Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study.

To estimate the rate of lower limb amputation among adults newly prescribed canagliflozin according to age and cardiovascular disease. Population based, new user, cohort study. Two commercial and Medicare claims databases, 2013-17. Patients newly prescribed canagliflozin were propensity score matched 1:1 with patients newly prescribed a glucagon-like peptide-1 (GLP-1) receptor agonist. Hazard ratios and rate differences per 1000 person years were computed for the rate of lower limb amputation in the following four groups: group 1, patients aged less than 65 years without baseline cardiovascular disease; group 2, patients aged less than 65 with baseline cardiovascular disease; group 3, patients aged 65 or older without baseline cardiovascular disease; group 4, patients aged 65 or older with baseline cardiovascular disease. Within each group, pooled hazard ratio and rate difference per 1000 person years were calculated by meta-analysis. Canagliflozin versus a GLP-1 agonist. Lower limb amputation requiring surgery. Across the three databases, 310 840 propensity score matched adults who started canagliflozin or a GLP-1 agonist were identified. The hazard ratio and rate difference per 1000 person years for amputation in adults receiving canagliflozin compared with a GLP-1 agonist for each group was: group 1, hazard ratio 1.09 (95% confidence interval 0.83 to 1.43), rate difference 0.12 (-0.31 to 0.55); group 2, hazard ratio 1.18 (0.86 to 1.62), rate difference 1.06 (-1.77 to 3.89); group 3, hazard ratio 1.30 (0.52 to 3.26), rate difference 0.47 (-0.73 to 1.67); and group 4, hazard ratio 1.73 (1.30 to 2.29), rate difference 3.66 (1.74 to 5.59). The increase in rate of amputation with canagliflozin was small and most apparent on an absolute scale for adults aged 65 or older with baseline cardiovascular disease, resulting in a number needed to treat for an additional harmful outcome of 556 patients at six months (that is, 18 more amputations per 10 000 people who received canagliflozin). These results help to contextualize the risk of amputation with canagliflozin in routine care.

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Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Division of Pharmacoepidemiology and Pharmacoeconomics for the submitted; MF received funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto and Canadian Institutes of Health Research through the Frederick Banting and Charles Best Canada Graduate Scholarship. EP is supported by a career development grant K08AG055670 from the National Institute on Ageing. She is investigator on grants to Brigham and Women’s Hospital from Boehringer Ingelheim and GlaxoSmithKline, not directly related to the topic of this manuscript. SS is consultant to WHISCON (World Health Information Science Consultants), and to Aetion, a software manufacturer of which he also owns equity. He is principal investigator of investigator initiated grants to Brigham and Women’s Hospital from Genentech, Bayer, and Boehringer Ingelheim not directly related to the topic of this manuscript. RJG reports grants from Pfizer, Novartis, and Kowa outside the submitted work. BME reports grant support or consulting for Amarin, Amgen, Merck, Novartis, and Roche Diagnostics, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and the US Food and Drug Administration. SCK has received research grants to Brigham and Women’s Hospital from Pfizer, Bristol-Myers Squibb, AstraZeneca, Roche, and Merck for unrelated topics.