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Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program

  • Matthews, David R.1, 2
  • Li, Qiang3
  • Perkovic, Vlado3, 4
  • Mahaffey, Kenneth W.5
  • de Zeeuw, Dick6
  • Fulcher, Greg4
  • Desai, Mehul7
  • Hiatt, William R.8
  • Nehler, Mark9
  • Fabbrini, Elisa7
  • Kavalam, Mary7
  • Lee, Mary7
  • Neal, Bruce3, 10
  • 1 University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK , Oxford (United Kingdom)
  • 2 University of Oxford, Harris Manchester College, Mansfield Road, Oxford, OX1 3TD, UK , Oxford (United Kingdom)
  • 3 UNSW Sydney, The George Institute for Global Health, Sydney, NSW, Australia , Sydney (Australia)
  • 4 The Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia , Sydney (Australia)
  • 5 Stanford University School of Medicine, Stanford Center for Clinical Research, Department of Medicine, Stanford, CA, USA , Stanford (United States)
  • 6 University Medical Center Groningen, University of Groningen, Groningen, the Netherlands , Groningen (Netherlands)
  • 7 Janssen Research & Development, LLC, Raritan, NJ, USA , Raritan (United States)
  • 8 University of Colorado School of Medicine, Division of Cardiology and CPC Clinical Research, Aurora, CO, USA , Aurora (United States)
  • 9 University of Colorado School of Medicine, Division of Vascular Surgery and CPC Clinical Research, Aurora, CO, USA , Aurora (United States)
  • 10 Imperial College London, Epidemiology and Biostatistics, London, UK , London (United Kingdom)
Published Article
Publication Date
Mar 12, 2019
DOI: 10.1007/s00125-019-4839-8
Springer Nature


Aims/hypothesisThe primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail.MethodsThe effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups.ResultsThere were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100 mg and 300 mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted.Conclusions/interpretationThe CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.

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