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.

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

“…20,28,32,[36][37][38][44][45][46] Increases in aldosterone may in part explain the effect of SGLT2 inhibitors to mitigate the risk of hyperkalemia (without inducing hypokalemia) in patients with diabetes or heart failure. 47,48 Activation of Tubuloglomerular Feedback Increased delivery of chloride to the macula densa after SGLT2 inhibition activates tubuloglomerular feedback, leading to afferent arteriolar vasoconstriction or efferent arteriolar vasodilation and a decline in glomerular filtration pressure. 20,[49][50][51] Tubuloglomerular feedback becomes saturated, and single-nephron glomerular filtration falls dramatically, but with time, there is partial adaptation caused by increased sodium reabsorption in the loop of Henle, in conjunction with resetting of tubuloglomerular feedback.…”

Use of guideline‐recommended medical therapy in patients with heart failure and chronic kidney disease: from physician's prescriptions to patient's dispensations, medication adherence and persistence

“…Moreover, concomitant SGLT2i use in HFrEF, as recommended by guidelines, 6 may also lower the risk of hyperkalaemia. 38 Finally, implementing nationwide registries might allow screening strategies to identify undertreated patients and refer them to specialist care. Similar approaches might involve the use of electronic decision support systems providing protocols and checklists to remind clinicians of steps to follow during the patient's workup.…”

Practical patient care appraisals with use of new potassium binders in heart failure and chronic kidney diseases

“…56,57 Despite this, in clinical practice, a common approach in patients with a history of hyperkalaemia is not to restart RAAS inhibition. Finally, it should be remembered that two foundational drugs, namely sacubitril/valsartan 58 and sodium-glucose cotransporter 2 inhibitors, [59][60][61][62] mitigate the risk of hyperkalaemia while having direct benefits on heart failure outcomes. Nevertheless, so far, only patiromer has data cited in the most recent ESC guidelines to support RAAS inhibitor use or uptitration.…”