May 8, 2019 -- Popular diabetes drugs known as SGLT2 inhibitors appear to raise the chance of getting gangrene of the genital area, a rare but potentially fatal side effect, according to a new report.
From March 2013, until Jan. 31, 2019, the FDA found 55 cases of this condition, known as Fournier gangrene, in people taking three different types of the SGLT2 inhibitors. The cases were reported to the FDA's Adverse Event Reporting System (FAERS) database. FAERS contains reports of harmful events from health care providers, drugmakers, patients, and others.
Three of four FDA-approved SGLT2 inhibitors were linked with the condition, including:
- Canagliflozin (Invokana), 21 patients
- Dapagliflozin (Farxiga), 16 patients
- Empagliflozin (Jardiance), 18 patients
A fourth, ertugliflozin (Steglatro), had no reports of gangrene associated with its use. But the report authors say that could be due to the limited time it has been on the U.S. market. It was approved in December 2017.
While it was already known that these drugs could cause Fournier gangrene, the new report highlights the importance of awareness about the risk of the condition and finding it early, says Susan Bersoff-Matcha, MD, an FDA medical officer and lead author of the report, published in the Annals of Internal Medicine.
In August 2018, the FDA required that the risk of gangrene be added to the information patients receive when prescribed the drugs.
More About Fournier Gangrene
"Fournier gangrene is considered a 'flesh-eating' infection," Bersoff-Matcha says. It gets worse rapidly and is found on the external genitals and the area around the anus. It is an emergency. Symptoms may include fatigue and fever, as well as tenderness, swelling, and redness of the skin in the genital area. Treatments may include antibiotics and surgery.
Diabetes, by itself, raises the odds of having Fournier gangrene, Bersoff-Matcha says. Alcoholism, HIV infection, and the use of cancer therapy drugs also make the disease more likely.
Invokana was the first of the SGLT2 inhibitors approved by the FDA, in 2013. The drugs block sodium glucose transport proteins; blood sugar is lowered as it passes out in the urine.
Explaining Fournier Gangrene
Scientists don’t know why it happens in only a small minority of people who have diabetes, but experts say a specific event may trigger it. Those can include trauma after sex, a urinary tract infection, piercing of the genitals, getting a prosthetic penile implant, or having a foreign object in the rectum.
"Still, most patients with diabetes have sexual intercourse or may have a urinary tract infection at some point, yet very few ever develop Fournier gangrene," Bersoff-Matcha says. So, she says, even for people who have something that makes the disease more likely and a triggering event, Fournier gangrene remains rare.
For instance, previous research has said about 1.6 men in every 100,000 will get Fournier gangrene, and among men 50 to 79, about 3 in every 100,000 will get it. The condition is more common in men than women, experts say.
The SGLT2 Link and Fournier Gangrene
The researchers found only 19 such gangrene cases in 35 years among patients receiving other classes of diabetes drugs.
So, they reason, if the Fournier gangrene were linked only with diabetes and not the specific drug, they would expect to find far more than 19 cases with the other types of drugs.
WebMD reached out to the three makers of the SGLT2 inhibitors involved.
Stephan Vincent Thalen, a spokesperson for Eli Lilly and Company, which with Boehringer Ingelheim makes Jardiance, says that "Patient safety is our utmost priority, and we actively monitor the safety of our products on an ongoing basis through clinical trials, observational studies and spontaneous reporting in everyday use." As requested, the label includes the information about the gangrene risk.
Likewise, Jessica Castles Smith of Janssen Pharmaceuticals Inc., maker of Invokana, says the company ''worked with the FDA as part of a class-wide label update to incorporate information about this extremely rare condition into our medicine's label so doctors and patients can make informed decisions."
AstraZeneca declined to comment on the report, but Brendan McEvoy, a spokesperson, said the company remains confident that the benefits outweigh the risks of its drug Farxiga.
''SGLT2 inhibitors, like all other anti-diabetes drugs, are associated with a variety of adverse effects,'' says Alan J. Garber, MD, PhD, a professor of medicine, biochemistry, and cell biology at Baylor College of Medicine in Houston. He reviewed the findings.
"This is the first attempt to gain some data on the frequency with which this happens [with the SGLT2 inhibitor drugs]. This is a very aggressive infection, and infection tends to be more aggressive in diabetics," he says.
His advice: If you get symptoms, ''don't minimize, don't neglect. Consult a physician as soon as possible."
The data does have limitations, he says, as the authors also point out. It can’t prove cause and effect.
Even so, the reports do point to the drugs as something that raises the odds of having Fournier gangrene, says Ahmet Selcuk Can, MD, adjunct assistant clinical professor at Arnot Ogden Medical Center in Elmira, NY. He also reviewed the findings.
The genital area, Can says, already has “microbes from fecal contamination, and SGLT2 inhibitors load sugar to urine. Bacteria and fungus like sugar, and they will feed on sugar." That environment is ideal for the gangrene to develop, he says.
While the condition is rare, awareness is needed, he says. "Of course I do not prescribe any SGLT2 inhibitor to any patient with frequent or recent urinary tract infection, at risk for dehydration or below the recommended kidney function status," he says. He also urges those on the drug to keep hydrated and practice good genital hygiene, such as wiping from front to back.
As rare as the condition, is, Can says, when patients are informed of all the possible risks linked with various diabetes drugs, he finds them more willing to accept a risk of cancer than Fournier gangrene.
The report is not a reason to take someone off an SGLT2 inhibitor if they are doing well on it, Garber says. It would definitely be a reason to discontinue the drug if Fournier gangrene happens.