Influence of MRA use on benefit of SGLT2i in HFpEF

Mineralocorticoid Receptor Antagonists and Empagliflozin in Patients With Heart Failure and Preserved Ejection Fraction

Literature - Ferreira JP, Butler J, Zannad F, et al. - J Am Coll Cardiol. 2022 Mar 29;79(12):1129-1137. doi: 10.1016/j.jacc.2022.01.029

Introduction and methods


While mineralocorticoid receptor antagonists (MRAs) are recommended in patients with HFrEF to reduce hospitalization for HF and mortality [1,2], the MRA spironolactone has yielded mixed results in patients with HFp EF, supposedly due to regional differences [3-8]. Nevertheless, MRAs are regularly prescribed to the latter group.

Studies in HFrEF patients have suggested that SGLT2 inhibitors are effective regardless of MRA therapy and can diminish hyperkalemia and MRA discontinuation rates [9,10]. In the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the SGLT2 inhibitor empagliflozin reduced cardiovascular mortality or HF hospitalization (–21%) and first and recurrent HF hospitalizations (–27%) in HFpEF patients, with no significant effect on mortality [11].

Aim of the study

In a prespecified secondary analysis of the EMPEROR-Preserved, the influence of background MRA use on the efficacy and safety of empagliflozin in HFpEF patients was investigated.



In this multicenter, international, randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, 5988 HFpEF patients were randomized (1:1 ratio) to receive empagliflozin 10 mg/day or placebo. Patients needed to meet HFpEF criteria (NYHA class II-IV symptoms for ≥3 months, LVEF >40%), show elevated NT-proBNP levels, and have evidence of structural heart disease or documented HF hospitalizations within 12 months. MRA use at baseline was not a stratification variable. 2244 Patients (37.5%) were taking MRAs at baseline .


The primary endpoint was time to first event of a composite outcome of adjudicated cardiovascular death or HF hospitalization. The first secondary endpoint was the occurrence of all adjudicated HF hospitalizations (including first and recurrent events), and the second secondary endpoint was the analysis of the slope of the change in eGFR.

Main results

First HF hospitalization or cardiovascular death

  • The effect of empagliflozin to reduce the primary composite outcome was not significantly different between MRA nonusers (hazard ratio (HR): 0.73 [95% CI: 0.62-0.87]) and MRA users (HR: 0.87 [95% CI: 0.71-1.06]) (interaction P = 0.22).
  • For first HF hospitalization, empagliflozin was more effective in MRA nonusers (HR: 0.60 (95% CI: 0.49-0.75]) than in MRA users (HR: 0.86 [95% CI: 0.68-1.09]) (interaction P = 0.032).
  • The nonsignificant effect of empagliflozin on cardiovascular death was not modified by MRA use at baseline: HR for MRA nonusers was 0.94 (95% CI: 0.74-1.18) and for MRA users 0.86 (95% CI: 0.64-1.16) (interaction P = 0.66).

Total HF hospitalizations

  • The effect of empagliflozin to reduce the first secondary outcome was greater in MRA nonusers (HR: 0.60 [95% CI: 0.47-0.77]) than in MRA users (HR: 0.90 [95% CI: 0.68-1.19]) (interaction P = 0.038).
  • This was even more evident in the subgroup of patients with LVEF ≥50%: HR for MRA nonusers was 0.64 (95% CI: 0.48-0.85) and for MRA users 1.19 (95% CI: 0.83-1.71) (interaction P = 0.009).

eGFR slope

  • The effect of empagliflozin to reduce the second secondary outcome was not significantly different between MRA nonusers (eGFR slope: +1.50 mL/min per 1.73 m2) and MRA users (eGFR slope: +1.13 mL/min per 1.73 m2) (interaction P = 0.23).

Additional results

  • Empagliflozin reduced the risk of hyperkalemia or initiation of potassium binder prescription, regardless of MRA use: HR for MRA nonusers was 0.90 (95% CI: 0.69-1.19) and for MRA users 0.74 (95% CI: 0.56-0.96) (interaction P = 0.29).
  • Empagliflozin did not significantly change the initiation or discontinuation of MRAs during follow-up.


Baseline MRA use had no significant influence on the reduction of the primary composite outcome by empagliflozin in HFpEF patients, nor on reducing the hyperkalemia rate. HFpEF patients not taking MRA treatment at baseline benefited more from the effect of empagliflozin to reduce all HF hospitalizations than MRA users. The authors state that “[a]lthough SGLT2 inhibitors may modestly lower eGFR after their initiation, aggregate results from numerous trials suggest that clinicians should not withhold these agents merely because of concerns about hyperkalemia; in fact, SGLT2 inhibitors may prevent hyperkalemia, which may enable the use of MRAs in patients with HFpEF.”


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2. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11–21.

3. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–1392.

4. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131(1):34–42.

5. De Denus S, O’Meara E, Desai AS, et al. Spironolactone metabolites in TOPCAT—new insights into regional variation. N Engl J Med. 2017;376(17):1690–1692.

6. Ferreira JP, Girerd N, Rossignol P, Zannad F. Geographic differences in heart failure trials. Eur J Heart Fail. 2015;17(9):893–905.

7. Solomon SD, Claggett B, Lewis EF, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J. 2016;37(5):455–462.

8. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70(6):776–803.

9. 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.

10. Shen L, Kristensen SL, Bengtsson O, et al. Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. J Am Coll Cardiol HF. 2021;9(4): 254–264.

11. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451–1461.

Find this article online at J Am Coll Cardiol.

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