FDA issues alert about interim safety results from ongoing clinical trial, but study of potential canagliflozin amputation risk is ongoing.
The FDA has not determined whether canagliflozin increases the risk of leg and foot amputations. They are currently investigating this new safety issue and will update the public when they have more information.
Canagliflozin belongs to a class of drugs called sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Canagliflozin lowers blood sugar by causing the kidneys to remove sugar from the body through the urine. It is available as a single-ingredient product under the brand name Invokana and also in combination with the diabetes medicine metformin under the brand name Invokamet, and even more are available today.
CANVAS (CANagliflozin cardioVascular Assessment Study) is a long-term study to look at whether canagliflozin reduces cardiovascular (heart and blood vessels) disease. It compares the effects of canagliflozin and placebo (a dummy treatment) together with standard care in diabetes patients at high risk of heart problems. CANVAS was authorized between 2009 and 2010 in the following EU countries: Belgium, Czech Republic, Estonia, France, Germany, Hungary, Luxembourg, Netherlands, Norway, Poland, Spain, Sweden and United Kingdom.
The Independent Data Monitoring Committee for CANVAS and CANVAS-R has recommended that the trials should continue.
In the ongoing Canagliflozin Cardiovascular Assessment Study (CANVAS) clinical trial, the trial’s independent data monitoring committee (IDMC) identified an increased risk of leg and foot amputations. The amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo, which is an inactive treatment. An interim analysis showed that over a year’s time, the risks of amputation for patients in the trial were equivalent to:
- 7 out of every 1,000 patients treated with 100 mg daily of canagliflozin
- 5 out of every 1,000 patients treated with 300 mg daily of canagliflozin
- 3 out of every 1,000 patients treated with placebo
Patients in the CANVAS trial have been followed for an average of 4.5 years to date. The IDMC has recommended, based on an overall assessment, that the CANVAS trial continue.
The IDMC has also reported that a second, similar trial evaluating canagliflozin, the CANVAS-R trial, has not shown the same risks of increased leg and foot amputations to date. Patients in the CANVAS-R trial have been followed for an average of nine months.
The European Medicines Agency (EMA) started a review of canagliflozin after an increase in amputations, mostly affecting toes, was observed in CANVAS. EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) will also ask for data on other medicines in the SGLT-2 inhibitors class. Based on this, the PRAC may decide to extend the scope of the review to cover these medicines. While the review on canagliflozin is ongoing, healthcare professionals will receive a letter reminding them about the importance of routine foot care to avoid cuts or sores of the feet and to treat them promptly should they occur to prevent infection and ulceration. Patients at increased risk of amputation (such as those who have had a previous amputation) should be carefully monitored. As a precautionary measure, doctors may consider stopping treatment with canagliflozin in patients who develop significant foot complications.
Patients who have any questions should speak to their doctor or pharmacist. It is important that patients with diabetes continue to take their prescribed treatment and do not stop treatment without first consulting a healthcare professional.
- The FDA has not determined whether canagliflozin increases the risk of leg and foot amputations.
- The medical community and the public will be updated once the FDA has more information.
- There are two trials that are on-going looking at this issue.
“Canagliflozin (Invokana, Invokamet): Drug Safety Communication – Clinical Trial Results Find Increased Risk of Leg and Foot Amputations.” FDA Safety Alert 5/18/2016.
“EMA reviews diabetes medicine canagliflozin.” European Medicines Agency, April 15, 2016.