Fournier gangrene (FG), a necrotizing infection of the perineum, is a relatively rare but potentially fatal complication of treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors, new data from the US Food and Drug Administration (FDA) suggest.

The FDA had previously added a warning about FG to the labels of all SGLT2 inhibitors, used to treat type 2 diabetes, in August 2018, based on 12 cases reported from March 2013 to May 2018.

Now, findings from a review of 55 cases reported to the FDA Adverse Event Reporting System (FAERS) through January 2019 have been published onlineMay 6 in Annals of Internal Medicine by Susan J. Bersoff-Matcha, MD, of the FDA's Center for Drug Evaluation and Research, Silver Spring, Maryland, and colleagues. 

All of the patients required hospitalization, some needed multiple surgeries, and there were three fatalities.

"Serious complications and death are likely if FG is not recognized immediately and surgical intervention is not carried out within the first few hours of diagnosis," Bersoff-Matcha and colleagues stress.

Pain Out of Proportion to Physical Exam Findings a Strong Clue 

Pain that seems out of proportion to physical exam findings is a strong clue to necrotizing fasciitis and FG, the authors say, while systemic symptoms of FG such as fatigue, fever, and malaise, may be variable and nonspecific. Local symptoms may include tenderness, erythema, and swelling.

While diabetes itself also increases the risk for FG, the 55 reports associated with SGLT2 inhibitors in the 6 years since canagliflozin (Invokana, Vokanamet, Janssen), the first in class, was approved far exceeds the 19 FG cases reported over 35 years among patients receiving other classes of glucose-lowering drugs.

"If FG were associated only with diabetes...and not SGLT2 inhibitors, we would expect far more cases reported with the other antiglycemic agents, considering the 35-year timeframe and the large number of agents," the authors write.

Awareness of the association between FG and SGLT2 inhibitor use should be considered when deciding whether to prescribe the drugs, they advise.

"Although the risk for FG is low, serious infection should be considered and weighed against the benefits of SGLT2 inhibitor therapy."

FG Is Serious, Disfiguring, and Can Be Fatal 

In their FAERS search, the authors included all reports of FG submitted between March 1, 2013, the day canagliflozin was approved, through January 31, 2019, in patients treated with FDA-approved SGLT2 inhibitors.

All patients had a necrotizing infection of the perineum (vulva/vagina or scrotum or buttocks), with surgical debridement in response to the infection.

A search of the medical literature yielded four such case reports, all of which had been reported to FAERS.

Cases were reported for all of the FDA-approved SGLT2 inhibitors except ertugliflozin (Steglatro, Merck), which was approved most recently (December 2017).

Patients were a median age of 56 years, most were men (39/55 cases), and most were reported in the United States (44 cases). The average time from initiation of the SGLT2 inhibitor to FG onset was 9 months, but the range was wide, from 5 days to 49 months.

All patients were severely ill with FG and were hospitalized. Although the number of surgeries was not consistently reported, at least 25 patients needed more than one surgical debridement, including one patient with a reported 17 trips to the operating room.

Eight patients underwent a procedure for fecal diversion and at least four patients had skin grafting. The clinical course for some patients was complicated by diabetic ketoacidosis (n = 8), sepsis or septic shock (n = 9), or acute kidney injury (n = 4). Some patients may have had more than one complication.

Necrotizing fasciitis of a lower extremity developed in two patients during hospitalization and required amputation. Another patient required a lower-extremity bypass procedure for gangrenous toes.

Three patients died.

Duration of acute hospitalization for the surviving patients ranged from 5 to 51 days. The SGLT2 inhibitor was discontinued in at least 22 of the 52 survivors.

Six patients had more than one visit with a provider before being diagnosed with FG, "indicating that the provider may not have recognized the diagnosis because of its nonspecific symptoms," Bersoff-Matcha and colleagues emphasize.

The authors are all FDA employees and have reported no further disclosures. 

Ann Intern Med. Published online May 6, 2019. 

www.medscape.com

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Abstract

https://annals.org/aim/article-abstract/2732837/fournier-gangrene-associated-sodium-glucose-cotransporter-2-inhibitors-review-spontaneous

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

Susan J. Bersoff-Matcha, MD; Christine Chamberlain, PharmD, CDE; Christian Cao, MPAS, PA-C; Cindy Kortepeter, PharmD; William H. Chong, MD

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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