SGLT2, Fournier Gangrene Link Is 'Compelling'--What to Do?

F. Perry Wilson, MD, MSCE


May 08, 2019

Welcome to Impact Factor, your weekly commentary on a breaking medical study. I'm Perry Wilson.

A new class of medications, the SGLT2 inhibitors, has been killing it lately, with study after study in the New England Journal of Medicine documenting their benefits in patients with diabetes. Many of us feel that these drugs will become a central part of diabetes therapy in the near future. The twitterverse is all atwitter.

But a publication in the Annals of Internal Medicine[1] may take a bit of bloom off that rose, as it links SGLT2 inhibitors with Fournier gangrene.

For the medical folks watching this, you know what Fournier gangrene is. For the nonmedical people, a word of advice: Do NOT google it. What we are talking about is the life-threatening necrosis and fasciitis of the perineal region—a rare condition representing about 0.02% of all inpatient hospitalizations in the United States.

The primary data source for the analysis was the US Food and Drug Administration (FDA) Adverse Events Reporting System. This is not a perfect data source. Reporting is voluntary, meaning we're not getting every case of Fournier gangrene. Reports are also unverified.

But most important, the database doesn't have a denominator. For example, the authors report that from 2013 to 2019, there were 55 cases of Fournier gangrene among patients taking SGLT2 inhibitors. But we have no idea how many patients were taking the drugs in total.

Nevertheless, inferences can be made. The researchers also searched for cases of Fournier gangrene reported in patients taking other diabetes medications. They found 19 cases. Over 35 years.


SGLT2 inhibitors: 55 cases in 6 years. All of the other diabetes drugs: 19 cases in 35 years. That seems real.

The FDA's adverse events database is open-access, and you can do a lot of cool stuff with it. Pick a drug and the database can show you how much more often a given complication occurs for that drug compared with the rest of the drugs in the database—a metric called the proportional reporting ratio.

Here's that list for empagliflozin, the most popular SGLT2 inhibitor in the United States, showing that diabetic ketoacidosis is reported 1200 times more often in patients taking empagliflozin than the background rate.


You can go backwards, too. I typed "gangrene" into the dataset and obtained this list of drugs, again ordered by how much more often gangrene appears as an adverse event compared with the background rate.


Canagliflozin has the top spot, with a gangrene rate about 100-fold above background. It's followed, interestingly, by insulin, at around eightfold.

But don't get too wrapped up in those numbers. There might be a self-fulfilling prophecy here. Because reports are voluntary, physicians—primed to worry about gangrene by a recent focus within this drug class—may be more likely to report this as an adverse drug event as opposed to attributing it to the patient's underlying disease and not reporting it at all.

On the other hand, there is strong biologic plausibility for a causal link between SGLT2 inhibitors and Fournier gangrene.


SGLT2 inhibitors work by decreasing glucose reabsorption in the kidney, making patients excrete it in the urine. That sugary urine is no doubt an excellent culture medium. In short, this is compelling evidence that these agents increase the risk for Fournier gangrene. Not airtight evidence, not perfect evidence, but compelling nonetheless. So, does it matter?

Remember that Fournier gangrene is vanishingly rare. I couldn't find any cases of Fournier gangrene in the landmark EMPA-REG, CANVAS, or CREDENCE trials of these drugs, with a total enrollment of 21,563 patients. Given the overall efficacy of the class, the chance is much higher that your patient will benefit from the drug than be harmed by it.

But still, the risk for harm is not 0. What to do? Because early intervention is key to the successful treatment of Fournier gangrene, vigilance for the complication, education of patients regarding early symptoms, and prompt referral for treatment if symptoms occur should be standard operating procedure as this drug class goes more mainstream.


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