Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial
Author(s)
Type
Journal Article
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.
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.
Date Issued
2021-12-21
Date Acceptance
2021-07-15
Citation
European Heart Journal, 2021, 42 (48), pp.4891-4901
ISSN
0195-668X
Publisher
European Society of Cardiology
Start Page
4891
End Page
4901
Journal / Book Title
European Heart Journal
Volume
42
Issue
48
Copyright Statement
© The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model). This is a pre-copy-editing, author-produced version of an article accepted for publication in European Heart Journal following peer review. The definitive publisher-authenticated version Brendon L Neuen, Megumi Oshima, Vlado Perkovic, Rajiv Agarwal, Clare Arnott, George Bakris, Christopher P Cannon, David M Charytan, Robert Edwards, Jose L Górriz, Meg J Jardine, Adeera Levin, Bruce Neal, Luca De Nicola, Carol Pollock, Norman Rosenthal, David C Wheeler, Kenneth W Mahaffey, Hiddo J L Heerspink, Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial, European Heart Journal, Volume 42, Issue 48, 21 December 2021, Pages 4891–4901 is available online at: https://doi.org/10.1093/eurheartj/ehab497
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model). This is a pre-copy-editing, author-produced version of an article accepted for publication in European Heart Journal following peer review. The definitive publisher-authenticated version Brendon L Neuen, Megumi Oshima, Vlado Perkovic, Rajiv Agarwal, Clare Arnott, George Bakris, Christopher P Cannon, David M Charytan, Robert Edwards, Jose L Górriz, Meg J Jardine, Adeera Levin, Bruce Neal, Luca De Nicola, Carol Pollock, Norman Rosenthal, David C Wheeler, Kenneth W Mahaffey, Hiddo J L Heerspink, Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial, European Heart Journal, Volume 42, Issue 48, 21 December 2021, Pages 4891–4901 is available online at: https://doi.org/10.1093/eurheartj/ehab497
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000736071100008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
Canagliflozin
SGLT2 inhibitors
Hyperkalaemia
Potassium
Type 2 diabetes mellitus
Chronic kidney disease
END-POINTS
HYPERKALEMIA
OUTCOMES
INHIBITION
MECHANISMS
RATIONALE
Publication Status
Published
Date Publish Online
2021-08-23