Sodium glucose cotransporter 2 (SGLT-2) inhibitors are one of the four pillars of evidence-based drug therapy for patients with heart failure with reduced ejection fraction (HFrEF). These are in addition to the other three pillars, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor neprilysin inhibitors (ACEI/ARB/ARNI), and mineralocorticoid receptor antagonists (MRAs). ) is used in combination with The guidelines strongly recommend the combination of these four drug classes with Class I recommendations, supported by compelling evidence demonstrating significant reductions in both cardiovascular deaths and heart failure hospitalizations. SGLT-2 inhibitors are currently also recommended for patients with preserved ejection fraction heart failure (HFpEF) with a class IIa recommendation, and ARBs, ARNIs, and MRAs have been assigned a class IIb recommendation.¹

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Hyperkalemia is a known side effect of ACEI/ARB/ARNI and MRA. Additionally, people diagnosed with heart failure often have chronic kidney disease, which makes them especially susceptible to hyperkalemia. Heart failure guidelines recommend starting MRA in patients with the following criteria: serum potassium <5 mEq/L, serum creatinine <2 mg/dl or <2.5 mg/dl for women and men, respectively; Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2.^1,2 This cautious approach has caused some anxiety among prescribers.

SGLT-2 inhibitors have dual diuretic and natriuretic effects. Naturally regulates and promotes potassium excretion by enhancing distal sodium and water excretion.³ A post hoc analysis of a recent clinical trial investigated the effect of SGLT-2 inhibitors on reducing the risk of hyperkalemia in patients with heart failure.

The EMPEROR-Reduced trial (NCT03057977) compared the SGLT-2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) with a placebo in HFrEF patients receiving standard heart failure medications.^Four The effect of empagliflozin on the rate of hyperkalemia in patients concurrently using MRA was examined in a secondary analysis. Patients were randomly assigned to receive either placebo or empagliflozin 10 mg daily. The primary endpoint, including adjudicated cardiovascular death or hospitalization for heart failure, analyzed as time to first event, was significantly reduced with empagliflozin. Of her 3,730 patients enrolled, 71% were on her MRA at baseline.^Four

The results demonstrated consistent efficacy of empagliflozin in reducing the primary endpoint, regardless of background MRA use. [HR 0.75 (0.63 – 0.88) for patients on MRAs and HR 0.76 (0.59 – 0.97) for patients not on MRAs]. Additionally, the empagliflozin group had fewer episodes of hyperkalemia than the placebo group, with a significant, but not statistically significant, reduction in severe hyperkalemia defined as potassium > 6 mmol/L. Did. [HR of 0.7 (0.47-1.04)]. The effect of empagliflozin on severe hyperkalemia was consistent between patients who underwent MRA and those who did not at baseline (P = 0.56).^Four

Empagliflozin also showed nephroprotective effects, slowing the decline in eGFR in both MRA users and non-users. Patients who received an MRA at baseline and were randomized to the empagliflozin group were more likely to discontinue or discontinue MRA treatment compared to patients who started an MRA and were randomized to the placebo group22 It is important to note that %low. .^Four This study highlights that empagliflozin may reduce hyperkalemia, preserve renal function, and promote continuation of MRA.

A pooled analysis of both the EMPEROR-Reduced and EMPEROR-Preserved trials (HFpEF patients, NCT03057951) provided further evidence of a significant effect of empagliflozin on hyperkalemia.^Five Empagliflozin reduced hyperkalemia compared to placebo [potassium > 5.5 mmol/L: 8.6% vs. 9.9%, HR 0.85 (0.74–0.97), p = 0.017; and potassium >6.0 mmol/L: 1.9% vs. 2.9%, HR 0.62 (0.48–0.81), p < 0.001]. Hyperkalemia and initiation of potassium binders were also significantly reduced, the researchers reported. [HR 0.82 (0.71 – 0.95), p = 0.01]And this effect was consistent regardless of MRA use.^Five

The Dapagliflozin and Reduced Ejection Fraction Study in Heart Failure Patients (DAPA-HF; NCT03036124) also showed a significant reduction in the risk of worsening heart failure and cardiovascular death, further deepening our understanding of the role of SGLT-2 inhibitors. I did. Similar to the EMPEROR trial.⁶ The study enrolled 4744 patients aged 18 years and older with left ventricular ejection fraction ≤40% and elevated N-terminal pro-B-type natriuretic peptide and were randomly assigned to dapagliflozin 10 mg/day or placebo. It was done. His 71% of patients with DAPA-HF had undergone her MRA at baseline.⁶

Of note, the positive impact of dapagliflozin on the primary outcome (a composite of worsening heart failure, including unplanned hospitalizations or emergency visits requiring intravenous treatment for heart failure, and cardiovascular death) was demonstrated using MRA. was consistent across all patients, regardless of whether they were The hazard ratio was 0.74 (0.63 to 0.87) for patients using MRA and 0.74 (0.57 to 0.95) for patients without MRA. Furthermore, dapagliflozin consistently reduced overall renal outcomes regardless of MRA use, highlighting its renoprotective effects.⁶ The risk of hyperkalemia was also assessed, with results mirroring those of the EMPEROR-Reduced trial. Patients using MRA and dapagliflozin concurrently experienced fewer hyperkalemic events, especially when serum potassium concentrations exceeded 6 mmol/L, with an HR of 0.50 (0.29 to 0.85).⁶

The potassium-lowering effects of SGLT-2 inhibitors have been demonstrated by a recent meta-analysis of randomized trials of SGLT-2 inhibitors in patients with type 2 diabetes or chronic kidney disease at high cardiovascular risk. It has also been observed in other patient groups. .⁷ This analysis revealed a reduced risk of significant hyperkalemia (≥6 mmol/L) with a hazard ratio of 0.84 (0.76 – 0.93).⁷

It is important to note that secondary analyzes of the EMPEROR and DAPA-HF trials suggest a reduced risk of clinically significant hyperkalemia.^6,7 Limited by its retrospective nature. Randomized controlled trials are needed to confirm these findings, but are unlikely to be conducted. However, these findings are mechanistically plausible considering the mechanism of action of SGLT-2 inhibitors.

In addition to pharmacological interventions in patients considered to be at high risk for hyperkalemia, dietary modifications may also reduce this risk. A low-potassium diet that limits intake of potassium-rich foods such as bananas, potatoes, and tomatoes and avoids salt substitutes containing potassium chloride can help maintain serum potassium levels within normal limits.⁸

The combination of SGLT-2 inhibitors with β-blockers, ACEI/ARB/ARNI, and MRA is supported by current guidelines, which recognize the potential to significantly reduce heart failure hospitalization and cardiovascular death in patients with HFrEF.¹ The aforementioned secondary analyzes of the EMPEROR and DAPA-HF trials provide insight into the impact of SGLT-2 inhibitors in reducing the risk of hyperkalemia, enhancing the management of heart failure, and reducing the decline in renal function. It emphasizes its role in mitigating and alleviating the decline in renal function. Optimize the use of MRA in patients.^6,7 It is important to remember that the risk of severe hyperkalemia has been reduced, but not eliminated. Regular monitoring of serum potassium levels, along with adherence to recommended dietary regimens, is essential to ensure optimal results and minimize the potential for adverse hyperkalemic events.

References

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Heart Failure Management Guidelines: Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063

2. Aldactone. Prescription information. Pfizer; 2023. Accessed February 25, 2024. https://labeling.pfizer.com/ShowLabeling.aspx?format=PDF&id=520

3. Palmer BF, Clegg DJ. SGLT-2 inhibition and renal potassium homeostasis. Clin Jam Sock Nephrol. 2024;19(3):399-405. doi:10.2215/CJN.00000000000000300

4. Ferreira JP, Zanado F, Pocock SJ, et al. Interaction of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-Reduced. J Am Col Cardiol, 2021;77(11):1397-1407. doi:10.1016/j.jacc.2021.01.044

5. Ferreira JP, Zanado F, Butler J Empagliflozin and serum potassium in other heart failure: analysis from EMPEROR-Pooled. [published correction appears in Eur Heart J. 2022 Jul 22;:]. euro heart j. 2022;43(31):2984-2993. doi:10.1093/eurheartj/ehac306

6. Shen L, Christensen SL, Bengtsson O, et al.Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC heart failure. 2021;9(4):254-264. doi:10.1016/j.jchf.2020.11.009

7. Neuen BL, Oshima M, Agarwal R, et al. Sodium-glucose cotransporter 2 inhibitors and the risk of hyperkalemia in patients with type 2 diabetes: a meta-analysis of individual participant data from randomized controlled trials. Circulation. 2022;145(19):1460-1470. doi:10.1161/CIRCULATIONAHA.121.057736

8. Heart Failure Diet: Potassium. cleveland clinic. Accessed. Last reviewed May 1, 2019. Accessed March 22, 2024. https://my.clevelandclinic.org/health/articles/17073-heart-failure-diet-potassium