Skip to main content
SpringerLink
Log in

MRAs may have lost their cornerstone position for heart failure treatment in the age of SGLT-2 inhibitors: A meta-analysis of randomized controlled trials

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Mineralocorticoid receptor antagonists (MRAs) are a cornerstone drug class for heart failure therapy. Several clinical studies have demonstrated its role in heart failure therapy. However, due to the recommendation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of heart failure, there is a lack of sufficient evidence regarding whether MRAs can continue to play a cornerstone role in heart failure treatment. A meta-analysis was performed on subgroups of the DAPA-HF and EMPEROR-Reduced trials. Using trial-level data, we performed a meta-analysis to assess the effects of SGLT-2 inhibitors and MRAs on various clinical endpoints of heart failure. The incidence of cardiovascular-related death or heart failure hospitalization was the primary outcome. In addition, we assessed cardiovascular death, all-cause death, heart failure hospitalization, renal outcomes, and hyperkalemia. This study has already been registered with PROSPERO, CRD42022385023. Compared with SGLT-2 inhibitor monotherapy, combined treatment did not demonstrate more significant advantages in terms of heart failure or cardiovascular death (RR = 1.00; 95% CI: 0.78–1.28), cardiovascular death (RR = 0.96; 95% CI: 0.61–1.52), heart failure hospitalization (RR = 0.92; 95% CI: 0.79–1.07), all-cause death (RR = 1.00; 95% CI: 0.63–1.59) and composite kidney endpoint (RR = 0.85; 95% CI: 0.49–1.46). Moreover, in comparison to SGLT-2 inhibitors, combined therapy increased the risk of moderate-severe hyperkalemia (blood potassium > 6.0 mmol/l) (RR = 4.13; 95% CI: 2.23–7.65). In patients with HFrEF who have started MRAs treatment, the addition of an SGLT-2 inhibitor provides significant clinical benefit. However, the addition of MRAs to SGLT-2 inhibitors to treat heart failure is not essential.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

eGFR:

Estimated glomerular filtration rate

RR:

Rate ratio

CI:

Confidence interval

SGLT-2:

Sodium-glucose co-transporter-2

MRA:

Mineralocorticoid Receptor Antagonists

References

  1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128

    Article  CAS  PubMed  Google Scholar 

  2. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N et al (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377(7):644–657

    Article  CAS  PubMed  Google Scholar 

  3. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A et al (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380(4):347–357

    Article  CAS  PubMed  Google Scholar 

  4. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM et al (2019) Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380(24):2295–2306

    Article  CAS  PubMed  Google Scholar 

  5. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B et al (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction [published correction appears in N Engl J Med 348(22):2271]. N Engl J Med 348(14):1309–1321

  6. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H et al (2011) Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 364(1):11–21

    Article  CAS  PubMed  Google Scholar 

  7. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A et al (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341(10):709–717

  8. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA et al (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381(21):1995–2008

    Article  CAS  PubMed  Google Scholar 

  9. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P et al (2020) Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 383(15):1413–1424

    Article  CAS  PubMed  Google Scholar 

  10. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G et al (2020) SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 396(10254):819–829

    Article  PubMed  Google Scholar 

  11. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM et al (2022) 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 [published correction appears in Circulation. 2022 May 3;145(18):e1033] [published correction appears in Circulation. 2022 Sep 27;146(13):e185]. Circulation 145(18):e895–e1032

  12. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM et al (2017) 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. Circulation 136(6):e137–e161

  13. Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, Pedro Ferreira J, Zannad F et al (2020) Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 396(10244):121–128

    Article  CAS  PubMed  Google Scholar 

  14. Vaduganathan M, Docherty KF, Claggett BL, Jhund PS, de Boer RA, Hernandez AF et al (2022)  SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials [published correction appears in Lancet. 2023 Jan 14;401(10371):104]. Lancet 400(10354):757–767

  15. Ferreira JP, Zannad F, Pocock SJ, Anker SD, Butler J, Filippatos G et al (2021) Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced. J Am Coll Cardiol 77(11):1397–1407

    Article  CAS  PubMed  Google Scholar 

  16. Shen L, Kristensen SL, Bengtsson O, Böhm M, de Boer RA, Docherty KF et al (2021) Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 9(4):254–264

    Article  PubMed  Google Scholar 

  17. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JPA et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H et al (2013) Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94–8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J 34(31):2453–2463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tromp J, Ouwerkerk W, van Veldhuisen DJ, Hillege HL, Richards AM, van der Meer P et al (2022) A systematic review and network meta-analysis of pharmacological treatment of heart failure with reduced ejection fraction [published correction appears in JACC Heart Fail. 2022 Apr;10(4):295–296]. JACC Heart Fail 10(2):73–84

  20. De Marzo V, Savarese G, Tricarico L, Hassan S, Iacoviello M, Porto I et al (2022) Network meta-analysis of medical therapy efficacy in more than 90,000 patients with heart failure and reduced ejection fraction. J Intern Med 292(2):333–349

    Article  PubMed  PubMed Central  Google Scholar 

  21. Vardeny O, Claggett B, Anand I, Rossignol P, Desai AS, Zannad F et al (2014) Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail 7(4):573–579

    Article  CAS  PubMed  Google Scholar 

  22. Vardeny O, Wu DH, Desai A, Rossignol P, Zannad F, Pitt B et al (2012) Influence of baseline and worsening renal function on efficacy of spironolactone in patients With severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol 60(20):2082–2089

    Article  CAS  PubMed  Google Scholar 

  23. Rossignol P, Dobre D, McMurray JJ, Swedberg K, Krum H, van Veldhuisen DJ et al (2014) Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail 7(1):51–58

    Article  CAS  PubMed  Google Scholar 

  24. Arima S, Kohagura K, Xu HL, Sugawara A, Abe T, Satoh F et al (2003) Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol 14(9):2255–2263

    Article  CAS  PubMed  Google Scholar 

  25. Lopaschuk GD, Verma S (2020) Mechanisms of cardiovascular benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: a state-of-the-art review. JACC Basic Transl Sci 5(6):632–644

    Article  PubMed  PubMed Central  Google Scholar 

  26. Griffin M, Rao VS, Ivey-Miranda J, Fleming J, Mahoney D, Maulion C et al (2020) Empagliflozin in heart failure: diuretic and cardiorenal effects. Circulation 142(11):1028–1039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M et al (2021) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. 2021 Oct 14]. Eur Heart J 42(36):3599–3726

  28. Dekkers CCJ, Sjöström CD, Greasley PJ, Cain V, Boulton DW, Heerspink HJL (2019) Effects of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes. Diabetes Obes Metab 21(12):2667–2673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A et al (2014) Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129(5):587–597

    Article  CAS  PubMed  Google Scholar 

  30. Eickhoff MK, Dekkers CCJ, Kramers BJ, Laverman GD, Frimodt-Møller M, Jørgensen NR et al (2019) Effects of dapagliflozin on volume status when added to renin-angiotensin system inhibitors. J Clin Med 8(6):779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zanchi A, Burnier M, Muller ME, Ghajarzadeh-Wurzner A, Maillard M, Loncle N et al (2020) Acute and chronic effects of SGLT2 inhibitor empagliflozin on renal oxygenation and blood pressure control in nondiabetic normotensive subjects: a randomized, placebo-controlled trial. J Am Heart Assoc 9(13):e016173

  32. Isshiki M, Sakuma I, Hayashino Y, Sumita T, Hara K, Takahashi K et al (2020) Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration. Endocr J 67(11):1127–1138

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was supported by the Natural Science Foundation of China (no. 81700321).

Author information

Author notes

  1. Xiangfeng Guan and Ju Zhang contributed equally.

Authors and Affiliations

  1. School of Clinical Medicine, Affiliated Hospital of Weifang Medical University, Weifang Medical University, Weifang, 261053, China

    Xiangfeng Guan, Ju Zhang, Shuting Chang & Tianlong Guo

  2. Department of Emergency, Zibo Central Hospital Affiliated to Binzhou Medical College, No. 10, South Shanghai Road, Zibo, 255000, China

    Guangxin Chen

  3. Department of Cardiology, Zibo Central Hospital Affiliated to Binzhou Medical College, No. 10, South Shanghai Road, Zibo, 255000, China

    Guanzhao Zhang, Zifan Nie, Wenhao Liu, Yunhe Zhao & Bo Li

Authors
  1. Xiangfeng Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ju Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guangxin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guanzhao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuting Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zifan Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenhao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tianlong Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yunhe Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XG and JZ has participated in study design, literature search, data collection, data analysis/interpretation, and drafting of the manuscript. GC, GZ and SC participated in content guidance and critical revision of the paper for important intellectual content. ZN, WL and TG participated in literature search and revision. YZ and BL supervised the work and revised the article critically. All authors have read and approved the submission of the manuscript, which has not been published and is not being considered for publication elsewhere in whole or part in any language.

Corresponding authors

Correspondence to Yunhe Zhao or Bo Li.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethics approval and consent to participate

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 68 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guan, X., Zhang, J., Chen, G. et al. MRAs may have lost their cornerstone position for heart failure treatment in the age of SGLT-2 inhibitors: A meta-analysis of randomized controlled trials. Heart Fail Rev 28, 1427–1436 (2023). https://doi.org/10.1007/s10741-023-10330-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-023-10330-5

Keywords

Search

Navigation