Meg J Jardine1,2, Zien Zhou3,4, Kenneth W Mahaffey5, Megumi Oshima3,6, Rajiv Agarwal7, George Bakris8, Harpreet S Bajaj9, Scott Bull10, Christopher P Cannon11,12, David M Charytan12,13, Dick de Zeeuw14, Gian Luca Di Tanna3, Tom Greene15, Hiddo J L Heerspink3,14, Adeera Levin16, Bruce Neal3,17,18, Carol Pollock19,20, Rose Qiu10, Tao Sun10, David C Wheeler3,21, Hong Zhang22, Bernard Zinman23, Norman Rosenthal10, Vlado Perkovic3,20. 1. The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia mjardine@georgeinstitute.org.au. 2. Concord Repatriation General Hospital, Sydney, New South Wales, Australia. 3. The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia. 4. Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 5. Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California. 6. Department of Nephrology and Laboratory Medicine, Kanazawa University, Ishikawa, Japan. 7. Indiana University School of Medicine and Veterans Affairs Medical Center, Indianapolis, Indiana. 8. Department of Medicine, University of Chicago Medicine, Chicago, Illinois. 9. LMC Healthcare, Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada. 10. Janssen Research & Development, LLC, Raritan, New Jersey. 11. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. 12. Baim Institute for Clinical Research, Boston, Massachusetts. 13. Nephrology Division, New York University Langone Medical Center, New York University School of Medicine, New York, New York. 14. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 15. Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah. 16. Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada. 17. The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia. 18. Imperial College London, London, United Kingdom. 19. Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. 20. Royal North Shore Hospital, Sydney, New South Wales, Australia. 21. Department of Renal Medicine, University College London Medical School, London, United Kingdom. 22. Renal Division, Peking University First Hospital, Beijing, China. 23. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND:Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). METHODS: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria tocanagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope. RESULTS: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). CONCLUSIONS:Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.
RCT Entities:
BACKGROUND:Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). METHODS: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope. RESULTS: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). CONCLUSIONS:Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.
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