Effects of Empagliflozin on Left Ventricular Diastolic Function Compared to Usual Care in Type 2 Diabetics

Study Overview
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Brief Summary
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The purpose of the EmDia trial is to compare the effects of empagliflozin with placebo in addition to standard diabetic treatment or dietetic treatment on cardiac diastolic function in patients with type 2 Diabetes mellitus.

Detailed Description
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Diabetes is a serious and increasing global health burden. It has been shown, that diabetes is associated with a two-fold higher risk for coronary heart disease, stroke and for the aggregate of other vascular death independently of other conventional risk factors. It is the leading cause of cardiovascular disease. Diabetes mellitus substantially increases the risk of macrovascular and microvascular complications, such as vascular dysfunction with developing coronary, cerebrovascular, and peripheral arterial disease, heart failure, nerve disorders (neuropathy), eye complications (e.g. cataracts, glaucoma diabetic retinopathy), kidney disease (nephropathy), foot ulcers, restriction of mental function, and psychosomatic diseases (e.g. stress, anxiety and depression). The most common of the cardiovascular complications in diabetics are ischemic cardiomyopathy and left ventricular (LV) dysfunction. Of particular interest here is the diastolic dysfunction, as an early sign of diabetic heart muscle disease followed by systolic damage. Although diabetes has a decisive role in the development of cardiovascular disease, traditional glucose lowering agents have failed to convincingly show that intensive glucose control significantly reduces CVD events. A new approach for treatment of adult patients with type 2 diabetes was found with the selective inhibition of sodium glucose cotransporter 2 (SGLT2). Studies have shown that empagliflozin, a potent SGLT2 inhibitor, not only effectively reduces the rates of hyperglycemia but also blood pressure and weight. (16, 18) In addition, beneficial effects on arterial stiffness and vascular resistance, visceral adiposity, albuminuria and plasma urate have been reported. The results of the EMPA-REG OUTCOME study suggest that empagliflozin added to the standard therapy has a positive influence on cardiovascular outcomes and heart failure hospitalization in individuals with diabetic mellitus. The aim of the present study is to investigate the effects of empagliflozin, in comparison with placebo, on cardiac and vascular function as well as on cardiac biomarker in individuals with type 2 diabetes with standard therapy, increased E/E' ratio and poor glycemic control.

Official Title
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A Phase IV, Single-center, Randomized, Double-blind, Placebo-controlled, Parallel Group Study on the Effects of Empagliflozin on Left Ventricular Diastolic Function Compared to Usual Care in Individuals With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2, Diastolic Dysfunction

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects meeting all of the following criteria at visit 0 (screening) will be considered for admission to the trial: Diagnosis of type 2-diabetes mellitus with stable glucose-lowering background therapy and/or dietetic treatment for at least 12 weeks In subjects without glucose-lowering background therapy: the application of Metformin was considered to be unsuitable due to drug intolerance HbA1c level of ≥6.5% and ≤10.0% at visit 0 (screening) for subjects on antidiabetic background therapy or HbA1c level of ≥6.5% and ≤9.0% for drug-naïve subjects with dietetic treatment Diastolic cardiac dysfunction E/E' ratio ≥8 (2D-echocardiography) Age 18 - 84 years BMI ≤ 45 kg/m² (Body Mass Index) For women: post-menopausal for more than 12 months without an alternative medical cause can participate in the trial. Women with childbearing potential can only participate, if they are surgically sterile or a negative pregnancy test (serum or urine) is available at visit 1 and they are willing to practice highly effective birth control method during trial. Reliable highly effective contraception comprises combined (estrogen and progesteron containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) progesteron-only hormonal contraception associated with inhibition of ovaluation (oral, injectable, implantable) intrauterine device (IUD) intrauterine hormone-releasing system (IUS) bilateral tubal occlusion vasectomised partner (provided that partner is the sole sexual partner and that the vasectomised partner has received medical assessment of the surgical success) sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Ability of subject to understand nature, importance and individual consequences of clinical trial Signed and dated informed consent of the subject must be available before start of any specific trial procedures which is consistent with ICH-GCP guidelines and local legislation Exclusion Criteria: Subjects presenting with any of the following criteria at visit 0 (screening) will not be included in the trial: Pretreatment with empagliflozin or other SGLT2 inhibitor within the last 3 months Pretreatment with known inducers of UGT enzymes Uncontrolled hyperglycemia with a glucose level > 240 mg/dl (>13.3 mmol/L) after an overnight fast Impaired renal function, defined as eGFR <45 ml/min/1.73 m² of body-surface-area End-stage renal failure or dialysis Severe hepatic dysfunction, defined by serum levels of either SGPT, SGOT, or alkaline phosphatase above 3 x upper limit of normal (ULN) Acute urinary tract infection (UTI) Known acute genital infection (GI) Symptomatic hypotension Hematocrit above the upper limit of the reference range Hypoglycemic tendencies Severe PAD (Fontaine classification Stage IIb - IV) Medical history of cancer and/or treatment for cancer within the last 5 years, subjects basalioma can be included in the study Medical history of pancreatitis or surgery on pancreas Known ketoacidosis (in the past) Acute febrile disease NYHA classification III - IV Pregnant and/or nursing women at visit 1 (baseline) Acute coronary syndrome, stroke or TIA within the last 2 months Planned cardiac surgery or angioplasty within 3 months Gastrointestinal surgeries that induce chronic malabsorption Blood dyscrasia or any disorders causing hemolysis or unstable Red Blood Cells (e.g. malaria, babesiosis, hemolytic anemia) History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product Alcohol or drug abuse within the last 3 months that would interfere with trial participation Medical or psychological conditions that would jeopardize an adequate and orderly completion of the trial (at visit 0 (screening) or at visit 1 (baseline)) Medical condition that does not allow enrollment in the trial at visit 1 (baseline) Current treatment with systemic steroids or change in dosage of thyroid hormones within the last 6 weeks or any other uncontrolled endocrine disorder except type 2 diabetes mellitus Hereditary glucose intolerance, galactose intolerance, Lapp-lactase deficiency or glucose-galactose-malabsorption Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial or participating in another trial (involving an investigational drug and/or follow-up)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 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 |
| --- | --- |
| Experimental: Empagliflozin<br>10 mg Empagliflozin daily per os for 12 weeks | Drug: Empagliflozin<br>* 10 mg per os daily for 12 weeks<br>* Other names: Jardiance;|
| Experimental: Placebo<br>amount of Placebo corresponding to empagliflozin 10 mg daily per os for 12 weeks | Drug: Placebo<br>* amount of Placebo corresponding to empagliflozin 10 mg per os daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| difference in E/E' ratio between 12 weeks after baseline and at baseline | difference in E/E' ratio (noninvasive surrogate marker for left ventricular diastolic function (LVEDP) measured by 2D-echocardiography) between 12 weeks after baseline and at baseline | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| difference in E/E' ratio (change from baseline (V1) to 1 week follow-up) | difference in E/E' ratio (change from baseline (V1) to 1 week follow-up (2D-echocardiography) | 1 week | 
| difference in Left ventricular systolic function (LVEF) | difference in Left ventricular systolic function (LVEF) from baseline to week 1 | 1 week | 
| difference in Left ventricular systolic function (LVEF) | difference in Left ventricular systolic function (LVEF) from baseline to week 12 | 12 weeks | 
| difference in Left end-diastolic volume (LEDV) | difference in Left end-diastolic volume (LEDV) from baseline to week 1 | 1 week | 
| difference in Left end-diastolic volume (LEDV) | difference in Left end-diastolic volume (LEDV) from baseline to week 12 | 12 weeks | 
| difference in Carotid-femoral pulse wave velocity | difference in Carotid-femoral pulse wave velocity (cf-PWV, vascular explorer - calculated) from baseline to week 1 | 1 week | 
| difference in Carotid-femoral pulse wave velocity | difference in Carotid-femoral pulse wave velocity (cf-PWV, vascular explorer - calculated) from baseline to week 12 | 12 weeks | 
| difference in Augmentation index (AIx) | difference in Augmentation index (AIx, vascular explorer) from baseline to week 1 | 1 week | 
| difference in Augmentation index (AIx) | difference in Augmentation index (AIx, vascular explorer) from baseline to week 12 | 12 week | 
| difference in Arterial stiffness index (SI) | difference in Arterial stiffness index (SI, photo plethysmography) from baseline to week 1 | 1 week | 
| difference in Arterial stiffness index (SI) | difference in Arterial stiffness index (SI, photo plethysmography) from baseline to week 12 | 12 weeks | 
| difference in Reflection index | difference in Reflection index (photo plethysmography) from baseline to week 1 | 1 week | 
| difference in Reflection index | difference in Reflection index (photo plethysmography) from baseline to week 12 | 12 weeks | 
| difference in Brain natriuretic peptide (BNP) | difference in Brain natriuretic peptide (BNP) from baseline to week 1 | 1 week | 
| difference in Brain natriuretic peptide (BNP) | difference in Brain natriuretic peptide (BNP) from baseline to week 12 | 12 weeks | 
| difference in High sensitive troponin I (hs TnI) | difference in High sensitive troponin I (hs TnI) from baseline to week 1 | 1 week | 
| difference in High sensitive troponin I (hs TnI) | difference in High sensitive troponin I (hs TnI) from baseline to week 12 | 12 weeks | 
| difference in High sensitive C-reactive protein (hs CRP) | difference in High sensitive C-reactive protein (hs CRP) from baseline to week 1 | 1 week | 
| difference in High sensitive C-reactive protein (hs CRP) | difference in High sensitive C-reactive protein (hs CRP) from baseline to week 12 | 12 weeks | 
| difference in E/E' ratio (change from baseline (V1) to 12 weeks follow-up) in the subgroup of patients with eGFR 45-59 ml/min/1.73 m² | difference in E/E' ratio (noninvasive surrogate marker for left ventricular diastolic function (LVEDP) measured by 2D-echocardiography) between 12 weeks after baseline and at baseline in the subgroup of patients with eGFR 45-59 ml/min/1.73 m² | 12 weeks | 
| difference in E/E' ratio (change from baseline (V1) to 12 weeks follow-up) in the subgroup of patients with HbA1c 6.5%-6.9% | difference in E/E' ratio (noninvasive surrogate marker for left ventricular diastolic function (LVEDP) measured by 2D-echocardiography) between 12 weeks after baseline and at baseline in the subgroup of patients with with HbA1c 6.5%-6.9% | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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empagliflozin, diastolic function, poorly controlled type 2 diabetes mellitus