In August 2018, the US Food and Drug Administration (FDA) added a warning about Fournier gangrene (FG) to the labels of all SGLT2 inhibitors, used to treat type 2 diabetes. And as reported by Medscape News this May, an update from the FDA Adverse Event Reporting System (FAERS) database found 55 cases in patients taking these drugs over the 6 years since the first SGLT2 inhibitor, canagliflozin (Invokana), entered the US market, compared with 19 cases in 35 years among patients on other classes of antiglycemic drugs.
FG is a rare necrotizing fasciitis of the external genitalia, perineum, and perianal region. Because FAERS reports are voluntary and unverified, the researchers limited their count to patients severely ill with FG who had documented surgical debridement. There were 41 other mentions of FG in patients on SGLT-2 inhibitors that did not document surgery.
At the time, lead author Susan J. Bersoff-Matcha, MD, of the FDA's Center for Drug Evaluation and Research (CDER), Silver Spring, Maryland, said "that if FG were associated only with diabetes mellitus and not SGLT2 inhibitors, we would expect far more cases reported with other antiglycemic agents."
In a related commentary on Medscape, Perry Wilson, MD, cautioned that physicians alerted to a potential problem with a drug class may be more likely to report a complication as an adverse drug event as opposed to attributing it to the patient's underlying disease and not reporting it at all. SGLT2 inhibitors work by decreasing glucose reabsorption in the kidney, leading to its excretion in the urine, which in turn increases the risk for infection.
DECLARE-TIMI 58 FG Data
At the recent American Diabetes Association (ADA) Scientific Sessions, more details were presented on the adverse events in DECLARE-TIMI 58, the first trial of SGLT2 inhibitors completed after the FDA warnings on FG. The investigators planned to collect serious adverse events and any adverse events leading to drug discontinuation, but went back and did an in-depth check for necrotizing fascitis in light of the concerns.
They identified six cases of FG among study participants; five occurred in the placebo group (Table). Lawrence A. Leiter, MD, University of Toronto, Ontario, Canada, said in a press conference at ADA that on the basis of the DECLARE-TIMI 58 data, SGLT2 inhibitors do not seem to increase the risk and that FG is a diabetes-associated complication.
Asked to respond, Bersoff-Matcha told Medscape that the DECLARE-TIMI 58 data are still under review by the FDA. "At this time, our opinion regarding the association between SGLT2 inhibitor use and FG has not changed. We, however, note that the DECLARE-TIMI 58 study only evaluated patients using dapagliflozin and may not be reflective for the SGLT2 inhibitor drug class [as a whole]."
SGLT2 inhibitors also carry a warning about increased risk for serious urinary tract infections (UTIs) and genital fungal infections, both known risk factors for FG.[1,2] Among the patients with FG in the FAERS analysis, two had UTI and one had recurrent genital fungal infection, according to the CDER.
In DECLARE-TIMI 58, the rate of genital fungal infections leading to drug discontinuation was higher in the SGLT2 inhibitor arm, but the rate of UTIs was no different. This is similar to what was seen in CREDENCE and the EMPA-REG experience with canagliflozin and empagliflozin, respectively, and a real-world analysis from Canada presented in the ADA poster sessions.
Table. DECLARE-TIMI 58 Genital and Urinary Tract Infections
|Dapagliflozin (n = 8574)||Placebo (n = 8569)|
|Genital infection: DAE (DAE)||
|Genital infection: SAE||
|Urinary tract infection: DAE||
|Urinary tract infection: SAE||
1 (< 0.1%)
5 (< 0.1%)
|DAE = adverse event leading to drug discontinuation; SAE = serious adverse event|
For that Canadian analysis, researchers plumbed the administrative databases in Ontario for women and men with diabetes older than 66 years who were taking SGLT2 inhibitors from January to December 2016.
There was a 2.5-fold higher risk for genital fungal infection within 30 days among the nearly 21,500 SGLT2 inhibitor users versus a comparator group of almost 22,500 new dipeptidyl peptidase-4 inhibitor users (adjusted hazard ratio [HR], 2.47; P < .001). The risk for UTIs did not appear to be higher (adjusted HR, 0.89; P = .05).
Lead author Iliana Lega, MD, Women's College Hospital, Toronto, Ontario, told Medscape that to address the possibility of confounding due to avoidance of SGLT2 inhibitors in patients with a history of genitourinary infections, they did sensitivity analyses where they excluded patients with a recent infection and the results were unchanged.
What to Do
Meanwhile, a small study from the United Kingdom presented at the ADA sessions examined whether hygiene advice could help prevent genital mycotic infections in 250 patients with type 2 diabetes starting SGLT2 inhibitor therapy.
Half were told to rinse the genital area with water after every void and before bed. Within the first 6 months of starting therapy, six patients (4.8%) who received hygiene advice experienced a fungal infection compared with 51 (40.8%) of those who didn't (P = .015). The infections were severe in 36 of the 51 patients and led to drug discontinuation. The other 15 patients continued SGLT2 inhibitor therapy with the addition of antifungal treatment.
So should hygiene advice such as this be given to all patients prescribed SGLT2 inhibitors? Although Lega would like to see this studied in a larger population, she told Medscape that "such recommendations are a good idea, and clinically, we do reiterate this to patients."
Bershoff-Matcha agrees that it intuitively sounds reasonable, but notes that the CDER "cannot make any specific recommendation for this practice because we are not aware of any data to support that such a recommendation will decrease the likelihood of Fournier gangrene."
Given the substantial morbidity and mortality associated with FG, the CDER recommends that healthcare providers who prescribe SGLT2 inhibitors to their patients with diabetes should be alerted to, and educated about, its signs and symptoms.
As previously noted, pain that seems out of proportion to findings on physical examination is a strong clinical indicator of FG and may be the most important diagnostic clue.
Drs Lega and Bersoff-Matcha report no disclosures. Dr Leiter reported being on Advisory boards for AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk Inc.; Sanofi; and Servier; receiving research support from AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly and Company; GlaxoSmithKline plc.; Janssen Pharmaceuticals, Inc.; Novo Nordisk Inc.; and Sanofi; and being on a speakers bureau for AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk Inc.; and Sanofi.
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Cite this: Fournier Gangrene and Genitourinary Infections With SGLT2 Inhibitors: ADA 2019 Update - Medscape - Jul 18, 2019.