FDA Tallies Cases of Fournier Gangrene in Patients Taking SGLT2 Inhibitors

The US Food and Drug Administration has identified 55 new cases of Fournier gangrene in patients with type 2 diabetes treated with sodium-glucose co-transporter-2 (SGLT2) inhibitors and recommend physicians prescribing the drugs “have a high index of suspicion” to identify the condition in its earliest stages.

Time from onset after starting the SGLT2 inhibitor ranged from 5 days to 49 months and all patients required “surgical debridement and were severely ill,” according to the new analysis of the FDA Adverse Event Reporting System (FAERS) database published May 6, 2017, in the Annals of Internal Medicine.

Susan Bersoff-Matcha, MD (Food and Drug Administration, Silver Spring, MD), who led the analysis, stressed that Fournier gangrene is a rare event.

“While our study shows an association between treatment with SGLT2 inhibitors and Fournier gangrene, we don’t know exactly what the risk is, or if Fournier gangrene can be predicted,” she told TCTMD via email. “Doctors should be aware of the association between Fournier gangrene and SGLT2 inhibitor use and discuss this potential complication as part of an informed prescriber-patient discussion regarding appropriate diabetes therapy. Although the risk for Fournier gangrene is low, serious infection should be considered and weighed against the benefits of SGLT2 inhibitor therapy.”

Also known as necrotizing fasciitis of perineum, the condition is a rapid and progressive infection of the external genitalia, perineum, and perianal region that is treated with antibiotics and immediate surgery. The overall incidence of Fournier gangrene in the general population is 1.6 per 100,000 men, with a peak incidence of 3.3 per 100,000 men aged 50 to 79 years. Recent studies have shown that Fournier gangrene can occur in both men and women, with cutaneous, anorectal, and urogenital infections attributed as the cause in the majority of these cases.

Bersoff-Matcha noted that diabetes is a known risk factor for Fournier gangrene, as is alcoholism, HIV infection, and use of cytotoxic drugs. The reason Fournier gangrene develops in a small minority of patients with diabetes is not well understood, she said.

Dear Doctor Letters Issued

The 55 cases of Fournier gangrene among patients taking SGLT2 inhibitors were reported to the FDA between March 2013 and January 2019. In total, 39 men and 16 women developed the necrotizing fasciitis. The average time from starting the SGLT2 inhibitor to the development of the condition was 9 months and cases included use of every SGLT2 inhibitor commercially available in the US except ertugliflozin (Steglatro; Merck). Complications of the gangrene included diabetic ketoacidosis, sepsis/septic shock, and acute kidney injury. Eight patients required fecal diversion surgery and two needed amputations of a lower extremity. Three patients died.

In September 2018, the FDA warned physicians about the possible risk of Fournier gangrene in diabetic patients treated with SGLT2 inhibitors. Health authorities in the United Kingdom also alerted physicians to reports of Fournier gangrene with SGLT2 inhibitor treatment.   

To TCTMD, Darren McGuire, MD (UT Southwestern Medical Center, Dallas, TX), noted that physicians have received “Dear Doctor” letters regarding the potential risk of this rare event, but said he is uncertain what to make of the association given that the number of cases is small and abstracted from the voluntarily-reported FDA adverse event registry. Additionally, it is impossible at present to make direct comparisons across treatments or to map observed-versus-expected events based on epidemiologic/natural history estimates of risk or incidence.

Nonetheless, even without definitive conclusions, “this does rise to the level of ‘risk signal’ that we are paying attention to moving forward in the randomized trials,” he told TCTMD in email.

McGuire, one of the investigators of the DECLARE TIMI-58 trial testing dapagliflozin (Farxiga; AstraZeneca), noted their group presented adverse event data at the American Heart Association 2018 Scientific Sessions showing eight total cases of Fournier gangrene, with only one case in the dapagliflozin-treated group and seven in the placebo arm. While these numbers are “way too small to draw any meaningful conclusions,” he says, they do suggest there was no safety signal in the randomized controlled trial.

For physicians, McGuire said, these new data should not be “prohibitive or adversely affect prescription” in patients eligible for SGLT2 inhibitors based on the randomized trial data and in accordance with the FDA label. The appropriate response is continued patient and provider education with a heightened awareness of signs and symptoms of Fournier gangrene, continued counseling on urinary hygiene when prescribing, and ongoing surveillance in the SGLT2 inhibitor trials, he said.