Effects of Dapagliflozin and Metformin on Vascular Function in Newly-Diagnosed Treatment-Naive Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
Trial Design: This is a 12 week randomised controlled open label trial comparing the impact of Dapagliflozin, Metformin and combination therapy on vascular function in newly diagnosed T2DM patients.

Detailed Description
-----------------
Trial Design: This is a 12 week randomised controlled open label trial comparing the impact of Dapagliflozin, Metformin and combination therapy on vascular function in newly diagnosed T2DM patients. Trial Participants: Approximately 150 newly diagnosed T2DM patients with randomization 1:1:1 to Metformin XR 500mg twice daily, Dapagliflozin 10 mg daily or Metformin XR 500/Dapagliflozin 5 mg daily Primary Aim : To evaluate the influence of intervention on vascular function. Secondary Aims: To evaluate the influence on other parameters of vascular function and beds. To evaluate the haemodynamics involving blood pressure regulation. To evaluate the effects of SGLT2i versus Metformin on endothelial interactions (vascular permeability) and leukocyte-endothelial interactions (leukocyte rolling, adherence), endothelial regenerative capacity and other endothelial related pathways.

Official Title
-----------------
Effects of Dapagliflozin and Metformin on Vascular Function in Newly-Diagnosed Treatment-Naive Type 2 Diabetes- A Randomised Controlled Trial (DMVascular Study)

Conditions
-----------------
Diabetes

Intervention / Treatment
-----------------
* Drug: Dapagliflozin
* Drug: MetFORMIN 500 Mg Oral Tablet
* Drug: Dapagliflozin / metFORMIN Pill


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ability to give informed consent Age 30-65 years Newly diagnosed (within the past 1 - 2 years) to have T2DM and not started on diabetes medications, HbA1c 6.4% to 10% (both inclusive) and/or OGTT 0 min glucose ≥7.0mmol/L and/or 120 min glucose ≥11.8mmol/L OR Recently diagnosed to have T2DM and treated with Metformin for not more than 5 years, HbA1c ≤ 8% No recent change in medications or new medications eGFR>60mL/min/1.73m2 Patient is otherwise well with no acute systemic illness in the last 2 weeks. Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the trial Exclusion Criteria: History of ketoacidosis or any other conditions causing acidosis e.g. Alcohol dependence Has a history of urinary tract infections or is at risk for urinary tract infections (e.g prostatomegaly, vesicoureteric reflux, kidney stones) Patients on corticosteroids or immunosuppressive agents Patients known to have HIV infection and/or on anti-retroviral agents Patients with typical clinical features suggestive of T1DM (young onset with no family history of diabetes or first presentation as DKA were excluded). The endocrinologist (PI or co-I) will look at the patient profile to confirm diagnosis of T2DM. Has severe liver dysfunction Considered inappropriate by investigators due to any other reason. Female participant who is pregnant, lactating or planning pregnancy during the course of the trial. Significant renal impairment. Scheduled elective surgery or other procedures requiring general anaesthesia during the trial. Participants who have participated in another research trial involving an investigational product in the past 12 weeks. Participants who have a history of Peripheral Arterial Disease or peripheral vascular disease or complains of lower limb claudication pain. -

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open Label Parallel Randomised Controlled Trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin<br>Metformin XR 500 mg tablets - up-to twice daily orally. | Drug: MetFORMIN 500 Mg Oral Tablet<br>* Metformin 500 mg tablets twice daily<br>|
| Experimental: Dapagliflozin<br>Dapagliflozin 10 mg tablets - once daily | Drug: Dapagliflozin<br>* Dapagliflozin 10mg tablets<br>|
| Experimental: MetforminXR 500/Dapagliflozin 5mg<br>MetforminXR 500/Dapagliflozin 5mg , tablets- once daily | Drug: Dapagliflozin / metFORMIN Pill<br>* Combination pill<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelial Function measured as reactive hyperaemia index (RHI-EndoPAT) |  | 3 months after initiation | 
| Carotid Femoral Pulse Wave Velocity | Sphygmocor determined cf-PWV | 3 months after initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Augmentation index | Augmentation index-sphygmocor derived and RHI-endoPAT derived | 3 months after initiation | 
| Central pulse pressure | CPP-Sphygmocor derived | 3 months after initiation | 
| Advanced glycation end products | AGE reader measurements | 3 months after initiation |