(ASPOT27) Risk of thyroid dysfunction associated with the concomitant use of amiodarone and sulfonylureas: a nationwide cohort study

Background: An increasing prevalence of atrial fibrillation (AF) in patients with type 2 diabetes (T2D) leads to the frequent use of antiarrhythmic and antidiabetic drugs concomitantly; these patients are likely to receive both amiodarone and sulfonylureas, which are the most common drugs for these indications. However, a concern about the risk of drug-drug interaction (DDI) exists due to CYP2C9-based metabolism of both drugs, particularly an additive risk of thyroid dysfunction from T3 accumulation and iodine-related potentiation.

Objectives: To assess the risk of thyroid dysfunction associated with the concomitant use of amiodarone and sulfonylureas in patients with T2D and AF.

Methods: Using Korea’s nationwide insurance claim data (2010-2022), we conducted an active comparator, new user cohort study by identifying the concomitant use of amiodarone and alternative antiarrhythmic drugs (Class I: sotalol, propafenone, and flecainide) with sulfonylureas. We defined exposure using as-treated approach, with patients followed from the start date of amiodarone or active comparators during the use of sulfonylureas until the earliest of the outcome occurrence, discontinuation or switch of treatment (study drugs or sulfonylureas), death, 180 days after the start date, or the end of study. The study outcome was thyroid dysfunction, comprised of hyperthyroidism and hypothyroidism. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using a Cox proportional model after propensity score matching to address potential confounding bias.

Results: Of 49,513 patients (mean age 65.8 years; 54.7% females) treated for AF while receiving sulfonylureas, 37,734 (76.2%) and 11779 (23.8%) received amiodarone or alternative antiarrhythmic drugs, respectively.
After PS matching with 10 751 pairs, the incidence rates were 3.32 and 1.74 per 100 person-years for amiodarone and alternative antiarrhythmic drugs users, respectively. The HR was 1.62 (95% CI 1.11-2.36) for the risk of thyroid dysfunction, comparing amiodarone versus alternative antiarrhythmic drugs while receiving sulfonylureas. Stratified analyses showed a marginally higher risk of thyroid dysfunction in females, the elderly, and individuals who were suffering from severe T2D or were at high risk of cardiovascular diseases.

Conclusions: In this nationwide cohort study, the concomitant use of amiodarone with sulfonylureas was associated with a significantly increased risk of thyroid dysfunction when compared to the concomitant use of alternative antiarrhythmic drugs with sulfonylureas. This finding could recommend, to achieve rhythm control in patients with T2D and AF, the alternative use of Class I antiarrhythmic drugs without the risk of DDI rather than amiodarone in a routine clinical setting.