Which medications used to treat diabetes, particularly in patients with impaired immune function or at risk of genital infections, are associated with an increased risk of Fournier's gangrene?

SGLT2 Inhibitors Are Associated with Fournier's Gangrene

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the diabetic medications definitively associated with Fournier's gangrene, though the absolute risk remains low. 1, 2

The Medication Class and Mechanism

SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) increase urinary glucose excretion, creating a favorable environment for bacterial and fungal growth in the genitourinary region. 3, 4

• The FDA issued a formal safety warning in 2018 specifically linking SGLT2 inhibitors to Fournier's gangrene in patients with type 2 diabetes. 3, 5
• The mechanism involves glycosuria-induced microbial proliferation in the genital and perineal areas, which can progress to severe necrotizing infection. 3
• All SGLT2 inhibitors carry this risk, with documented cases reported for empagliflozin, canagliflozin, and dapagliflozin. 2, 4, 5, 6

Quantifying the Risk

The absolute risk of Fournier's gangrene with SGLT2 inhibitors is extremely low, but the consequences are catastrophic:

• Genital mycotic infections occur in 6% of SGLT2 inhibitor users versus 1% with placebo, with higher rates in women. 1
• Most genital infections are mild and easily treated, but severe cases can progress to Fournier's gangrene. 1
• The FDA drug label for dapagliflozin explicitly warns about necrotizing fasciitis of the perineum (Fournier's gangrene) as a rare but serious complication requiring urgent surgical intervention. 2

High-Risk Patient Populations

Certain patient characteristics substantially increase the risk of progression from simple genital infection to Fournier's gangrene:

• Diabetes mellitus itself is the single most important risk factor for Fournier's gangrene independent of medication use. 7, 8
• Immunosuppression (including post-transplant patients on immunosuppressive therapy) significantly amplifies infection risk with SGLT2 inhibitors. 1
• Obesity, poor genital hygiene, recurrent urinary tract infections, and history of genital fungal infections increase vulnerability. 3, 4
• Female gender paradoxically carries higher mortality rates despite lower overall incidence. 9
• Advanced age (mean age 61 years in non-survivors) and HIV infection (54% mortality rate) represent particularly high-risk groups. 9

Clinical Recognition and Action Algorithm

When a patient on SGLT2 inhibitors presents with genital or perineal symptoms:

1. Immediately assess for pain or tenderness, erythema, swelling in the genital/perineal area, especially if accompanied by fever or malaise. 2
2. Discontinue the SGLT2 inhibitor immediately if Fournier's gangrene is suspected - do not wait for confirmation. 10, 2
3. Start broad-spectrum antibiotics and arrange emergency surgical consultation for debridement. 2
4. Multiple preceding episodes of genital thrush or recurrent infections should raise suspicion for progression to more severe infection. 4

Critical Management Pitfalls

Never delay surgical intervention to obtain imaging when clinical suspicion is high - proceed directly to emergency surgery in unstable patients or those with obvious signs of necrosis or crepitation. 7

• The FDA label explicitly states that patients presenting with genital/perineal pain, erythema, swelling, fever, or malaise should be assessed for necrotizing fasciitis. 2
• Discontinue SGLT2 inhibitors immediately for severe infections or confirmed Fournier's gangrene - this is non-negotiable. 10, 2
• Most simple genital mycotic infections can be treated with standard antifungal therapy without discontinuing SGLT2 inhibitors, but close monitoring is essential. 10

Preventive Strategies

Before initiating SGLT2 inhibitors:

• Counsel all patients on proper genital hygiene and early symptom recognition. 10
• Consider alternative agents in patients with recurrent genital infections, multiple risk factors, or immunosuppression. 10
• In kidney transplant recipients, theoretical concerns about increased infection risk due to immunosuppression warrant caution, though definitive data are lacking. 1

During SGLT2 inhibitor therapy:

• Monitor for symptoms of genitourinary infections at follow-up visits. 10
• Educate patients to seek immediate medical attention for genital/perineal pain, swelling, or systemic symptoms. 2
• Consider temporary discontinuation during acute illness or periods of increased infection risk. 10

Balancing Benefits and Risks

Despite this serious complication, the cardiovascular and renal benefits of SGLT2 inhibitors generally outweigh the low absolute risk of Fournier's gangrene in most patients. 1, 10, 3

• SGLT2 inhibitors remain strongly recommended for patients with type 2 diabetes, chronic kidney disease, and eGFR ≥20 mL/min/1.73 m². 1
• The key is vigilance, patient education, and prompt recognition with immediate action when infection occurs. 3
• No other diabetic medication class has been definitively linked to Fournier's gangrene in the same manner as SGLT2 inhibitors. 1, 2