A popular diabetes drug has been shown to double patients’ risk of losing a limb to amputation, according to WebMD.

Dapagliflozin, the generic form of Farxiga, is part of a class of drugs known as sodium glucose cotransporter-2 inhibitors (SGLT2). It has come to light that one of the side effects of Farxiga is twice the risk of losing a limb to amputation.

According to WebMD, not only do the side effects of Farxiga include amputation—most commonly of the toe and foot—but the medication  also increases the risk, twofold, of developing diabetic ketoacidosis.

How Do SGLT2 Inhibitors Work?

As indicated in an article on endocrineweb.com, SGLT2 inhibitors work on the kidneys, interrupting the renal system’s natural process of reabsorbing excess glucose and sending it back into the bloodstream. By inhibiting this function, it allows sugars to be excreted regularly through the urination.

Can The Side Effects of Farxiga Be Brought On By Another Health Issue?

A doctor interviewed by endocrineweb.com speculates that the constant flushing action by the kidneys with SGLT2 inhibitors can lead to a state of patient dehydration. Dehydration can cause constriction in blood vessels feeding the lower extremities where foot ulcers can form and become infected.

Additionally, preexisting conditions common to diabetes such as peripheral artery disease (PAD) may play a role. In a separate WebMD article, PAD is noted to sometimes develop sneakily with symptoms such as achy leg muscles, leading to a decrease in movement, or slow-healing wounds on the legs or feet.

PAD can stem from heart disease, high blood pressure and high cholesterol. Tobacco use is also strongly linked to its development. PAD is characterized by a narrowing of the arteries of the legs which reduces blood flow and oxygenation of the tissues.

Signs of PAD may include shiny skin on the legs, loss of leg hair, reduced pulse in the ankles and feet, and leg skin cooler to the touch than arms.

What Studies Have Supported The Conclusion of Health Risks?

It is also important to remember that the original SGLT2 inhibitor—Invokana—found an increased amputation risk during the preapproval clinical trial CANVAS and the post-approval clinical trial CANVAS-R. Additionally, those trials used participants with type 2 diabetes that had been in full force and effect for a long period of time. These patients were at high risk for heart problems as a byproduct of diabetes and the disease process may have already started in a good many of them.

In May 2017, the U.S. Food and Drug Administration (FDA) released a warning about the link between Invokana and an increased risk of amputation, but Farxiga and other SGLT2 inhibitors were not included. The warning at that time led to the inclusion of a high-level black box warning on the labels of Invokana, Invokamet, Invokamet XR.

A study that specifically enrolled patients taking Farxiga and Jardiance in Sweden and Denmark between 2013 and 2016 reviewed 17,000 cases. Sixty-one percent of the participants were taking Farxiga and 38 percent were taking Jardiance to manage type 2 Diabetes. The findings, published in the British Medical Journal (BMJ), indicated that, like Invokana, these two SGLT2 inhibitors were linked to an amputation risk doubled than the general diabetic population or those taking a placebo.