Concomitant use of sodium-glucose co-transporter 2 inhibitors and metformin and the risk of osteomyelitis reporting: a disproportionality analysis based on FAERS database

Background: Recent clinical case reports have generated controversy concerning the adverse events (AEs) of amputation linked to sodium-glucose co-transporter 2 inhibitors (SGLT2i). We assessed the risk of osteomyelitis AE reporting linked to SGLT2i or SGLT2i-metformin co-medication.

Research design and methods: Investigated the FDA Adverse Event Reporting System for osteomyelitis-related AEs associated with SGLT2i or SGLT2i-metformin co-medication from 2013q2 to 2023q1. Comprehensive disproportionality analysis and Bayesian confidence propagation methods were used to detect safe signals. The additive interaction model, multiplicative interaction model, and Ω shrinkage measure were employed to explore the latent interactions between SGLT2i and metformin. A Venn diagram was utilized to estimate the coincidence of related osteomyelitis and amputation.

Results: Among 2,569 SGLT2i-associated osteomyelitis reports, we identified 2,509 related to canagliflozin (ROR 104.47; PRR 99.70, χ2 = 214840.90; EBGM05 = 84.38; IC025 = 4.78) and 103 related to the SGLT2i-metformin compound. Drug-drug interaction detection revealed a negative correlation (RERI=-21.73, e^β3 = 0.699, Ω025=-1.370). The coincidence of osteomyelitis and amputation linked to SGLT2i（2,672 vs. 3,548）was 2,150(80%) by Venn diagram.

Conclusions: This study showed an increased risk of SGLT2i-associated osteomyelitis, focusing on canagliflozin, and presented a potential association between amputation and osteomyelitis, providing a reference for the clinical practice of diabetes with SGLT2i medication.