TY - JOUR
T1 - Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People with Type 2 Diabetes
T2 - A Meta-Analysis of Individual Participant Data from Randomized, Controlled Trials
AU - Neuen, Brendon L.
AU - Oshima, Megumi
AU - Agarwal, Rajiv
AU - Arnott, Clare
AU - Cherney, David Z.
AU - Edwards, Robert
AU - Langkilde, Anna Maria
AU - Mahaffey, Kenneth W.
AU - McGuire, Darren K.
AU - Neal, Bruce
AU - Perkovic, Vlado
AU - Pong, Annpey
AU - Sabatine, Marc S.
AU - Raz, Itamar
AU - Toyama, Tadashi
AU - Wanner, Christoph
AU - Wheeler, David C.
AU - Wiviott, Stephen D.
AU - Zinman, Bernard
AU - Heerspink, Hiddo J.L.
N1 - Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/5/10
Y1 - 2022/5/10
N2 - Background: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease. However, their effect on hyperkalemia has not been systematically evaluated. Methods: A meta-analysis was conducted using individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease in whom serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory-determined serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios and corresponding 95% CIs pooled with random-effects models to obtain summary treatment effects, overall and across key subgroups. Results: Results from 6 trials were included comprising 49 875 participants assessing 4 SGLT2 inhibitors. Of these, 1754 participants developed serious hyperkalemia, and an additional 1119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (hazard ratio, 0.84 [95% CI, 0.76-0.93]), an effect consistent across studies (Pheterogeneity=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (hazard ratio, 0.80 [95% CI, 0.68-0.93]; Pheterogeneity=0.21). Reductions in serious hyperkalemia were observed across a range of subgroups, including baseline kidney function, history of heart failure, and use of renin-angiotensin-aldosterone system inhibitor, diuretic, and mineralocorticoid receptor antagonist. SGLT2 inhibitors did not increase the risk of hypokalemia (hazard ratio, 1.04 [95% CI, 0.94-1.15]; Pheterogeneity=0.42). Conclusions: SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease without increasing the risk of hypokalemia.
AB - Background: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease. However, their effect on hyperkalemia has not been systematically evaluated. Methods: A meta-analysis was conducted using individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease in whom serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory-determined serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios and corresponding 95% CIs pooled with random-effects models to obtain summary treatment effects, overall and across key subgroups. Results: Results from 6 trials were included comprising 49 875 participants assessing 4 SGLT2 inhibitors. Of these, 1754 participants developed serious hyperkalemia, and an additional 1119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (hazard ratio, 0.84 [95% CI, 0.76-0.93]), an effect consistent across studies (Pheterogeneity=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (hazard ratio, 0.80 [95% CI, 0.68-0.93]; Pheterogeneity=0.21). Reductions in serious hyperkalemia were observed across a range of subgroups, including baseline kidney function, history of heart failure, and use of renin-angiotensin-aldosterone system inhibitor, diuretic, and mineralocorticoid receptor antagonist. SGLT2 inhibitors did not increase the risk of hypokalemia (hazard ratio, 1.04 [95% CI, 0.94-1.15]; Pheterogeneity=0.42). Conclusions: SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease without increasing the risk of hypokalemia.
KW - chronic
KW - diabetes mellitus
KW - heart failure
KW - hyperkalemia
KW - potassium
KW - renal insufficiency
KW - sodium-glucose transporter 2 inhibitors
KW - type 2
UR - http://www.scopus.com/inward/record.url?scp=85130001554&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130001554&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.121.057736
DO - 10.1161/CIRCULATIONAHA.121.057736
M3 - Article
C2 - 35394821
AN - SCOPUS:85130001554
SN - 0009-7322
VL - 145
SP - 1460
EP - 1470
JO - Circulation
JF - Circulation
IS - 19
ER -