Brendon L Neuen1, Megumi Oshima2, Vlado Perkovic3, Rajiv Agarwal4, Clare Arnott1,5,6, George Bakris7, Christopher P Cannon8, David M Charytan9, Robert Edwards10, Jose L Górriz11, Meg J Jardine12,13, Adeera Levin14, Bruce Neal1,15, Luca De Nicola16, Carol Pollock17, Norman Rosenthal10, David C Wheeler18, Kenneth W Mahaffey19, Hiddo J L Heerspink20. 1. Renal and Metabolic Division, The George Institute for Global Health, UNSW Sydney, Sydney, NSW 2042, Australia. 2. Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. 3. Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia. 4. Indiana University School of Medicine and VA Medical Center, Indianapolis, IN 46202, USA. 5. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia. 6. Sydney Medical School, University of Sydney, Sydney, NSW 2050, Australia. 7. Department of Medicine, University of Chicago Medicine, Chicago, IL 60637, USA. 8. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. 9. Nephrology Division, New York University Langone Medical Center, New York University School of Medicine, New York, NY 10016, USA. 10. Janssen Research & Development, LLC, Raritan, NJ 08869, USA. 11. Department of Nephrology, Hospital Clínico Universitario, University of Valencia, Valencia, Spain. 12. Concord Repatriation General Hospital, Sydney, NSW 2139, Australia. 13. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia. 14. Division of Nephrology, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada. 15. The Charles Perkins Centre, University of Sydney, Sydney, NSW 2050, Australia. 16. Department of Advanced Medical and Surgical Sciences, Nephrology and Dialysis Unit, University Vanvitelli, Naples, Italy. 17. Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2064, Australia. 18. Department of Renal Medicine, UCL Medical School, London WC1E 6DE, UK. 19. Stanford University School of Medicine, Stanford, CA 94305, USA. 20. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 AD Groningen, the Netherlands.
Abstract
AIMS: Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. METHODS AND RESULTS: The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin-angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo. CONCLUSION: Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. METHODS AND RESULTS: The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin-angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo. CONCLUSION: Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Peter Rossing; Gerasimos Filippatos; Rajiv Agarwal; Stefan D Anker; Bertram Pitt; Luis M Ruilope; Juliana C N Chan; Adriaan Kooy; Kieran McCafferty; Guntram Schernthaner; Christoph Wanner; Amer Joseph; Markus F Scheerer; Charlie Scott; George L Bakris Journal: Kidney Int Rep Date: 2021-10-14
Authors: Michele Provenzano; Niels Jongs; Priya Vart; Bergur V Stefánsson; Glenn M Chertow; Anna Maria Langkilde; John J V McMurray; Ricardo Correa-Rotter; Peter Rossing; C David Sjöström; Robert D Toto; David C Wheeler; Hiddo J L Heerspink Journal: Kidney Int Rep Date: 2021-12-14