Fournier gangrene: A challenge for risk–benefit communication
The recent postmarketing data on Fournier gangrene in people taking sodium-glucose cotransporter (SGLT)2 inhibitors has increased concerns about this very rare but potentially fatal side effect. medwireNews takes a look at what is known on the subject and asks a primary care diabetes specialist how it affects risk–benefit considerations.
An adverse effect confirmed
In May this year, the Annals of Internal Medicine published a postmarketing survey of Fournier gangrene – a rapidly progressing bacterial necrotizing fasciitis of the external genitalia – in people using SGLT2 inhibitors to treat type 2 diabetes .
The researchers identified 55 cases of Fournier gangrene over approximately 6 years, compared with just 19 cases over 35 years in people using other glucose-lowering medications. This supports the theory that the glycosuria induced by SGLT2 inhibition can contribute to an optimal environment for Fournier gangrene to take hold.
The publication prompted an alert, sent out from the pharmaceutical companies to healthcare providers, warning of the risk for the complication.
“I’ve had a lot of questions about this,” says Kevin Fernando, a general practitioner with a special interest in diabetes, from North Berwick in the UK.
But he adds: “I was a bit disappointed that this letter was sent out. We want to try and grow the appropriate use of SGLT2 inhibitors, but getting a mailshot like that of course makes everyone a bit more reluctant to prescribe it – we’ve been stung several times before in primary care, with adverse effects, so this is the last thing we needed.”
Rare, but serious
And the condition is extremely rare – the most recent epidemiologic report for the US population, using data for 2001/2004, identified 1641 cases in men, giving an annual rate of 1.6 per 100,000 males, and just 39 cases in women .
On the other hand, Fournier gangrene can have very serious consequences, leading rapidly to bacteremia, septicemia, and death if not promptly treated. Surviving patients often require multiple surgeries, with one in the postmarketing report undergoing 17 operations, and a substantial proportion require ongoing specialized care after hospital discharge.
Case series from tertiary centers have reported mortality rates as high as 88%; however, the aforementioned population-based study found a mortality rate of 7.5% in men and 12.8% in women. Likewise, a study using data for 165 patients treated in Washington state between 2007 and 2013 found a mortality rate of 6.7% . It also showed that the sole high-volume center, which treated approximately 12 cases/year, with these predominantly hospital transfers, had similar outcomes to the low-volume centers (fewer than two cases/year), despite treating more severely ill patients.
The postmarketing study also found that six of the 55 patients with Fournier gangrene had more than one healthcare provider contact before receiving their diagnosis, suggesting the diagnosis was delayed by providers being misled by the relatively nonspecific symptoms.
Fernando agrees that early symptoms “may well be mistaken for thrush,” but stresses that Fournier gangrene will produce “more significant” symptoms, as well as signs or symptoms of sepsis.
The authors of the postmarketing report emphasize that “[p]ain that seems out of proportion to findings on physical examination is a strong clinical indicator of necrotizing fasciitis and may be the most important diagnostic clue.”
They highlight the need for a “high index of suspicion” when assessing genital problems in people taking SGLT2 inhibitors.
Despite the current heightened concern about Fournier gangrene, Fernando says he is “not personally too worried about it.”
Set against such a rare complication are the benefits of SGLT2 inhibitors in people with type 2 diabetes – the glucose-lowering ability, the proven cardioprotective effects, particularly against heart failure, and the more recent evidence of a renoprotective effect.
Fernando informs SGLT2 inhibitor users of the more common side effects, including thrush, urinary tract infections, and diabetic ketoacidosis (DKA), but says: “If I was to list every rare side effect of every drug I prescribe no one would take anything.”
He adds: “I know other colleagues do specifically mention it [but] to me the message is to reinforce the importance of personal hygiene, particularly in men, when using SGLT2 inhibitors.
“Men and women must wash and dry themselves thoroughly, because of the glycosuria that’s caused by the SGLT2 inhibitor, and we need to ask them to check in with us in primary care if they do develop any signs or symptoms of inflammation or infection in their external genitalia.”
Relaying risk is I suppose one of the greatest challenges of working in primary care.
A potential issue here is that, without knowing of the existence of such a serious side effect, SGLT2 users, particularly men, may be reluctant to approach healthcare providers about issues relating to their genitalia until the problem has become serious.
Nevertheless, Fernando says: “I personally feel if I told people there’s this rare risk of a bacterial necrotizing fasciitis of your penis, for example, most men would immediately say no I’m not going to take it when in fact the benefits of this class as I say do outweigh the risks.”
He adds: “Relaying risk is I suppose one of the greatest challenges of working in primary care.
“If of course they bring it up – they read it in the Daily Mail or whatever – I will discuss it, but I won’t proactively mention it; I will mention the genital infections and the importance of keeping clean.”
Who is at risk?
The male predominance seen for Fournier gangrene in the general population seems to translate to its occurrence in SGLT2 inhibitor users, with 39 of the postmarketing cases occurring in men versus 16 in women.
According to Fernando, other people who might be prone to Fournier gangrene include those who:
- are malnourished;
- on long-term steroid therapy;
- drink alcohol to excess; and
- have longer-standing insulin-dependent diabetes.
In general, people who are more prone to DKA would also be more prone to Fournier gangrene, he says.
So would the presence of multiple risk factors sway Fernando toward proactively informing a patient of the Fournier gangrene risk?
“On an individual basis I might consider it,” he concedes. “I suppose I might rarely change my decision if someone’s had some sort of significant genital infection in the past.”
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- Bersoff-Matcha SJ, Chamberlain C, Cao C, et al. Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: A review of spontaneous postmarketing cases. Ann Intern Med 2019; doi:10.7326/M19-0085 http://annals.org/aim/article/doi/10.7326/M19-0085
- Sorensen MD, Krieger JN. Fournier’s gangrene: Epidemiology and outcomes in the general US population. Urol Int 2016; 97: 249–259 https://doi.org/10.1159/000445695
- Osbun N, Hampson LA, Holt SK, et al. Low-volume vs high-volume centers and management of Fournier’s gangrene in Washington state. J Am Coll Surg 2017; 224: 270–275 https://doi.org/10.1016/j.jamcollsurg.2016.11.012