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Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program

Aims/hypothesis An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of t... Full description

Journal Title: Diabetologia 2019, Vol.62 (10), p.1854-1867
Main Author: Zhou, Zien
Other Authors: Jardine, Meg , Perkovic, Vlado , Matthews, David R , Mahaffey, Kenneth W , de Zeeuw, Dick , Fulcher, Greg , Desai, Mehul , Oh, Richard , Simpson, Roger , Watts, Nelson B , Neal, Bruce
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
ID: ISSN: 0012-186X
Link: https://www.ncbi.nlm.nih.gov/pubmed/31399845
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title: Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program
format: Article
creator:
  • Zhou, Zien
  • Jardine, Meg
  • Perkovic, Vlado
  • Matthews, David R
  • Mahaffey, Kenneth W
  • de Zeeuw, Dick
  • Fulcher, Greg
  • Desai, Mehul
  • Oh, Richard
  • Simpson, Roger
  • Watts, Nelson B
  • Neal, Bruce
subjects:
  • 1103 Clinical Sciences
  • 1114 Paediatrics
  • 1117 Public Health
  • BASE-LINE CHARACTERISTICS
  • BONE
  • Canagliflozin
  • CANVAS Program
  • CARDIOVASCULAR ASSESSMENT
  • Cardiovascular diseases
  • Clinical trials
  • DESIGN
  • Diabetes
  • Diabetes mellitus
  • Diabetes mellitus (non-insulin dependent)
  • DISEASE
  • Endocrinology & Metabolism
  • Fracture
  • Fractures
  • Health Services
  • Human Physiology
  • Internal Medicine
  • Life Sciences & Biomedicine
  • Medicine
  • Medicine & Public Health
  • Metabolic Diseases
  • Nephropathy
  • PROGRESSION
  • RATIONALE
  • Reproductive Medicine
  • Risk factors
  • Science & Technology
  • Sodium glucose co
  • Sodium glucose co-transporter 2 inhibitors
  • transporter 2 inhibitors
  • Type 2 diabetes mellitus
ispartof: Diabetologia, 2019, Vol.62 (10), p.1854-1867
description: Aims/hypothesis An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. Methods This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. Results A total of 496 participants recorded >= 1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. Conclusions/interpretation There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.
language: eng
source:
identifier: ISSN: 0012-186X
fulltext: no_fulltext
issn:
  • 0012-186X
  • 1432-0428
url: Link


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titleCanagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program
creatorZhou, Zien ; Jardine, Meg ; Perkovic, Vlado ; Matthews, David R ; Mahaffey, Kenneth W ; de Zeeuw, Dick ; Fulcher, Greg ; Desai, Mehul ; Oh, Richard ; Simpson, Roger ; Watts, Nelson B ; Neal, Bruce
creatorcontribZhou, Zien ; Jardine, Meg ; Perkovic, Vlado ; Matthews, David R ; Mahaffey, Kenneth W ; de Zeeuw, Dick ; Fulcher, Greg ; Desai, Mehul ; Oh, Richard ; Simpson, Roger ; Watts, Nelson B ; Neal, Bruce
descriptionAims/hypothesis An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. Methods This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. Results A total of 496 participants recorded >= 1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. Conclusions/interpretation There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.
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subject1103 Clinical Sciences ; 1114 Paediatrics ; 1117 Public Health ; BASE-LINE CHARACTERISTICS ; BONE ; Canagliflozin ; CANVAS Program ; CARDIOVASCULAR ASSESSMENT ; Cardiovascular diseases ; Clinical trials ; DESIGN ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; DISEASE ; Endocrinology & Metabolism ; Fracture ; Fractures ; Health Services ; Human Physiology ; Internal Medicine ; Life Sciences & Biomedicine ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Nephropathy ; PROGRESSION ; RATIONALE ; Reproductive Medicine ; Risk factors ; Science & Technology ; Sodium glucose co ; Sodium glucose co-transporter 2 inhibitors ; transporter 2 inhibitors ; Type 2 diabetes mellitus
ispartofDiabetologia, 2019, Vol.62 (10), p.1854-1867
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descriptionAims/hypothesis An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. Methods This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. Results A total of 496 participants recorded >= 1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. Conclusions/interpretation There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.
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24Metabolic Diseases
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26PROGRESSION
27RATIONALE
28Reproductive Medicine
29Risk factors
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34Type 2 diabetes mellitus
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titleCanagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program
authorZhou, Zien ; Jardine, Meg ; Perkovic, Vlado ; Matthews, David R ; Mahaffey, Kenneth W ; de Zeeuw, Dick ; Fulcher, Greg ; Desai, Mehul ; Oh, Richard ; Simpson, Roger ; Watts, Nelson B ; Neal, Bruce
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21117 Public Health
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abstractAims/hypothesis An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. Methods This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. Results A total of 496 participants recorded >= 1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. Conclusions/interpretation There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.
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pmid31399845
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