Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.

Abstract

BACKGROUND:

Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention.

OBJECTIVES:

This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload.

METHODS:

This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment.

RESULTS:

Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients.

CONCLUSIONS:

Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

• Authors: Milton Packer, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Joao Pedro Ferreira, Stuart J Pocock, Naveed Sattar, Martina Brueckmann, Waheed Jamal, Daniel Cotton, Tomoko Iwata, Faiez Zannad, EMPEROR-Reduced Trial Committees and Investigators
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 77 Issue 11 Pg. 1381-1392 (03 23 2021) ISSN: 1558-3597 [Electronic] United States
• PMID: 33736819 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Benzhydryl Compounds
• Diuretics
• Glucosides
• Natriuretic Peptides
• Sodium Potassium Chloride Symporter Inhibitors
• Sodium-Glucose Transporter 2 Inhibitors
• empagliflozin

Topics

• Aged
• Benzhydryl Compounds (administration & dosage, adverse effects)
• Blood Volume (drug effects)
• Diabetes Mellitus, Type 2 (diagnosis, drug therapy)
• Diuretics (pharmacology)
• Drug Synergism
• Female
• Glomerular Filtration Rate
• Glucosides (administration & dosage, adverse effects)
• Heart Failure (blood, mortality, physiopathology, therapy)
• Hematocrit
• Humans
• Male
• Natriuretic Peptides (blood)
• Outcome Assessment, Health Care
• Sodium Potassium Chloride Symporter Inhibitors (pharmacology)
• Sodium-Glucose Transporter 2 Inhibitors (administration & dosage, adverse effects)
• Stroke Volume (drug effects)
• Water-Electrolyte Imbalance (physiopathology, therapy)