Cited by 5,206Heart Failure Treatment and ManagementChronic Kidney Disease and DiabetesDiabetes Treatment and Management

Cardiovascular and renal outcomes with empagliflozin in heart failure

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Packer, Milton, Anker, Stefan D., Butler, Javed, Filippatos, Gerasimos, Pocock, Stuart J., Carson, Peter, Januzzi, James, Verma, Subodh +31 more·2020·New England Journal of Medicine

Abstract

BACKGROUNDSodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes.More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODSIn this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy.The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTSDuring a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001).The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes.The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001).The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28ml per minute per 1.73 m 2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes.Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONSAmong patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes.(Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.govnumber, NCT03057977.

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Crossref · 10.1056/nejmoa2022190

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  • SGLT2 inhibitors are safe and effective at eGFR levels of >20 mL/min/1.73m2.

    “Subgroup analyses from DAPA-CKD (117) and analyses from the EMPEROR heart failure trials suggest that SGLT2 inhibitors are safe and effective at eGFR levels of >20 mL/min/1.73m 2 .”

    From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [119]

    The Results and Discussion report cardiovascular and renal benefits with empagliflozin in patients with heart failure, and the Discussion says several safety concerns were not evident. Our copy does not establish that these findings hold specifically down to an eGFR just above 20 mL/min/1.73 m², or for SGLT2 inhibitors as a class; searches for that threshold and low-eGFR subgroup findings did not locate supporting passages. (LLM, conf=0.85)

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  • Direct evidence for safety and benefit of SGLT2i in eGFR 20-29 is provided by the DAPA-CKD, SCORED, EMPEROR-Reduced, and EMPEROR-Preserved trials, which enrolled such participants by design.

    “Direct evidence is provided by the DAPA-CKD, SCORED, EMPEROR-Reduced, and EMPEROR-Preserved trials, which enrolled such participants by design.”

    From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [101]

    The paper reports benefits and safety outcomes from EMPEROR-Reduced, and its renal-outcome definition explicitly accounts for patients with baseline eGFR below 30 (Table 1 notes; Discussion). But our copy does not establish that the trial enrolled patients specifically at eGFR 20–29 by design or report outcomes for that subgroup. It also does not provide direct evidence from the other three named trials. (LLM, conf=0.82)

    Experimental — accuracy not yet measured
  • SGLT2i have been studied among patients without T2D who have CKD in the DAPA-CKD trial (and the soon-to-be-published EMPA-KIDNEY trial) or who have heart failure (in the DAPA-HF, EMPEROR-Reduced, and EMPEROR-Preserved trials) and did not confer any increased risk of severe hypoglycemia or diabetic ketoacidosis among individuals without T2D.

    “However, notably, SGLT2i have been studied among patients without T2D who have CKD in the DAPA-CKD trial (and the soonto-be-published EMPA-KIDNEY trial) or who have heart failure (in the DAPA-HF, EMPEROR-Reduced, and EMPEROR-Preserved trials) and did not confer any increased risk of severe hypoglycemia or diabetic ketoacidosis among individuals without T2D.”

    From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [101]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • In EMPEROR-Preserved and EMPEROR-Reduced, efficacy was seen at eGFR >20 mL/min/1.73m2 in people with heart failure.

    “enrollment criteria included eGFR >60 mL/min/1.73m 2 , but efficacy was seen at eGFR >20 mL/min/1.73m 2 in people with heart failure.”

    From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [135]

    The Abstract reports cardiovascular benefit with empagliflozin in EMPEROR-Reduced, and the baseline-characteristics passage reports that 48% of participants had eGFR below 60 mL/min/1.73 m². But our copy does not establish efficacy specifically down to eGFR >20. The Statistical Analysis section mentions EMPEROR-Preserved only as a parallel trial for a future analysis; it does not report that trial’s efficacy results. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • SGLT2 inhibitors reduce the incidence of heart failure and improve heart failure-related outcomes, including hospitalization for heart failure and heart failure-related symptoms, in people with diabetes with preserved or reduced ejection fraction.

    “SGLT2 inhibitors reduce the incidence of heart failure and improve heart failurerelated outcomes, including hospitalization for heart failure and heart failure-related symptoms, in people with diabetes with preserved or reduced ejection fraction (250,(255)(256)(257)(298)(299)(300)(301)(302)(303)(304)(305)(306).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [303]

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  1. [5]5. Packer M, Butler J, Filippatos GS, et al. Evaluation of the effect of sodium- glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced tri- al. Eur J Heart Fail 2019; 21: 1270-8.

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Authors
Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson, P., Januzzi, J., Verma, S., Tsutsui, H., Brueckmann, M., Jamal, W., Kimura, K., Schnee, J., Zeller, C., Cotton, D., Bocchi, E., Böhm, M., Choi, D.-J., Chopra, V., Chuquiure, E., Giannetti, N., Janssens, S., Zhang, J., Gonzalez Juanatey, J. R., Kaul, S., Brunner-La Rocca, H.-P., Merkely, B., Nicholls, S. J., Perrone, S., Pina, I., Ponikowski, P., Sattar, N., Senni, M., Seronde, M.-F., Spinar, J., Squire, I., Taddei, S., Wanner, C., & Zannad, F.
Affiliations
  • University of Leicester (GB)
  • Harvard University (US)
  • St. Michael's Hospital (CA)
  • Kyushu University (JP)
  • Boehringer Ingelheim (Germany) (DE)
  • Seoul National University (KR)
  • From Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.); Imperial College (M.P.) and the Department of Medical Statistics, London School of Hygiene and Tropical Medicine (S.J.P.), London, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow (N.S.), and the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Biomedical Research Centre, Glenfield Hospital, Leicester (I.S.) — all in the United...
  • Cedars-Sinai Medical Center (US)
  • University of Pisa (IT)
Venue
New England Journal of Medicine
Published
2020-10-08
Volume
383
Issue
15
Pages
1413-1424
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
OpenAlex
W3081830235
Cited by
5,206
References
10
Citations by year
2026: 638 · 2025: 757 · 2024: 820 · 2023: 965 · 2022: 936 · 2021: 910 · 2020: 163 · 2019: 2 · 2018: 1 · 2014: 1 · 2013: 1
FWCI
459.86
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • HAL (submittedVersion, other-oa)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Lirias (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Boehringer Ingelheim
  • Eli Lilly
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
empagliflozin, SGLT2 inhibitors, heart failure with reduced ejection fraction, cardiovascular mortality, hospitalization for worsening heart failure, renal outcomes, estimated glomerular filtration rate decline, genital tract infection, diabetes status, EMPEROR-Reduced trial
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Aged, Benzhydryl Compounds, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Glomerular Filtration Rate, Glucosides, Heart Failure, Hospitalization, Humans, Male, Middle Aged, Stroke Volume, Proportional Hazards Models, Disease Progression, Renal Insufficiency, Chronic

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