According to the online journal P&T Community, the FDA recently warned about certain diabetes medications linked to amputations, with data indicating that canagliflozin-based drugs may cause an increased risk of lower limb amputations.

The FDA reportedly issued this warning after reviewing data from two large clinical trials, which concluded that Invokana, Invokamet, and Invokamet XR could increase the chances of leg and foot amputations. Now, the FDA is requiring new warnings to be added to these medications, with the FDA advising patients to talk to their doctors if they notice any swelling or tenderness in their feet or legs.

The two trials are the CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R, which was a study that examined the side effects of canagliflozin on renal endpoints in adult type-2 diabetes patients. The studies showed that lower limb amputations were about twice as likely in patients with canagliflozin compared to patients prescribed the placebo.

In a year’s time, the CANVAS trial revealed the following statistics regarding lower limb amputation:

• 5.9 out of 1,000 patients treated with canagliflozin experienced lower limb amputation
• 2.8 out of 1,000 patients treated with placebo experienced lower limb amputation

The CANVAS-R trial showed similar results, with the risk of lower limb amputation in the following statistics:

• 7.5 out of every 1,000 patients treated with canagliflozin experienced lower limb amputation
• 4.2 out of every 1,000 patients treated with placebo experienced lower limb amputation

Dr. Bruce Neal of the University of New South Wales Sydney led the study, along with six other scientists who collaborated to investigate whether or not these diabetes medications linked to amputations pose an increased risk.

The most common amputations noted were those involved one of the toes and middle of the foot, according to the New England Journal of Medicine, but above the knee amputations were also recorded, with other serious cases involving multiple amputations.

Overview of SGLT2 Inhibitor Amputation Correlation

These canagliflozin medications are part of the sodium-glucose cotransporter-2 (SGLT2) inhibitor drug family, which helps the body regulate blood sugar by signaling the kidneys to expel excess glucose through urination. The FDA issued a warning on May 16, 2017, alerting patients and doctors to diabetes medications linked to amputations.

Type-2 diabetes is one of the most prevalent health concerns in the United States, according to the Mayo Clinic, and typically causes problems related to unstable blood sugar levels. Lower limb amputation is one of the most significant risks associated with this disease, which typically stems from peripheral artery disease (PAD) and other circulation issues that causes blood vessels to narrow in the legs and feet.

Diabetes can also cause peripheral neuropathy, which can prevent patients from feeling pain. According to Healthline, if blood vessels and nerves in the legs die out, ulcers and swelling can buildup creating the need for amputation.

At this time, it is not known why SGLT2 inhibitors may be increasing the risk of lower limb amputations, but the FDA is currently warning doctors to carefully evaluate whether or not these diabetes medications are the right prescription choice for patients. Patients with a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers may be at the highest risk for amputation.