Fournier Gangrene Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Pharmacovigilance Study with Data from the U.S. FDA Adverse Event Reporting System

Abstract

<jats:p><jats:italic>Background</jats:italic>. The U.S. Food and Drug Administration (FDA) released a safety warning of Fournier gangrene (FG), a rare but serious adverse effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors in August 2018. However, existing studies have focused mainly on individual FG case reports. Although several previous studies conducted reviews of cases, objective scientific analysis was not applied, and the prognosis data were inadequate. <jats:italic>Objective</jats:italic>. This study is aimed at presenting data supplementary to existing studies by analysing postmarketing adverse event reports in the FDA Adverse Events Reporting System (FAERS) database. Multiple statistical analysis methods were applied to evaluate the potential association between SGLT2 inhibitors and FG, thus providing reliable and professionalized medication usage recommendations for SGLT2 inhibitors in clinical practice. <jats:italic>Methods</jats:italic>. Disproportionality analysis and Bayesian analysis were applied for data mining among the suspected adverse event reports of FG associated with SGLT2 inhibitors recorded in the FAERS database during the period from January 2004 to September 2019. <jats:italic>Results</jats:italic>. There were 542 FG cases identified in the FAERS database in patients receiving SGLT2 inhibitors. Among all SGLT2 inhibitor therapies, empagliflozin was associated with the highest number of FG reports (232 in total), while empagliflozin plus metformin had the strongest association with FG occurrence with the reporting odds ratio (ROR 54.79, 95% two-sided CI 31.56 to 95.12) and proportional reporting ratio (PRR 53.36, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>χ</mml:mi></mml:math><jats:sup>2</jats:sup> 666.70). There were 391 patients who underwent initial or prolonged hospitalization (72.14%), and 26 patients died (4.81%). Three new FG cases caused by ertugliflozin were found in 2019. <jats:italic>Conclusion</jats:italic>. The analysis of SGLT2 inhibitor-associated FG reports in the FAERS database identified signals between the drug and adverse events of interest. It also provides comprehensive information on the characteristics of FG onset and prognosis. Clinicians should pay more attention to this rare but severe adverse event when prescribing SGLT2 inhibitors in clinical practice.</jats:p>

Sodium–Glucose Cotransporter 2 Inhibitor Use Associated With Fournier’s Gangrene: A Review of Case Reports and Spontaneous Post-Marketing Cases

“…Patients' underlying risk factors for FG should be carefully considered before initiation of an SGLT2 inhibitor. The number of cases identified from the FAERS database is consistent with findings reported by Hu et al (41), reaffirming our concerns of under-reporting in the literature. These concerns warrant further investigation.…”

“…Therefore, patients with pre-existing risk factors require careful monitoring to preemptively evaluate signs and symptoms for the development of urinary tract infections and genital infections, especially in patients who are immunocompromised. It is imperative that clinicians weigh the benefits and risks associated with this drug class in patients with high risks of FG (41,42).…”

Polypharmacology of clinical sodium glucose co‐transport protein 2 inhibitors and relationship to suspected adverse drug reactions

“…The incident rate for Fournier's gangrene, an ADR that has been reported to have an increased association with SGLT2i, 61–63 was similar between all SGLT2i studied (0.35–0.67). Dapagliflozin had the highest ADRs of the renal and urinary system (9.50), followed by canagliflozin (8.33) and empagliflozin the lowest (3.73).…”

Sodium glucose‐linked transport protein 2 inhibitors: An overview of genitourinary and perioperative implications

“…It is possible the resulting increase in reports could be due to enhanced physician vigilance that may have followed the FDA warning 29 . A study which analyzed data from the FDA adverse events reporting system found the number of SGLT2 inhibitor‐related FG cases reported rose from 103 in 2018 to 407 in 2019 30 . FG is a rapidly progressive necrotizing fasciitis that typically requires surgical debridement and antibiotic treatment 31 .…”