SGLT-2 Inhibitors Associated with Reduced Hyperkalemia in Patients With Heart Failure

Sodium glucose co-transporter-2 (SGLT-2) inhibitors are one of the 4 pillars of evidenced-based pharmacotherapy for patients with heart failure with reduced ejection fraction (HFrEF). They are used in combination with the other 3 pillars: ß-blockers, angiotensin converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitors (ACEI/ARB/ARNIs), and mineralocorticoid receptor antagonists (MRAs). Guidelines strongly advocate for the combined use of these 4 medication classes with a class I recommendation, backed by compelling evidence proving significant reductions in both cardiovascular deaths and heart failure hospitalizations. SGLT-2 inhibitors are also now recommended for patients with heart failure with preserved ejection fraction (HFpEF) with a class IIa recommendation, with ARBs, ARNIs, and MRAs assigned a class IIb recommendation.¹

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Hyperkalemia is a known adverse effect of ACEI/ARB/ARNIs and MRAs. Moreover, individuals diagnosed with heart failure often have concurrent chronic kidney disease, making them particularly susceptible to hyperkalemia. The heart failure guidelines recommend initiation of MRAs in patients with the following criteria: serum potassium less than 5 mEq/L, serum creatinine ≤ 2mg/dl or ≤ 2.5mg/dl in women and men respectively, and an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2.^1,2 This cautious approach has led to some apprehension among prescribers.

SGLT-2 inhibitors have a dual diuretic and natriuretic effect. By enhancing distal sodium and water excretion, they naturally regulate and promote potassium excretion.³ Recent post-hoc analyses of clinical trials have explored the effect of SGLT-2 inhibitors on mitigating the risk of hyperkalemia in patients with heart failure.

In the EMPEROR-Reduced trial (NCT03057977), the SGLT-2 inhibitor empagliflozin (Jardiance; Boehringer Ingelheim) was compared to placebo in patients with HFrEF on standard heart failure medications.⁴ The impact of empagliflozin on the rate of hyperkalemia in patients concurrently using MRAs was examined in a secondary analysis. Patients were randomized to receive either placebo or empagliflozin at a dose of 10 mg daily. The primary endpoint, comprising adjudicated cardiovascular death or hospitalization for heart failure, was analyzed as the time to first event and was significantly reduced with empagliflozin. Among the 3730 patients enrolled, 71% were utilizing an MRA at baseline.⁴

The findings showed empagliflozin's consistent efficacy in reducing the primary endpoint, irrespective 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]. Furthermore, the empagliflozin group experienced fewer hyperkalemia events compared to the placebo group, with a notable, albeit non-statistically significant, reduction in severe hyperkalemia defined as potassium > 6 mmol/L [HR of 0.7 (0.47-1.04)]. The effect of empagliflozin on severe hyperkalemia was consistent between patients taking an MRA at baseline and those that did not (P = 0.56).⁴

Empagliflozin also demonstrated renal protective effects, slowing the decline in eGFR in both MRA users and non-users. It is important to note that patients who were receiving an MRA at baseline and who were then randomized to the empagliflozin group showed a 22% lower likelihood of discontinuing or interrupting MRA treatment compared to those who started with an MRA and were randomized to the placebo group.⁴ This study underscores empagliflozin's potential to mitigate hyperkalemia, preserve renal function, and promote continuation of MRAs.

A pooled analysis of both the EMPEROR-Reduced and EMPEROR-Preserved (patients with HFpEF; NCT03057951) trials provided further evidence of the significant effect of empagliflozin on hyperkalemia.⁵ Empagliflozin reduced hyperkalemia versus 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]. There was also a significant reduction in investigator reported hyperkalemia and initiation of potassium binders [HR 0.82 (0.71 – 0.95), p = 0.01], and this effect was consistent regardless of MRA use.⁵

The Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction trial (DAPA-HF; NCT03036124) added further depth to our understanding of the role of SGLT-2 inhibitors by also showing a significant reduction in the risk of worsening heart failure and cardiovascular death, similar to the EMPEROR trial.⁶ This trial enrolled 4744 patients aged 18 or older with a left ventricular ejection fraction of ≤ 40% and an elevated N-terminal pro-B-type natriuretic peptide, and randomized them to dapagliflozin 10 mg daily or placebo. Seventy one percent of patients in DAPA-HF were taking an MRA at baseline.⁶

Remarkably, the positive impact of dapagliflozin on the primary outcome—a composite of worsening heart failure, including unplanned hospitalizations or urgent visits requiring intravenous therapy for heart failure, or cardiovascular death—remained consistent across all patients, regardless of whether they were using MRAs. The hazard ratio was 0.74 (0.63-0.87) for patients using MRAs and 0.74 (0.57-0.95) for those not using MRAs. Additionally, dapagliflozin consistently reduced composite renal outcomes irrespective of MRA usage, highlighting its renal protective effects.⁶ The risk of hyperkalemia was also assessed, with findings mirroring those of the EMPEROR-Reduced trial. Patients concurrently using an MRA and dapagliflozin experienced fewer hyperkalemic events, particularly instances where serum potassium levels exceeded 6 mmol/L, with a HR of 0.50 (0.29–0.85).⁶

The potassium-lowering impacts of SGLT-2 inhibitors are also observed across other patient groups, as evidenced by a recent meta-analysis of randomized trials involving SGLT-2 inhibitors in patients with type 2 diabetes at elevated cardiovascular risk or those with chronic kidney disease.⁷ This analysis revealed a decreased risk of significant hyperkalemia (≥ 6 mmol/L) with a HR of 0.84 (0.76 – 0.93).⁷

It is important to note that the secondary analyses of the EMPEROR trials and DAPA-HF trial, suggesting reduced risk of clinically significant hyperkalemia,^6,7 are limited by their retrospective nature. Randomized controlled trials are needed to confirm these findings, but are unlikely to be performed; however, these findings are mechanistically plausible considering the mechanisms of action of SGLT-2 inhibitors.

In addition to pharmacological interventions in patients deemed to be at elevated risk of hyperkalemia, dietary modifications can also mitigate this risk. A low potassium diet that restricts the intake of potassium-rich foods such as bananas, potatoes, and tomatoes, and avoiding salt substitutes that contain potassium chloride can help maintain serum potassium levels within the normal limits.⁸

The use of SGLT-2 inhibitors alongside ß-blockers, ACEI/ARB/ARNIs, and MRAs is now supported by current guidelines recognizing the potential to significantly reduce heart failure hospitalizations and cardiovascular death in patients with HFrEF.¹ The aforementioned secondary analyses of the EMPEROR trials and DAPA-HF trial have provided insight into the impact of SGLT-2 inhibitors to reduce the risk of hyperkalemia and highlight their role to enhance the management of heart failure, reduce the decline in renal function, and optimize the use of MRAs in patients.^6,7 It is crucial to remember that although the risk of significant hyperkalemia is mitigated, it has not been eliminated. Regular monitoring of serum potassium levels, in conjunction with adherence to dietary recommendations, is essential to ensure optimal outcomes and minimize the potential for adverse hyperkalemic events.

References

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A 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. Prescribing 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 Kidney Potassium Homeostasis. Clin J Am Soc Nephrol. 2024;19(3):399-405. doi:10.2215/CJN.0000000000000300

4. 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(11):1397-1407. doi:10.1016/j.jacc.2021.01.044

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

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(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 Risk of Hyperkalemia in People 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 01, 2019. Accessed March 22, 2024. https://my.clevelandclinic.org/health/articles/17073-heart-failure-diet-potassium