Pharmacovigilance analysis of the association between SGLT-2 inhibitors and diabetic foot infections using the FAERS database: An observational study.

BACKGROUND Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are widely used for the management of type 2 diabetes mellitus (T2DM) and heart failure (HF). SGLT-2 inhibitors reduce cardiovascular events in T2DM, but concerns persist about diabetic foot infection (DFI).

OBJECTIVE To quantify the association between individual SGLT-2 inhibitors and DFI using real-world pharmacovigilance data.

METHODS The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) reports (2004 Q1-2024 Q2) were screened; 62 098 records listed an SGLT-2 inhibitor as the "primary suspect" drug. DFI was identified via eight Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) plus 324 MedDRA Preferred Terms (PTs). Disproportionality was evaluated by Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Information Component (IC), and Empirical Bayes Geometric Mean (EBGM); only "primary suspect" events were retained.

RESULTS Among 8 312 293 reports, 565 DFI cases implicated an SGLT-2 inhibitor. Canagliflozin showed the highest signal (ROR 162.84; 95 % CI 134.14-197.68), whereas empagliflozin (ROR 0.56) and dapagliflozin (ROR 2.19) did not reach positive criteria. The class-level ROR was 55.51 (45.18-68.21). Additionally, this study examined the time-dependent association between SGLT-2 inhibitors and DFI. The results indicated a significant increase in the ROR for DFI with increasing duration of exposure: the ROR was 11.25 (95% CI: 8.14-15.56) when the exposure duration was ≤30 days; it escalated to 48.77 (95% CI: 39.88-59.64) when the exposure duration exceeded 365 days. The EBGM analysis further corroborated this time-dependent signal, demonstrating that as the duration of exposure lengthened, the envelope of the EBGM and its 95%CI (EBO5/EB95) progressively intensified.

CONCLUSIONS A strong, agent-specific signal links canagliflozin to DFI. Clinicians should prioritise foot surveillance and consider safer SGLT-2 inhibitor alternatives in high-risk patients.