SGLT2i reduces incidence of hyperkalemia in HF patients
Hyperkalemia frequently leads to the interruption or discontinuation of treatment with RAAS inhibitors, which may worsen the prognosis of patients with HF. The SGLT2 inhibitor empagliflozin may offer relief here.
Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-PooledLiterature - Ferreira JP, Zannad F, Butler J, et al. - Eur Heart J. 2022 Jun 10;ehac306. doi: 10.1093/eurheartj/ehac306
Introduction and methods
Background
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.
Methods
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.
Outcomes
The main outcome was a composite of the incidence of investigator-reported hyperkalemia and the new initiation of potassium binders.
Main results
Hyperkalemia
- 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).
Hypokalemia
- 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.
Conclusion
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.
References
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.