The most common AEs were pancreatitis, nausea, and weight decrease. Unexpected significant AEs were detected, such as ileus, osteomyelitis, renal cell carcinoma, nephrolithiasis, and drug-induced liver injury.

Conclusion: The majority of AEs have been listed in the prescribing information or reported in previous studies, however we found significant disproportionality in some specific tumor- and liver-related AEs. Clinicians should pay more attention to the newly detected disproportionality that may be triggered by GLP-1RAs, especially in the vulnerable population after long-term use. Considering the limitations of the FAERS database, there is a need for additional pharmacoepidemiological approaches to validate the results of this study.