Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial
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AIMS: In 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 RESULTS: A 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. CONCLUSIONS: Changes 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.
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Effects on the cardiometabolic profile may be effective in HFpEF.
“So, these findings validated the concept that effects on the cardiometabolic profile may be effective in HFpEF.12,13”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [12]
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Sodium-glucose co-transporter-2 (SGLT-2) inhibitors and uric acid: More good news!
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- Authors
- Fitchett, D., Inzucchi, S. E., Zinman, B., Wanner, C., Schumacher, M., Schmoor, C., Ohneberg, K., Ofstad, A. P., Salsali, A., George, J. T., Hantel, S., Bluhmki, E., Lachin, J. M., & Zannad, F.
- Affiliations
- St. Michael's Hospital (CA)
- Yale University (US)
- Mount Sinai Hospital (CA)
- Universitätsklinikum Würzburg (DE)
- University of Freiburg (DE)
- Boehringer Ingelheim (Norway) (NO)
- Boehringer Ingelheim (United States) (US)
- Boehringer Ingelheim (Germany) (DE)
- George Washington University (US)
- Inserm (FR)
- Corresponding author
- Fitchett, David
- ORCID
- Venue
- ESC Heart Failure
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-10-04
- Volume
- 8
- Issue
- 6
- Pages
- 4517-4527
- ISSN
- 2055-5822 (ISSN-L)
- PMC
- PMC8712833
- OpenAlex
- W3204839494
- Cited by
- 85
- References
- 37
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 13 · 2023: 27 · 2022: 19 · 2021: 2 · 2020: 1
- FWCI
- 11.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- ESC Heart Failure (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- Funders
- Boehringer Ingelheim
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- empagliflozin, heart failure hospitalization, heart failure mortality, mediation analysis, type 2 diabetes, established cardiovascular disease, hemoglobin, hematocrit, albumin, uric acid, albumin-creatinine ratio, SGLT2 inhibitors, EMPA-REG OUTCOME trial
- MeSH terms
- Benzhydryl Compounds, Diabetes Mellitus, Type 2, Glucosides, Heart Failure, Humans
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