Impact of EMpagliflozin on Cardiac Function and Biomarkers of Heart Failure in Patients With Acute MYocardial Infarction

Study Overview
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Brief Summary
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This study is planned to investigate the impact of Empagliflozin on biomarkers of heart failure in patients with myocardial infarction with and without type 2 diabetes mellitus within 6 months after the event.

Detailed Description
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Type 2 diabetes mellitus (T2DM) is associated with an about two to three-fold increased risk for cardiovascular events as compared to subjects without diabetes. Sodium-dependent glucose cotransporter 2 (SGLT-2) is mainly expressed in human kidneys and small intestinal cells. In the proximal tubule of the nephron SGLT-2 is responsible for the reabsorption of approximately 90% of the filtrated glucose. Inhibition of SGLT-2 was shown to increase renal glucose excretion and to lower glucose. Subsequently, a number of SGLT-2 inhibitors were developed and are currently approved for the treatment of type 2 diabetes. Recently, Zinman et al published the results of the EMPA-REG-OUTCOME (Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patient) trial where the cardiovascular impact of a glucose lowering regimen including Empagliflozin as compared to usual glucose control without an SGLT-2 inhibitor was investigated. The trial demonstrated an unexpected reduction in the primary composite endpoint, comprising cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The reduction was mainly driven by a 38% relative risk reduction in cardiovascular deaths; moreover they demonstrated an impressive 35% relative risk reduction in the secondary endpoint hospitalization for heart failure. Of note, the beneficial effects observed in the Empagliflozin group seem to occur very rapidly after commencing the treatment, as suggested by the early separation of the Kaplan-Meier curves. However, the mechanisms responsible for this finding remain unclear. Diuretic effects with subsequent impact on hemodynamics or potential cardioprotective effects of glucagon, which levels rise under the treatment with SGLT-2 inhibitors and the resulting rise in ketone bodies or a small increase in hematocrit have been suggested. The aim of our trial is to investigate whether Empagliflozin treatment commenced within 72-h after acute myocardial infarction has an impact on heart failure in subjects with and without diabetes mellitus type 2.

Official Title
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Impact of EMpagliflozin on Cardiac Function and Biomarkers of Heart Failure in Patients With Acute MYocardial Infarction

Conditions
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Acute Myocardial Infarction

Intervention / Treatment
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* Drug: Empagliflozin 10 mg
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Myocardial infarction with evidence of significant myocardial necrosis defined as a rise in creatinine kinase >800 U/l and a troponin T-level (or troponin I-level) >10x ULN (upper limit of normal). In addition at least 1 of the following criteria must be the met: Symptoms of ischemia ECG (electrocardiogram) changes indicative of new ischemia (new ST-T changes or new LBBB) Imaging evidence of new regional wall motion abnormality 18 - 80 years of age Informed consent has to be given in written form eGFR (glomerular filtration rate) > 45 ml/min/1.73m2 Blood pressure before first drug dosing: RR systolic >110 mmHg Blood pressure before first drug dosing: RR diastolic >70 mmHg ≤72h after myocardial infarction (after the performance of a coronary angiography) Exclusion Criteria: Any other form of diabetes mellitus than type 2 diabetes mellitus, history of diabetic ketoacidosis Blood pH (potential hydrogen) < 7,32 Known allergy to SGLT-2 inhibitors Hemodynamic instability as defined by intravenous administration of catecholamine, calcium sensitizers or phosphodiesterase inhibitors >1 episode of severe hypoglycemia within the last 6 months and treatment with insulin or sulfonylurea Females of childbearing potential without adequate contraceptive methods (i.e. sterilization, intrauterine device, vasectomized partner; or medical history of hysterectomy) Acute symptomatic urinary tract infection (UTI) or genital infection Patients currently being treated with any SGLT-2 inhibitor or having received treatment with any SGLT-2 inhibitor within the 4 weeks prior to the screening visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Empagliflozin<br>The subjects will receive Empagliflozin 10mg. | Drug: Empagliflozin 10 mg<br>* The subject will receive Empagliflozin 10 mg orally once daily for 26 weeks.<br>* Other names: Jardiance;|
| Placebo Comparator: Placebo Oral Tablet<br>The subjects will receive placebo. | Drug: Placebo Oral Tablet<br>* The subject will receive Placebo orally once daily for 26 weeks.<br>* Other names: Sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change of nt-proBNP levels | Difference in the change of nt-proBNP levels between treatment groups from randomization to week 26 | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes of ejection fraction | Difference in the change of ejection fraction between treatment groups from randomization to week 26 | 26 weeks | 
| changes of ejection fraction | Difference in the change of ejection fraction between treatment groups from randomization to week 6 | 6 weeks | 
| changes of left ventricular diastolic function | Difference in the change of left ventricular diastolic function from randomization to week 26 | 26 weeks | 
| changes of left ventricular diastolic function | Difference in the change of left ventricular diastolic function from randomization to week 6 | 6 weeks | 
| changes of nt-proBNP levels | Difference in the change of nt-proBNP levels between treatment groups from randomization to week 6 | 6 weeks | 
| changes of HbA1c | Difference in the change of HbA1c between treatment groups from randomization to week 26 (in subjects with known diabetes mellitus Type 2) | 26 weeks | 
| changes of body weight | Difference in the change of body weight between treatment groups from randomization to week 6 | 6 weeks | 
| changes of body weight | Difference in the change of body weight between treatment groups from randomization to week 26 | 26 weeks | 
| changes of blood beta-hydroxybutyrate levels | Difference in the change of blood beta-hydroxybutyrate levels between the treatment groups from randomization to week 6 | 6 weeks | 
| changes of blood beta-hydroxybutyrate levels | Difference in the change of blood beta-hydroxybutyrate levels between the treatment groups from randomization to week 26 | 26 weeks | 
| number of hospital re-admissions due to heart failure | Difference in the number of hospital re-admissions due to heart failure between the treatment groups | 30 weeks | 
| number of hospital re-admissions for any cause | Difference in the number of hospital re-admissions for any cause between the treatment groups | 30 weeks | 
| duration of hospital stay | Difference in the duration of hospital stay between the treatment groups after initiation of the study treatment | 30 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biomarker, Heart failure, SGLT-2 inhibitor, Empagliflozin, Randomized controlled trial