Original Research
7 May 2019

Fournier Gangrene Associated With Sodium–Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases

Publication: Annals of Internal Medicine
Volume 170, Number 11

Abstract

Background:

Use of sodium–glucose cotransporter-2 (SGLT2) inhibitors has been associated with Fournier gangrene (FG), a rare urologic emergency characterized by necrotizing infection of the external genitalia, perineum, and perianal region.

Objective:

To describe and compare reported cases of FG in diabetic adults receiving treatment with SGLT2 inhibitors or other antiglycemic agents.

Design:

Descriptive case series.

Setting:

U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and published case reports.

Patients:

Adults receiving SGLT2 inhibitors or other antiglycemic agents.

Measurements:

Clinical and laboratory data.

Results:

The FDA identified 55 unique cases of FG in patients receiving SGLT2 inhibitors between 1 March 2013 and 31 January 2019. The patients ranged in age from 33 to 87 years; 39 were men, and 16 were women. Time to onset after initiation of SGLT2-inhibitor therapy ranged from 5 days to 49 months. All patients had surgical debridement and were severely ill. Reported complications included diabetic ketoacidosis (n = 8), sepsis or septic shock (n = 9), and acute kidney injury (n = 4). Eight patients had fecal diversion surgery, 2 patients developed necrotizing fasciitis of a lower extremity that required amputation, and 1 patient required a lower-extremity bypass procedure because of gangrenous toes. Three patients died. For comparison, the FDA identified 19 FG cases associated with other antiglycemic agents between 1984 and 31 January 2019: metformin (n = 8), insulin glargine (n = 6), short-acting insulin (n = 2), sitagliptin plus metformin (n = 2), and dulaglutide (n = 1). These patients ranged in age from 42 to 79 years; 12 were men, and 7 were women. Two patients died.

Limitation:

Inability to establish causality or incidence, variable quality of reports, possible underreporting, and confounding by indication.

Conclusion:

FG is a newly identified safety concern in patients receiving SGLT2 inhibitors. Physicians prescribing these agents should be aware of this possible complication and have a high index of suspicion to recognize it in its early stages.

Primary Funding Source:

None.

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Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 170Number 114 June 2019
Pages: 764 - 769

History

Published online: 7 May 2019
Published in issue: 4 June 2019

Keywords

Authors

Affiliations

Susan J. Bersoff-Matcha, MD
U.S. Food and Drug Administration, Silver Spring, Maryland (S.J.B., C.C., C.C., C.K., W.H.C.)
Christine Chamberlain, PharmD, CDE
U.S. Food and Drug Administration, Silver Spring, Maryland (S.J.B., C.C., C.C., C.K., W.H.C.)
Christian Cao, MPAS, PA-C
U.S. Food and Drug Administration, Silver Spring, Maryland (S.J.B., C.C., C.C., C.K., W.H.C.)
Cindy Kortepeter, PharmD
U.S. Food and Drug Administration, Silver Spring, Maryland (S.J.B., C.C., C.C., C.K., W.H.C.)
William H. Chong, MD
U.S. Food and Drug Administration, Silver Spring, Maryland (S.J.B., C.C., C.C., C.K., W.H.C.)
Disclaimer: The views expressed are those of the authors and do not necessarily represent the position of, nor imply endorsement from, the FDA or the U.S. government.
Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0085.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement: Study protocol: See Methods. Statistical code: Not applicable. Data set: Not available.
Corresponding Author: Susan J. Bersoff-Matcha, MD, CDER/OMP/DCTQ, White Oak, Building 51, Room 3355, 10903 New Hampshire Avenue, Silver Spring, MD 20993; e-mail, [email protected].
Current Author Addresses: Dr. Bersoff-Matcha: CDER/OMP/DCTQ, White Oak, Building 51, Room 3355, 10903 New Hampshire Avenue, Silver Spring, MD 20993.
Dr. Chamberlain: CDER/OSE/DPVI, White Oak, Building 22, Room 3492, 10903 New Hampshire Avenue, Silver Spring, MD 20993.
Mr. Cao: CDER/OSE/DPVI, White Oak, Building 22, Room 3468, 10903 New Hampshire Avenue, Silver Spring, MD 20993.
Dr. Kortepeter: CDER/OSE/DPVI, White Oak, Building 22, Room 3496, 10903 New Hampshire Avenue, Silver Spring, MD 20993.
Dr. Chong: CDER/OND/DMEP, White Oak, Building 22, Room 3346, 10903 New Hampshire Avenue, Silver Spring, MD 20993.
Author Contributions: Conception and design: S.J. Bersoff-Matcha, C. Chamberlain, C. Cao, C. Kortepeter.
Analysis and interpretation of the data: S.J. Bersoff-Matcha, C. Chamberlain, C. Cao, W.H. Chong.
Drafting of the article: S.J. Bersoff-Matcha, C. Chamberlain, C. Cao.
Critical revision for important intellectual content: S.J. Bersoff-Matcha, C. Chamberlain, C. Cao, W.H. Chong.
Final approval of the article: S.J. Bersoff-Matcha, C. Chamberlain, C. Cao, C. Kortepeter, W.H. Chong.
Administrative, technical, or logistic support: S.J. Bersoff-Matcha, C. Chamberlain.
Collection and assembly of data: S.J. Bersoff-Matcha, C. Chamberlain, C. Cao.
This article was published at Annals.org on 7 May 2019.

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