Samenvatting
Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.
Study Design: Secondary analysis of a randomized controlled trial.
Setting & Participants: Participants in the CREDENCE trial.
Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.
Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention-to-treat population using Cox regression models.
Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and ≥70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.
Limitations: This was a post hoc analysis with multiple comparisons.
Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.
Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.
Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.
| Originele taal-2 | English |
|---|---|
| Pagina's (van-tot) | 84-96.e1 |
| Aantal pagina's | 14 |
| Tijdschrift | American Journal of Kidney Diseases |
| Volume | 82 |
| Nummer van het tijdschrift | 1 |
| DOI's | |
| Status | Published - jul.-2023 |
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In: American Journal of Kidney Diseases, Vol. 82, Nr. 1, 07.2023, blz. 84-96.e1.
Onderzoeksoutput › Academic › peer review
TY - JOUR
T1 - Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex
T2 - A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial
AU - CREDENCE Trial Investigators
AU - Yi, Tae Won
AU - Smyth, Brendan
AU - Di Tanna, Gian Luca
AU - Arnott, Clare
AU - Cardoza, Kathryn
AU - Kang, Amy
AU - Pollock, Carol
AU - Agarwal, Rajiv
AU - Bakris, George
AU - Charytan, David M.
AU - de Zeeuw, Dick
AU - Heerspink, Hiddo J.L.
AU - Neal, Bruce
AU - Wheeler, David C.
AU - Cannon, Christopher P.
AU - Zhang, Hong
AU - Zinman, Bernard
AU - Perkovic, Vlado
AU - Levin, Adeera
AU - Mahaffey, Kenneth W.
AU - Jardine, Meg J.
AU - Brenner, Barry M.
AU - Greene, Tom
AU - Jardine, Meg J.
AU - Meininger, Gary
AU - Li, Nicole
AU - Kolesnyk, Inna
AU - Aizenberg, Diego
AU - Pecoits-Filho, Roberto
AU - Cherney, David
AU - Obrador, Gregorio
AU - Chertow, Glenn
AU - Chang, Tara
AU - Hawley, Carmel
AU - Ji, Linong
AU - Wada, Takashi
AU - Jha, Vivekanand
AU - Lim, Soo Kun
AU - Lim-Abrahan, Mary Anne
AU - Santos, Florence
AU - Chae, Dong Wan
AU - Hwang, Shang Jyh
AU - Vazelov, Evgueniy
AU - Rychlík, Ivan
AU - Hadjadj, Samy
AU - Krane, Vera
N1 - Funding Information: A full list of the CREDENCE Trial Investigators is provided in Item S1. Tae Won Yi, MD, Brendan Smyth, PhD, Gian Luca Di Tanna, PhD, Clare Arnott, PhD, Kathryn Cardoza, MD, Amy Kang, MBBS, Carol Pollock, MBBS, Rajiv Agarwal, MD, George Bakris, MD, David M. Charytan, MD, Dick de Zeeuw, PhD, Hiddo J.L. Heerspink, PhD, Bruce Neal, PhD, David C. Wheeler, MD, Christopher P. Cannon, MD, Hong Zhang, PhD, Bernard Zinman, MDCM, Vlado Perkovic, PhD, Adeera Levin, MD, Kenneth W. Mahaffey, MD, and Meg Jardine, PhD, on behalf of the CREDENCE Trial Investigators. Research area and study design: TY, BS, AL, MJ; data acquisition: BS and GD; data analysis and interpretation: TY, BS, GD, KC, AK, AL, MJ; statistical analysis: BS and GD; supervision or mentorship: CA, CP, RA, GB, DC, DZ, HH, BN, DW, CC, HZ, BZ, VP, AL, KW, MJ. 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. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical. This post hoc analysis of the CREDENCE trial was not specifically funded. Dr Arnott received a Medical Research Future Fund Priority Investigator Grant and a New South Wales Health Early- and Mid-Career Researcher Grant. Dr Smyth is supported by a Jacquot Research Establishment Fellowship from the Royal Australasian College of Physicians. Dr Yi is supported by the Clinician Investigator Program at the University of British Columbia. Dr Kang is supported by a National Health and Medical Research Council Postgraduate Scholarship (no. 1150349) via the University of New South Wales and an Australian Government Research Training Program Fee Offset and has received a George Institute Scholarship. The funders were not involved in the design, analysis, reporting, or decision to submit this manuscript for publication. Dr Arnott reports honoraria from Amgen. Dr Pollock reports consulting fees for study advisory board and travel support from Janssen. Dr Agarwal reports research funding from the National Institutes of Health (NIH) and the US Department of Veterans Affairs (VA); royalties from UpToDate; consulting fees from Akebia, Bayer, Boehringer Ingelheim, Diamedica, Merck, Reata, Relypsa, Lexicon; honoraria from Medscape, Cardiometabolic Health, and various universities; and consulting fees for advisory board positions from Akebia, Bayer, Relypsa, Sanofi, Chinook, and AstraZeneca. He is an associate editor of Nephrology Dialysis and Transplantation and the American Journal of Nephrology. Dr Bakris reports consulting fees for advisory board positions for Bayer, Vascular Dynamics, Quantum, Genomics, Janssen, Alnylam, and Novo Nordisk; has received consulting fees from Merck, Bayer, KBP Biosciences, Ionis, Alnylam, Astra Zeneca, Quantum Genomics, Horizon, and Novo Nordisk; has received travel support from Novo Nordisk, Merck, AstraZeneca, Quantum Genomics, Ionis, and Alnylam; and sits on an advisory board for the NIH RO1 study. Dr Charytan reports personal fees from Janssen during the conduct of the study: consulting for Eli Lilly/Boehringer Ingelheim, Janssen (steering committee), PLC medical (clinical events committee), Astra Zeneca, Allena Pharmaceuticals (data safety monitoring board [DSMB]), Fresenius, Amgen, Gilead, Novo Nordisk, GSK, Medtronic, Merck, Amgen, CSL Behring, Zogenix, and Renalytix; research funding from Medtronic clinical trial support, Bioporto clinical trial support, Gilead, NovoNordisk, and Amgen; advisory or leadership role in the Clinical Journal of the American Society of Nephrology; and expert witness fees related to proton pump inhibitors. Dr de Zeeuw reports serving on advisory boards and/or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Travere Pharmaceuticals, and Mitsubishi Tanabe; serving on steering committees and/or as a speaker for AbbVie and Janssen; and serving on data safety and monitoring committees for Bayer. Dr Heerspink reports grants from Astra Zeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk and consulting fees from AstraZeneca, Abbvie, Boehringer Ingelheim, CSL Behring, Bayer, Chinook, Dimerix, Gilead, Goldfinch, Merck, NovoNordisk, Janssen, and Travere Pharmaceuticals. Dr Neal has received funding for conduct of the CREDENCE study from Janssen and consulting fees for advisory board positions for Janssen and Mitsubishi Tanabe Pharma. All fees were paid to institutions. Dr Wheeler has received fees and travel funding from Janssen for his role as a member of the CREDENCE steering committee; he has also received fees for advisory boards, steering committee roles, or scientific presentations from Amgen, AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Mundipharma, Merck Sharp & Dohme, Napp, Tricida, Vifor, and Zydus. Dr Cannon reports research grants from Amgen, Better Therapeutics, Boehringer-Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, Novo Nordisk, and Pfizer and consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, and Sanofi; he serves on the DSMBs for the VA, Applied Therapeutics, and NovoNordisk. Dr Zhang reports consulting fees from Janssen. Dr Zinman reports consulting fees from Janssen. Dr Perkovic reports support for the CREDENCE trial as the chair of the steering committee from Janssen and consulting fees from AbbVie, Bayer, Boehringer Ingelheim, Chinook, GlaxoSmithKline, Janssen, Pfizer, Astellas, AstraZeneca, Baxter, Eli Lilly, Gilead, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier, and Vitae; honoraria from AbbVie, Bayer, Boehringer Ingelheim, Chinook, GlaxoSmithKline, Janssen, Pfizer, Astellas, AstraZeneca, Bayer, Baxter, BMS, Durect, Eli Lilly, Gilead, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier, and Vitae. Dr Levin was a member of the steering committee for CREDENCE and has received grant support from Janssen. Dr Mahaffey has received research support from AHA, Apple, Bayer, California Institute for Regenerative Medicine, Eidos, Ferring, Gilead, Google (Verily), Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, and Sanifit; consulting fees from Amgen, Applied Therapeutics, AstraZeneca, Bayer, CSL Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Precordior, Quidel, Sanofi, and Theravance; and honoraria from Inova, Intermountain Health, Medscape, Mount Sinai, and CSL Behring. Dr Jardine is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro, and MSD; has received advisory, steering committee, and/or speaker fees from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Lynx, Chinook, Medscape, CSL, Janssen, MSD, Roche, and Vifor, with any consultancy, honoraria, or travel support paid to her institution. The remaining authors declare that they have no relevant financial interests. We thank the participants in this trial and thank the study investigators, who are listed in the Supplementary Appendix to the primary CREDENCE study publication. Presented in part at the American Diabetes Association 81st Scientific Sessions; June 25-29, 2021; virtual. Data from this study is available in the public domain via the Yale University Open Data Access Project (http://yoda.yale.edu/). This includes deidentified individual participant data, data definition specification, annotated case report form, protocol with amendments and primary statistical analysis plan. Received June 30, 2022. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and a Deputy Editor who served as Acting Editor-in-Chief. Accepted in revised form December 21, 2022. The involvement of an Acting Editor-in-Chief was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies. Funding Information: The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical. This post hoc analysis of the CREDENCE trial was not specifically funded. Dr Arnott received a Medical Research Future Fund Priority Investigator Grant and a New South Wales Health Early- and Mid-Career Researcher Grant. Dr Smyth is supported by a Jacquot Research Establishment Fellowship from the Royal Australasian College of Physicians. Dr Yi is supported by the Clinician Investigator Program at the University of British Columbia. Dr Kang is supported by a National Health and Medical Research Council Postgraduate Scholarship (no. 1150349) via the University of New South Wales and an Australian Government Research Training Program Fee Offset and has received a George Institute Scholarship. The funders were not involved in the design, analysis, reporting, or decision to submit this manuscript for publication. Publisher Copyright: © 2023 National Kidney Foundation, Inc.
PY - 2023/7
Y1 - 2023/7
N2 - Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and ≥70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.
AB - Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and ≥70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.
KW - age
KW - canagliflozin
KW - cardiovascular outcomes
KW - chronic kidney disease
KW - diabetes
KW - Diabetic kidney disease
KW - kidney outcomes
KW - sex
KW - sodium/glucose cotransporter 2 inhibitors
U2 - 10.1053/j.ajkd.2022.12.015
DO - 10.1053/j.ajkd.2022.12.015
M3 - Article
C2 - 36889425
AN - SCOPUS:85153964624
SN - 0272-6386
VL - 82
SP - 84-96.e1
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 1
ER -