Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
Condition: Diabetes Mellitus Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      Dapagliflozin leads to improved vascular function in the micro- and macrocirculation by
      action on various cardiovascular risk factors, in particular by effectively controlling
      hyperglycemia, arterial hypertension and reducing whole sodium content amongst others.
    

Detailed description: 
      Diabetes mellitus, considered at the beginning as a metabolic disorder, mutates into a
      predominantly vascular disease, once its duration extends over several years or/and when
      additional cardiovascular risk factors coexist, 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
      [1]. 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
      [2]. 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 [3].

      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

      #0284 CSP 130911 v1.4.docx 8 parameters to be assessed already at the diagnosis of the
      disease in order to analyze early organ damage of the arteries [4]. 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 [5]. Wall to lumen ratio of retinal arteries, retinal
      capillary flow and flow mediated vasodilation are tools to detect changes in the
      microvascular circulation [6]. 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.

      Dapagliflozin 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. Dapagliflozin produced dose
      dependent increases in glucosuria and clinically meaningful changes of glycemic parameters in
      type 2 diabetes in addition to weight loss. Most striking, dapagliflozin 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 [7] and catecholamines.

      In summary, dapagliflozin 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 function in the micro- and macrocirculation. Moreover,
      increased total body content of sodium that now can be measured in humans by a specific MRI
      technique [8] may also be reduced by dapagliflozin that may lead to less vasoreactive
      responses since the tubular SGLT-2 mediated glucose uptake is sodium related, i.e. blockade
      should lead to sodium loss. However, the latter is nothing more than hypothesis and requires
      clear proof by clinical studies in patients with type 2 diabetes.
    

Intervention name(s): Dapagliflozin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 10 mg, oral for 6 weeks; oral for 6 weeks
Other intervention name(s): Forxiga
Intervention MeSH terms: Dapagliflozin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Dapagliflozin; diabetes mellitus; vascular