since the US Food and Drug Administration (FDA) issued a 2018 warning about this rare but serious infection, researchers say.
Health care providers prescribing SGLT2 inhibitors to patients with diabetes should have a high index of suspicion for the signs and symptoms of Fournier gangrene, given its substantial morbidity and mortality, according to Susan J. Bersoff-Matcha, MD, and her colleagues at the FDA.
“Although the risk for [Fournier gangrene] is low, serious infection should be considered and weighed against the benefits of SGLT2 inhibitor therapy,” said Dr. Bersoff-Matcha and co-authors in their recent report published in the Annals of Internal Medicine (2019 May 6. doi: 10.7326/M19-0085).
In the previous warning, FDA officials said 12 cases of Fournier gangrene in patients taking an SGLT2 inhibitor had been reported to the agency or in medical literature from March 2013, when the first such inhibitor was approved, and May 2018.
In this latest report, a total of 55 Fournier gangrene cases had been reported in patients receiving SGLT2 inhibitors from March 2, 2013 through January 31, 2019.
The influx of reports may have been prompted by growing awareness of the safety issue, investigators said, but could also reflect the increasing prevalence of diabetes combined with SGLT2 inhibitor use. The researchers also noted that diabetes is a comorbidity in 32% to 66% of cases of Fournier gangrene.
But the likliehood that diabetes mellitus alone causes Fournier gangrene seems unlikley, given that Dr. Bersoff-Matcha and co-authors only found 19 Fournier gangrene cases associated with other classes of antiglycemic agents reported to the FDA or in the literature over a 35-year time frame.
“If Fournier gangrene were associated only with diabetes mellitus 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,” they said in their report.
Cases were reported for all FDA-approved SGLT2 inhibitors besides ertugliflozin, an agent approved for use in the U.S. in December 2017. The lack of cases reported for this drug could be related to its limited time on the market, the investigators said.
Fournier gangrene, marked by rapidly progressing necrotizing infection of the genitalia, perineum, and perianal region, requires antibiotics and immediate surgery, according to Dr. Bersoff-Matcha and colleagues.
“Serious complications and death are likely if Fournier gangrene is not recognized immediately and surgical intervention is not carried out within the first few hours of diagnosis,” they said in the report.
Of the 55 cases reported in patients receiving SGLT2 inhibitors, 39 were men and 16 were women, with an average of 9 months from the start of treatment to the event, investigators said.
At least 25 patients required multiple surgeries, including one patient who had 17 trips to the operating room, they said. A total of 8 patients had a fecal diversion procedure, and 4 patients had skin grafting.
Six patients had multiple encounters with a provider before being diagnosed, suggesting that the provider may have not recognized the infection due to its nonspecific symptoms, which include fatigue, fever, and malaise.
“Pain that seems out of proportion to findings on physical examination is a strong clinical indicator of necrotizing fasciitis and may be the most important diagnostic clue,” Dr. Bersoff-Matcha and co-authors said in their report.
The incidence of Fournier gangrene in patients taking SGLT2 inhibitors can’t be established by these cases reported to the FDA, which are spontaneously provided by health care providers and patients, investigators said.
“We suspect that our numbers underestimate the true burden,” they said in their report.
Dr. Bersoff-Matcha and co-authors disclosed no conflicts of interest related to their report.
SOURCE: Bersoff-Matcha SJ, et al. Ann Intern Med. 2019 May 6. Doi: doi:10.7326/M19-0085.
This article was updated May 9, 2019.