TY - JOUR
T1 - Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories
T2 - Findings From the CANVAS Program
AU - Neuen, Brendon L.
AU - Ohkuma, Toshiaki
AU - Neal, Bruce
AU - Matthews, David R.
AU - de Zeeuw, Dick
AU - Mahaffey, Kenneth W.
AU - Fulcher, Greg
AU - Blais, Jaime
AU - Li, Qiang
AU - Jardine, Meg J.
AU - Perkovic, Vlado
AU - Wheeler, David C.
N1 - Funding Information:
This post hoc analysis was undertaken independently by the study authors and was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development , LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical. Medical writing support was provided by Dana Tabor, PhD, of MedErgy and funded by Janssen Global Services, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.
Funding Information:
Dr Neuen is supported by an Australian National Health and Medical Research Council (NHMRC) Postgraduate Scholarship, a University Postgraduate Award from UNSW Sydney, and an Oxford Australia Clarendon Scholarship from the University of Oxford; he has received travel support from Janssen. Dr Ohkuma is supported by the John Chalmers Clinical Research Fellowship of The George Institute for Global Health. Dr Neal is supported by an NHMRC of Australia Principal Research Fellowship (APP1106947); has served on advisory boards and/or as a consultant for Janssen and Merck Sharp & Dohme; and has received lecture fees from Janssen, with any consultancy, honoraria, or travel support paid to his institution. Dr Matthews has received research support from Janssen; has served on advisory boards and as a consultant for Novo Nordisk, Novartis, Sanofi-Aventis, Janssen, and Servier; and has given lectures for Novo Nordisk, Servier, Sanofi-Aventis, Novartis, Janssen, Mitsubishi Tanabe, and Aché Laboratories. Dr de Zeeuw has served on advisory boards and/or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi Tanabe; has served on steering committees and/or as a speaker for AbbVie and Janssen; and has served on Data Safety and Monitoring Committees for Bayer. Dr Mahaffey reports receipt of personal income for consulting or other services from Abbott, Amgen, Anthos, AstraZeneca, Baim Institute, Boehringer Ingelheim, CSL Behring, Elsevier, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundi Pharma, Myokardia, National Institutes of Health (NIH), Novartis, Novo Nordisk, Portola, Regeneron, Sanofi, SmartMedics, and Theravance; receipt of research grant or contract funds from Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, and St. Jude. Dr Fulcher has received research support from Novo Nordisk and has served on advisory boards and as a consultant for Janssen, Novo Nordisk, Boehringer Ingelheim, and Merck Sharp & Dohme. Dr Blais is a full-time employee of Janssen Scientific Affairs, LLC. Mr Li is a full-time employee of The George Institute for Global Health. Dr Jardine is supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship; is responsible for research projects that have received unrestricted funding from Gambro, Baxter, CSL, Amgen, Eli Lilly, and Merck; has served on advisory boards sponsored by Akebia, Baxter, Boehringer Ingelheim, and MSD; and has spoken at scientific meetings sponsored by Janssen, Amgen, and Roche, with any consultancy, honoraria, or travel support paid to her institution. Dr Perkovic has received research support from the Australian NNMRC (Senior Research Fellowship and Program Grant); has served on Steering Committees for AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, and Pfizer; and has served on advisory boards and/or as a speaker at scientific meetings for AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Roche, Sanofi, Servier, and Vitae. Dr Wheeler has received consultancy fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Mitsubishi, Mundipharma, Napp, Ono Pharma, and Vifor Fresenius.
Funding Information:
Brendon L. Neuen, MBBS (Hons), Toshiaki Ohkuma, PhD, Bruce Neal, PhD, David R. Matthews, DPhil, Dick de Zeeuw, MD, PhD, Kenneth W. Mahaffey, MD, Greg Fulcher, MD, Jaime Blais, PhD, Qiang Li, MBiostat, Meg J. Jardine, PhD, Vlado Perkovic, PhD, and David C. Wheeler, MD. Research idea and study design: BN, DRM, DdZ, KWM, GF, VP, DCW; data interpretation/analysis: BLN, TO, BN, DRM, DdZ, KWM, GF, JB, QL, MJJ, VP, DCW; statistical analysis: TO, QL. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. This post hoc analysis was undertaken independently by the study authors and was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development, LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical. Medical writing support was provided by Dana Tabor, PhD, of MedErgy and funded by Janssen Global Services, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. Dr Neuen is supported by an Australian National Health and Medical Research Council (NHMRC) Postgraduate Scholarship, a University Postgraduate Award from UNSW Sydney, and an Oxford Australia Clarendon Scholarship from the University of Oxford; he has received travel support from Janssen. Dr Ohkuma is supported by the John Chalmers Clinical Research Fellowship of The George Institute for Global Health. Dr Neal is supported by an NHMRC of Australia Principal Research Fellowship (APP1106947); has served on advisory boards and/or as a consultant for Janssen and Merck Sharp & Dohme; and has received lecture fees from Janssen, with any consultancy, honoraria, or travel support paid to his institution. Dr Matthews has received research support from Janssen; has served on advisory boards and as a consultant for Novo Nordisk, Novartis, Sanofi-Aventis, Janssen, and Servier; and has given lectures for Novo Nordisk, Servier, Sanofi-Aventis, Novartis, Janssen, Mitsubishi Tanabe, and Ach? Laboratories. Dr de Zeeuw has served on advisory boards and/or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi Tanabe; has served on steering committees and/or as a speaker for AbbVie and Janssen; and has served on Data Safety and Monitoring Committees for Bayer. Dr Mahaffey reports receipt of personal income for consulting or other services from Abbott, Amgen, Anthos, AstraZeneca, Baim Institute, Boehringer Ingelheim, CSL Behring, Elsevier, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundi Pharma, Myokardia, National Institutes of Health (NIH), Novartis, Novo Nordisk, Portola, Regeneron, Sanofi, SmartMedics, and Theravance; receipt of research grant or contract funds from Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, and St. Jude. Dr Fulcher has received research support from Novo Nordisk and has served on advisory boards and as a consultant for Janssen, Novo Nordisk, Boehringer Ingelheim, and Merck Sharp & Dohme. Dr Blais is a full-time employee of Janssen Scientific Affairs, LLC. Mr Li is a full-time employee of The George Institute for Global Health. Dr Jardine is supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship; is responsible for research projects that have received unrestricted funding from Gambro, Baxter, CSL, Amgen, Eli Lilly, and Merck; has served on advisory boards sponsored by Akebia, Baxter, Boehringer Ingelheim, and MSD; and has spoken at scientific meetings sponsored by Janssen, Amgen, and Roche, with any consultancy, honoraria, or travel support paid to her institution. Dr Perkovic has received research support from the Australian NNMRC (Senior Research Fellowship and Program Grant); has served on Steering Committees for AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, and Pfizer; and has served on advisory boards and/or as a speaker at scientific meetings for AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Roche, Sanofi, Servier, and Vitae. Dr Wheeler has received consultancy fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Mitsubishi, Mundipharma, Napp, Ono Pharma, and Vifor Fresenius. Data from the CANVAS Program are available in the public domain via the Yale University Open Data Access Project (YODA; http://yoda.yale.edu/). Received January 2, 2020. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form June 30, 2020.
Publisher Copyright:
© 2020
PY - 2021/1
Y1 - 2021/1
N2 - Rationale & Objective: Canagliflozin reduces the risk for cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different KDIGO (Kidney Disease: Improving Global Outcomes) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio. Study Design: Post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Settings & Participants: The CANVAS Program randomly assigned 10,142 participants with type 2 diabetes at high cardiovascular risk and with eGFR ≥ 30 mL/min/1.73 m2 to treatment with canagliflozin or placebo. Intervention(s): Canagliflozin or matching placebo. Outcomes: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a set of other cardiovascular and kidney prespecified outcomes. Results: Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and urinary albumin-creatinine ratio data. The proportion of participants in low-, moderate-, high-, and very high–risk KDIGO categories was 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR, 0.86; 95% CI, 0.75-0.97) was consistent across KDIGO risk categories (P trend = 0.2), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P trend = 0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P trend = 0.06) and for chronic eGFR slope (P trend = 0.04). Limitations: Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR < 30 mL/min/1.73 m2. Conclusions: Although the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin. Funding: This post hoc analysis was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development, LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical. Trial Registration: The original trials of the CANVAS Program were registered at ClinicalTrials.gov with study numbers NCT01032629 and NCT01989754.
AB - Rationale & Objective: Canagliflozin reduces the risk for cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different KDIGO (Kidney Disease: Improving Global Outcomes) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio. Study Design: Post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Settings & Participants: The CANVAS Program randomly assigned 10,142 participants with type 2 diabetes at high cardiovascular risk and with eGFR ≥ 30 mL/min/1.73 m2 to treatment with canagliflozin or placebo. Intervention(s): Canagliflozin or matching placebo. Outcomes: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a set of other cardiovascular and kidney prespecified outcomes. Results: Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and urinary albumin-creatinine ratio data. The proportion of participants in low-, moderate-, high-, and very high–risk KDIGO categories was 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR, 0.86; 95% CI, 0.75-0.97) was consistent across KDIGO risk categories (P trend = 0.2), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P trend = 0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P trend = 0.06) and for chronic eGFR slope (P trend = 0.04). Limitations: Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR < 30 mL/min/1.73 m2. Conclusions: Although the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin. Funding: This post hoc analysis was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development, LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical. Trial Registration: The original trials of the CANVAS Program were registered at ClinicalTrials.gov with study numbers NCT01032629 and NCT01989754.
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U2 - 10.1053/j.ajkd.2020.06.018
DO - 10.1053/j.ajkd.2020.06.018
M3 - Article
C2 - 32971190
AN - SCOPUS:85096096477
SN - 0272-6386
VL - 77
SP - 23-34.e1
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 1
ER -
