Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Tae Won Yi, Brendan Smyth*, Gian Luca Di Tanna, Clare Arnott, Kathryn Cardoza, Amy Kang, Carol Pollock, Rajiv Agarwal, George Bakris, David M. Charytan, Dick de Zeeuw, Hiddo J.L. Heerspink, Bruce Neal, David C. Wheeler, Christopher P. Cannon, Hong Zhang, Bernard Zinman, Vlado Perkovic, Adeera Levin, Kenneth W. MahaffeyMeg Jardine, Barry M. Brenner, Tom Greene, Gary Meininger, Nicole Li, Inna Kolesnyk, Diego Aizenberg, Roberto Pecoits-Filho, David Cherney, Gregorio Obrador, Glenn Chertow, Tara Chang, Carmel Hawley, Linong Ji, Takashi Wada, Vivekanand Jha, Soo Kun Lim, Mary Anne Lim-Abrahan, Florence Santos, Dong Wan Chae, Shang Jyh Hwang, Evgueniy Vazelov, Ivan Rychlík, Samy Hadjadj, Vera Krane, László Rosivall, Luca De Nicola, Robert Walker, On behalf of the CREDENCE Trial Investigators including, Srikanth Bellary

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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. 

Original languageEnglish
Pages (from-to)84-96
JournalAmerican Journal of Kidney Diseases
Volume82
Issue number1
Early online date7 Mar 2023
DOIs
Publication statusPublished - 21 Jun 2023

Keywords

  • age
  • canagliflozin
  • cardiovascular outcomes
  • chronic kidney disease
  • diabetes
  • Diabetic kidney disease
  • kidney outcomes
  • sex
  • sodium/glucose cotransporter 2 inhibitors

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