Exploratory Signal Detection of Arrhythmia Reports for Empagliflozin, Sitagliptin, and Linagliptin in the Korea Adverse Event Reporting System

Abstract

Studies have reported cardiovascular effects of Sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4) inhibitors.Although cardiovascular and renal benefits of SGLT2 inhibitors have been reported, their specific association with arrhythmias such as atrial fibrillation (AF), atrial flutter, and ventricular fibrillation remains less clearly defined.Therefore, this study aims to investigate the association between empagliflozin, sitagliptin, and linagliptin and reporting patterns of selected arrhythmias in Koreans.Raw data from the Korea Adverse Event Reporting System database were analyzed from January 2019 to December 2023.The drugs of interest were SGLT2 and DPP-4 inhibitors; however, the final disproportionality analysis was limited to empagliflozin, sitagliptin, and linagliptin because these were the drugs with relevant analyzable arrhythmia reports in the study dataset.The analyzed adverse events included atrial fibrillation (AF), atrial flutter, and ventricular fibrillation.The association between the drugs and adverse events was evaluated using disproportionality analysis and chi-squared testing in SAS software version 9.7.Disproportionality analyses revealed that empagliflozin, sitagliptin, and linagliptin showed no positive reporting signals for AF, atrial flutter, and ventricular fibrillation based on the prespecified signal detection criteria.The chi-squared test showed a statistically significant association between each drug and adverse events (p < 0.001); which was interpreted as a difference in reporting distributions within the spontaneous reporting dataset, not as evidence of clinical risk or causality.The findings indicate that selected arrhythmia terms were not disproportionately reported for empagliflozin, sitagliptin, and linagliptin in the KAERS DB during the study period.However, since this analysis was based on collected unsolicited data and the statistical results are limited to signal detection, further studies using global datasets and large-scale clinical trials are needed.