Comparative pharmacovigilance of glycaemic adverse-event reporting for alpelisib and capivasertib: A disproportionality analysis of the FDA adverse event monitoring system
Yongjian Liu, Hao Zhong, Xingjun Huang, Yige Yu, Shuzhen Liu, Yingyu YuBackground
Alpelisib and capivasertib inhibit adjacent nodes of the phosphatidylinositol 3-kinase/protein kinase B pathway and disrupt glucose homeostasis. Their overlapping fulvestrant-based treatment contexts support comparison despite different biomarker eligibility.
Objectives
To compare the post-marketing adverse-event reporting profiles of alpelisib and capivasertib and assess whether broad glucose-metabolism and severe metabolic-decompensation groupings showed distinct pharmacovigilance patterns.
Design
Retrospective disproportionality analysis of spontaneous individual case safety reports.
Methods
Public quarterly reports from 2004 Q1 through 2026 Q2 were obtained from the FDA Adverse Event Monitoring System (AEMS; formerly the FDA Adverse Event Reporting System). Reports were analysed irrespective of indication. Primary-suspect reports underwent four-method Preferred Term screening followed by clinically guided exclusion of non-adverse-event and clinically non-informative terms. Comparative reporting odds ratios (RORs) were estimated for clinically curated Preferred Term groupings. Sensitivity analyses addressed calendar period, fulvestrant co-reporting, indicators of pre-existing diabetes, healthcare-professional reporting and matched early post-approval periods. Time-to-onset and report-level analyses characterised severe hyperglycaemic/diabetic ketoacidosis (DKA) reports.
Results
The analysis included 7,717 alpelisib and 2,292 capivasertib reports. The broad glucose-metabolism grouping was identified in 2,654 (34.4%) and 420 (18.3%) reports, respectively (ROR 2.336, 95% confidence interval (CI) 2.081-2.623), and this direction persisted across all sensitivity analyses. Severe hyperglycaemic/DKA events were identified in 187 (2.4%) and 84 (3.7%) reports, respectively (ROR 0.653, 95% CI 0.502-0.848). This severe-event comparison was not robust in the fulvestrant co-reported subset, and its 95% CI included 1 after matching the first 11 post-approval quarters (ROR 0.769, 95% CI 0.578-1.024). DKA-related Preferred Terms comprised 60.4% and 83.3% of the severe report sets, respectively.
Conclusion
Alpelisib showed a consistent signal of greater broad glucose-metabolism reporting concentration. The capivasertib severe-event reporting concentration was sensitive to analysis conditions and remains exploratory. These findings may support pharmacovigilance signal prioritisation and reinforce label-consistent glycaemic monitoring, but do not estimate causality, incidence or comparative clinical risk.