In late August, the FDA issued a 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.” The SGLT2s affected by the warning include canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and their combinations.

The FDA identified 12 reports of the infection, called necrotizing fasciitis of the perineum or Fournier’s gangrene, between March 2013 and May 2018 from adverse event reports and a literature review. In Fournier’s gangrene, bacteria enter the body through a break in the skin then quickly spread, killing the tissues, muscles, nerves, and blood vessels around the perineum and beyond.

All 12 patients developed the infection with a few months of starting an SGLT2 inhibitor, and all required hospitalization and surgery. One patient died, several experienced disfiguration associated with multiple surgeries, and a number developed complications. While diabetes increases the risk of Fournier’s gangrene, the FDA found only six cases of the infection among patients treated with other classes of antihyperglycemic medications in the last 30 years. Notably, all six of those infections occurred in men; five of the 12 associated with SGLT2 inhibitors affected women.

SGLT2 inhibitors lower blood glucose by causing the kidneys to excrete more sugar in urine, making the genital area more conducive to bacterial infections. Urinary tract and vaginal yeast infections are also associated with SGLT2 inhibitors for the same reason.

In addition to the FDA warning, SGLT2 inhibitors received a double whammy of bad news in August. First, researchers at the European Society of Cardiology Congress found that the drugs more than doubled the risk of lower limb amputation and diabetic ketoacidosis compared to glucagon-like peptide-1 receptor agonists in an analysis of 17,213 Swedish and Danish patients. Cardiologists have been interested in SGLT2 inhibitors because of a large observational study that showed they reduced the risk of heart failure.

Then, Johns Hopkins researchers published a study in JAMA Internal Medicine showing the same doubling of amputation risk for SGLT2 inhibitors compared to sulfonylureas, metformin, and thiazolidinediones in an analysis of 953,906 diabetic patients. The class has carried a black box warning for this risk in the U.S. and Europe for the last year.

On the other hand, a major observational study presented at the American Diabetes Association in June had very different results. That study found no increase in the risk of amputation with the SGLT2 inhibitor canagliflozin compared to other SGLT2 inhibitors or other classes of diabetes medications among more than 700,000 patients followed for a median of 6 years.

The news stories may have patients with diabetes on edge and questioning whether they should continue to take their prescribed medication. What should you say?

The FDA said that more than 1.7 million patients filled a prescription for an SGLT2 inhibitor in 2017, so the risk of Fournier’s gangrene appears quite small, though the warning noted that there may be additional unreported cases. Patients are encouraged to seek immediate medical attention if they have any tenderness, redness, swelling in the genital or perineal area, a fever of 100.4 F or higher, or otherwise feel unwell. If the infection is suspected, the drug should be discontinued and broad-spectrum antibiotics administered. Surgical debridement may be required. Patients with concerns, but no symptoms, should discuss their treatment options with their physician before stopping their medication.

As for the amputation risk, the JAMA study authors advised, “Given the uncertainty regarding the true nature of the association between SLGT-2 inhibitors and amputation, clinicians and patients will have to navigate treatment choices while balancing the potential risks of these products against their benefits and alternatives.”

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