Evidence map›Paper›PMID 34605192›Full record

ArticleESC heart failure2021

Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial.

David Fitchett, Silvio E Inzucchi, Bernard Zinman, Christoph Wanner, Martin Schumacher, Claudia Schmoor, Kristin Ohneberg, Anne Pernille Ofstad, Afshin Salsali, Jyothis T George and 4 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in ESC heart failure, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
49citing papers in PubMed, 4 pooled it
9.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

49 citing papers in PubMed, 4 syntheses or guidelines pooled it, 85 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Trial
  6. Trial
  7. Canagliflozin and iron metabolism in the CREDENCE trial.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025 · on this map
    Trial
  8. How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2024
    Trial
  9. Trial
  10. Trial
  11. Trial
  12. Trial
  13. Trial
  14. Trial
  15. Trial
  16. Review
  17. Review
  18. Review
  19. Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 9 institutions in 6 countries.

David FitchettDivision of Cardiology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Silvio E InzucchiSection of Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Bernard ZinmanLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Christoph WannerDepartment of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg, Germany.
Martin SchumacherInstitute for Medical Biometry and Statistics and Clinical Trials Unit, Faculty of Medicine, and Medical Center, University of Freiburg, Freiburg, Germany.
Claudia SchmoorInstitute for Medical Biometry and Statistics and Clinical Trials Unit, Faculty of Medicine, and Medical Center, University of Freiburg, Freiburg, Germany.
Kristin OhnebergInstitute for Medical Biometry and Statistics and Clinical Trials Unit, Faculty of Medicine, and Medical Center, University of Freiburg, Freiburg, Germany.
Anne Pernille OfstadBoehringer Ingelheim Norway Ks, Asker, Norway.
Afshin SalsaliBoehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
Jyothis T GeorgeBoehringer Ingelheim International GmbH, Ingelheim, Germany.
Stefan HantelBoehringer Ingelheim International GmbH, Ingelheim, Germany.
Erich BluhmkiBoehringer Ingelheim International GmbH, Ingelheim, Germany.
John M LachinBiostatistics Center, The George Washington University, Rockville, MD, USA.
Faiez ZannadUniversite de Lorraine, INSERM, Centre d'Investigations Cliniques-1433 and INSERM U1116, CHRU Nancy, Lorraine, France.
Boehringer Ingelheim (China) · CNUniversity Medical Center Freiburg · DEUniversity of Toronto · CABoehringer Ingelheim (France) · FRBoehringer Ingelheim (Norway) · NOGeorge Washington University · USUniversitätsklinikum Würzburg · DEUniversité de Lorraine · FRYale University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

aimsIn the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death. METHODS AND

resultsA mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated.

conclusionsChanges in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.

Indexed as

Diabetes Mellitus, Type 2Heart FailureBenzhydryl CompoundsGlucosidesHumansBenzhydryl CompoundsempagliflozinGlucosidesDiabetesEmpagliflozinHeart failureMediation analysisSGLT2 inhibitor

Identifiers

PMID34605192
PMCPMC8712833
OpenAlexW3204839494

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.