Meg Jardine1,2, Zien Zhou1,3, Hiddo J Lambers Heerspink1,4, Carinna Hockham5, Qiang Li1, Rajiv Agarwal6,7, George L Bakris8, Christopher P Cannon9, David M Charytan10,11, Tom Greene12, Adeera Levin13, Jing-Wei Li1, Brendon L Neuen1, Bruce Neal1,14,15, Richard Oh16, Megumi Oshima1, Carol Pollock17, David C Wheeler1,18, Dick de Zeeuw4, Hong Zhang18, Bernard Zinman19, Kenneth W Mahaffey20, Vlado Perkovic1,21. 1. The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia. 2. Renal Department, Concord Repatriation General Hospital, Sydney, Australia. 3. Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 4. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 5. The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia chockham@georgeinstitute.org.au. 6. Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana. 7. Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana. 8. Department of Medicine, University of Chicago Medicine, Chicago, Illinois. 9. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. 10. Nephrology Division, New York University School of Medicine and New York University Langone Medical Center, New York, New York. 11. Baim Institute for Clinical Research, Boston, Massachusetts. 12. Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah. 13. Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada. 14. Charles Perkins Centre, University of Sydney, Sydney, Australia. 15. School of Public Health, Imperial College London, London, United Kingdom. 16. Metabolism, Janssen Research and Development, LLC, Raritan, New Jersey. 17. Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, Sydney, Australia. 18. Department of Renal Medicine, University College London Medical School, London, United Kingdom. 19. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada. 20. Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California. 21. Royal North Shore Hospital, Sydney, Australia.
Abstract
BACKGROUND AND OBJECTIVES: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. RESULTS: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (P heterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years (P heterogeneity=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories. CONCLUSIONS: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov: CREDENCE, NCT02065791. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.
BACKGROUND AND OBJECTIVES: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. RESULTS: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (P heterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years (P heterogeneity=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories. CONCLUSIONS: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov: CREDENCE, NCT02065791. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.
Authors: Meg J Jardine; Zien Zhou; Kenneth W Mahaffey; Megumi Oshima; Rajiv Agarwal; George Bakris; Harpreet S Bajaj; Scott Bull; Christopher P Cannon; David M Charytan; Dick de Zeeuw; Gian Luca Di Tanna; Tom Greene; Hiddo J L Heerspink; Adeera Levin; Bruce Neal; Carol Pollock; Rose Qiu; Tao Sun; David C Wheeler; Hong Zhang; Bernard Zinman; Norman Rosenthal; Vlado Perkovic Journal: J Am Soc Nephrol Date: 2020-05 Impact factor: 10.121
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