Article Text
Abstract
Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with increased occurrence of Fournier’s gangrene (FG), a rare but serious form of necrotizing fasciitis, leading to a warning from the Food and Drug Administration. Real-world evidence on FG is needed to validate this warning.
Methods We used data from IBM MarketScan (2013–2017) to compare the incidence of FG among adult patients who initiated either SGLT2i, a dipeptidyl peptidase-4 inhibitor (DPP4i), or any non-SGLT2i antihyperglycemic medication. FG was defined using inpatient International Classification of Diseases, Ninth Edition and Tenth Edition diagnosis codes 608.83 and N49.3, respectively, combined with procedure codes for debridement, surgery, or systemic antibiotics. We estimated crude incidence rates (IRs) using Poisson regression, and crude and adjusted HRs (aHR) and 95% CIs using standardized mortality ratio-weighted Cox proportional hazards models. Sensitivity analyses examined the impact of alternative outcome definitions.
Results We identified 211 671 initiators of SGLT2i (n=93 197) and DPP4i (n=118 474), and 305 329 initiators of SGLT2i (n=32 868) and non-SGLT2i (n=272 461). Crude FG IR ranged from 3.2 to 3.8 cases per 100 000 person-years during a median follow-up of 0.51–0.58 years. Compared with DPP4i, SGLT2i initiation was not associated with increased risk of FG for any outcome definition, with aHR estimates ranging from 0.25 (0.04–1.74) to 1.14 (0.86–1.51). In the non-SGLT2i comparison, we observed an increased risk of FG for SGLT2i initiators when using FG diagnosis codes alone, using all diagnosis settings (aHR 1.80; 0.53–6.11) and inpatient diagnoses only (aHR 4.58; 0.99–21.21).
Conclusions No evidence of increased risk of FG associated with SGLT2i was observed compared with DPP4i, arguably the most relevant clinical comparison. However, uncertainty remains based on potentially higher risk in the broader comparison with all non-SGLT2i antihyperglycemic agents and the rarity of FG.
Trial registration number EUPAS Register Number 30018.
- analytic methods
- claims database analysis
- epidemiology
- sodium glucose cotransporter
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Footnotes
Contributors JYY designed the study, performed the analyses, interpreted the results and drafted the manuscript. TW contributed to study design decisions, interpreted the results and edited the manuscript. VP performed data extraction and provided data analysis support and verification. JBB provided clinical oversight and expertise, contributed to study design decisions, interpreted the results and edited the manuscript. TS provided methods oversight and expertise, contributed to study design decisions, interpreted the results and edited the manuscript. JYY served as the guarantor.
Funding This research was supported, in part, by grants from the National Institutes of Health (R01 AG056479, T32 DK007634, UL1TR002489) and from the University of North Carolina Royster Society of Fellows. The database infrastructure used for this project was funded by the Department of Epidemiology, UNC Gillings School of Global Public Health; the Cecil G Sheps Center for Health Services Research, UNC; the CER Strategic Initiative of UNC’s Clinical Translational Science Award (UL1TR002489); and the UNC School of Medicine.
Competing interests VP: receives salary support from the National Institute on Aging (R01 AG056479), National Institutes of Health (NIH) (R01 HL118255), and the National Center for Advancing Translational Sciences (NCATS, UL1TR002489), NIH. JBB: outside of the submitted work, JBB reports contracted consulting fees and associated travel support paid to his employer from Adocia, AstraZeneca, Dance Biopharm, Dexcom, Eli Lilly, Fractyl, GI Dynamics, Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, vTv Therapeutics, and Zafgen; grants and related travel support from AstraZeneca, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Sanofi, Theracos and vTv Therapeutics; personal fees from Cirius Therapeutics, CSL Behring; stock or stock options from Mellitus Health, PhaseBio, Stability Health, and Pendulum Health; grants from the US National Institutes of Health (UL1TR002489, U01DK098246, UC4DK108612, U54DK118612), PCORI and American Diabetes Association. TS: receives investigator-initiated research funding and support as principal investigator (R01 AG056479) from the National Institute on Aging (NIA), and as coinvestigator (R01 CA174453, R01 HL118255, R21-HD080214), National Institutes of Health (NIH). He also receives salary support as Director of Comparative Effectiveness Research (CER), NC TraCS Institute, UNC Clinical and Translational Science Award (UL1TR002489), the Center for Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Merck, Takeda), from pharmaceutical companies (Amgen, AstraZeneca, Novo Nordisk), and from a generous contribution from Dr Nancy A Dreyer to the Department of Epidemiology, University of North Carolina at Chapel Hill. TS does not accept personal compensation of any kind from any pharmaceutical company. He owns stock in Novartis, Roche, BASF, AstraZeneca, and Novo Nordisk.
Patient consent for publication Not required.
Ethics approval The study was determined to be exempt from full Institutional Review Board review by the University of North Carolina at Chapel Hill.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article. The attached study uses administrative claims data from the MarketScan Commercial Claims and Encounters (CCAE) database, to which UNC-Chapel Hill holds a data use agreement. Under this data use agreement, aggregate-level summaries and results are allowed to be published and shared with external parties, but not the raw de-identified patient-level claims data.