Hiddo J L Heerspink1, Megumi Oshima2, Hong Zhang3, Jingwei Li4, Rajiv Agarwal5, George Capuano6, David M Charytan7, Jagriti Craig6, Dick de Zeeuw8, Gian Luca Di Tanna9, Adeera Levin10, Bruce Neal11, Vlado Perkovic12, David C Wheeler13, Yshai Yavin6, Meg J Jardine14. 1. The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: h.j.lambers.heerspink@umcg.nl. 2. The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan. 3. Renal Division of Peking University First Hospital, Beijing. 4. The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Cardiology, Xinqiao Hospital, Army Military Medical University, Chongqing, China. 5. Indiana University School of Medicine and VA Medical Center, Indianapolis, IN. 6. Janssen Research & Development, LLC, Raritan, NJ. 7. Nephrology Division, NYU School of Medicine and NYU Langone Medical Center, New York, NY; Baim Institute for Clinical Research, Boston, MA. 8. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 9. The George Institute for Global Health, UNSW Sydney, Sydney, Australia. 10. Division of Nephrology, University of British Columbia, Vancouver, BC, Canada. 11. The George Institute for Global Health, UNSW Sydney, Sydney, Australia; The Charles Perkins Centre, University of Sydney, Sydney, Australia; Imperial College London, London, United Kingdom. 12. The George Institute for Global Health, UNSW Sydney, Sydney, Australia; The Royal North Shore Hospital, Sydney, Australia. 13. The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Renal Medicine, UCL Medical School, London, United Kingdom. 14. The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Concord Repatriation General Hospital, Sydney, Australia.
Abstract
RATIONALE & OBJECTIVE: Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs). STUDY DESIGN: A randomized, double-blind, placebo-controlled, multicenter international trial. SETTING & PARTICIPANTS: 4,401 trial participants with T2DM, CKD, and urinary albumin-creatinine ratio >300-5,000 mg/g. INTERVENTIONS: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo. OUTCOMES: Rates of kidney-related AEs were analyzed using an on-treatment approach, overall and by screening estimated glomerular filtration rate (eGFR) strata (30-<45, 45-<60, and 60-<90 mL/min/1.73 m2). RESULTS: Canagliflozin was associated with a reduction in the overall incidence rate of kidney-related AEs (60.2 vs 84.0 per 1,000 patient-years; hazard ratio [HR], 0.71 [95% CI, 0.61-0.82]; P < 0.001), with consistent results for serious kidney-related AEs (HR, 0.72 [95% CI, 0.51-1.00]; P = 0.05) and acute kidney injury (AKI; HR, 0.85 [95% CI, 0.64-1.13]; P = 0.3). The rates of kidney-related AEs were lower with canagliflozin relative to placebo across the 3 eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90 mL/min/1.73 m2, respectively; P = 0.3 for interaction), with similar results for AKI (P = 0.9 for interaction). Full recovery of kidney function within 30 days after an AKI event occurred more frequently with canagliflozin versus placebo (53.1% vs 35.4%; odds ratio, 2.2 [95% CI, 1.0-4.7]; P = 0.04). LIMITATIONS: Kidney-related AEs including AKI were investigator-reported and collected without central adjudication. Biomarkers of AKI and structural tubular damage were not measured, and creatinine data after an AKI event were not available for all participants. CONCLUSIONS: Compared with placebo, canagliflozin was associated with a reduced incidence of serious and nonserious kidney-related AEs in patients with T2DM and CKD. These results highlight the safety of canagliflozin with regard to adverse kidney-related AEs. FUNDING: The CREDENCE trial and this analysis 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 CREDENCE trial was registered at ClinicalTrials.gov with identifier number NCT02065791.
RATIONALE & OBJECTIVE: Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs). STUDY DESIGN: A randomized, double-blind, placebo-controlled, multicenter international trial. SETTING & PARTICIPANTS: 4,401 trial participants with T2DM, CKD, and urinary albumin-creatinine ratio >300-5,000 mg/g. INTERVENTIONS: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo. OUTCOMES: Rates of kidney-related AEs were analyzed using an on-treatment approach, overall and by screening estimated glomerular filtration rate (eGFR) strata (30-<45, 45-<60, and 60-<90 mL/min/1.73 m2). RESULTS: Canagliflozin was associated with a reduction in the overall incidence rate of kidney-related AEs (60.2 vs 84.0 per 1,000 patient-years; hazard ratio [HR], 0.71 [95% CI, 0.61-0.82]; P < 0.001), with consistent results for serious kidney-related AEs (HR, 0.72 [95% CI, 0.51-1.00]; P = 0.05) and acute kidney injury (AKI; HR, 0.85 [95% CI, 0.64-1.13]; P = 0.3). The rates of kidney-related AEs were lower with canagliflozin relative to placebo across the 3 eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90 mL/min/1.73 m2, respectively; P = 0.3 for interaction), with similar results for AKI (P = 0.9 for interaction). Full recovery of kidney function within 30 days after an AKI event occurred more frequently with canagliflozin versus placebo (53.1% vs 35.4%; odds ratio, 2.2 [95% CI, 1.0-4.7]; P = 0.04). LIMITATIONS: Kidney-related AEs including AKI were investigator-reported and collected without central adjudication. Biomarkers of AKI and structural tubular damage were not measured, and creatinine data after an AKI event were not available for all participants. CONCLUSIONS: Compared with placebo, canagliflozin was associated with a reduced incidence of serious and nonserious kidney-related AEs in patients with T2DM and CKD. These results highlight the safety of canagliflozin with regard to adverse kidney-related AEs. FUNDING: The CREDENCE trial and this analysis 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 CREDENCE trial was registered at ClinicalTrials.gov with identifier number NCT02065791.
Authors: Melanie J Davies; Vanita R Aroda; Billy S Collins; Robert A Gabbay; Jennifer Green; Nisa M Maruthur; Sylvia E Rosas; Stefano Del Prato; Chantal Mathieu; Geltrude Mingrone; Peter Rossing; Tsvetalina Tankova; Apostolos Tsapas; John B Buse Journal: Diabetologia Date: 2022-09-24 Impact factor: 10.460