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Trial record 1 of 1 for:    Randomized, double-blind, placebo controlled, crossover clinical study to analyse the effect of empagliflozin
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Effect of Empagliflozin on Macrovascular and Microvascular Circulation and on Endothelium Function

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02471963
First Posted: June 15, 2015
Last Update Posted: October 31, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Roland E. Schmieder, University of Erlangen-Nürnberg Medical School
  Purpose
Empagliflozin may lead to improved vascular and endothelial function in the macro- (pulse wave reflection) and microcirculation (retinal circulation) and improve cardiovascular risk factors, imparticular by effectively controlling hyperglycemia, arterial hypertension and obesity.

Condition Intervention Phase
Diabetes Mellitus Type 2 Drug: Empagliflozin Drug: Placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Randomized, Double-blind, Placebo Controlled, Crossover Clinical Study to Analyse the Effect of Empagliflozin on Macrovascular and Microvascular Circulation and on Endothelium Function

Resource links provided by NLM:


Further study details as provided by Roland E. Schmieder, University of Erlangen-Nürnberg Medical School:

Primary Outcome Measures:
  • Effect of empagliflozin after 6 weeks of treatment on macrocirculation [ Time Frame: 6 weeks ]
    To analyse the effect of empagliflozin after 6 weeks of treatment on macrocirculation as assessed by the pulse wave reflection in the peripheral arterial tree with the composite parameters: central (aortic) systolic pressure, central (aortic) pulse pressure, augmentation pressure, forward wave amplitude, backward wave amplitude and the ratio of forward and backward (pulse wave velocity) compared to placebo.


Secondary Outcome Measures:
  • Effect of empagliflozin after 6 weeks of treatment on microcirculation [ Time Frame: 6 weeks ]
    To analyse the effect of empagliflozin after 6 weeks of treatment on retinal capillary flow (as key measurement of vascular remodeling in the microcirculation) and retinal vascular structural components.

  • Endothelium Function [ Time Frame: 6 weeks ]
    To analyse the effect of empagliflozin after 6 weeks of treatment on peripheral endothelial function by measuring endothelium-mediated changes in arterial tone using a reactive hyperemia procedure

  • Biomarkers [ Time Frame: 6 weeks ]
    To analyse the effect of empagliflozin after 6 weeks of treatment on biomarkers for inflammation, metabolic disorders and albuminuria.


Enrollment: 74
Study Start Date: December 2014
Study Completion Date: June 2016
Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Empagliflozin
Empagliflozin, 25 mg/day, oral administration, 6 weeks
Drug: Empagliflozin
Other Name: Jardiance
Placebo Comparator: Placebo
Placebo, oral administration, 6 weeks
Drug: Placebo

Detailed Description:

Diabetes mellitus, considered as a metabolic disorder, mutates into a predominantly vascular disease, once its duration extends over several years and/or when additional cardiovascular risk factors coexists, in particular arterial hypertension. In accordance, patients with type 2 diabetes die because of microvascular and macrovascular complications, and only rarely because of hypoglycaemic or hyperglycaemic shock syndromes. As a consequence, treatment of type 2 diabetes should focus not only on metabolic control but also on improving the global vascular risk. Analyses that have compared the importance of the various cardiovascular risk factors concluded that reductions of blood pressure and lipid levels are significantly more important than reduction of hyperglycemia. Of course, a multidisciplinary approach is desirable and the STENO-2 study has clearly indicated that in mid-term microvascular complications and in long-term macrovascular complications can be prevented in type 2 diabetes.

Vascular changes occurring in the course of type 2 diabetes, arterial hypertension and elevated global cardiovascular risk can now reliably assessed non-invasively, and already at the very early stage of vascular remodeling processes. For example, the guidelines of the European Society of Hypertension recommend several vascular parameters to be assessed already at the diagnosis of the disease in order to analyze early organ damage of the arteries. The measurement of pulse wave velocity, pulse wave analysis, central (aortic) systolic pressure and pulse pressure are tools to detect early vascular changes in the large arteries related to a faster wave reflection in the arterial tree. Wall to lumen ratio of retinal arteries, retinal capillary flow and flow mediated vasodilation are tools to detect changes in the microvascular circulation. These parameters are only infrequently measured in studies with type 2 diabetes, mainly due to lack of awareness that the vascular changes are the key prognostic factor in type-2 diabetes that ultimately determine the fate of the patient.

Empagliflozin is a novel selective SLGT-2 inhibitor that has been shown to improve glycaemic control after 2, 12, and 24 weeks as well as after 1 and 2 years. Empagliflozin produced dose dependent increases in glucosuria and clinically meaningful changes of glycemic parameters in type 2 diabetes in addition to weight loss. Most striking, empagliflozin was also found to lower systolic blood pressure by 5 mmHg. This reduction in blood pressure might be related to weight loss or/and concomitant loss of total body sodium content. However, the precise mechanism of the blood pressure reduction needs to be elucidated. Loss of sodium would lead to a less reactive contraction of the small arteries in response to increased sympathetic activity, angiotensin II and catecholamines.

Moreover, the endothelium dependent vasodilation after reactive hyperemia is a new non-invasive tool to detect changes on the organ perfusion level. To further assess flow-mediated/Endothelium dependent vasodilation we can assess the EndoPAT Risk Score.

These parameters are only infrequently measured in studies with type 2 diabetes, mainly due to the lack of expertise required to assess these vascular parameters and lack of awareness that vascular changes are the key prognostic factor in type 2 diabetes (and not glycosylated hemoglobin).

In summary, empagliflozin exert beneficial effects on a variety of cardiovascular risk factors, such as hyperglycaemia, hypertension and obesity. These changes should lead (so the hypothesis) to improved vascular and endothelial function in the micro- and macrocirculation.

However, the latter is nothing more than hypothesis and requires clear proof by clinical studies in patients with type 2 diabetes.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes mellitus defined by fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% or on blood glucose lowering medication
  • Age of 18 - 75 years
  • Male and Female patients (females of child bearing potential must be using adequate contraceptive precautions)
  • Females of childbearing potential or within two years of the menopause must have a negative urine pregnancy test at screening visit
  • Informed consent (§ 40 Abs. 1 Satz 3 Punkt 3 AMG) has to be given in written form.

Exclusion Criteria:

  • Any other form of diabetes mellitus than type 2 diabetes mellitus
  • Use of insulin, glitazone, gliptine or SGLT-2 inhibitor within the past 3 months
  • Patients with more than one oral blood glucose lowering medication
  • Any other oral antidiabetic drug that cannot be discontinued for the study period
  • HbA1c ≥ 10%
  • Fasting plasma glucose > 240 mg/dl
  • Any history of stroke, transient ischemic attack, instable angina pectoris, or myocardial infarction within the last 6 months prior to study inclusion
  • UACR ≥ 300 mg/g (early morning spot urine)
  • eGFR < 60 ml/min/1.73m²
  • Uncontrolled arterial hypertension (RR ≥ 180/110 mmHg)
  • Congestive heart failure (CHF) NYHA stage III and IV
  • Severe disorders of the gastrointestinal tract or other diseases which interfere the pharmacodynamics and pharmakinetics of study drugs
  • Significant laboratory abnormalities such as SGOT or SGPT levels more than 3 x above the upper limit of normal range
  • Drug or alcohol abusus
  • Pregnant or breast-feeding patients
  • Use of loop diuretics
  • History of repetitive urogenital infection per year
  • Body mass index > 40 kg/m²
  • Triglyceride levels > 1000 mg/dl
  • HDL-cholesterol levels < 25 mg/dl
  • Any patient currently receiving chronic (>30 consecutive days) treatment with an oral corticosteroid
  • History of epilepsia or history of seizures
  • Patients being treated for severe auto immune disease e.g. lupus
  • Participation in another clinical study within 30 days prior to visit 1
  • Individuals at risk for poor protocol or medication compliance
  • Subject who do not give written consent, that pseudonymous data will be transferred in line with the duty of documentation and the duty of notification according to § 12 and § 13 GCP-V
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02471963


Locations
Germany
University of Erlangen-Nuremberg
Erlangen, Bavaria, Germany, 91054
Sponsors and Collaborators
University of Erlangen-Nürnberg Medical School
Investigators
Principal Investigator: Roland E Schmieder, Prof. Department of Medicine 4, University of Erlangen-Nuernberg
  More Information

Responsible Party: Roland E. Schmieder, Prof. Dr. med. Roland E. Schmieder, University of Erlangen-Nürnberg Medical School
ClinicalTrials.gov Identifier: NCT02471963     History of Changes
Other Study ID Numbers: CRC2014EMPA
First Submitted: June 5, 2015
First Posted: June 15, 2015
Last Update Posted: October 31, 2016
Last Verified: October 2016

Keywords provided by Roland E. Schmieder, University of Erlangen-Nürnberg Medical School:
Empagliflozin
Diabetes mellitus
Macro- and Microcirculation
Vascular Improvement
Endothelium function

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Empagliflozin
Hypoglycemic Agents
Physiological Effects of Drugs