Effect of Dapagliflozin on Vascular Functions in Patients With Type 2 Diabetes Compared to Gliclazide

Study Overview
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Brief Summary
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The investigators set up a clinical trial to compare effect of dapagliflozin, a sodium glucose co-transporter 2 inhibitor, with gliclazide on vascular function in patients with type 2 diabetes

Detailed Description
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Obesity, and especially visceral/abdominal adiposity, is associated with diabetes and increased cardiovascular risk. In previous randomized, double-blind, placebo-controlled study, dapagliflozin reduced total body weight, predominantly by reducing fat mass, visceral adipose tissue and sc adipose tissue in type 2 diabetes. This study supported that caloric loss from glycosuria, and not fluid loss, was principally responsible for decrease in total body weight and fat mass. In fact, there have been several reports proving that inhibition of SGLT2 improves β-cell function and reduces body weight and blood pressure. However, effects of SGLT2 inhibitors on lipid profiles have not been decided yet in patients with type 2 diabetes. Furthermore, there are few data to demonstrate the effects of SGLT2 inhibitors on CV risk. Many systems and pathways are involved in development of atherosclerosis in the arterial wall. Accumulating evidence suggests that endothelial dysfunction plays an important role particularly in the first stage of atherogenesis in patients with diabetes. Approaches designed to improve endothelial function may therefore have additional therapeutic value in the prevention and treatment of atherosclerotic disease. Endothelial dysfunction is related to decreased production and bioavailability of nitric oxide (NO). Endothelial function was measured through several circulating biomarker such as NO, endothelin-1 or non-invasive techniques such as flow-mediated dilation (FMD), skin laser doppler. Among them, FMD is known to as the optimal tool. In addition, several noninvasive techniques including measurement of the ankle-brachial index (ABI), carotid intima-media thickness (IMT) and pulse wave velocity (PWV) have been used for evaluation of atherosclerosis. If a participant's HbA1c dose not decreas by >0.4% at 12 weeks, rescue therapy can be added at the investigator's discretion.

Official Title
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Effect of Dapagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, on Vascular Functions in Patients With Type 2 Diabetes Compared to Gliclazide

Conditions
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Diabetes

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Gliclazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes with HbA1c ≥ 7.5% at screening visit Male or female between 40 and 70 years of age Patients taking metformin (≥ 1000 mg or maximum tolerated dose) for more than 3 months BMI ≥23 kg/m² Estimated GFR ≥ 60 ml/min/1.73m² Exclusion Criteria: Patients with acute coronary syndrome within 3 months prior to screening visit Pregnant or breast feeding women or reproductive-age women who refuse contraception Type 1 diabetes, gestational diabetes, or diabetes with secondary cause Chronic hepatitis B or C (except healthy carrier of HBV), liver disease (AST/ALT > 3-fold the upper limit of normal) Cancer within 5 years (except squamous cell cancer, cervical cancer, thyroid cancer with appropriate treatment) except thyroid cancer or carcinoma in situ Other clinical trial within 30 days Alcohol abuse Contraindication to SGLT2 inhibitors or sulfonylurea

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin<br>Dapagliflozin will be started in patient with type 2 diabetes mellitus | Drug: Dapagliflozin<br>* Dapagliflozin 10 mg, orally once daily at any time of day with or without food. If HbA1c does not decrease by > 0.4% at 12 week, rescue therapy (sitagliptin 100 mg) can be added at investigator's discretion.<br>* Other names: Forxiga;|
| Active Comparator: Gliclazide<br>Gliclazide will be started in patient with type 2 diabetes mellitus | Drug: Gliclazide<br>* Gliclazide MR 30 mg, orally once daily at any time of day with or without food. If HbA1c does not decrease by > 0.4% at 12 week, rescue therapy (gliclazide MR 30 mg) can be added at investigator's discretion.<br>* Other names: Diamicron MR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vascular function assessed by Flow-mediated vasodilation (FMD) | The diameter of the target artery is measured by high-resolution external vascular ultrasound in response to an increase in blood flow (causing shear-stress) during reactive hyperaemia (induced by cuff inflation and then deflation). This leads to endothelium-dependent dilatation; the response is contrasted with that to sublingual nitroglycerin, an endothelium-independent dilator. The artery is scanned and the diameter measured during three conditions; at baseline, during reactive hyperaemia (induced by inflation and then deflation of a sphygmomanometer cuff around the limb, distal to the scanned part of the artery) and finally after administration of sublingual nitroglycerin (which causes endothelium-independent smooth muscle mediated vasodilatation). | 24weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of blood pressure |  | 24weeks | 
| Lipid metabolism assessed by triglyceride, low density lipoprotein-cholesterol and high density lipoprotein-cholesterol |  | 24weeks | 
| Inflammatory markers assessed by hsCRP |  | 24weeks | 
| Change of body composition assessed by bioelectrical impedance analysis (BIA) methods |  | 24weeks | 
| Glucose metabolism assessed by glycated hemoglobin and fasting plasma glucose |  | 24weeks | 
| Microcirculation assessed by laser doppler |  | 24weeks | 
| Vascular health assessment by pulse wave velocity (PWV) | PWV, by definition, is the distance traveled (Delta x) by the wave divided by the time (Delta t) for the wave to travel that distance | 24weeks | 
| Vascular health assessment by Ankle-brachial index (ABI) | The ankle-brachial pressure index (ABPI) or ankle-brachial index (ABI) is the ratio of the blood pressure at the ankle to the blood pressure in the upper arm (brachium). | 24weeks | 
| Carotid intima-media thickness (cIMT) assessed by ultrasound | Intima-media thickness (IMT), also called intimal medial thickness, is a measurement of the thickness of tunica intima and tunica media, the innermost two layers of the wall of an artery. | 24weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Atherosclerosis, Cardiovascular disease, Endothelial dysfunction, Vascular function, Dapagliflozin, Gliclazide