Effects of Empagliflozin on Exercise Capacity and Left Ventricular Diastolic Function in Patients With Heart Failure With Preserved Ejection Fraction and Type-2 Diabetes Mellitus

Study Overview
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Brief Summary
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Patients enrolled into the study will be randomly allocated either to Empagliflozin group or control group. In the Empagliflozin group patients will be receiving standard care + Empagliflozin 10 mg o.d., in the control group patients will be receiving standard care without sodium glucose contransporter 2 (SGLT2) inhibitors.

Official Title
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A Phase 4, Single-center, Randomized, Parallel Group Study to Assess Effects of Empagliflozin on Exercise Capacity and Left Ventricular Diastolic Function in Patients With Heart Failure With Preserved Ejection Fraction and Type-2 Diabetes Mellitus

Conditions
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Heart Failure, Diastolic, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Empagliflozin
* Other: Standard care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females aged 45 to 80 years at screening Diagnosis of type-2 diabetes mellitus with stable glucose-lowering background therapy for at least 12 weeks HbA1c ≥ 6,5% and ≤ 10% at screening Diagnosis of HFpEF which includes: Symptoms ± signs (as defined in 2016 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure) Ejection fraction ≥ 50% (by Simpson) Increased LV filling pressures at rest or during exercise determined by echocardiography (LV diastolic dysfunction grade II/III and/or positive diastolic stress test) [according to American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography, 2016] Signed and dated informed consent Exclusion Criteria: Pretreatment with empagliflozin or other SGLT-2 inhibitor within the last 2 months Type-1 diabetes mellitus NYHA classification IV or acute decompensated heart failure at screening Impaired renal function, defined as eGFR <30 ml/min/1.73 m² of body-surface-area (CKD-EPI) Systolic blood pressure > 180 mmHg or < 90 mmHg Permanent atrial flutter or atrial fibrillation Other conditions that may be responsible for impaired diastolic function such as hypertrophic/restrictive cardiomyopathy, constrictive pericarditis and etc. Anemia (Hb < 100 g/l) Myocardial infarction, coronary artery bypass graft surgery within the last 3 months Stroke or TIA within the last 3 months Indications of liver disease Acute genital infection or urinary tract infection Pregnancy Additional exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 45 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>Patients will receive standard care for Heart Failure and Diabetes Mellitus + Empagliflozin 10mg once daily | Drug: Empagliflozin<br>* 10 mg tablet<br>|
| Active Comparator: Control<br>Patients will receive standard care for Heart Failure and Diabetes Mellitus with no SGLT-2 inhibitors | Other: Standard care<br>* Standard care with no SGLT-2 inhibitors<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-minute walking distance (6MWD) | Difference in distance walked during 6-minute walking test (6MWT) between 24 weeks after baseline and at baseline | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular mass index (LVMI) | Difference in LVMI assessed by echocardiography between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in left atrial volume index (LAVI) | Difference in LAVI assessed by echocardiography between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in left atrial stiffness | Difference in left atrial stiffness assessed as a ratio of mitral E/e' ratio to left atrial strain s between 24 weeks after baseline and at baseline | 24 weeks | 
| Change estimated pulmonary artery systolic pressure (PASP) | Difference in PASP assessed by echocardiography both at rest and during diastolic stress test (DST) between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in average e' velocity | Difference in average e' velocity assessed by echocardiography both at rest and during diastolic stress test (DST) between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in average E/e' ratio | Difference in average E/e' ratio assessed by echocardiography both at rest and during diastolic stress between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) | Difference in NT-proBNP plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in Cyclic guanosine monophosphate (cGMP) | Difference in cGMP plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in Endothelin 1 (ET-1) | Difference in ET-1 plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in Growth/differentiation factor 15 (GDF-15) | Difference in GDF-15 plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in ST2 | Difference in ST2 plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in Galectin-3 | Difference in Galectin-3 plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in carboxyterminal propeptide of type I collagen (PICP) | Difference in PICP plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in Human Pentraxin 3 (PTX3) | Difference in PTX3 plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in high-sensitivity C-reactive protein (hsCRP) | Difference in hsCRP plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in Interleukin-6 (IL-6) | Difference in IL-6 plasma levels between 24 weeks after baseline and at baseline | 24 weeks | 
| Change of New York Heart Association (NYHA) functional classification | Difference in NYHA class between 24 weeks after baseline and at baseline | 24 weeks | 
| Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) score | Difference in MLHFQ score between 24 weeks after baseline and at baseline. The questionnaire is comprised of 21 important physical, emotional and socioeconomic ways heart failure can adversely affect a patient's life. After receiving brief standardized instructions, the patient marks a 0 (zero) to 5 scale to indicate how much each itemized adverse of heart failure has prevented the patient from living as he or she wanted to live during the past 4 weeks. The questionnaire is simply scored by summation of all 21 responses. Score ranges from 0 (best quality of life) to 105 (worst quality of life). | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HF, HFpEF, DM, Empagliflozin, Jardiance