Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? (ATRU-4).

NCT03485222 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: GCO 17-2457
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

Purpose: The overall hypothesis of the study is that the benefits attained in the EMPA-OUTCOME were, at least in part, mediated by a glucose-independent mechanism. Thus, to demonstrate the existence of the postulated non-glucose dependent effects, the researchers will investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in heart failure patients with reduced ejection fraction without diabetes.

Conditions

Cardiovascular Diseases

Keywords

Cardiovascular diseases; Heart Failure; LV remodeling; SGLT-2 Inhibitors; Empagliflozin; Cardiac MRI

Outcome Measures

Primary Outcomes (2)

• Change in Left Ventricle-end Systolic Volume (ESV)

  End-systolic volume (ESV) is the volume of blood in a ventricle at the end of contraction of the left ventricle (LV). Change from baseline to study end at 6 months.

  Baseline and 6 months

• Change in LV-end Diastolic Volume (EDV)

  End-diastolic volume (EDV) is the volume of blood in the left ventricle at end load or filling in (diastole) or the amount of blood in the ventricles just before systole. Change from baseline to study end at 6 months.

  Baseline and 6 months

Secondary Outcomes (4)

• Change in LV-Ejection Fraction Index

  Baseline and 6 months

• Change in VO2 Consumption

  Baseline and 6 months

• Change in 6 Min Walk Test

  Baseline and 6 months

• Change in Kansas Cardiomyopathy Questionnaire (KCCQ-12)

  Baseline and 6 months

Study Arms (2)

Empagliflozin

EXPERIMENTAL

10mg once a day

Drug: Empagliflozin

Placebos

PLACEBO COMPARATOR

placebo once a day

Drug: Placebos

Interventions

Empagliflozin DRUG

6 months

Empagliflozin

Placebos DRUG

placebo equivalent for 6 months

Placebos

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ambulatory patients age 18-85 years
• Diagnosis of Heart failure (NYHA II to III)
• LVEF\<50% on echocardiography or CMRI in the previous 6 months
• Have stable symptoms and therapy for HF within the last 3 months.

You may not qualify if:

• Pregnant or lactating women.
• Any history of diabetes by medical history or by any of the established criteria by the American Diabetes Association. It also includes patients with history of diabetes in remission.
• ACS or cardiac surgery within the last 3 months.
• Cancer or any other life-threatening condition.
• Pancreatitis.
• Glomerular Filtration Rate \< 45 ml/Kg/min.
• Use of continuous parental inotropic agents.
• Systolic BP \< 90 mm Hg.
• Psychiatric disease incompatible with being in study.
• Any contraindication to MRI procedures.
• Any other medical or physical condition considered to be inappropriate by a study physician.

Sponsors & Collaborators

• Icahn School of Medicine at Mount Sinai: lead
• Boehringer Ingelheim: collaborator
• Eli Lilly and Company: collaborator

Study Sites (1)

Mount Sinai Heart - Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Related Publications (5)

• Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, Garcia-Ropero A, Mancini D, Pinney S, Macaluso F, Sartori S, Roque M, Sabatel-Perez F, Rodriguez-Cordero A, Zafar MU, Fergus I, Atallah-Lajam F, Contreras JP, Varley C, Moreno PR, Abascal VM, Lala A, Tamler R, Sanz J, Fuster V, Badimon JJ; EMPA-TROPISM (ATRU-4) Investigators. Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2021 Jan 26;77(3):243-255. doi: 10.1016/j.jacc.2020.11.008. Epub 2020 Nov 13.

  PMID: 33197559 RESULT

• Angermann CE, Sehner S, Gerhardt LMS, Santos-Gallego CG, Requena-Ibanez JA, Zeller T, Maack C, Sanz J, Frantz S, Ertl G, Badimon JJ. Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial. Eur Heart J. 2025 Apr 22;46(16):1507-1523. doi: 10.1093/eurheartj/ehae917.

  PMID: 39907687 DERIVED

• Angermann CE, Santos-Gallego CG, Requena-Ibanez JA, Sehner S, Zeller T, Gerhardt LMS, Maack C, Sanz J, Frantz S, Fuster V, Ertl G, Badimon JJ. Empagliflozin effects on iron metabolism as a possible mechanism for improved clinical outcomes in non-diabetic patients with systolic heart failure. Nat Cardiovasc Res. 2023 Nov;2(11):1032-1043. doi: 10.1038/s44161-023-00352-5. Epub 2023 Oct 26.

  PMID: 39196095 DERIVED

• Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650. doi: 10.1002/14651858.CD013650.pub2.

  PMID: 34693515 DERIVED

• Requena-Ibanez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP, Mancini D, Sartori S, Atallah-Lajam F, Giannarelli C, Macaluso F, Lala A, Sanz J, Fuster V, Badimon JJ. Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study. JACC Heart Fail. 2021 Aug;9(8):578-589. doi: 10.1016/j.jchf.2021.04.014.

  PMID: 34325888 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Heart Failure

Interventions

empagliflozin

Condition Hierarchy (Ancestors)

Heart Diseases

Limitations and Caveats

This is a single-site trial with a relatively small number of patients; however, the high reproducibility of CMR allows for the utilization of reduced sample sizes. A second limitation is the relatively high number of dropouts in the CPET. Third, this trial have exclusively studied heart failure with reduced ejection fraction(HFrEF) patients; whether patients with heart failure with preserved ejection fraction can benefit from SGLT2i cannot be answered by this study and remains to be determined.

Results Point of Contact

• Title: Dr. Juan Badimon
• Organization: Icahn School of Medicine at Mount Sinai

juan.badimon@mssm.edu

(212) 241-8484

Study Officials

• Juan J Badimon, PhD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 26, 2018
• First Posted: April 2, 2018
• Study Start: May 21, 2018
• Primary Completion: February 13, 2020
• Study Completion: February 13, 2020
• Last Updated: March 25, 2021
• Results First Posted: March 25, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)