George Bakris1, Megumi Oshima2,3, Kenneth W Mahaffey4, Rajiv Agarwal5, Christopher P Cannon6, George Capuano7, David M Charytan8,9, Dick de Zeeuw10, Robert Edwards7, Tom Greene11, Hiddo J L Heerspink2,10, Adeera Levin12, Bruce Neal2,13,14, Richard Oh7, Carol Pollock15, Norman Rosenthal7, David C Wheeler2,16, Hong Zhang17, Bernard Zinman18, Meg J Jardine2,19, Vlado Perkovic2,20. 1. Department of Medicine, University of Chicago Medicine, Chicago, Illinois gbakris@gmail.com. 2. The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia. 3. Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan. 4. Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California. 5. Indiana University School of Medicine and Veterans Affairs Medical Center, Indianapolis, Indiana. 6. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. 7. Janssen Research & Development, LLC, Raritan, New Jersey. 8. Nephrology Division, New York University School of Medicine and New York University Langone Medical Center, New York, New York. 9. Baim Institute for Clinical Research, Boston, Massachusetts. 10. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 11. Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah. 12. Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada. 13. Charles Perkins Centre, University of Sydney, Sydney, Australia. 14. Imperial College London, London, United Kingdom. 15. Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia. 16. Department of Renal Medicine, University College London Medical School, London, United Kingdom. 17. Renal Division, Peking University First Hospital, Beijing, China. 18. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. 19. Concord Repatriation General Hospital, Sydney, Australia. 20. Royal North Shore Hospital, Sydney, Australia.
Abstract
BACKGROUND AND OBJECTIVES: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2). RESULTS: From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m2 per year; difference, -2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.12). CONCLUSIONS: This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2.
BACKGROUND AND OBJECTIVES: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2). RESULTS: From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m2 per year; difference, -2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.12). CONCLUSIONS: This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2.
Authors: David Z I Cherney; Claire C J Dekkers; Sean J Barbour; Daniel Cattran; Abdul Halim Abdul Gafor; Peter J Greasley; Gozewijn D Laverman; Soo Kun Lim; Gian Luca Di Tanna; Heather N Reich; Marc G Vervloet; Muh Geot Wong; Ron T Gansevoort; Hiddo J L Heerspink Journal: Lancet Diabetes Endocrinol Date: 2020-07 Impact factor: 32.069
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