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
Overview
- Phase
- Phase 4
- Intervention
- Empagliflozin
- Conditions
- Diabetes Mellitus, Type 2
- Sponsor
- Johannes Gutenberg University Mainz
- Enrollment
- 144
- Locations
- 1
- Primary Endpoint
- difference in E/E' ratio between 12 weeks after baseline and at baseline
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
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
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.
Investigators
Philipp Wild, MD, MSc
principal investigator
Johannes Gutenberg University Mainz
Eligibility Criteria
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)
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
Arms & Interventions
Empagliflozin
10 mg Empagliflozin daily per os for 12 weeks
Intervention: Empagliflozin
Placebo
amount of Placebo corresponding to empagliflozin 10 mg daily per os for 12 weeks
Intervention: Placebo
Outcomes
Primary Outcomes
difference in E/E' ratio between 12 weeks after baseline and at baseline
Time Frame: 12 weeks
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
Secondary Outcomes
- difference in E/E' ratio (change from baseline (V1) to 1 week follow-up)(1 week)
- difference in Left ventricular systolic function (LVEF)(12 weeks)
- difference in Carotid-femoral pulse wave velocity(12 weeks)
- difference in Augmentation index (AIx)(12 week)
- difference in Arterial stiffness index (SI)(12 weeks)
- difference in Reflection index(12 weeks)
- difference in Brain natriuretic peptide (BNP)(12 weeks)
- difference in High sensitive troponin I (hs TnI)(12 weeks)
- difference in High sensitive C-reactive protein (hs CRP)(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(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%(12 weeks)
- difference in Left end-diastolic volume (LEDV)(12 weeks)