Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial

Brendon L Neuen¹, Megumi Oshima², Vlado Perkovic³, Rajiv Agarwal⁴, Clare Arnott^{1

5

6}, George Bakris⁷, Christopher P Cannon⁸, David M Charytan⁹, Robert Edwards¹⁰, Jose L Górriz¹¹, Meg J Jardine^{12

13}, Adeera Levin¹⁴, Bruce Neal^{1

15}, Luca De Nicola¹⁶, Carol Pollock¹⁷, Norman Rosenthal¹⁰, David C Wheeler¹⁸, Kenneth W Mahaffey¹⁹, Hiddo J L Heerspink²⁰

Affiliations

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.

PMID: 34423370
DOI: 10.1093/eurheartj/ehab497

Randomized Controlled Trial

Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial

Brendon L Neuen et al. Eur Heart J. 2021.

. 2021 Dec 21;42(48):4891-4901.

doi: 10.1093/eurheartj/ehab497.

Authors

Affiliations

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.

PMID: 34423370
DOI: 10.1093/eurheartj/ehab497

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.

Keywords: Canagliflozin; Chronic kidney disease; Hyperkalaemia; Potassium; SGLT2 inhibitors; Type 2 diabetes mellitus.

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Comment in

SGLT2 inhibitors: the story continues to unfold.
Piña IL. Piña IL. Eur Heart J. 2021 Dec 21;42(48):4902-4904. doi: 10.1093/eurheartj/ehab561. Eur Heart J. 2021. PMID: 34423356 No abstract available.

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Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial

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Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial

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Medical