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

Aims/hypothesis The 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... Full description

Journal Title: Diabetologia 2019-06, Vol.62 (6), p.926-938
Main Author: Matthews, David R
Other Authors: Li, Qiang , Perkovic, Vlado , Mahaffey, Kenneth W , de Zeeuw, Dick , Fulcher, Greg , Desai, Mehul , Hiatt, William R , Nehler, Mark , Fabbrini, Elisa , Kavalam, Mary , Lee, Mary , 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/30868176
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6509073
title: Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program
format: Article
creator:
  • Matthews, David R
  • Li, Qiang
  • Perkovic, Vlado
  • Mahaffey, Kenneth W
  • de Zeeuw, Dick
  • Fulcher, Greg
  • Desai, Mehul
  • Hiatt, William R
  • Nehler, Mark
  • Fabbrini, Elisa
  • Kavalam, Mary
  • Lee, Mary
  • Neal, Bruce
subjects:
  • 1103 Clinical Sciences
  • 1114 Paediatrics
  • 1117 Public Health
  • Administration, Oral
  • Aged
  • Amputation
  • Article
  • BASE-LINE CHARACTERISTICS
  • Canagliflozin - administration & dosage
  • Canagliflozin - therapeutic use
  • CARDIOVASCULAR ASSESSMENT
  • Cardiovascular diseases
  • Clinical diabetes
  • Clinical science
  • DESIGN
  • Diabetes
  • Diabetes mellitus
  • Diabetes mellitus (non-insulin dependent)
  • Diabetes Mellitus, Type 2 - drug therapy
  • Diabetes Mellitus, Type 2 - metabolism
  • Diabetic foot
  • Diabetic Foot - drug therapy
  • EMPAGLIFLOZIN
  • Endocrinology & Metabolism
  • Female
  • Foot diseases
  • Health Services
  • Human
  • Human Physiology
  • Humans
  • Hypoglycemic Agents - therapeutic use
  • INHIBITORS
  • Internal Medicine
  • Life Sciences & Biomedicine
  • Male
  • Medicine
  • Medicine & Public Health
  • Metabolic Diseases
  • Middle Aged
  • Multivariate Analysis
  • Neuropathy
  • Oral pharmacological agents
  • Population studies
  • RATIONALE
  • Reproductive Medicine
  • Risk factors
  • SAFETY
  • Science & Technology
  • Vascular diseases
ispartof: Diabetologia, 2019-06, Vol.62 (6), p.926-938
description: Aims/hypothesis The 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. Methods The 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. Results There 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 100mg and 300mg 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/interpretation The 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.
language: eng
source:
identifier: ISSN: 0012-186X
fulltext: no_fulltext
issn:
  • 0012-186X
  • 1432-0428
url: Link


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titleEffects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program
creatorMatthews, David R ; Li, Qiang ; Perkovic, Vlado ; Mahaffey, Kenneth W ; de Zeeuw, Dick ; Fulcher, Greg ; Desai, Mehul ; Hiatt, William R ; Nehler, Mark ; Fabbrini, Elisa ; Kavalam, Mary ; Lee, Mary ; Neal, Bruce
creatorcontribMatthews, David R ; Li, Qiang ; Perkovic, Vlado ; Mahaffey, Kenneth W ; de Zeeuw, Dick ; Fulcher, Greg ; Desai, Mehul ; Hiatt, William R ; Nehler, Mark ; Fabbrini, Elisa ; Kavalam, Mary ; Lee, Mary ; Neal, Bruce
descriptionAims/hypothesis The 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. Methods The 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. Results There 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 100mg and 300mg 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/interpretation The 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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subject1103 Clinical Sciences ; 1114 Paediatrics ; 1117 Public Health ; Administration, Oral ; Aged ; Amputation ; Article ; BASE-LINE CHARACTERISTICS ; Canagliflozin - administration & dosage ; Canagliflozin - therapeutic use ; CARDIOVASCULAR ASSESSMENT ; Cardiovascular diseases ; Clinical diabetes ; Clinical science ; DESIGN ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Diabetic foot ; Diabetic Foot - drug therapy ; EMPAGLIFLOZIN ; Endocrinology & Metabolism ; Female ; Foot diseases ; Health Services ; Human ; Human Physiology ; Humans ; Hypoglycemic Agents - therapeutic use ; INHIBITORS ; Internal Medicine ; Life Sciences & Biomedicine ; Male ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Middle Aged ; Multivariate Analysis ; Neuropathy ; Oral pharmacological agents ; Population studies ; RATIONALE ; Reproductive Medicine ; Risk factors ; SAFETY ; Science & Technology ; Vascular diseases
ispartofDiabetologia, 2019-06, Vol.62 (6), p.926-938
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9Fabbrini, Elisa
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11Lee, Mary
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descriptionAims/hypothesis The 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. Methods The 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. Results There 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 100mg and 300mg 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/interpretation The 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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18Diabetes Mellitus, Type 2 - drug therapy
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titleEffects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program
authorMatthews, David R ; Li, Qiang ; Perkovic, Vlado ; Mahaffey, Kenneth W ; de Zeeuw, Dick ; Fulcher, Greg ; Desai, Mehul ; Hiatt, William R ; Nehler, Mark ; Fabbrini, Elisa ; Kavalam, Mary ; Lee, Mary ; Neal, Bruce
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11Cardiovascular diseases
12Clinical diabetes
13Clinical science
14DESIGN
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16Diabetes mellitus
17Diabetes mellitus (non-insulin dependent)
18Diabetes Mellitus, Type 2 - drug therapy
19Diabetes Mellitus, Type 2 - metabolism
20Diabetic foot
21Diabetic Foot - drug therapy
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23Endocrinology & Metabolism
24Female
25Foot diseases
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47Science & Technology
48Vascular diseases
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abstractAims/hypothesis The 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. Methods The 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. Results There 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 100mg and 300mg 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/interpretation The 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.
copBerlin/Heidelberg
pubSpringer Berlin Heidelberg
pmid30868176
doi10.1007/s00125-019-4839-8
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