Abstract
BACKGROUND: Insulin autoimmune syndrome (IAS) is a rare immune-mediated hypoglycemic disorder predominantly triggered by pharmacological agents. Despite the established links to thiol-containing drugs, emerging non-thiol triggers and significant geographical reporting biases limit comprehensive risk profiling. This study integrated pharmacovigilance data and published evidence to establish the first systematic epidemiological and pharmacological profile of drug-induced IAS. METHODS: We analysed 228 IAS cases from the FDA AE Reporting System (FAERS; 2004-Q2 2024) and a systematic review of 263 published cases (1980-2024). Multimodal disproportionality analysis-including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN)-identified drug-induced adverse event signals. Associations were stratified into a three-tier evidence framework (Levels 1-3) based on methodological concordance, case counts, and strength of the supporting literature. RESULTS: Fifty-eight agents showed potential IAS associations, including 12 novel pharmacovigilance signals (e.g., bevacizumab, sitagliptin, amlodipine, and olmesartan). Thiol-containing drugs exhibit the strongest signals (PRR > 200; e.g., captopril, methimazole, and clopidogrel). Level 1 evidence (highest confidence) implicated the use of clopidogrel, captopril, omeprazole, and methimazole. IAS was predominantly affected in older patients (median age, 66 years; IQR, 58-77 years), with a male predominance (59.21%), reflecting sex-specific prescription patterns. Geographical disparities persisted, with 85.17% of the cases reported in the literature in Asia. Reports of hypoglycemia exceeded IAS cases for most agents, suggesting an underdiagnosis. CONCLUSIONS: This study established the first evidence-based hierarchy for drug-induced IAS, identifying 58 agents warranting clinical vigilance. Thiol-containing drugs dominate the high-risk profile; however, novel associations (e.g., proton pump inhibitors (PPIs), dipeptidyl peptidase-4 (DPP-4) inhibitors) reveal broader immunological mechanisms. Clinicians should prioritize IAS in older patients with unexplained hypoglycemia exposed to antiplatelet agents or PPIs. Standardized diagnostic criteria and pharmacogenetic profiling (e.g., human leukocyte antigen DRB1 (HLA-DRB1) *04:06) are urgently required to improve detection.