Effect of Empagliflozin on Macrovascular and Microvascular Circulation and on Endothelium Function

Sponsor

University of Erlangen-Nürnberg Medical School (Other)

Overall Status

Completed

CT.gov ID

NCT02471963

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

4.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Diabetes Mellitus Type 2	Drug: Empagliflozin Drug: Placebo	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

74 participants

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

Study Start Date :

Dec 1, 2014

Actual Primary Completion Date :

Nov 1, 2015

Actual Study Completion Date :

Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Empagliflozin Empagliflozin, 25 mg/day, oral administration, 6 weeks	Drug: Empagliflozin Other Names: Jardiance
Placebo Comparator: Placebo Placebo, oral administration, 6 weeks	Drug: Placebo

Arm

Intervention/Treatment

Active Comparator: Empagliflozin

Empagliflozin, 25 mg/day, oral administration, 6 weeks

Drug: Empagliflozin

Other Names:

Jardiance

Placebo Comparator: Placebo

Placebo, oral administration, 6 weeks

Drug: Placebo

Outcome Measures

Primary Outcome Measures

Effect of empagliflozin after 6 weeks of treatment on macrocirculation [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 [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 [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 [6 weeks]
To analyse the effect of empagliflozin after 6 weeks of treatment on biomarkers for inflammation, metabolic disorders and albuminuria.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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