Canagliflozin belongs to a relatively new class of drugs called sodium-glucose cotransporter 2 (SGLT2) inhibitors. It is available under the brand name Invokana® and also in combination with metformin under the brand name Invokamet®.
The US Food and Drug Administration (FDA) recently issued a safety alert that canagliflozin has been associated with an approximately two-fold risk for leg and foot amputations compared with placebo in an ongoing clinical trial.1 However, the FDA has not yet made a clear determination as to whether the SGLT2 inhibitor actually increases the risk for amputations and is investigating further. In the meantime, healthcare professionals are advised to follow the recommendations in |
 Vivian A. Fonseca, MD |
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the canagliflozin drug label and monitor patients for signs and symptoms of foot problems.
The data come from a trial called CANVAS (CANagliflozin cardioVascular Assessment Study), a long-term study assessing whether canagliflozin reduces cardiovascular disease.2 It compares the effects of canagliflozin and placebo (a dummy treatment) together with standard care in diabetes patients at high risk of heart problems. |
The Independent Data Monitoring Committee for CANVAS and another study CANVAS-R has recommended that the trials should continue. However, the committee identified an increased risk of leg and foot amputations. The amputations occurred about twice as often in patients treated with canagliflozin compared with patients treated with placebo, although the number of such amputations was low, making it difficult to determine causality. An interim analysis showed that over a year’s time, the risks |
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of amputation for patients in the trial was 7 out of every 1,000 patients treated with canagliflozin 100 mg daily, 5 out of every 1,000 patients treated with canagliflozin 300 mg daily, and 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.
Also, the CANVAS-R trial, has not shown the same risks of increased leg and foot amputations to date, but patients in the CANVAS-R trial have been followed for an average of only 9 months.
These studies are being conducted in a population at high risk of diabetes complications, including peripheral vascular disease (PVD) and neuropathy leading to amputations. It is ironic that this warning, along with others, has come very soon after a clinical trial of a drug in the same class with similar mechanism of action showed a decrease in cardiovascular mortality.3 Thus, there are striking pros and cons for these drugs that raise red flags for clinicians.
Will this warning change practice? In my opinion, it probably should not. The benefits of the class are clear, and the data on this side effect are unclear and conclusions may be premature. This is a high-risk population, and it is important to evaluate the foot appropriately in all patients with diabetes, recognizing 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 and wear appropriate footwear. Evaluation of PVD is probably underutilized and may need to be done more often in such a high-risk population, as per guidelines. Smoking cessation counselling is important in this context. This class of drugs causes mild dehydration that increases the hematocrit, which may be further raised by smoking. This, in turn, could lead to obstruction in small blood vessels in the foot. Much of this could be avoided or promptly treated if recognized. As a precautionary measure, doctors may consider stopping treatment with canagliflozin in patients who develop significant foot complications.
References 1. US FDA. Canagliflozin (Invokana, Invokamet): Drug safety Communication - clinical trial results find increased risk of leg and foot amputations. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm501565.htm. Accessed June 6, 2016. 2. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217-233. 3. Zinman B, Wanner C, Lachin JM, et al; for the EMPA-REG OUTCOMES Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128. |
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About the author Vivian A. Fonseca, MD, is a Professor of Medicine in the Division of Endocrinology and Chief of the Section of Endocrinology at Tulane University Medical Center in New Orleans, Louisiana.
Dr Fonseca has reported the following financial disclosures: grant/research support from Novo Nordisk Asahi, Eli Lilly, Abbott, Endo Barrier, and Gilead Sciences; honoraria for consulting and lectures from Takeda, Novo Nordisk, Sanofi-Aventis, Eli Lilly, Pamlabs, AstraZeneca, Abbott, Amgen, Boehringer Ingelheim, and Jansenn.
Pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual package inserts for use outside of the United States.
June 2016
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