Effect of Empagliflozin on Macrovascular and Microvascular Circulation and on Endothelium Function
|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.|
|ClinicalTrials.gov Identifier: NCT02471963|
Recruitment Status : Completed
First Posted : June 15, 2015
Last Update Posted : May 15, 2018
|Condition or disease||Intervention/treatment||Phase|
|Diabetes Mellitus Type 2||Drug: Empagliflozin Drug: Placebo||Phase 3|
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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||74 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||Double (Participant, Investigator)|
|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 :||December 2014|
|Actual Primary Completion Date :||November 2015|
|Actual Study Completion Date :||June 2016|
Active Comparator: Empagliflozin
Empagliflozin, 25 mg/day, oral administration, 6 weeks
Other Name: Jardiance
Placebo Comparator: Placebo
Placebo, oral administration, 6 weeks
- 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.
- 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.
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
|University of Erlangen-Nuremberg|
|Erlangen, Bavaria, Germany, 91054|
|Principal Investigator:||Roland E Schmieder, Prof.||Department of Medicine 4, University of Erlangen-Nuernberg|