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Research ArticleTools for Practice

Sodium-glucose cotransporter-2 inhibitors for heart failure with reduced ejection fraction

Jamie Falk, Jennifer Potter and Ricky D. Turgeon
Canadian Family Physician September 2021, 67 (9) 678; DOI: https://doi.org/10.46747/cfp.6709678
Jamie Falk
Associate Professor in the College of Pharmacy at the University of Manitoba in Winnipeg.
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Jennifer Potter
Family physician in Winnipeg.
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Ricky D. Turgeon
Assistant Professor in the Faculty of Pharmaceutical Sciences at the University of British Columbia in Vancouver.
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Clinical question

What is the role of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with chronic heart failure with reduced ejection fraction?

Bottom line

An SGLT2i reduces mortality, heart failure hospitalizations, and improves quality of life when added to other medications for heart failure with reduced ejection fraction—with or without diabetes. Compared with placebo, for every 100 patients treated with SGLT2i for about 1.5 years, about 2 fewer will die, roughly 4 fewer will be hospitalized for heart failure, and roughly 7 more will have improved quality of life.

Evidence

There were 2 industry-funded RCTs1,2 of patients with heart failure (and ejection fraction of ≤ 40%) (mainly class 2-3; 47% with diabetes; average systolic blood pressure = 122 mm Hg3). Differences are statistically significant unless indicated otherwise.

  • DAPA-HF trial1 (4744 patients treated with 10 mg of dapagliflozin daily): At 18 months, mortality was 12% versus 14% (placebo; number needed to treat [NNT] = 44). Heart failure hospitalization was 10% versus 13% (placebo; NNT = 27). At 8 months, 58% versus 51% (placebo) achieved minimal improvement in quality of life (≥ 5 points on a 100-point scale; NNT = 14). There was no difference in adverse events.

  • EMPEROR-Reduced trial2 (3730 patients treated with 10 mg of empagliflozin daily): At 16 months, mortality was 13% versus 14% (placebo); not statistically different. Heart failure hospitalization was 13% versus 18% (placebo; NNT = 20). Genital infection was an adverse event (1.7% vs 0.6% [placebo]; number needed to harm = 91).

  • In a meta-analysis4 including both trials, there was a reduction in mortality (NNT = 61) and heart failure hospitalization (NNT = 24). There was similar efficacy in those with or without diabetes, and in those treated with or without sacubitril-valsartan.

Context

  • Efficacy of SGLT2i was indirectly compared with other heart failure medications.5,6 For mortality, the relative risk reduction was about 13% (others 16%-35%), and for heart failure hospitalization was about 30% (others 20%-35%).

  • Unlike other heart failure medications, SGLT2i do not seem to cause statistically significant hypotension or electrolyte abnormalities.1,2,4

  • Canadian guidelines7 recommend SGLT2i for all patients with symptomatic heart failure, although the sequence was not specified (eg, whether to consider SGLT2i before sacubitril-valsartan).

  • Splitting 25 mg of empagliflozin in half (12.5 mg; trial dose is 10 mg) cuts cost in half (about $560/year).8

Implementation

All patients starting SGLT2i should receive education on sick day management (ie, pause SGLT2i when acutely ill and dehydrated) and be given written guidance.9 Similar to renin-angiotensin system blockers, starting SGLT2i acutely decreases estimated glomerular filtration rate (average 4 mL/min/1.73 m2), which does not require change to therapy2,7; reductions greater than 30%, which occur in less than 5% of patients starting SGLT2i, should prompt clinicians to hold SGLT2i, assess for and correct hypovolemia, and assess for potential use of nephrotoxic drugs.10

Notes

Tools for Practice articles in Canadian Family Physician are adapted from articles published on the Alberta College of Family Physicians (ACFP) website, summarizing medical evidence with a focus on topical issues and practice-modifying information. The ACFP summaries and the series in Canadian Family Physician are coordinated by Dr G. Michael Allan, and the summaries are co-authored by at least 1 practising family physician and are peer reviewed. Feedback is welcome and can be sent to toolsforpractice{at}cfpc.ca. Archived articles are available on the ACFP website: www.acfp.ca.

Footnotes

  • Competing interests

    None declared

  • The opinions expressed in Tools for Practice articles are those of the authors and do not necessarily mirror the perspective and policy of the Alberta College of Family Physicians.

  • This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to www.cfp.ca and click on the Mainpro+ link.

  • La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro de septembre 2021 à la page e247.

  • Copyright © the College of Family Physicians of Canada

References

  1. 1.↵
    1. McMurray JJV,
    2. Solomon SD,
    3. Inzucchi SE,
    4. Køber L,
    5. Kosiborod MN,
    6. Martinez FA, et al.
    Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008. Epub 2019 Nov 21.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Packer M,
    2. Anker SD,
    3. Butler J,
    4. Filippatos G,
    5. Pocock SJ,
    6. Carson P, et al.
    Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383(15):1413-24. Epub 2020 Aug 28.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Docherty KF,
    2. Jhund PS,
    3. Inzucchi SE,
    4. Køber L,
    5. Kosiborod MN,
    6. Martinez FA, et al.
    Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J 2020;41(25):2379-92.
    OpenUrlPubMed
  4. 4.↵
    1. Zannad F,
    2. Ferreira JP,
    3. Pocock SJ,
    4. Anker SD,
    5. Butler J,
    6. Filippatos G, et al.
    SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396(10254):819-29. Epub 2020 Aug 30.
    OpenUrlPubMed
  5. 5.↵
    1. Lindblad AJ,
    2. Allan GM.
    Aldosterone antagonists in systolic heart failure. Can Fam Physician 2014;60:e104.
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  6. 6.↵
    1. Sehn E,
    2. McDonald T,
    3. Lindblad AJ.
    Sacubitril-valsartan: novel therapy for heart failure. Can Fam Physician 2017;63:697 (Eng), 698 (Fr).
    OpenUrlFREE Full Text
  7. 7.↵
    1. McDonald M,
    2. Virani S,
    3. Chan M,
    4. Ducharme A,
    5. Ezekowitz JA,
    6. Giannetti N, et al.
    CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction. Can J Cardiol 2021;37(4):531-46.
    OpenUrl
  8. 8.↵
    1. Kolber M,
    2. Lee J,
    3. Allan GM,
    4. Korownyk CS,
    5. Nickonchuck T.
    Price comparison of commonly prescribed pharmaceuticals in Alberta 2019. Edmonton, AB: Alberta College of Family Physicians; 2019. Available from: https://acfp.ca/wp-content/uploads/2019/02/ACFPPricingDoc2019.pdf. Accessed 2021 Aug 5.
  9. 9.↵
    Heart failure sick days. Saskatoon, SK: RxFiles; 2020. Available from: https://www.rxfiles.ca/rxfiles/uploads/documents/Heart-Failure-Sick-Days.pdf. Accessed 2021 Jun 12.
  10. 10.↵
    1. Oshima M,
    2. Jardine MJ,
    3. Agarwal R,
    4. Bakris G,
    5. Cannon CP,
    6. Charytan DM, et al.
    Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice. Kidney Int 2021;99(4):999-1009. Epub 2020 Dec 11.
    OpenUrl
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Canadian Family Physician: 67 (9)
Canadian Family Physician
Vol. 67, Issue 9
1 Sep 2021
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Sodium-glucose cotransporter-2 inhibitors for heart failure with reduced ejection fraction
Jamie Falk, Jennifer Potter, Ricky D. Turgeon
Canadian Family Physician Sep 2021, 67 (9) 678; DOI: 10.46747/cfp.6709678

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Sodium-glucose cotransporter-2 inhibitors for heart failure with reduced ejection fraction
Jamie Falk, Jennifer Potter, Ricky D. Turgeon
Canadian Family Physician Sep 2021, 67 (9) 678; DOI: 10.46747/cfp.6709678
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