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

Abstract

Aims: Hyperkalaemia frequently leads to interruption and discontinuation of neurohormonal antagonists, which may worsen heart failure prognosis. Some studies suggested that sodium-glucose cotransporter 2 inhibitors reduce hyperkalaemia, an effect that may have important clinical implications. This analysis evaluates the effect of empagliflozin on the occurrence of hyper- and hypokalaemia in HF.

Methods and results: EMPEROR-Pooled (i.e. EMPEROR-Reduced and EMPEROR-Preserved combined) included 9583 patients with available serum potassium levels at baseline (98.6% of the total EMPEROR-Pooled population, n = 9718). Hyperkalaemia was identified by investigators' reports of adverse events, and by a laboratory serum potassium value above 5.5 mmol/L and 6.0 mmol/L. The main outcome was a composite of investigator-reported hyperkalaemia or initiation of potassium binders. Patients with high potassium at baseline were more frequently diagnosed with diabetes and ischaemic HF aetiology and had lower left ventricular ejection fraction and estimated glomerular filtration rate but were more frequently treated with sacubitril/valsartan or mineralocorticoid receptor antagonists. Empagliflozin (compared with placebo) reduced the composite of investigator-reported hyperkalaemia or initiation of potassium binders [6.5% vs. 7.7%, hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71-0.95, P = 0.01]. Empagliflozin reduced hyperkalaemia rates regardless of the definition used (serum potassium >5.5 mmol/l: 8.6% vs. 9.9%, HR 0.85, 95% CI 0.74-0.97, P = 0.017; serum potassium >6.0 mmol/l: 1.9% vs. 2.9%, HR 0.62, 95% CI 0.48-0.81, P < 0.001). The incidence of hypokalaemia (investigator-reported or serum potassium <3.0 mmol/l) was not significantly increased with empagliflozin.

Conclusions: Empagliflozin reduced the incidence of hyperkalaemia without significant increase in hypokalaemia.

Trial registration: ClinicalTrials.gov NCT03057977 NCT03057951.

Keywords: Empagliflozin; Heart failure; Hyperkalaemia; Potassium.

Conflict of interest statement

Conflict of interest: J.P.F. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. F.Z. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer and, Cellprothera, other from CVCT, and Cardiorenal, outside the submitted work. J.B. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave and Vifor, outside the submitted work. G.F. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Medtronic, Vifor, Servier, Novartis, Bayer, Amgen and Boehringer Ingelheim, outside the submitted work. I.R. and B.J.K. are employees of Boehringer Ingelheim. ES is employee of mainanalytics GmbH, contracted by Boehringer Ingelheim. SJP reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. S.A. reports personal fees from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Abbott Vascular, Vifor, personal fees from Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis and Servier, outside the submitted work. M.P. reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Abbvie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Cytokinetics, Johnson & Johnson, Eli Lily & Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, Theravance, and Casana, outside the submitted work.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Figures

Structured Graphical Abstract

Empagliflozin reduced the incidence of hyperkalemia without increasing the risk of hypokalemia.

Figure 1

Effect of empagliflozin on the incidence of investigator-reported hyperkalaemia or initiation of potassium binders. Considering all-cause mortality as a competing risk and only including patients not receiving potassium-binding agents at baseline.

Figure 2

Effect of empagliflozin on investigator-reported hyperkalaemia or the initiation of potassium binders in subgroups of interest. Based on Cox proportional hazard model adjusted for age (continuous), baseline estimated glomerular filtration rate (continuous), baseline left ventricular ejection fraction (continuous), study, region, baseline diabetes status, sex, treatment, subgroup, and subgroup and treatment interaction. In subgroups with more than two categories (except for race), an interaction trend test was performed. BMI, body mass index; CI, confidence interval; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; Empa, empagliflozin; HHF, hospitalization for heart failure; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; UACR, urine albumin-to-creatinine ratio.

Figure 3

Effect of empagliflozin on potassium over time by baseline potassium. AllP-values for the treatment differences are >0.05; except for baseline potassium < 4.0 mmol/L: week 12 (P < 0.05), baseline potassium 4.0–5.0 mmol/L: week 172 (P < 0.05), baseline potassium > 5.0 mmol/L: week 32 (P < 0.001). Based on mixed model repeated measures analysis. All covariate effects are set equal to their mean values within subgroup for the calculation of adjusted means.