Three popular diabetes drugs called SGLT-2 inhibitors may have a dark side—they have recently been associated with increased risk for having a foot or leg amputated. If your doctor prescribed an SGLT-2 inhibitor for you, should you stop taking it? That depends.

SGLT-2 inhibitors—short for sodium glucose cotransporter 2 inhibitors—work by stimulating the kidneys to remove sugar from the blood. The excess sugar is then eliminated through the urine. Canagliflozin (Invokana), dapagliflozin (Farxiga) and empagliflozin (Jardiance) are the three SGLT-2 inhibitors on the market. While these drugs also have been found to have beneficial effects beyond blood sugar control, such as protecting the heart and kidneys, recent studies and case reports also suggest they carry serious risks.

The FDA has received case reports linking them to kidney infection, blood clots, pancreatitis and ketoacidosis (a serious diabetes complication that causes too much acid to accumulate in blood). In 2016, two large clinical trials found an increased risk for lower limb amputation associated with Invokana, which prompted the FDA to issue a warning for that drug. No such risk was found in the trials for Farxiga or Jardiance.

To get a clearer picture of the risks associated with SGLT-2 inhibitors, researchers from Karolinska Institute in Sweden looked at data from a nationwide registry of type 2 diabetes patients in Sweden and Denmark. The researchers compared about 17,000 patients who were taking an SGLT-2 inhibitor with about 17,000 patients who were taking a GLP-1 agonist, another type of diabetes drug. (GLP-1 agonists include exenatide/Byetta, dulaglutide/Trulicity and semaglutide/Ozempic.) About 1% of the patients taking an SGLT-2 inhibitor were taking Invokana.

Results: Over the three years of the study, patients on SGLT-2 inhibitors were twice as likely as patients taking a GLP-1 agonist to have an amputation or develop ketoacidosis. No increased risk was found for kidney infection, blood clots or pancreatitis.

While a doubled risk sounds scary, the researchers point out that the overall risk for both amputation and ketoacidosis is still very low—in the study, 2.7% for SGLT-2 inhibitors compared with 1.1% for GLP-1 agonists for amputation risk…and 1.3% vs. 0.6% for ketoacidosis risk.

The authors also note that SGLT-2 inhibitors have been associated with important benefits, such as reducing heart disease risk and kidney failure in diabetics, that need to be weighed when deciding what diabetic medication is most appropriate for a patient. They advise doctors to counsel their patients about both risks and benefits of SGLT-2 inhibitors…and to be cautious about prescribing them for patients who are at higher risk for amputation, such as because of a history of peripheral arterial disease, a previous amputation or foot ulcers.

The only warning of amputation risk currently attached to SGLT-2 inhibitors is the FDA’s safety alert for Invokana, which they updated in 2017. The European Medicines Agency would like to see that warning extended to all SGLT-2 inhibitors. The FDA is warning that all SGLT-2 inhibitors carry a risk for ketoacidosis.

If you’re taking an SGLT-2 inhibitor: Make sure to take good care of your feet. Diabetic foot care includes washing your feet daily…drying them well…checking your feet daily for signs of ulceration or redness…and keeping your feet soft and smooth with lotion to avoid skin cracks. While ketoacidosis is rare, it’s smart to know the symptoms.

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