Clinical trial NCT02932436: Effects of Empagliflozin on Left Ventricular Diastolic Function Compared to Usual Care in Type 2 Diabetics
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Diastolic Dysfunction
Keywords: empagliflozin
diastolic function
poorly controlled type 2 diabetes mellitus
Lead sponsor: Johannes Gutenberg University Mainz
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2016-10-13
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Maximum age (years): 84
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)
  * 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)

Primary outcomes:
measure: difference in E/E' ratio between 12 weeks after baseline and at baseline
timeFrame: 12 weeks
Secondary outcomes:
measure: difference in E/E' ratio (change from baseline (V1) to 1 week follow-up)
timeFrame: 1 week
measure: difference in Left ventricular systolic function (LVEF)
timeFrame: 1 week
measure: difference in Left ventricular systolic function (LVEF)
timeFrame: 12 weeks
measure: difference in Left end-diastolic volume (LEDV)
timeFrame: 1 week
measure: difference in Left end-diastolic volume (LEDV)
timeFrame: 12 weeks
measure: difference in Carotid-femoral pulse wave velocity
timeFrame: 1 week
measure: difference in Carotid-femoral pulse wave velocity
timeFrame: 12 weeks
measure: difference in Augmentation index (AIx)
timeFrame: 1 week
measure: difference in Augmentation index (AIx)
timeFrame: 12 week
measure: difference in Arterial stiffness index (SI)
timeFrame: 1 week
measure: difference in Arterial stiffness index (SI)
timeFrame: 12 weeks
measure: difference in Reflection index
timeFrame: 1 week
measure: difference in Reflection index
timeFrame: 12 weeks
measure: difference in Brain natriuretic peptide (BNP)
timeFrame: 1 week
measure: difference in Brain natriuretic peptide (BNP)
timeFrame: 12 weeks
measure: difference in High sensitive troponin I (hs TnI)
timeFrame: 1 week
measure: difference in High sensitive troponin I (hs TnI)
timeFrame: 12 weeks
measure: difference in High sensitive C-reactive protein (hs CRP)
timeFrame: 1 week
measure: difference in High sensitive C-reactive protein (hs CRP)
timeFrame: 12 weeks
measure: 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
timeFrame: 12 weeks
measure: 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%
timeFrame: 12 weeks
Other outcomes:
measure: difference in biomarkers of cardiac diseases
timeFrame: 1 week
measure: difference in biomarkers of cardiac diseases
timeFrame: 12 weeks
measure: difference in biomarkers of vascular diseases
timeFrame: 1 week
measure: difference in biomarkers of vascular diseases
timeFrame: 12 weeks
measure: difference in biomarkers of metabolic/diabetic status
timeFrame: 1 week
measure: difference in biomarkers of metabolic/diabetic status
timeFrame: 12 weeks
measure: changes in vascular/endothelial function
timeFrame: 1 week
measure: changes in vascular/endothelial function
timeFrame: 12 weeks
measure: changes in carotid atherosclerosis
timeFrame: 1 week
measure: changes in carotid atherosclerosis
timeFrame: 12 weeks
measure: changes in pulmonary function
timeFrame: 1 week
measure: changes in pulmonary function
timeFrame: 12 weeks
measure: changes in ophthalmological diseases
timeFrame: 1 week
measure: changes in ophthalmological diseases
timeFrame: 12 weeks
measure: changes in psychosomatic diseases
timeFrame: 1 week
measure: changes in psychosomatic diseases
timeFrame: 12 weeks
measure: association analysis for selected SNPs
timeFrame: baseline
Locations:
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Zentrum für Kardiologie, Präventive Kardiologie und Medizinische Prävention
Study officials:
affiliation: Johannes Gutenberg University Mainz
name: Philipp Wild, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Junger C, Prochaska JH, Gori T, Schulz A, Binder H, Daiber A, Koeck T, Rapp S, Lackner KJ, Munzel T, Wild PS. Rationale and design of the effects of EMpagliflozin on left ventricular DIAstolic function in diabetes (EmDia) study. J Cardiovasc Med (Hagerstown). 2022 Mar 1;23(3):191-197. doi: 10.2459/JCM.0000000000001267.