Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial

Jesper Jensen, Massar Omar, Caroline Kistorp, Christian Tuxen, Ida Gustafsson, Lars Køber, Finn Gustafsson, Jens Faber, Mariam Elmegaard Malik, Emil Loldrup Fosbøl, Niels Eske Bruun, Julie Lyng Forman, Lars Thorbjørn Jensen, Jacob Eifer Møller, Morten Schou*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

Background: SGLT2 inhibitors are a promising treatment option in patients with heart failure and reduced ejection fraction. We aimed to investigate the effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate (GFR) in patients with heart failure and reduced ejection fraction. Methods: Empire HF Renal was a prespecified substudy of the investigator-initiated, double-blind, randomised, placebo-controlled Empire HF trial. The study was done at Herlev and Gentofte University Hospital (Herlev, Denmark), with patients recruited from four Danish heart failure outpatient clinics. Patients with New York Heart Association class I–III symptoms, with a left ventricular ejection fraction of 40% or lower, and on guideline-directed heart failure therapy were randomly assigned (1:1) to receive either oral empagliflozin 10 mg or matched placebo once daily for 12 weeks. The allocation sequence was computer-generated. Patients and study investigators were masked to treatment allocation. The coprimary prespecified renal outcomes were the between-group difference in the changes in estimated extracellular volume, estimated plasma volume, and measured GFR from baseline to 12 weeks. All analyses were done in the intention-to-treat population (apart from safety analyses, which were done in patients who received at least one dose of study drug), with no interim analyses done during the trial. The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585, and EudraCT, 2017-001341-27. Findings: Between June 29, 2017, and July 15, 2019, we assessed 391 patients for eligibility, of whom 120 (31%) were randomly assigned to empagliflozin or placebo, including 105 (88%) without diabetes. In intention-to-treat analyses, 60 (100%) patients in the empagliflozin group and 59 (98%) patients in the placebo group were included for estimated extracellular volume and estimated plasma volume, and 59 (98%) patients in the empagliflozin group and 58 (97%) patients in the placebo group were included for measured GFR. Empagliflozin treatment resulted in reductions in estimated extracellular volume (adjusted mean difference −0·12 L, 95% CI −0·18 to −0·05; p=0·00056), estimated plasma volume (−7·3%, −10·3 to −4·3; p<0·0001), and measured GFR (−7·5 mL/min, −11·2 to −3·8; p=0·00010) compared with placebo. Five (8%) of 60 patients in the empagliflozin group and three (5%) of 60 patients in the placebo group had one or more serious adverse events. Interpretation: In patients with heart failure and reduced ejection fraction, empagliflozin reduced estimated extracellular volume, estimated plasma volume, and measured GFR after 12 weeks. Fluid volume changes might be an important mechanism underlying the beneficial clinical effects of SGLT2 inhibitors. Funding: Research Council at Herlev and Gentofte University Hospital, Research and Innovation Foundation of the Department of Cardiology at Herlev and Gentofte University Hospital, Capital Region of Denmark, Danish Heart Foundation, and AP Møller Foundation for the Advancement of Medical Science.

OriginalsprogEngelsk
TidsskriftThe Lancet Diabetes and Endocrinology
Vol/bind9
Udgave nummer2
Sider (fra-til)106-116
ISSN2213-8587
DOI
StatusUdgivet - feb. 2021

Bibliografisk note

Funding Information:
JJ reports grants from the Research Council at Herlev and Gentofte University Hospital (Herlev, Denmark), the Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP) at Herlev and Gentofte University Hospital, and the AP Møller Foundation for the Advancement of Medical Science (Copenhagen, Denmark), related to the present study. MO reports grants from the Steno Diabetes Center Odense (Odense, Denmark), related to the present study. CK reports personal fees for participation in scientific advisory panels and speaker fees from Boehringer Ingelheim, Merck Sharp & Dohme, AstraZeneca, Amgen, Novartis, Novo Nordisk, and Shire, unrelated to the present work. LK reports personal fees from speaker honoraria from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim, unrelated to the present work. FG reports personal fees for participation in scientific advisory panels and speaker fees from AstraZeneca, Boehringer Ingelheim, Abbott, Orion Pharma, Pfizer, and Novartis, and acting as an unpaid advisor for Corvia, unrelated to the present work. ELF and NEB report grants from the Novo Nordisk Foundation, unrelated to the present work. JEM reports grants from Abiomed and personal fees from speaker honoraria from Novartis and Orion Pharma, unrelated to the present work. MS reports grants from the Capital Region of Denmark and the Danish Heart Foundation, related to the present study. MS also reports personal fees from speaker honoraria and non-financial support as the national lead investigator of the DAPA-HF trial from AstraZeneca and personal fees from speaker honoraria from Novo Nordisk and Boehringer Ingelheim, unrelated to the present work. All other authors declare no competing interests.

Funding Information:
Empire HF Renal was an investigator-initiated study and was supported by public funding. The manufacturer of empagliflozin was not involved in any part of the study. This work was supported by an institutional research grant from the Research Council at Herlev and Gentofte University Hospital (Herlev, Denmark), an institutional research grant from the Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP) at Herlev and Gentofte University Hospital (Herlev, Denmark), the Capital Region of Denmark (Copenhagen, Denmark; grant A6058), the Danish Heart Foundation (Copenhagen, Denmark; grants 17-R116-A7714-22076 and 18-R124-A8573-22107), and the AP Møller Foundation for the Advancement of Medical Science (Copenhagen, Denmark; grant 17-L-0002).

Publisher Copyright:
© 2020 Elsevier Ltd

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Fingeraftryk

Dyk ned i forskningsemnerne om 'Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial'. Sammen danner de et unikt fingeraftryk.

Citationsformater