Effect of Empagliflozin on Macrovascular and Microvascular Circulation and on Endothelium Function
Condition: Diabetes Mellitus Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

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.
    

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.
    

Intervention name(s): Empagliflozin; Placebo
Intervention type(s): Drug; Drug
Other intervention name(s): Jardiance
Intervention MeSH terms: Empagliflozin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Empagliflozin; Diabetes mellitus; Macro- and Microcirculation; Vascular Improvement; Endothelium function