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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Cardiovascular Diseases

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>10mg once a day | Drug: Empagliflozin<br>* 6 months<br>|
| Placebo Comparator: Placebos<br>placebo once a day | Drug: Placebos<br>* placebo equivalent for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LV-Ejection Fraction Index | 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 | 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 | 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) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular diseases, Heart Failure, LV remodeling, SGLT-2 Inhibitors, Empagliflozin, Cardiac MRI