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

March 2, 2021 updated by: Juan Badimon, Icahn School of Medicine at Mount Sinai

EMPA-TROPISM Trial: Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity?

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Heart failure (HF) is a frequent co-morbid condition associated with poor prognosis in diabetes, particularly among older patients. HF accounts for more than 1 Million hospitalizations annually in USA. In addition, HF hospitalizations are associated with significant high risk of post-discharge mortality and recurrent hospitalizations. Almost one-half of patients will be re-hospitalized within 6 months and one-third will die within 12 months of discharge. Median survival after HF diagnosis is about 5 years and is similar for HFpEF and heart failure with reduced ejection fraction (HFrEF) patients. Diabetes as co-morbidity multiplies risk of hospital admissions in HF patients.

Type 2 Diabetes Mellitus (T2DM) is a pathological condition characterized by elevated glucose levels and it is associated with high incidence of cardiovascular (CV) events. Several hypoglycemic agents have successfully managed the elevated glucose levels but with little or no impact on CV events. Management of concomitant HF in T2DM is particularly challenging, as some glucose-lowering agents, such as TZDs, are contraindicated in the treatment of HF patients. Thus, there was a need for an oral agent that improved glycemia as well as provided CV benefits. Empagliflozin is the first glucose-lowering agent showing that not only improves glycemic control but also has cardiovascular benefits. The recent EMPA-OUTCOME trial has shown significant reductions in major adverse cardiac events (MACE), cardiovascular mortality, and hospitalization for Heart Failure (HF) by Empagliflozin given on top of standard-of-care therapy for T2DM patients with Cardiovascular disease (CVD). The dramatic change driving the superiority of the primary composite outcome was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35% and 38% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively.

Empagliflozin is a member of a new class of hypoglycemic agents, the SGLT-2 inhibitors. There are a couple of characteristics that single out the SGLT2 inhibitors from other hypoglycemic drugs. One is their low hypoglycemic risk since they act on the urinary excretion of glucose without interfering with the physiologic response to hypoglycemia. And the other is their "positive" cardiovascular effects such as lowering blood pressure, arterial stiffness, urinary microalbuminuria and triglycerides while increasing HDL-Cholesterol levels. Therefore, the combination of the above-mentioned observations led to some investigators to suggest that these benefits may be, at least in part, independent of its hypoglycemic activity and thus, Empagliflozin could be considered a "cardiac" drug.

Study Type

Interventional

Enrollment (Actual)

84

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10029
        • Mount Sinai Heart - Icahn School of Medicine at Mount Sinai

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients should meet the following inclusion criteria:
  • 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.

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Empagliflozin
10mg once a day
Drug: Empagliflozin
6 months
PLACEBO_COMPARATOR: Placebos
placebo once a day
Drug: Placebos
placebo equivalent for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Left Ventricle-end Systolic Volume (ESV)
Time Frame: Baseline and 6 months
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)
Time Frame: Baseline and 6 months
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in LV-Ejection Fraction Index
Time Frame: Baseline and 6 months
The volumetric fraction of blood ejected from the left ventricle of the heart with each heartbeat. Change from baseline to study end at 6 months.
Baseline and 6 months
Change in VO2 Consumption
Time Frame: Baseline and 6 months
Oxygen consumption - the amount of oxygen consumed by the tissues of the body, usually measured as the oxygen uptake in the lung, also called the V02max measure. Change from baseline to study end at 6 months.
Baseline and 6 months
Change in 6 Min Walk Test
Time Frame: Baseline and 6 months
The distance covered over a time of 6 minutes. Change from baseline to study end at 6 months.
Baseline and 6 months
Change in Kansas Cardiomyopathy Questionnaire (KCCQ-12)
Time Frame: Baseline and 6 months
The KCCQ-12 is an instrument most widely used to evaluate QoL in Heart Failure (HF) patients. It is a questionnaire containing 12 questions with full scores ranging from 12 (poor quality of life) to 70 (good quality of life). Higher score indicates better quality of life. Change from baseline to study end at 6 months.
Baseline and 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Icahn School of Medicine at Mount Sinai

Collaborators

Eli Lilly and Company
Boehringer Ingelheim

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

May 21, 2018

Primary Completion (ACTUAL)

February 13, 2020

Study Completion (ACTUAL)

February 13, 2020

Study Registration Dates

First Submitted

March 26, 2018

First Submitted That Met QC Criteria

March 26, 2018

First Posted (ACTUAL)

April 2, 2018

Study Record Updates

Last Update Posted (ACTUAL)

March 25, 2021

Last Update Submitted That Met QC Criteria

March 2, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GCO 17-2457

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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