FormalPara Key Points

Fournier’s gangrene (FG) is a severe polymicrobial infection that results in necrosis of the perineal and genital fasciae, with rapid progression and a high mortality rate.

It is important to know that sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, may potentially cause FG even when a patient has good glycemic management.

Introduction

Fournier’s gangrene (FG), named by Jean Alfred Fournier in 1883 [1], is a severe polymicrobial infection that results in necrosis of the perineal and genital fasciae. The common symptoms of FG are perianal or genital pain, redness, swelling, and skin necrosis, followed by gangrenous changes. Reports of case series have indicated rapid progression and 20% mortality rates for patients with FG [2]. Alcoholism, liver or kidney failure, cancer, obesity, and smoking are known risk factors [3]. Diabetes mellitus is a comorbid condition in approximately 50% of cases. Early diagnosis is important, and standard management consists of broad-spectrum antibiotics, resuscitation, and aggressive debridement [4].

The mechanism of action of sodium glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes mellitus (T2DM) involves the inhibition of SGLT2 in the proximal convoluted tubule to prevent the reabsorption of glucose and facilitate its excretion in urine. As glucose is excreted, its plasma levels fall, leading to improvements in all glycemic parameters [5].

Several SGLT2 inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, are already available in many countries. Empagliflozin is one of the SGLT2 inhibitors currently approved for use in adult patients with T2DM as an adjunct to diet and exercise to improve glycemic control [6]. Similar to other SGLT2 inhibitors, empagliflozin is associated with a higher rate of genital infections and urinary tract infections [7].

Several case reports have suggested that SGLT2 inhibitors may be implicated as a possible cause of FG [8,9,10,11,12,13]. Here, we describe a Japanese male who developed FG during empagliflozin treatment.

Case Presentation

A 34-year-old Japanese man was referred to our hospital with a 3-day history of pain and swelling in the perineum and the groin. His T2DM had been moderately well managed for 2 years.

A general physician prescribed sitagliptin 50 mg/day, glibenclamide 2.5 mg/day, and empagliflozin 10 mg/day to this patient as first-line antidiabetic therapy. At 19 days after initiating these medications, the glibenclamide was increased to 5 mg/day. He had no complications of diabetes. His body mass index was 28 kg/m2 and he was otherwise in good general health and had no history of genital or urinary infections. He had no significant past medical history and received no concomitant medications. He had a history of smoking but not of alcohol intake.

The first episode of pain in the perineal region occurred 142 days after medication initiation. On admission to our hospital, his body temperature was 38.0 °C. He was not in a state of shock and vital signs were stable: blood pressure 137/76 mmHg, heart rate 120 beats per min, and respiratory rate 13 breaths per min. Skin redness, induration, swelling, and tenderness were observed in the perineum, the scrotum, and the left inguinal region. There was no urinary tract infection or trauma.

Routine laboratory data revealed a white blood cell count 21.7 × 109/L, C-reactive protein 41 mg/L, and glycated hemoglobin 6.5% (per the National Glycohemoglobin Standardization Program). Table 1 summarizes the patient’s baseline clinical data. Computed tomography scan of the lower abdomen and pelvis revealed findings consistent with FG (Fig. 1).

Table 1 Laboratory data at baseline
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Fig. 1
figure 1

A computed tomography scan of the lower abdomen and pelvis showing pathologic Fournier’s gangrene. Evidence of fat stranding and gas (arrow) in the perineum, the scrotum, and the left inguinal region

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The patient underwent emergency surgery under general anesthesia, consisting of incision, debridement, and drainage. Intravenous administration of meropenem 3 g/day and clindamycin 1800 mg/day was initiated. The patient’s antibiotic was changed from a combination of meropenem and clindamycin to intravenous vancomycin 2 g/day because methicillin-resistant Staphylococcus aureus (MRSA) was cultured from the resected tissue on the second postoperative day (Fig. 2).

Fig. 2
figure 2

Clinical course and laboratory data. CRP C-reactive protein, Glu glucose, HbA1c glycated hemoglobin, NGSP National Glycohemoglobin Standardization Program, RBC red blood cell, WBC white blood cell

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We suspected empagliflozin as a possible cause of FG because the pharmacist in our hospital knew about the warning regarding the association of SGLT2 inhibitors with an increased risk of FG issued by the US FDA [13], although FG is not cited in the prescribing information for empagliflozin in Japan. In addition, assessment using the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 5) between FG and empagliflozin therapy in the patient [14]. However, “improvement after drug withdrawal”, as an axis of the Naranjo scale, cannot be considered truly informative, as factors other than the suspected drug, such as surgery and antibiotic treatment, may have caused resolution of the adverse event in this case. Furthermore, alternative causes could have contributed to the onset of FG, including diabetes, smoking habits, and obesity. Given this information, we downgraded the Naranjo scale score from “probable” to “possible”.

Postoperatively, the medications for T2DM were discontinued, and insulin injections were started according to a sliding scale. Sitagliptin 50 mg/day was restarted 9 days after surgery, and metformin 500 mg/day was started 21 days after surgery. The patient’s wounds healed gradually. He was discharged from the hospital 41 days after surgery and continued his treatment for T2DM.

Discussion

Empagliflozin was approved by the FDA in 2014 [6]. Similar to other SGLT2 inhibitors, empagliflozin is associated with high rates of genital infections, urinary tract infections, and lower limb amputations [7, 15]. In this case, we propose that empagliflozin facilitated the occurrence and/or progression of FG. Our rationale is outlined as follows.

First, 12 case reports (seven men and five women) of FG after treatment with SGLT2 inhibitors have been documented from May 2013 to May 2018, although FG is a rare disease [13]. SGLT2 inhibitors are associated with an increased risk for FG, according to an analysis performed by the FDA and an initial warning they issued in 2018 about the potential association [13]. A search of the FDA Adverse Event Reporting System (FAERS) database until January 2019 as per Bersoff-Matcha et al. [16], identified 55 cases of FG in patients receiving SGLT2 inhibitors between March 2013 and January 2019. In comparison, 19 cases of FG associated with other antihyperglycemic agents were identified between 1984 and 2019 [16]. There have been many previous reports of FG associated with SGLT2 inhibitors, compared with few reports of associations with other hypoglycemic drugs. However, there have been too few cases to be sure that FG is related to the use of SGLT2 inhibitors.

We searched the medical literature in PubMed and Google Scholar between May 2013 and July 2019 with the keywords SGLT2 inhibitors and Fournier’s gangrene and retrieved five reports that were described in detail. Each report described a patient who developed FG after commencing treatment with dapagliflozin and empagliflozin (Table 2) [8,9,10,11,12]. Most of those cases involved patients who had T2DM that was reasonably or poorly managed [glycated hemoglobin (HbAlc) > 7.0%], unlike our patient, who had good glycemic management (HbAlc < 7.0%) at the time of FG onset. Thus, the risk for development of FG remains despite good glycemic management with SGLT2 inhibitors.

Table 2 Summary of 6 case reports of Fournier’s gangrene associated with SGLT2 inhibitor treatment
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Second, the pharmacologically induced increased urinary glucose concentration associated with SGLT2 inhibitors might provide a favorable growth environment for otherwise commensal genital microorganisms and could potentially increase the risk for FG, although the mechanism through which SGLT2 inhibitors causes FG is unclear. It cannot be ruled out that the pharmacological effects of SGLT2 inhibitors, such as the stimulation of urinary glucose excretion, play a role in the onset of FG.

The patient in our case had T2DM, was obese, and had a smoking habit, all of which are factors that elevate the risk for FG [3]. These risk factors may have contributed to the development of FG during empagliflozin treatment, although there was no predisposing genital infection or urinary intervention.

Concomitant medications, such as sitagliptin and glibenclamide, may not have been related to the development and/or progression of FG in this case. The inflammatory reactions did not increase in severity when sitagliptin was discontinued and subsequently reintroduced. To the best of our knowledge, a relationship between glibenclamide and FG has not been reported. The mechanism of action of glibenclamide consists of inhibition of the ATP-sensitive K+ channels, which leads to depolarization of the cells, insulin secretion, and a subsequent decrease in plasma glucose levels [17]. Although the mechanism by which FG occurs is unknown, given the pharmacological mechanism of glibenclamide, it may be less likely to be associated with FG. It can be conjectured that the FG likely developed in response to empagliflozin and not glibenclamide.

We report a case of FG in a patient whose glycemic management was good as a result of empagliflozin treatment. In addition, this is the first confirmed case report in Japan of FG that may have been related to treatment with SGLT2 inhibitors.

Conclusion

If FG is suspected in a patient receiving SGLT2 inhibitors, we recommend ceasing that medication and immediately starting combination treatment with broad-spectrum antibiotics and surgical debridement.