Neuen, Brendon L; Oshima, Megumi; Agarwal, Rajiv; Arnott, Clare; Cherney, David Z; Edwards, Robert; Langkilde, Anna Maria; ... Heerspink, Hiddo JL; + view all Neuen, Brendon L; Oshima, Megumi; Agarwal, Rajiv; Arnott, Clare; Cherney, David Z; Edwards, Robert; Langkilde, Anna Maria; Mahaffey, Kenneth W; McGuire, Darren K; Neal, Bruce; Perkovic, Vlado; Pong, Annpey; Sabatine, Marc S; Raz, Itamar; Toyama, Tadashi; Wanner, Christoph; Wheeler, David C; Wiviott, Stephen D; Zinman, Bernard; Heerspink, Hiddo JL; - view fewer (2022) Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data From Randomized, Controlled Trials. Circulation , 145 (9) pp. 1460-1470. 10.1161/CIRCULATIONAHA.121.057736.

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Abstract

Background: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists (MRAs), which improve clinical outcomes in people with chronic kidney disease (CKD) and/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 CKD. 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 and/or with CKD, in which serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory determine 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 (HR) and corresponding 95% CI pooled using random effects models to obtain summary treatment effects, overall and across key subgroups. / Results: Results from six trials were included comprising 49,875 participants assessing four SGLT2 inhibitors. 1,754 participants developed serious hyperkalemia and an additional 1,119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (HR 0.84, 95% CI 0.76-0.93), an effect consistent across studies (P-heterogeneity=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (HR 0.80, 95% CI 0.68-0.93; P-heterogeneity=0.21). Reductions in serious hyperkalemia were observed across a range of subgroups including baseline kidney function, history of heart failure, RAAS inhibitor, diuretic and MRA use. SGLT2 inhibitors did not increase the risk of hypokalemia (HR 1.04, 95% CI 0.94-1.15; P-heterogeneity=0.42). / Conclusions: SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk and/or with CKD, without increasing the risk of hypokalemia.

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