Identifying cardiovascular toxicity associated with sphingosine 1-phosphate receptor modulators: A case-control study based on the FDA adverse event reporting system.

INTRODUCTION

Cardiovascular events represent a significant safety concern associated with sphingosine 1-phosphate receptor (S1PR) modulators. However, as S1PR modulators are primarily indicated for rare diseases characterized by multiple complex confounding factors, evidence regarding potential or long-term cardiovascular risks related to these drugs remains limited. This study aimed to comprehensively assess cardiovascular safety signals associated with S1PR modulators.

METHODS

This case-control study was conducted based on the FDA adverse event reporting system (FAERS) database. The dataset included reports from September 10, 2010 to September 30, 2023. Reporting odds ratios (ROR) were calculated by logistic regression in four different models to examine the robustness of the results. Additionally, to assess adverse event profiles based on clinical trial data, a systematic literature review and subsequent data synthesis were conducted.

RESULTS

We included 81,077 cases treated with S1PR modulators (median [IQR] age, 45 [36-54]; 60,245 [74.31 %] female), and 12,087,627 cases with no prior use of S1PR modulators as comparators. Besides signals of hypertension and bradyarrhythmias, QT interval prolongation in the fingolimod group (ROR = 1.92 [95 % CI, 1.73-2.12]; P < 0.001), and central nervous system ischemia in the siponimod group (ROR = 1.26 [95 % CI, 1.04-1.52]; P = 0.02) were also detected in all models. Signals of tachyarrhythmias and ischaemic heart disease in the fingolimod group as well as QT interval prolongation in the siponimod group were consistent in all adjusted models.

CONCLUSION

In this study, signals of bradyarrhythmias, hypertension, QT interval prolongation, central nervous system ischemia, tachyarrhythmias, and ischaemic heart disease were significant with one or more S1PR modulators, which warrant clinical attention and ongoing monitoring.