SGLT2i reduces incidence of hyperkalemia in HF patients

Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled

Literature - Ferreira JP, Zannad F, Butler J, et al. - Eur Heart J. 2022 Jun 10;ehac306. doi: 10.1093/eurheartj/ehac306

Introduction and methods


Hyperkalemia frequently leads to the interruption or discontinuation of treatment with RAAS inhibitors [1], which may worsen the prognosis of patients with HF [2-4]. The CREDENCE, DAPA-HF, and EMPEROR-Reduced trials suggest that the SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin may reduce the incidence of hyperkalemia in patients with T2DM and CKD [5], and in patients with HFrEF using an MRA [6,7].

Aim of the study

This secondary analysis of EMPEROR-Pooled examined the effect of empagliflozin on the incidence of hyper- and hypokalemia in patients with HF.


EMPEROR-Pooled combined individual patient data from the EMPEROR-Reduced and EMPEROR-Preserved trials (n = 9583). Both trials are international, multicenter, double-blind phase 3 studies in which adult patients with chronic HF were randomized to empagliflozin 10 mg daily or placebo in addition to their usual therapy. Patients with NYHA class II-IV symptoms for 3 or more months, an elevated NT-proBNP concentration, and an LVEF ≤ 40% (EMPEROR-Reduced) or > 40% (EMPEROR-Preserved) were eligible to participate. Hyper- and hypokalemia were determined based on investigator-reported adverse events and also defined by serum potassium concentration, with > 5.5 mmol/L (‘hyperkalemia’), > 6.0 mmol/L (‘severe hyperkalemia’), and < 3.0 mmol/L (‘severe hypokalemia’) used as cut-off values.


The main outcome was a composite of the incidence of investigator-reported hyperkalemia and the new initiation of potassium binders.

Main results


  • Treatment with empagliflozin resulted in a lower incidence of investigator-reported hyperkalemia or new initiation of potassium binders compared with placebo (6.5 vs. 7.7%; HR 0.82; 95%CI: 0.71-0.95; P=0.01).
  • Treatment with empagliflozin showed a lower incidence of investigator-reported hyperkalemia (6.1 vs. 7.2%; HR 0.83; 95%CI: 0.71-0.97; P=0.018) and hyperkalemia based on serum potassium concentration, regardless of the chosen cut-off point , compared with placebo (> 5.5 mmol/L: 8.6 vs. 9.9%; HR 0.85; 95%CI: 0.74-0.97; p = 0.017; > 6.0 mmol/L: 1.9 vs. 2.9%; HR: 0.62; 95%CI: 0.48-0.81; p < 0.001).
  • The percentage of patients in whom treatment with potassium binders had to be initiated did not differ between the intervention and placebo groups (1.5 vs. 1.8%; HR: 0.80; 95%CI: 0.59-1.10; P=0.174).


  • Treatment with empagliflozin did not result in a lower incidence of investigator-reported hypokalemia or new initiation of potassium supplementation compared with placebo (6.4 vs. 6.7%; HR 0.95; 95%CI: 0.80-1.12; P=0.533).
  • The percentage of patients with investigator-reported hypokalemia did not differ between the intervention and placebo groups, nor did the percentage of patients in whom potassium needed to be supplemented or in whom severe hypokalemia (<3.0 mmol/L) occurred.


In patients with HF, treatment with empagliflozin resulted in a lower incidence of hyperkalemia, compared with placebo. The percentage of patients in whom hypokalemia occurred was similar between the two groups.


1. Rossignol P, Lainscak M, Crespo-Leiro MG, et al. Unravelling the interplay between hyperkalaemia, renin-angiotensin-aldosterone inhibitor use and clinical outcomes. Data from 9222 chronic heart failure patients of the ESC-HFA-EORP heart failure long-term registry. Eur J Heart Fail 2020;22:1378-1389.

2. Aldahl M, Jensen AC, Davidsen L, et al. Associations of serum potassium levels with mortality in chronic heart failure patients. Eur Heart J 2017;38:2890-2896.

3. Nunez J, Bayes-Genis A, Zannad F, et al. Long-term potassium monitoring and dynamics in heart failure and risk of mortality. Circulation 2018;137:1320-1330.

4. Ferreira JP, Mogensen UM, Jhund PS, et al. Serum potassium in the PARADIGM-HF trial. Eur J Heart Fail 2020;22:2056-2064.

5. Neuen BL, Oshima M, Perkovic V, et al. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial. Eur Heart J 2021;42:4891-4901.

6. Shen L, Kristensen SL, Bengtsson O, et al. Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021;9:254-264.

7. Ferreira JP, Zannad F, Pocock SJ, et al. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-reduced. J Am Coll Cardiol 2021;77:1397-1407.

Find this article online at Eur Heart J.

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