FDA Warns About Serious Genital Infections With Newest Class of Diabetes Drugs

On Aug. 29, 2018, the Food and Drug Administration (FDA) issued a safety warning about the occurrence of a rare but serious infection of the genitals and surrounding tissue in patients taking one of the diabetes drugs known as sodium-glucose cotransporter-2 inhibitors, commonly called "flozins."[1] The infection is called necrotizing fasciitis of the perineum, also known as Fournier's gangrene.

The first flozin available in the U.S., canagliflozin (INVOKAMET, INVOKANA) was approved by the FDA in 2013. The flozin drug class rapidly expanded to include the following FDA-approved products: dapagliflozin (FARXIGA, QTERN, XIGDUO XR), empagliflozin (GLYXAMBI, JARDIANCE, SYNJARDY) and ertugliflozin (SEGLUROMET, STEGLATRO, STEGLUJAN). Many of the brandname products combine a flozin with another diabetes drug. These medications are approved only for treatment of type 2 diabetes.

The newest FDA warning reinforces our earlier decision to designate all flozins as Do Not Use, in part because they carry numerous risks — including a significant risk of kidney disease — and offer no major advantages over several older, safer diabetes drugs.[2]

Prior FDA warning about serious infections

Flozins lower blood sugar levels by causing the kidneys to dump glucose into the urine. Predictably, the increased levels of glucose in the urine caused by flozins, which is the drugs' desired effect, promotes bacteria growth in the urine, making patients susceptible to more frequent and more serious urinary tract infections (UTIs). When the first three flozins were initially approved, their labels indicated that UTIs were among the most frequent adverse events associated with the drugs.[3],[4],[5]

In December 2015, the FDA announced that it had revised the labels for all flozins to include warnings about a risk of more serious types of UTIs, including kidney infections and urosepsis.[6] Urosepsis is a life-threatening complication of UTIs, particularly kidney infections, that involves the spread of bacteria from the urinary tract to the bloodstream, which can lead to low blood pressure, shock and organ failure.

FDA’s new warning[7]

Fournier's gangrene is an extremely rare but potentially fatal bacterial infection of tissues under the skin that covers the muscles, nerves, fat and blood vessels of the perineum (the part of the body between the anus and the genitals). The bacteria that cause this infection typically get into the body through a break or cut in the skin. Diabetes is a risk factor for this dangerous infection, but the condition is still rare even in patients with diabetes. The FDA noted that based on its review of medical journals, the condition historically has occurred predominantly in men, most frequently in those ages 50 to 79.

The FDA's August 2018 warning was prompted by a review of adverse event reports submitted to the agency and case reports published in medical journals. From March 2013, when the first flozin was approved, through May 2018, the FDA was able to identify 12 cases of Fournier’s gangrene in patients taking flozins. The FDA acknowledged that there may have been additional cases that were not reported.

Notably, these 12 patients ranged in age from 38 to 78 and five were women. They had been taking a flozin for an average of nine months prior to being diagnosed with Fournier’s gangrene. All patients were hospitalized, and one died. All required surgery to remove gangrenous tissue from the perineum. In four cases, the patients developed diabetic ketoacidosis (a serious complication of uncontrolled diabetes in which the body produces high levels of acids called ketones), kidney failure and septic shock.

All flozins except ertugliflozin, the newest member of the flozin family that was approved by the FDA in December 2017, were associated with cases of this serious infection. The FDA noted in its warning that ertugliflozin would be expected to have the same risk of this serious infection as the three older flozins.

Because diabetes is a known risk factor for Fournier’s gangrene, the FDA also searched its adverse event reporting system for cases of the infection that occurred in patients using other classes of diabetes drugs. The agency found that from 1984 to 2018, only six additional cases of Fournier’s gangrene in patients using other diabetes drugs had been reported. All were men, and they had a median age of 57. This significantly contrasts with the cases involving patients taking flozins: There have been more reported cases associated with flozins over a much shorter timeframe, and these cases involved both men and women.

What You Can Do

You should not use any flozin drug. If you are currently taking one of these drugs, talk to your doctor about changing to a safer alternative. Never stop taking a prescription drug without first talking to your doctor.

References

[1] Food and Drug Administration. SGLT2 (sodium-glucose cotransporter-2) inhibitors for diabetes: Drug safety communication - Regarding rare occurrences of a serious infection of the genital area. August 29, 2018. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm618908.htm. Accessed October 23, 2018.

[2] Risks but no benefits to taking newest drugs for type 2 diabetes. Worst Pills, Best Pills News. August 2015. /newsletters/view/981. Accessed October 23, 2018.

[3] Janssen Pharmaceuticals. Label: canagliflozin (INVOKANA). March 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf. Accessed October 23, 2018.

[4] Bristol-Myers Squibb. Label: dapagliflozin (FARXIGA). January 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s000lbl.pdf. Accessed October 23, 2018.

[5] Boehringer Ingelheim. Label: empagliflozin (JARDIANCE). August 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf. Accessed October 23, 2018.

[6] Food and Drug Administration. FDA drug safety communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. December 4, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Accessed October 23, 2018.

[7] Food and Drug Administration. SGLT2 (sodium-glucose cotransporter-2) inhibitors for diabetes: Drug safety communication - Regarding rare occurrences of a serious infection of the genital area. August 29, 2018. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm618908.htm. Accessed October 23, 2018.