AbstractBackground and ObjectiveHypoglycemia induced by direct‐acting antiviral agents (DAAs) for chronic hepatitis C virus (HCV) infection is a rare but potentially life‐threatening adverse reaction, which led to warnings by competent authorities. We therefore aimed to examine the hypoglycemic safety signal for DAAs.MethodsReports to the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 1 October 2012 to 31 March 2020 were analyzed. The Medical Dictionary for Regulatory Activities was used to identify hypoglycemia cases. A case by non‐case disproportionality approach was used whereby reporting odds ratio (ROR) with 95% confidence intervals (CI) were calculated.ResultsIn HCV infection with diabetes patients, the cumulative frequency of hypoglycemic ADRs was 21.85/1000 for reports involving DAAs versus 13.50/1000 for reports involving other medications; For DAAs as a class drug, a nearly double increased reporting odds for hypoglycemia was observed (ROR: 1.63, 95% CI: 1.11–2.41). However, in DAAs subgroup analysis, only telaprevir (ROR: 1.66, 95% CI: 1.01–2.74) and elbasvir/grazoprevir (ROR: 2.25, 95% CI: 1.05–4.83) were associated with increased reporting risk of hypoglycemia during corresponding marketing period; when combined with insulins and sulfonylureas, DAAs were associated with increased reporting risk for hypoglycemia (ROR: 1.98, 95% CI: 1.36–2.88; ROR: 1.62, 95% CI: 1.06–2.48), but concomitant biguanides, dipeptidyl peptidase IV (DPP‐4) inhibitors or glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) were not significant.ConclusionsThis study supports the current recommendation for cautious about hypoglycemic risk relating to the use of DAAs. Treatment with DAAs and antidabetic agents (especially insulins and sulfonylureas) will increase hypoglycemia reporting risk. Physicians and pharmacists should be aware of this risk when prescribing DAAs for patients suffering from diabetes, advanced age or liver decompensation.