ESC 2022: Evidence of SGLT2i Effectiveness in HFrEF Treatment is Growing: How to Integrate Them into Routine Practice?

Patients with HFrEF are Often Not Treated According to Guidelines

Treatment options for patients with HFrEF have significantly improved over the past 30 years. As a result, cardiovascular (CV) deaths and heart failure (HF) hospitalizations have decreased. Guidelines [1, 2] emphasize that for maximum CV benefit, it is crucial for HFrEF patients to promptly initiate all four fundamental pillars of therapy:

• angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitor (ACEi/ARB/ARNI)
• beta-blocker
• mineralocorticoid receptor antagonist (MRA)
• sodium-glucose co-transporter 2 inhibitor (SGLT2i, i.e., gliflozin)

Key characteristics to consider in managing HFrEF are highlighted by the Heart Failure Association of the European Society of Cardiology (HFA-ESC) consensus. All the aforementioned drug groups are suitable for patients with blood pressure >90/60 mmHg, normal heart rate, regardless of chronic kidney disease, and regardless of the presence of atrial fibrillation [3]. Inadequate implementation of recommendations for HFrEF patients is associated with increased mortality [4].

Implementing SGLT2i in HFrEF Practice − Experience from the United Kingdom

The EMPEROR-Reduced study demonstrated the ability of empagliflozin to significantly reduce the relative risk of CV death and HF hospitalization by 25% in HFrEF patients [5]. Professor Andrew Coats from Warwick University in Coventry shared his experience with one of his patients.

A 71-year-old man was diagnosed with HFrEF 18 months ago. According to the NYHA classification, he is in class II, with an EF of 27%, is a former smoker, without type 2 diabetes, and had a significant myocardial infarction without residual ischemia, with no aneurysm detected on echocardiography. The patient exhibited mild HF symptoms, including shortness of breath and fatigue during exertion, progressively worsening over time. Upon examination, his blood pressure was 130/95 mmHg, BMI 28 kg/m², no peripheral edema observed, and lab results showed an estimated glomerular filtration rate (eGFR) of 40 ml/min/1.73 m² and a potassium concentration of 4.7 mmol/L. He was taking bisoprolol 1.25 mg once daily and valsartan 80 mg twice daily.

In line with the guidelines, empagliflozin 10 mg once daily was added to his current medication; blood pressure reduced to 125/90 mmHg, eGFR to 35 ml/min/1.73 m², and potassium concentration to 4.5 mmol/L. The choice was based on the fact that gliflozins are administered once daily, do not require dose titration, and empagliflozin can be prescribed until eGFR drops to 20 ml/min/1.73 m² according to the SPC [6]. Additionally, data from the EMPEROR-Reduced study showed that empagliflozin provided early and sustained benefits in CV outcomes – statistical significance was achieved 12 days post-randomization and sustained from day 34 [5].

Adjusting Existing Medication

The speaker emphasized that medications not providing CV benefits based on evidence should be removed from the HFrEF treatment regimen. For chronic HFrEF patients, there is a reason to switch from an ARB to an ARNI: ARBs are only recommended for patients who cannot tolerate ACEi or ARNI due to severe adverse effects. No ARB has yet reduced all-cause mortality in clinical studies [1].

After changing the medication, the patient was taking bisoprolol 1.25 mg, sacubitril/valsartan 49/51 mg, and empagliflozin 10 mg once daily. Upon examination, blood pressure was 120/86 mmHg, no peripheral edema was observed, and lab results showed an eGFR of 38 ml/min/1.73 m² and potassium concentration of 4.6 mmol/L.

Missing Pillar

Guidelines emphasize the importance of promptly initiating all four core drug groups forming the foundation of HFrEF therapy [1, 2]. If initiated simultaneously, starting with lower doses is recommended; however, during sequential initiation, target doses do not need to be reached before starting subsequent medication [2].

One primary concern when starting MRA in HFrEF patients is hyperkalemia – if it occurs, MRA is usually discontinued. According to the EMPEROR-Reduced study, empagliflozin does not increase the risk of hyperkalemia irrespective of MRA use. Among participants taking MRA at study entry, the empagliflozin arm had a 22% lower likelihood of discontinuing MRA due to hyperkalemia [7].

Therefore, spironolactone 25 mg once daily was added to the current medication, and the patient is now taking all four pillars of HFrEF foundational therapy. This medication adjusted blood pressure to 120/80 mmHg, eGFR to 40 ml/min/1.73 m², and potassium levels to 4.8 mmol/L.

What's Next?

The next steps for this case patient, fully aligned with the guidelines, will be the titration of beta-blockers, ARNI, and MRA to target doses.

Eva Srbová
editor at proLékaře.cz

Sources:
1. McDonagh T. A., Metra M., Adamo M. et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42 (36): 3599–3726, doi: 10.1093/eurheartj/ehab368.
2. Heidenreich P. A., 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. J Am Coll Cardiol 2022; 79 (17): e263–e421, doi: 10.1016/j.jacc.2021.12.012.
3. Rosano G. M. C., Moura B., Metra M. et al. Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2021; 23 (6): 872–881, doi: 10.1002/ejhf.2206.
4. McCullough P. A., Mehta H. S., Barker C. M. et al. Mortality and guideline-directed medical therapy in real-world heart failure patients with reduced ejection fraction. Clin Cardiol 2021; 44 (9): 1192–1198, doi: 10.1002/clc.23664.
5. Packer M., Anker S. D., Butler J. et al. Cardiovascular and renal Outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383 (15): 1413–1424, doi: 10.1056/NEJMoa2022190.
6. SPC Jardiance. Available at: www.ema.europa.eu/en/documents/product-information/jardiance-epar-product-information_cs.pdf
7. Ferreira J. P., Zannad F., Pocock S. J. 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.
8. Butler J. Introduction, recap and overview of evidence for SGLT2 inhibitors in HFrEF. SGLT2 inhibitors in practice (part 3): The case for early intervention in HFrEF. ESC 2022, Barcelona, 2022 Aug 27.
9. Coats A. Implementing an SGLT2i for HFrEF treatment in my practice. SGLT2 inhibitors in practice (part 3): The case for early intervention in HFrEF. ESC 2022, Barcelona, 2022 Aug 27.