Antithyroid drugs and the dose-risk balance: a meta-analysis on agranulocytosis in hyperthyroidism

Agranulocytosis is a rare but serious adverse effect associated with antithyroid drug (ATD) therapy for hyperthyroidism. The relative risk between methimazole (MMI) and propylthiouracil (PTU), and the potential dose-dependent effect of MMI remain unclear. To evaluate the incidence and relative risk of agranulocytosis associated with MMI and PTU, and to determine whether higher MMI doses are linked to increased risk.

We conducted a systematic review and meta-analysis of clinical studies reporting agranulocytosis in patients treated with MMI or PTU. A comprehensive search was performed in MEDLINE, Cochrane Library, and LILACS up to March 2025. Studies were selected based on predefined inclusion criteria. Risk of bias was assessed using RoB 2.0 and ROBINS-I tools. Meta-analyses were performed using random-effects models. Publication bias was evaluated using funnel plots, Egger's test, and the trim-and-fill method. The protocol was registered in PROSPERO (CRD42024548791).

Thirteen studies were included in the meta-analysis, comprising 313 cases of agranulocytosis. No significant difference in risk was found between MMI and PTU (OR = 0.87; 95% CI: 0.40-1.88; I² = 74.1%). In the dose-comparison analysis, patients receiving <30 mg/day of MMI had a significantly lower risk of agranulocytosis compared to those receiving ≥30 mg/day (OR = 0.34; 95% CI: 0.22-0.54; I² = 0%). No publication bias was detected. Sixteen additional studies were included in the qualitative synthesis but excluded from quantitative analysis due to methodological limitations. A lower incidence of agranulocytosis was observed in randomized controlled trials compared to retrospective studies.

This meta-analysis found no significant difference in agranulocytosis risk between MMI and PTU. However, higher MMI doses (≥30 mg/day) were associated with an increased risk. These findings support the use of the lowest effective MMI dose and emphasize the importance of standardized reporting and methodological rigor in studies assessing the safety of ATD.