SGLT2 inhibitors associated with rare, life-threatening necrotizing genital infections

In the past six years, nearly three times as many cases of Fournier gangrene were reported in patients taking sodium-glucose cotransporter-2 (SGLT2) inhibitors as in the past 35 years in patients taking other antiglycemic agents.

The number of cases of Fournier gangrene, also known as necrotizing fasciitis of the perineum, has increased in recent years and is associated with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, according to an FDA case series.

Fournier gangrene is a rare urologic emergency characterized by a rapidly progressive necrotizing infection of the external genitalia, perineum, and perianal region. Researchers compared reported cases of the infection in adults with diabetes receiving SGLT2 inhibitors versus other antiglycemic agents using the FDA's Adverse Event Reporting System. Reports were excluded if they did not mention whether the perineal infection was necrotizing or if there was no surgical intervention. Results were published May 7 by Annals of Internal Medicine.

From March 1, 2013 (when the first SGLT2 inhibitor, canagliflozin, was approved in the U.S.), to Jan. 31, 2019, the FDA identified 55 unique cases of Fournier gangrene in patients receiving SGLT2 inhibitors. Thirty-nine patients were in men and 16 were in women, with an age range from 33 to 87 years. The average time to onset after initiating therapy with SGLT2 inhibitors was nine months (range, five days to 49 months). All patients were severely ill and hospitalized, and three patients died. At least 25 patients needed more than one procedure, including one patient with a reported 17 trips to the operating room. Complications included diabetic ketoacidosis (n=8), sepsis or septic shock (n=9), and acute kidney injury (n=4). Eight patients had fecal diversion surgery, two developed necrotizing fasciitis of a lower extremity that required amputation, and one required a lower-extremity bypass procedure due to gangrenous toes. Cases involved every drug in the SGLT2 inhibitor class marketed in the U.S. except ertugliflozin, and at least 31 patients were receiving an additional antiglycemic agent.

For comparison, the FDA identified 19 cases of Fournier gangrene from 1984 (the year of glipizide approval in the U.S.) through Jan. 31, 2019, that were associated with other antiglycemic agents: metformin (n=8), insulin glargine (n=6), short-acting insulin (n=2), sitagliptin plus metformin (n=2), and dulaglutide (n=1). Twelve patients were men and seven were women, with an age range from 42 to 79 years. All were hospitalized, and two patients died.

Limitations of the study include a variable quality of reports and potential confounding by indication, the study authors noted. In addition, there may have been possible underreporting of the infection. The authors added that the uptick in reports may reflect a growing awareness of Fournier gangrene and an increased prevalence of diabetes in addition to the use of SGLT2 inhibitors.

“Health care providers who prescribe SGLT2 inhibitors to their patients with diabetes should be alerted to and educated about the signs and symptoms of [Fournier gangrene], given the substantial morbidity and mortality associated with this life-threatening and potentially devastating disease,” the authors wrote. While the risk of serious infection is low, it should be weighed against the benefits of SGLT2-inhibitor therapy in prescriber-patient discussions, they concluded.