- Medicines and Healthcare products Regulatory Agency
- 15 June 2016
- Therapeutic area:
- Endocrinology, diabetology and metabolism
A signal of increased lower limb amputation (primarily of the toe) in people taking canagliflozin compared with placebo in a clinical trial in high cardiovascular risk patients is currently under investigation.
See updated advice after a European review of SGLT2 inhibitors.
Advice for healthcare professionals:
- As a precaution, consider stopping canagliflozin if a patient develops a significant lower limb complication (eg, skin ulcer, osteomyelitis, or gangrene), at least until the condition has resolved, and continue to monitor the patient closely
- carefully monitor patients receiving canagliflozin who have risk factors for amputation (eg, previous amputations, existing peripheral vascular disease, or neuropathy)
- monitor all patients for signs and symptoms of water or salt loss; ensure patients stay sufficiently hydrated to prevent volume depletion in line with recommendations in the product information (see footnotes); note that diuretics can exacerbate dehydration
- advise patients to:
- stay well hydrated
- carry out routine preventive foot care
- seek medical advice promptly if they develop skin ulceration, discolouration, or new pain or tenderness
- start treatment for foot problems (eg, ulceration, infection, or new pain or tenderness) as early as possible
- continue to follow standard treatment guidelines for routine preventive foot care for people with diabetes
Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated in adults with type 2 diabetes mellitus to improve glycaemic control when diet and exercise alone do not provide adequate glycaemic control. Canagliflozin is given as monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications.
Canagliflozin can also be given as add-on therapy with other glucose-lowering drugs, including insulin, when these do not provide adequate glycaemic control.
The incidence of lower limb amputation (primarily of the toe) is higher in the canagliflozin groups compared with the placebo group in a clinical trial of high cardiovascular risk patients (CANVAS, an on-going long-term cardiovascular outcomes trial). The trial is fully enrolled with 4,330 randomised participants. The mean and median follow-up time is approximately 4.5 years.
The incidence of lower limb amputation is 7 per 1000 patient-years in the canagliflozin 100 mg group and 5 per 1000 patient-years in the canagliflozin 300 mg group, compared with 3 per 1000 patient-years in the placebo group.
This increased risk was observed independent of risk factors. However, the absolute risk was higher in patients with previous amputations, existing peripheral vascular disease, or neuropathy. No dose response was observed.
Any possible mechanism behind these events is as yet unknown. However, dehydration and volume depletion might increase this risk. We therefore recommend that you follow the interim advice outlined above while this signal is being investigated by the European Medicines Agency. The results of the review will be communicated when available.
Other trials: no significantly increased risk observed
In an ongoing outcome trial with a similar population to CANVAS, the CANVAS-R trial, there have been 16 amputations in the canagliflozin group and 12 amputations in the placebo group. The estimated annualised incidence of amputations is 7 per 1000 patient-years in the canagliflozin group compared with 5 per 1000 patient-years in the placebo group (no statistically significant difference).
12 completed phase 3 or 4 trials have shown no increase in amputation incidence with canagliflozin (incidence of 0.6 per 1000 patient-years in canagliflozin groups and 2 per 1000 patient-years in control groups; mean follow-up of 0.9 years).
Reporting of suspected adverse reactions
Suspected side effects to canagliflozin or any other medicine should be reported to us on a Yellow Card.
NICE guideline on diabetic foot problems: prevention and management
Letter sent to health professionals, April 2016
European Medicines Agency statement, April 2016
1 Invokana▼ (canagliflozin) summary of product characteristics, section 4.4 special warnings and precautions for use: Use in patients at risk for adverse reactions related to volume depletion (last updated May 2016)
2 Vokanamet▼ (canagliflozin and metformin) summary of product characteristics, section 4.4 special warnings and precautions for use: Use in patients at risk for adverse reactions related to volume depletion (last updated May 2016)
Article citation: Drug Safety Update vol 9 issue 11, June 2016: 1.
Published: 15 June 2016
Therapeutic area: Endocrinology, diabetology and metabolism