Some Diabetes Drugs Can Trigger Perineal Gangrene

Do you know what the perineum is? A lot of people do not know what doctors or drug companies mean when they say the “skin of the perineum.” When a television commercial for a type 2 diabetes drug warns about a skin infection that could lead to perineal gangrene, it may not mention where that is. This is a part of the human anatomy that most people would prefer not to think or talk about. I suspect that most non-medical individuals don’t even know it has a name. The perineum is the territory between the genitals and the anus. Now you realize why most people prefer not to talk about it. That includes a lot of health professionals. But when certain diabetes drugs are prescribed, physicians and pharmacists must warn about potential infections in that area!

TV Commercials and Perineal Gangrene:

On August 29, 2018 the FDA issued a warning about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes:

“The U.S. Food and Drug Administration (FDA) is warning that cases of a rare but serious infection of the genitals and area around the genitals have been reported with the class of type 2 diabetes medicines called sodium-glucose cotransporter-2 (SGLT2) inhibitors. This serious rare infection, called necrotizing fasciitis of the perineum, is also referred to as Fournier’s gangrene. We are requiring a new warning about this risk to be added to the prescribing information of all SGLT2 inhibitors and to the patient Medication Guide.”

Let’s be honest, the description “sodium-glucose cotransporter-2 (SGLT2) inhibitors” does not come trippingly to the tongue. But I will bet your have seen the commercials for some of these drugs:

• Bexagliflozin (Brenzavvy)
• Canagliflozin (Invokana)
• Dapagliflozin  (Farxiga)
• Empagliflozin (Jardiance)
• Ertugliflozin (Steglatro)

The pharmaceutical companies behind both Jardiance and Farxiga are big spenders when it comes to TV commercials. If you have somehow missed these ads, here are some links:

Farxiga for chronic kidney disease

Farxiga for type 2 diabetes

Jardiance for type 2 diabetes

Does the Jardiance jingle trigger your memory?

• “I have type 2 diabetes, but I manage it well.
• “It’s a little pill with a big story to tell…
• “Jardiance is really swell
• The little pill with a big story to tell”

After you watch people singing and dancing about lowering their A1C, you hear an announcer rattling off a list of possible complications:

“Serious side effects may include ketoacidosis that may be fatal, dehydration that can lead to sudden worsening of kidney function and genital yeast or urinary tract infections. A rare life-threatening bacterial infection in the skin of the perineum could occur. Stop Jardiance and call your doctor right away if you have symptoms of this infection, ketoacidosis or an allergic reaction. You may have an increased risk for lower limb loss. Call your doctor right away if you have symptoms of infection of your legs or feet.”

The Potential for Perineal Gangrene Slides Past Pretty Fast:

During the rapid-fire voice-over in the Jardiance commercial, the video includes words that scroll past quickly at the bottom of the screen. Some people may have a hard time reading this additional information if the screen is small or far away.

Here is what flashes past:

“Symptoms of ketoacidosis include nausea, vomiting, stomach pain, tiredness, trouble breathing, and ketones in your urine or blood. Dehydration can make you feel dizzy, faint, lightheaded, or weak upon standing. Genital yeast infections can occur in men or women. The perineum is the area between the anus and genitals. Symptoms of infection include fever, feeling weak or tired, pain, tenderness, swelling or redness in the genitals and the area around them. Symptoms of an allergic reaction include rash, swelling, and difficulty breathing or swallowing. Symptoms of infection include new pain or tenderness, sores or ulcers in your legs or feet.”

Now the commercial does not mention perineal gangrene. Rather, it describes the symptoms of infection in the skin of the perineum “between the anus and genitals.”

The FDA is a bit more specific:

“Patients should seek medical attention immediately if you experience any symptoms of tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell. These symptoms can worsen quickly, so it is important to seek treatment right away.

“Health care professionals should assess patients for Fournier’s gangrene if they present with the symptoms described above. If suspected, start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary. Discontinue the SGLT2 inhibitor, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

“Fournier’s gangrene is an extremely rare but life-threatening bacterial infection of the tissue under the skin that surrounds muscles, nerves, fat, and blood vessels of the perineum. The bacteria usually get into the body through a cut or break in the skin, where they quickly spread and destroy the tissue they infect.”

Other Names for Perineal Gangrene:

The official name for this kind of perineal infection is “Fournier’s gangrene.”

Here is how StatPearls describes it (Jan. 2024):

“Fournier gangrene, a relatively rare form of necrotizing fasciitis, is a rapidly progressive disease that affects the deep and superficial tissues of the perineal, anal, scrotal, and genital regions. Named after Dr. Alfred Fournier, the French dermatology and venereal specialist, it was initially described in 1883 as necrotizing fasciitis of the external genitalia, perineal, and perianal region in five of Dr. Fournier’s patients. Also known as necrotizing fasciitis, the disease involves the rapid spread of severe inflammatory and infectious processes along fascial planes affecting adjacent soft tissue; therefore, the disease may initially go unnoticed or unrecognized as there may be minimal or no skin manifestations in its early stages.”

The authors go on to report that Fournier’s gangrene has a fatality rate of 40%.

Other Names for Fournier’s or perineal gangrene:

• Necrotizing fasciitis
• Flesh eating bacteria
• Phagedena
• Idiopathic gangrene of the scrotum,
• Streptococcal scrotal gangrene,
• Periurethral phelgmon,
• Synergistic necrotising cellulitis.

The Controversy Surrounding SGLT2 inhibitors:

The FDA issued a warning about SGLT2 inhibitors in 2018, but it only identified 12 cases of Fournier’s gangrene. That has been interpreted as a really rare complication of this class of  medications.

The agency added this:

“This number includes only reports submitted to FDA and found in the medical literature, so there may be additional cases about which we are unaware.”

Since then, scientists at the FDA reported additional cases of Fournier’s gangrene (FG)  in the Annals of Internal Medicine (June 4, 2019):

“The FDA identified 55 unique cases of FG in patients receiving SGLT2 inhibitors between 1 March 2013 and 31 January 2019. The patients ranged in age from 33 to 87 years; 39 were men, and 16 were women. Time to onset after initiation of SGLT2-inhibitor therapy ranged from 5 days to 49 months. All patients had surgical debridement and were severely ill. Reported complications included diabetic ketoacidosis (n = 8), sepsis or septic shock (n = 9), and acute kidney injury (n = 4). Eight patients had fecal diversion surgery, 2 patients developed necrotizing fasciitis of a lower extremity that required amputation, and 1 patient required a lower-extremity bypass procedure because of gangrenous toes. Three patients died.”

A more up-to-date article in Cureus, June, 2024 adds this:

“While the exact mechanism is unknown, it is hypothesized that the elevated glycosuria induced by SGLT2is fosters an environment for infection growth in the urinary and genital regions, potentially resulting in the onset of FG. We present a case of FG that occurred following the initiation of dapagliflozin in a patient with predisposing factors for the development of FG. The goal of this case report is to inform clinicians of a rare side effect of SGLT2is, a medication that is now a staple in the management of heart failure, renal disease, and diabetes.”

Glycosuria is excess sugar (glucose) in the urine. FG is Fournier’s gangrene.

Medications That Contain an SGLT2 Inhibitor:

In its 2018 warning, the FDA listed the following medications as containing an SFLT2 inhibitor:

Final Words:

We do not doubt that perineal gangrene is an extremely rare side effect of SGLT2 inhibitors. But it is not clear how many doctors, pharmacists, patients or patients’ relatives are reporting adverse drug effects to the FDA. As a result, we do not know exactly how many cases have occurred over the last decade in the US or abroad.

Because this is such a sensitive topic, many prescribers or dispensers may not mention this potential adverse reaction. That could mean that patients may not realize that there is a life-threatening infection developing until it is quite advanced. My goal in writing this article is to alert patients to this rare complication so that they can follow the FDA’s guidance to:

“…seek medical attention immediately if you experience any symptoms of tenderness, redness, or swelling of the genitals back to the rectum…”

Please share your thoughts in the comment section below. If you were prescribed an SGLT2 inhibitor such as Brenzavvy, Invokana, Farxiga, Jardiance, Steglatro or one of the combination medications listed above, were your informed of this rare, but dangerous side effect? Please share this article with friends or family members who may have been prescribed one of these medications. Yes, it is a delicate topic, but forewarned is forearmed.