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

• Sponsor: Icahn School of Medicine at Mount Sinai (Other)
• Overall Status: Completed
• CT.gov ID: NCT03485222
• Collaborator: Boehringer Ingelheim (Industry), Eli Lilly and Company (Industry)
• Enrollment: 84
• Location: 1
• Arms: 2
• Actual Duration (Months): 20.8
• Patients Per Site Per Month: 4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Diseases	Drug: Empagliflozin; Drug: Placebos	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: EMPA-TROPISM Trial: Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity?
• Actual Study Start Date: May 21, 2018
• Actual Primary Completion Date: Feb 13, 2020
• Actual Study Completion Date: Feb 13, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change in Left Ventricle-end Systolic Volume (ESV) [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.

2. Change in LV-end Diastolic Volume (EDV) [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.

Secondary Outcome Measures

1. Change in LV-Ejection Fraction Index [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.

2. Change in VO2 Consumption [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.

3. Change in 6 Min Walk Test [Baseline and 6 months]

   The distance covered over a time of 6 minutes. Change from baseline to study end at 6 months.

4. Change in Kansas Cardiomyopathy Questionnaire (KCCQ-12) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mount Sinai Heart - Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Juan J Badimon, PhD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 28, 2017

More Information

Publications

None provided.

• Responsible Party: Juan Badimon, Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT03485222
• Other Study ID Numbers: GCO 17-2457
• First Posted: Apr 2, 2018
• Last Update Posted: Mar 25, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Juan Badimon, Professor, Icahn School of Medicine at Mount Sinai: Cardiovascular diseases; Heart Failure; LV remodeling; SGLT-2 Inhibitors; Empagliflozin; Cardiac MRI
• Additional relevant MeSH terms: Cardiovascular Diseases; Empagliflozin

Study Results

Participant Flow

Arm/Group Title	Empagliflozin	Placebos
Arm/Group Description	10mg once a day for 6 months	Placebo equivalent once a day for 6 months
Period Title: Overall Study
STARTED	42	42
COMPLETED	40	40
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Empagliflozin	Placebos	Total
Arm/Group Description	10mg once a day for 6 months	Placebo equivalent once a day for 6 months	Total of all reporting groups
Overall Participants	42	42	84
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.2 (10.9)	59.9 (13.1)	62 (12.1)
Age, Customized (Count of Participants)
<65 yrs	24 57.1%	28 66.7%	52 61.9%
>65 yrs	18 42.9%	14 33.3%	32 38.1%
Sex: Female, Male (Count of Participants)
Female	15 35.7%	15 35.7%	30 35.7%
Male	27 64.3%	27 64.3%	54 64.3%
Race/Ethnicity, Customized (Count of Participants)
White	16 38.1%	7 16.7%	23 27.4%
Hispanic/Latino	19 45.2%	23 54.8%	42 50%
African American	7 16.7%	9 21.4%	16 19%
Asian	0 0%	3 7.1%	3 3.6%
Hypertension (Count of Participants)
Count of Participants [Participants]	34 81%	28 66.7%	62 73.8%
Hyperlipidemia (Count of Participants)
Count of Participants [Participants]	32 76.2%	30 71.4%	62 73.8%
Cigarette smoking (past or present) (Count of Participants)
Count of Participants [Participants]	18 42.9%	12 28.6%	30 35.7%
Atrial fibrillation (Count of Participants)
Count of Participants [Participants]	10 23.8%	8 19%	18 21.4%
Cause of Heart Failure (HF) (Count of Participants)
Ischemic	23 54.8%	19 45.2%	42 50%
Nonischemic	19 45.2%	23 54.8%	42 50%
Devices (Count of Participants)
Count of Participants [Participants]	9 21.4%	8 19%	17 20.2%
Statin History (Count of Participants)
Count of Participants [Participants]	33 78.6%	30 71.4%	63 75%
Number of participants taking ACE inhibitor/ARB (alone) at baseline (Count of Participants)
Count of Participants [Participants]	16 38.1%	19 45.2%	35 41.7%
Angiotensin receptor-neprilysin inhibitor (ARNi) (Count of Participants)
Count of Participants [Participants]	21 50%	15 35.7%	36 42.9%
B-blockers (Count of Participants)
Count of Participants [Participants]	36 85.7%	38 90.5%	74 88.1%
Loop diuretics (Count of Participants)
Count of Participants [Participants]	22 52.4%	24 57.1%	46 54.8%
Thiazide diuretics (Count of Participants)
Count of Participants [Participants]	3 7.1%	2 4.8%	5 6%
Mineralocorticoid antagonists (Count of Participants)
Count of Participants [Participants]	13 31%	15 35.7%	28 33.3%
Ca-blockers (Count of Participants)
Count of Participants [Participants]	5 11.9%	5 11.9%	10 11.9%
Antiplatelet (Count of Participants)
Count of Participants [Participants]	29 69%	26 61.9%	55 65.5%
Anticoagulants (Count of Participants)
Count of Participants [Participants]	10 23.8%	9 21.4%	19 22.6%

Outcome Measures

1. Primary Outcome

Title	Change in Left Ventricle-end Systolic Volume (ESV)
Description	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.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Empagliflozin	Placebos
Arm/Group Description	10mg once a day for 6 months	Placebo equivalent once a day for 6 months
Measure Participants	40	40
Mean (Standard Deviation) [ml]	-26.6 (20.5)	-0.5 (21.9)

2. Primary Outcome

Title	Change in LV-end Diastolic Volume (EDV)
Description	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.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Empagliflozin	Placebos
Arm/Group Description	10mg once a day for 6 months	Placebo equivalent once a day for 6 months
Measure Participants	40	40
Mean (Standard Deviation) [ml]	-25.1 (26)	-1.5 (25.4)

3. Secondary Outcome

Title	Change in LV-Ejection Fraction Index
Description	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.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Empagliflozin	Placebos
Arm/Group Description	10mg once a day for 6 months	Placebo equivalent once a day for 6 months
Measure Participants	40	40
Mean (Standard Deviation) [percent ejection fraction]	6.0 (4.2)	-0.1 (3.9)

4. Secondary Outcome

Title	Change in VO2 Consumption
Description	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.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Empagliflozin	Placebos
Arm/Group Description	10mg once a day for 6 months	Placebo equivalent once a day for 6 months
Measure Participants	40	40
Mean (Standard Deviation) [ml/min/kg]	1.1 (2.6)	-0.5 (1.9)

5. Secondary Outcome

Title	Change in 6 Min Walk Test
Description	The distance covered over a time of 6 minutes. Change from baseline to study end at 6 months.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Empagliflozin	Placebos
Arm/Group Description	10mg once a day for 6 months	Placebo equivalent once a day for 6 months
Measure Participants	40	40
Mean (Standard Deviation) [m]	81 (64)	-35 (68)

6. Secondary Outcome

Title	Change in Kansas Cardiomyopathy Questionnaire (KCCQ-12)
Description	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.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Empagliflozin	Placebos
Arm/Group Description	10mg once a day for 6 months	Placebo equivalent once a day for 6 months
Measure Participants	40	40
Mean (Standard Deviation) [score on a scale]	21 (18)	1.9 (15)

Adverse Events

Time Frame	6 months
Arm/Group Title	Empagliflozin		Placebos
Arm/Group Description	10mg once a day for 6 months		Placebo equivalent once a day for 6 months
All Cause Mortality
	Empagliflozin		Placebos
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		1/40 (2.5%)
Serious Adverse Events
	Empagliflozin		Placebos
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/40 (2.5%)		2/40 (5%)
Cardiac disorders
Malignant Ventricular Tachycardia	1/40 (2.5%)		0/40 (0%)
Ventricular Fibrillation	0/40 (0%)		2/40 (5%)
Worsening Heart Failure	0/40 (0%)		1/40 (2.5%)
New ICD Implant	1/40 (2.5%)		2/40 (5%)
New Cardiomems Implant	1/40 (2.5%)		0/40 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	0/40 (0%)		2/40 (5%)
Other (Not Including Serious) Adverse Events
	Empagliflozin		Placebos
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/40 (5%)		1/40 (2.5%)
Hepatobiliary disorders
Hepatic Injury	0/40 (0%)		1/40 (2.5%)
Nervous system disorders
Migraine	1/40 (2.5%)		0/40 (0%)
Social circumstances
Motor Vehicle Accident	1/40 (2.5%)		0/40 (0%)

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.