Effect of Empagliflozin 10 vs 25 mg on LV Remodeling in Diabetic Patients With Anterior STEMI With Reduced LVEF Who Underwent Primary PCI
Phase: PHASE2
Conditions: Diabete Mellitus, Heart Failure, Remodeling, Left Ventricle
Sponsor: Ain Shams University

 
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 Official title: Effect of Empagliflozin 10 vs 25 mg on LV remodeling in 
diabetic patients with anterior STEMI with reduced LVEF who 
underwent primary PCI 
 
 NCT Number: Not yet assigned 
 
 Date: June, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol of a thesis for partial fulfillment of  
MD Degree in Cardiology   
     
Title of the Protocol: Effect of Empagliflozin ten versus twenty five 
milligrams on left ventricular remodeling in diabetic patients with anterior 
ST segment elevation myocardial infarction with reduced left ventricular 
ejection fraction who underwent primary percutaneous coronary 
angioplasty. 
  
Postgraduate Student: - Hany Nazmy Taalab     
Degree: MSc,Cardiology 
   
Director: Prof. Dr. Zainab Abdel Salam Fahmy 
Academic Position:  Professor   
Department: Cardiology, Ain Shams University   
   
Co-DIRECTOR: Asst. Prof Dr. Adel Mohamed Shabana 
Academic Position: Assistant professor   
Department:  Cardiology department, Ain Shams University   
   
Co- DIRECTOR:  Asst. Prof Dr. Sameh Attia Amin 
Academic Position: Associate Professor   
Department: Cardiology, Ain Shams University   
Co-DIRECTOR: Dr. Mina Maged Abdullah  
Academic Position: Lecturer     
Department:  Cardiology department, Ain Shams University   
Faculty of Medicine   
Ain Shams University   
2023   
  
    

 
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1.INTRODUCTION/ REVIEW :    
Anterior STEMI (A-STEMI) has the worst prognosis among all infarct sites mostly 
due to larger infarct size. Patients with A-STEMI experience a more complicated in-hospital 
and follow-up course and are at greater risk for acute regional dilatation and thinning of the 
infarct zone.(1) 
Adverse post infarction left ventricular (LV) remodeling is a major cause of heart 
failure (HF) in the United States today. This is due in part to the welcomed increase in 
patient survival due to early initiation of reperfusion therapies after acute myocardial 
infarction (AMI).(2) 
While angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta 
blockers and sacubitril/valsartan are the pillars of pharmacologic therapy for HF with 
reduced ejection fraction (HFrEF), the benefits are most often seen in patients with large 
infarcts and individuals who are not candidates for reperfusion therapies. Their use, 
however, relates to no more than a 20–25% reduction in major adverse cardiac events 
(MACE). Thus, there is clearly a need to develop additional therapeutic strategies. (2) 
One approach that holds considerable promise is the use of a relatively new class of 
drugs used to treat type 2 diabetes mellitus (T2DM), specifically sodium–glucose co-
transporter 2 (SGLT-2) inhibitors (gliflozin class). A major driver for the use of these drugs 
in the setting of HF is the EMPA-REG OUTCOME trial. This was the first large randomized 
clinical trial that showed empagliflozin (EMPA), a specific SGLT-2 inhibitor, was not only 
effective in reducing MACE but that the outcome was driven primarily by a reduction in 
cardiovascular deaths and hospitalization for heart failure.(2) 
Myocardial metabolic remodeling is integral to HF development, with a shift from 
free fatty acids (FFA) utilization (which produce many ATP (adenosine triphosphate) 
molecules but also requires many oxygen molecules) in healthy myocardium toward 
glucose consumption (which produce less ATP but is more oxygen-efficient in failing 
hearts. Although past research focused exclusively on FFA and glucose, the heart possesses 
metabolic flexibility and is an omnivore capable of oxidizing other substrates such as ketone 
bodies (KB), lactate, and branched-chain amino acid (BCAA). Importantly, KB are the most 
energetically efficient fuel because they produce many ATP molecules while showing the 
lowest oxygen requirements. Of note, empagliflozin-induced glycosuria reduces both 
plasma glucose and insulin levels and increases both lipolysis and plasma glucagon 
concentration (thus resembling fasting state), which causes ketogenesis and 
hyperketonemia. (3) 
Accurate measurements of left ventricular volumes and function are important in the 
management of patients with various cardiac abnormalities. M mode and cross-sectional 
echocardiography are the most commonly used methods to measure left ventricular volumes 
and function.(4) 

 
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Recently, improvements in 2D echocardiographic image resolution have enabled 
detection of tissue pixels and tracking of these acoustic markers from frame to frame. The 
tissue velocity is estimated from the local frame-to-frame displacement; the automatic 
evaluation of the velocity at a point is determined by comparison of the displacement of the 
image data around that point in two consecutive frames. These methods have been used, in 
several different formulations, in many research fields and fall in the category known as 
Optical Flow commonly referred as Speckle Tracking in ultrasound imaging. (5) 
Speckle tracking echocardiography has shown to be accurate in detecting subclinical 
myocardial dysfunction when most of the conventional echocardiograph parameters were 
normal or reported inconsistent results.(6) 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
     

 
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2. AIM/ OBJECTIVES   
 The study aims to compare the doses of 10 versus 25 milligrams of Empagliflozin 
among diabetic patients with Anterior STEMI with reduced LVEF who underwent PPCI 
regarding MACE and LV remodeling for 6 months duration. 
     
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   

 
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3. Methodology:    
• Type of Study: a prospective clinical trial.  
• Study Setting: Patients presenting to Ain shams university hospitals   
• Study Population:  anterior STEMI patients    
• Study Period: 6 months    
• Sample Size:  Patients diagnosed with anterior STEMI in the ER fulfilling the 
inclusion criteria. (200 patients) divided into two groups the first will receive 10 mg 
of Empagliflozin and the other will receive 25 mg. 
• Ethical considerations:                                                                                 ,    
   The clinical research study will be conducted in accordance with the current policies, 
requirements, and regulations of Ain Shams University. Information will be recorded in 
an appropriate manner to ensure that potential subjects or their authorized representatives 
are fully aware of the nature and objectives of the clinical study, and the potential risks 
and benefits of participating in the study. Written informed consent will be obtained from 
each patient or their authorized representative, prior to any study procedures being carried 
out.    
• Inclusion Criteria:   
1- Diabetic patients with anterior STEMI with reduced LVEF who underwent 
PPCI with successful revascularization and resulting into TIMI III flow and 
who are receiving SGLTi for the first time. 
  Exclusion Criteria:      
1- patients who did not undergo primary PCI, those treated medically or 
had thrombolysis   
2- Non diabetic patient. 
3- Diabetic patient already on SGLTi 
4- STEMIs other than anterior. 
5- NSTEMI patients. 
6- Patients having valvular heart diseases. 
7- Patients having renal impairment. 
8- Patients with LV myopathies of non-ischemic origin.  
 
  
 
4. Study Tools:  
A-  history taking:  including  
a- personal history” name, age, marital status and special habits of 
medical importance e.g smoking and alcohol consumption ” 
b- past history with special comment on diabetes and other 
comorbidities e.g hypertension, CKD and dyslipidemia 

 
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c- History of present illness with special comment on pain to door 
interval. 
d- Positive family history. 
e- Drug history: and to make sure whether patients are receiving SGLTi 
or not. 
 
B-  Examination: 
1- General examination: including vital signs and complexion. 
2- Local examination including heart and chest auscultation. 
 
C-   ECG: all patients will have 12 lead surface ECG at start of the study and 
during follow up. 
D-  Echocardiographic Assessment:  
1- Standard transthoracic 2D echocardiographic examination: 
Standard 2D echocardiography will be performed using GE vivid 
E70 echocardiography machine; the whole study will be ECG gated in 
supine or left lateral position. Standard images will be obtained in the 
parasternal (long- and short-axis views) and apical (2, 3, 4, and 5-
chamber images) views. Standard 2D and color Doppler data, triggered 
to the QRS complex, will be saved in cine-loop format. 
M-mode, 2D, TDI as well as pulsed and continuous Doppler flow 
across the different heart valves in all the standard views will be done 
according to the recommendations of the American Society of 
Echocardiography (7).   
Heart failure with reduced ejection fraction (HFrEF) was defined 
as EF less than 40% , Also referred to as systolic HF. Randomized 
controlled trials have mainly enrolled patients with HFrEF, and it is only 
in these patients that efficacious therapies have been demonstrated to 
date.(8) 
The definition of left ventricular remodeling using cardiac 
magnetic resonance following ST-elevation myocardial infarction is 
highly variable, among studies including highly selected patients. The 
most frequent left ventricular remodeling criterion were a 20% increase 
in end-diastolic volumes or a 15% increase in end-systolic volumes.(9) 
A composite cut-off value of a 12% to 15% increase in end-systolic 
volume and a 12% to 20% increase in end-diastolic volume using a 
follow-up cardiac magnetic resonance imaging 1 to 3 months after 
myocardial infarction might be proposed as a consensual cut-off for 
defining adverse left ventricular remodeling.(9) 
 

 
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The following measurements will be focused on and recorded: 
1- Assessment of LV systolic function :  
By applying M-Mode modality to LV in parasternal long axis view, we 
will measure LV end-diastolic diameter (EDD), LV end-systolic diameter (ESD), 
IVS and PWT in both systole and diastole LVEF and FS. Also estimation of EF by 
Simpson biplane method and 2D will be done. 
2- LA dimension measurement: 
Left Atrial dimensions and aorta: The anteroposterior diameter of the 
left atrium will be measured in the parasternal long-axis view using M mode 
perpendicular to the aortic root long axis at the level of the aortic sinuses by 
using the leading-edge to leading-edge convention. 
3- Wall motion abnormalities: 
Using 2D echocardiography in apical and para- sternal windows to 
assess RSWMA. 
 
4- Assessment of LV diastolic function: 
Pulsed-wave (PW) Doppler will be applied in the apical 4-chamber view 
to obtain mitral inflow velocities and assess LV filling. The following 
measurements of mitral inflow will be recorded: the peak early filling (E-wave) 
and late diastolic filling (A-wave) velocities, the E/A ratio. 
Tissue Doppler imaging (TDI): in apical 4- chamber view, TDI will be 
applied in the pulse-Doppler mode to allow for a spectral display and 
recording of mitral annulus velocities at the lateral mitral annulus, medial 
mitral annulus, and the mean value will be recorded. The measurements 
obtained are Systolic velocity of the mitral annulus (S), early diastolic annular 
velocity (E`), and late diastolic annular velocity (A`). The average of 3 readings 
of lateral E` will be recorded. E/E' ratio (mitral peak early filling velocity/peak 
mitral lateral annular velocity in early diastole) will be automatically 
calculated. 
5- Assessment of RV systolic function: 
The TAPSE method is a relatively simple technique used to assess RV 
longitudinal performance. To perform this measurement, an M-mode cursor 
will be aligned through the lateral tricuspid annulus in the apical four-chamber 
view and measurement of the amount of longitudinal motion of the annular 
plane in systole. TAPSE < 17 mm suggests RV dysfunction. 
Also, TDI will be applied in the pulse-Doppler mode to allow for a 
spectral display and recording of tricuspid annulus velocities at the lateral 
tricuspid annulus in apical 4 chamber view to assess S of RV with value less 
than 9.5 suggestive of RV dysfunction. 

 
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E- Speckle tracking echocardiography of the left ventricle: 
 speckle tracking could be used as a predictor for LV remodeling post 
myocardial infarction with best cut-off value was >-12.5 (Sensitivity 87%, 
Specificity 85%).(10) 
Loops of multiple ECG- gated entire cardiac cycles of the LV from 
apical 4, 3 and 2 chamber, parasternal long and short axis views will be 
obtained. The recorded data will be stored and later analyzed with the 
offline-workstation software EchoPAC Dimension [12.0, General Electrics 
(GE) Medical Systems GmbH, Germany]. 
In the end-systolic frame, the endocardial border is traced beginning 
at one end of the mitral annulus and ending at the other end in each of the 
apical views. 
The software then generates a region-of-interest (ROI) to include the 
entire myocardial thickness. The width of the ROI can be manually adjusted 
as required. Care should be taken to avoid including bright, echogenic 
pericardium in the ROI. 
The software then divides the LV myocardium into six segments and 
generates segmental and global longitudinal strain. As the myocardium 
usually shortens in the longitudinal direction during systole, the longitudinal 
strain is displayed below the baseline. 
 
From these curves, peak systolic longitudinal strain is recorded for 
each of the myocardial segments.  The strain values for all the segments are 
recorded and averaged to obtain the global longitudinal strain (GLS). A 
topographic representation of the regional and global longitudinal strain of 
all 17 analyzed segments (Bull’s eye configuration) is then automatically 
generated. 
F- 2D Speckle Tracking Echocardiography of the left Atrial Phasic functions 
(apical four chamber view and apical two chamber view) Parameters: 
 Left Atrial Strain during Reservoir phase (LASr): Reflects the left 
atrium's ability to store blood during ventricular systole. 
 Left Atrial Strain during Conduit phase (LAScd): Assesses the passive 
filling of the left ventricle during early diastole. 
 Left Atrial Strain during Contraction phase (LASct): Evaluates the 
active contraction of the left atrium during late diastole. 
 Left atrial maximum volume (LAVmax): It is measured just before the 
mitral valve opens, at the end of left ventricular systole. 
 

 
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G- Major adverse cardiac events (MACE): composite point of death, 
repeated hospitalization, re-infarction and new onset heart failure will be 
observed for six months post catheterization and initiation of SGLTi.    
H- Follow up: patients will be followed up for 6 months regarding symptoms 
and MACE. All echocardiographic study parameters will be repeated at the 
end of the study period.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
  
 
 
 
 

 
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5-Statistical Analysis:      
       All data will be statistically analyzed to compare results in different time ( day one then 6 
months later )    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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6. References: 
1- Ferrante, G., Barbieri, L., Spoonbill, C., et al. (2021). Predictors of mortality and long-
term outcome in patients with anterior STEMI: Results from a single center study. 
Journal of Clinical Medicine, 10(23), 5634. https://www.mdpi.com/2077-
0383/10/23/5634 
2- Song, Y., et al. (2021). Attenuation of adverse postinfarction left ventricular 
remodeling with empagliflozin enhances mitochondria-linked cellular energetics and 
mitochondrial biogenesis. International Journal of Molecular Sciences, 23(1), 437. 
https://www.mdpi.com/1422-0067/23/1/437 
3- Santos-Gallego, C. G., Requena-Ibanez, J. A., San Antonio, R., et al. (2019). 
Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart 
failure by enhancing myocardial energetics. Journal of the American College of 
Cardiology, 73(15), 1931–1944. https://doi.org/10.1016/j.jacc.2019.01.056 
4- Poutanen, T., Jokinen, E., Sairanen, H., et al. (2003). Left atrial and left ventricular 
function in healthy children and young adults assessed by three-dimensional 
echocardiography. Heart, 89(5), 544–549. 
https://heart.bmj.com/content/89/5/544.short 
5- Bussadori, C., Moreo, A., Di Donato, M., et al. (2009). A new 2D-based method for 
myocardial velocity strain and strain rate quantification in a normal adult and 
paediatric population: Assessment of reference values. Cardiovascular Ultrasound, 7, 
Article 8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657114 
6- Jashari, H., Rydberg, A., Ibrahimi, P., et al. (2015). Normal ranges of left ventricular 
strain in children: A meta-analysis. Cardiovascular Ultrasound, 13, Article 37. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528396 
7- Roberto, M., Luigi, P., Victor, M., et al. (2014). Recommendations for cardiac chamber 
quantification by echocardiography in adults: An update from the American Society of 
Echocardiography and the European Association of Cardiovascular Imaging. Journal of 
the American Society of Echocardiography, 27(9), 785–801. 
https://pubmed.ncbi.nlm.nih.gov/25559473/ 
8- Yancy, C. W., Jessup, M., Bozkurt, B., et al. (2013). 2013 ACCF/AHA guideline for the 
management of heart failure: A report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. 
Circulation, 128(16), 1810–1852. 
https://www.ahajournals.org/doi/full/10.1161/cir.0b013e31829e8807 
9- Legallois, D., Hodzic, A., Alexandre, J., et al. (2020). Definition of left ventricular 
remodelling following ST-elevation myocardial infarction: A systematic review of 

 
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cardiac magnetic resonance studies. European Heart Journal, 41(Supplement_2), 
ehaa946.1613. https://doi.org/10.1093/ehjci/ehaa946.1613 
10- Bastawy, I., Ismail, M., Hanna, H. F., et al. (n.d.). Speckle tracking imaging as a 
predictor of left ventricular remodeling 6 months after first anterior ST elevation 
myocardial infarction in patients managed by primary percutaneous coronary 
intervention. The Egyptian Heart Journal, 70(1), 43–48. 
https://pubmed.ncbi.nlm.nih.gov/30591753/