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Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content (Dapa)

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ClinicalTrials.gov Identifier: NCT02383238
Recruitment Status : Completed
First Posted : March 9, 2015
Last Update Posted : May 11, 2018
Sponsor:
Information provided by (Responsible Party):
Roland E. Schmieder, University of Erlangen-Nürnberg Medical School

Tracking Information
First Submitted Date  ICMJE July 24, 2014
First Posted Date  ICMJE March 9, 2015
Last Update Posted Date May 11, 2018
Study Start Date  ICMJE March 2014
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 2, 2015)
Microcirculation [ Time Frame: 6 weeks ]
To analyse the effects after 6 weeks of treatment with dapagliflozin on retinal capillary flow (given as AU) as the key measurement of vascular remodeling in the microcirculation compared to placebo.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2015)
Macrovascular circulation [ Time Frame: 6 weeks ]
To analyse the effects after 6 weeks of treatment with dapagliflozin on central (aortic) systolic pressure, central (aortic) pulse pressure and augmentation pressure, on retinal capillary flow after flicker light exposure, parameters that all are determined by pulse wave reflection (i.e. arterial wall properties) in the arterial tree compared to placebo.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
Official Title  ICMJE Randomized, Placebo Controlled, Crossover Clinical Study to Analyse the Effect of Dapagliflozin on Microvascular and Macrovascular Circulation and Total Body Sodium Content
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus Type 2
Intervention  ICMJE
  • Drug: Dapagliflozin
    10 mg, oral for 6 weeks
    Other Name: Forxiga
  • Drug: Placebo
    oral for 6 weeks
Study Arms  ICMJE
  • Active Comparator: Dapagliflozin
    Dapagliflozin, 10 mg/day, oral administration, 6 weeks
    Intervention: Drug: Dapagliflozin
  • Placebo Comparator: Placebo
    Placebo, oral administration, 6 weeks
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 9, 2018)
59
Original Estimated Enrollment  ICMJE
 (submitted: March 2, 2015)
63
Actual Study Completion Date  ICMJE October 2015
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Type 2 diabetes
  2. HbA1c > 6.5%
  3. age > 18 years
  4. male and females

Exclusion Criteria:

  1. age > 75 years
  2. HbA1c > 10 %,
  3. reduced renal function (eGFR < 60 ml/min/1.73 m²).
  4. insulin therapy, or any antidiabetic medication other than metformin.
  5. uncontrolled hypertension (> 180/>110 mmHg)
  6. cardiovascular event within the last 3 months
  7. Use of loop diuretics
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02383238
Other Study ID Numbers  ICMJE MB102-210
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Roland E. Schmieder, University of Erlangen-Nürnberg Medical School
Study Sponsor  ICMJE University of Erlangen-Nürnberg Medical School
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Roland Schmieder, Prof. Department of Medicine 4, University of Erlangen-Nuernberg
PRS Account University of Erlangen-Nürnberg Medical School
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP