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 A. Pollock, Rajiv Agarwal, George L. 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. Mahaffey, Meg Jardine, Vlado Perkovic, Kenneth W. Mahaffey, Rajiv Agarwal, George L. Bakris, Barry M. Brenner, Christopher P. Cannon, David M. Charytan, Dick de Zeeuw, Tom Greene, Meg Jardine, Hiddo J.L. Heerspink, Adeera Levin, Gary Meininger, Bruce Neal, Carol A. Pollock, David C. Wheeler, Hong Zhang, Bernard Zinman, Meg Jardine, Hiddo J.L. Heerspink, David M. Charytan, Nicole Li, Inna Kolesnyk, Diego Aizenberg, Roberto Pecoits‐Filho, Adeera Levin, David Z.I. Cherney, Gregorio T. Obrador, Glenn M. Chertow, Tara I. Chang, Carmel M. Hawley, Linong Ji, Hong Zhang, 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, Alexander Dreval, Michał Nowicki, Adalbert Schiller, Larry A. Distiller, José Luis Górriz, Mykola Kolesnyk, David, Caroline P. D. Wheeler, Rodolfo Andrés Ahuad Guerrero, Diego Aizenberg, Juan Pablo Albisu, Andres Alvarisqueta, Ines Bartolacci, Mario Alberto Berli, Anselmo P. Bordonava, Pedro Calella, Maria Cecilia Cantero, Luis R Cartasegna, Esteban Cercos, Gabriela Cecilia Coloma, Hugo Colombo, Víctor Commendatore, Jesus Cuadrado, Carlos Alberto Cuneo, Ana María Cusumano, Walter Douthat, Ricardo D. Dran, Eduardo Farias, María Florencia Fernández, Hernan Finkelstein, Guillermo Fragale, Jose Osvaldo Fretes, Néstor H. García
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 100mg/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=0.3for 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=0.8for 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.