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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

59 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-03-31

Study Completion Date

2015-10-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Diabetes Mellitus Type 2

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Dapagliflozin

Dapagliflozin, 10 mg/day, oral administration, 6 weeks

Group Type ACTIVE_COMPARATOR

Dapagliflozin

Intervention Type DRUG

10 mg, oral for 6 weeks

Placebo

Placebo, oral administration, 6 weeks

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

oral for 6 weeks

Interventions

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Dapagliflozin

10 mg, oral for 6 weeks

Intervention Type DRUG

Placebo

oral for 6 weeks

Intervention Type DRUG

Other Intervention Names

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Forxiga

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No