Sodium-glucose cotransporter 2 (SGLT2) inhibitors and risk of necrotising fasciitis of the perineum (Fournier’s gangrene)

HSA would like to inform healthcare professionals about overseas cases of necrotising fasciitis of the perineum reported in patients who were treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors. This rare but serious soft tissue infection of the genital, perineal, and/or perianal regions, also referred to as Fournier’s gangrene, is a potentially life-threatening event that requires urgent surgical intervention and broad-spectrum antibiotic therapy.

Background

SGLT2 inhibitors are oral glucose-lowering agents that increase the renal excretion of glucose (i.e. glycosuria) through the inhibition of SGLT2-mediated renal glucose reabsorption. Three SGLT2 inhibitors have been registered in Singapore since 2014, either as single ingredient or fixed-dose combination products. They are canagliflozin (Invokana™; Johnson & Johnson Pte Ltd), dapagliflozin (Forxiga^®, Xigduo XR^®; AstraZeneca Singapore Pte Ltd) and empagliflozin (Jardiance^®, Jardiance Duo^®, Glyxambi^®; Boehringer Ingelheim Singapore Pte Ltd). These drugs are indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus (T2DM), as monotherapy and as an add-on combination therapy with other glucose-lowering agents including insulin. In addition, Forxiga^® is indicated as an initial combination therapy with metformin, and Jardiance^® and Jardiance Duo^® are indicated for use in T2DM patients with established cardiovascular disease.

Fournier’s gangrene usually presents as a polymicrobial infection with common clinical features of swelling of the external genitalia, fever and pain that may rapidly progress to skin necrosis if not treated promptly. It occurs almost exclusively in males with an estimated male:female ratio of 10:1. A US study, based on hospitalisation data, reported an estimated incidence rate of Fournier’s gangrene of 1.6-3.3 per 100,000 males annually and overall fatality rate of 7.5%.¹ The identified predisposing factors for Fournier’s gangrene include diabetes mellitus, obesity, older age, and other conditions leading to impaired microcirculation and/or immunosuppression.²

Overseas cases of Fournier’s gangrene with SGLT2 inhibitors

In September 2018, the US Food and Drug Administration (FDA) issued a drug safety communication warning that cases of Fournier’s gangrene have been reported in SGLT2 inhibitor-treated patients.³ The agency conducted a search of its adverse event reporting system database (FAERS) from March 2013 to February 2018 as well as the medical literature through 2018, and identified a total of 12 cases of Fournier’s gangrene associated with SGLT2 inhibitors. In contrast, the agency identified only six cases of Fournier’s gangrene (all in men) associated with several other antidiabetic drug classes (insulins, biguanides, sulfonylureas, and dipeptidyl peptidase-4 inhibitors) in the search of the FAERS over a period of 34 years.

Of the 12 SGLT2 inhibitor-associated Fournier’s gangrene cases, seven cases involved men and the remaining five cases involved women, with ages ranging from 38 to 78 years. The average time from the initiation of a SGLT2 inhibitor to the onset of Fournier’s gangrene was 9.2 months (range 7 days to 25 months).

Patients in all 12 cases were hospitalised and required surgical debridement, of which five cases required multiple surgeries and one case required skin grafting. The clinical course for four cases was complicated by diabetic ketoacidosis, acute kidney injury, and septic shock, which prolonged the patients’ hospitalisation or led to death. The SGLT2 inhibitor was discontinued in eight cases; one patient had died; and information on drug continuation or discontinuation was not included in the remaining three cases.

International regulatory actions

Following assessment of the available data, the US FDA³ and the European Medicines Agency (EMA)⁴ had requested for the package inserts of SGLT2 inhibitor products to be updated on the warning concerning the risk of Fournier’s gangrene. 

Local situation and HSA’s advisory

HSA has not received any local reports of Fournier’s gangrene associated with SGLT2 inhibitors. The local package inserts for SGLT2 inhibitor-containing products are being updated to warn about this risk.

Healthcare professionals are encouraged to take into consideration the above safety information when prescribing a SGLT2 inhibitor, and to consider the possibility of Fournier’s gangrene in SGLT2 inhibitor-treated patients who present with pain, tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If Fournier’s gangrene is suspected, healthcare professionals should consider the discontinuation of SGLT2 inhibitor with the initiation of prompt treatment.

Healthcare professionals are also encouraged to report any serious adverse reactions, including Fournier’s gangrene, related to SGLT2 inhibitors to the Vigilance and Compliance Branch of HSA.

References

1. J Urol 2009; 181: 2120-6

2. Nat Rev Urol 2017; 14: 205-14

3. https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm

4. https://www.ema.europa.eu/documents/prac-recommendation/prac-recommendations-signals-adopted-26-29-november-2018-prac-meeting_en.pdf