Canagliflozin was associated with an increased risk of lower-limb amputation in the CANVAS trial. Prior trials of younger adults did not detect an increased risk of amputation, which raises the question of whether this was a chance finding or specific to older adults.

We conducted a new-user cohort study from March 29th, 2013 to September 30th, 2017 in three U.S. healthcare databases. Patients with diabetes mellitus type 2 newly prescribed canagliflozin were 1:1 propensity score-matched to patients newly prescribed a glucagon-like peptide-1 (GLP-1) receptor agonist. The primary outcome was lower-limb amputation requiring surgery. Hazard ratios (HR) and 95% confidence intervals (CI) were computed for the risk of subsequent amputation among patients <65 and ≥65 years old.

We identified 464,827 patients who were newly prescribed canagliflozin or a GLP-1 agonist. Adults over age 65 prescribed canagliflozin had a 66% higher rate of amputation compared to adults prescribed a GLP-1 agonist (HR=1.66, 95% CI 1.33-2.07, I2=0%). For adults under 65 years of age, the rate of amputation was similar for canagliflozin compared to GLP-1 agonists (HR=1.09, 95% CI 0.89-1.34, I2=0%).

Canagliflozin may be associated with an increased rate of amputation compared to GLP-1 agonists among adults over the age of 65 years, but not among adults under 65 years of age.


M. Fralick: None. S.C. Kim: Research Support; Self; Bristol-Myers Squibb Company, Genentech, Inc., Pfizer Inc. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC. B.M. Everett: Advisory Panel; Self; American College of Cardiology. Consultant; Self; Abbott Laboratories, Amgen Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Novartis Pharmaceuticals Corporation, Roche Diagnostic USA. Research Support; Self; Novartis Pharmaceuticals Corporation. Other Relationship; Spouse/Partner; Merck & Co., Inc. Other Relationship; Self; UpToDate. Other Relationship; Spouse/Partner; UpToDate. R.J. Glynn: Research Support; Self; AstraZeneca, Kowa Pharmaceutical Europe Co. Ltd., Novartis Pharmaceuticals Corporation, Pfizer Inc. E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH.

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