Assessment of Dapagliflozin on Vascular Health in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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Patients with Type 2 Diabetes Mellitus (T2DM) have changes in blood vessel health that can lead to a higher chance of developing heart attacks or strokes. New medications for T2DM including dapagliflozin, which is a Sodium-Glucose Cotransporter-2 inhibitor (SGLT2) inhibitor, may help protect the heart and blood vessels. The overarching objective of this mechanistic study is to learn how a Sodium-Glucose Cotransporter-2 (SGT2) inhibitor, dapagliflozin, impacts vascular health in patients with Type 2 Diabetes Mellitus (T2DM). The investigators will compare the changes in vascular health to changes in endothelial cell (EC) phenotype including non-coding RNA (ncRNA) to develop evidence supporting the mechanism of cardiovascular benefit of SGLT2 inhibitors. This study will provide novel information regarding the mechanism of effects of novel treatments for endothelial function and vascular health in patients with T2DM to reduce cardiovascular (CV) risk. The research aims to assess the: effects of dapagliflozin on EC phenotype. impact of dapagliflozin on vasodilator function and additional measures of vascular health including arterial stiffness and circulating markers of vascular health.

Detailed Description
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The study design is a two-treatment, two-period crossover, double-blind, placebo-controlled design study to investigate the effect of the SGLT2 inhibitor, dapagliflozin, on EC phenotype, EC RNA levels, circulating microRNA (miRNA), and biomarkers in patients with T2DM. Subjects will be randomized to treatment order in a 1:1 ratio to receive SGLT2 inhibitor (dapagliflozin) and then placebo or vice versa in a crossover design. Total study period for each study subject is 14 weeks consisting of: two treatment periods (dapagliflozin and placebo) lasting 6 weeks each (12 weeks total) and a 2 week washout period between treatment periods. Each subject undergoes a washout period of 2 weeks after completing first 6 weeks of treatment with either placebo or dapagliflozin. This is followed by crossover to the alternate treatment period of 6 weeks with dapagliflozin or placebo depending on their first treatment. Randomization will be done in block sizes of 2 or 4. Once assigned to treatment, participants will receive dapagliflozin 10 mg/day or placebo for 6 weeks.

Official Title
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Assessment of Dapagliflozin on Vascular Health in Patients With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2, Endothelial Dysfunction

Intervention / Treatment
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* Drug: Dapagliflozin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of T2DM for minimum of 3 months defined as fasting glucose greater than or equal to 120 mg/dL, hemoglobin A1C (HbA1C) ≥6.5% Body mass index (BMI) >25 Willing to give written informed consent and able to understand, to participate in and to comply with the study requirements. Exclusion Criteria: Treatment with anticoagulation Treatment with SGLT-2 inhibitor HbA1c >9.5% within the last 3 months Systolic blood pressure less than 120mm Hg History of genital mycotic infections: more than one genital mycotic infection in the past two years History of recurrent urinary tract infections: history of chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year) History of allergy to SGLT-2 inhibitor History of bladder cancer or prior pelvic radiation More than one hypoglycemic events in the past 6 months and/or HbA1c <7.0% Women lactating or pregnant. All women with childbearing potential will undergo a blood pregnancy test at each visit to exclude pregnancy. Treatment with an investigational product within the last 30 days. Clinically evident major illness of other organ systems, including clinically evident cancer, renal failure (GFR<60 mL/min), or other conditions that in the opinion of the principal investigator make a clinical study inappropriate

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin then Placebo<br>Participants in this arm will receive dapagliflozin and then placebo with a 2 week wash out period in between. | Drug: Dapagliflozin<br>* 10 mg/day (in capsule form) of dapagliflozin for 6 weeks<br>* Other names: Sodium-Glucose Cotransporter-2 (SGLT2) inhibitor;Other: Placebo<br>* Placebo capsule for 6 weeks<br>|
| Placebo Comparator: Placebo then dapagliflozin<br>Participants in this arm will receive placebo and then dapagliflozin with a 2 week wash out period in between. | Drug: Dapagliflozin<br>* 10 mg/day (in capsule form) of dapagliflozin for 6 weeks<br>* Other names: Sodium-Glucose Cotransporter-2 (SGLT2) inhibitor;Other: Placebo<br>* Placebo capsule for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin-mediated endothelial nitric oxide synthase (eNOS) phosphorylation measured in endothelial cells (ECs) at 6 weeks | The percentage change in the phosphorylation of eNOS is measured using quantitative immunofluorescence microscopy in EC collected before and after each treatment period. | 6 weeks | 
| Insulin-mediated endothelial nitric oxide synthase (eNOS) phosphorylation measured in endothelial cells (ECs) at 14 weeks | The percentage change in the phosphorylation of eNOS is measured using quantitative immunofluorescence microscopy in EC collected before and after each treatment period. | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow-mediated dilation of the brachial artery at 6 weeks | The percentage change in the diameter of the brachial artery will be measured before and after a 5 minute cuff occlusion on the arm as a measure of endothelial cell (EC) function. | 6 weeks | 
| Flow-mediated dilation of the brachial artery at 14 weeks | The percentage change in the diameter of the brachial artery will be measured before and after a 5 minute cuff occlusion on the arm as a measure of endothelial cell (EC) function. | 14 weeks | 
| Arterial stiffness at 6 weeks | Arterial stiffness/compliance of the central aorta and upper extremity will be assessed by measuring carotid-femoral and carotid-radial pulse wave velocity (PWV). A small probe is used to record signals from the carotid, radial, and femoral arteries. | 6 weeks | 
| Arterial stiffness at 14weeks | Arterial stiffness/compliance of the central aorta and upper extremity will be assessed by measuring carotid-femoral and carotid-radial pulse wave velocity (PWV). A small probe is used to record signals from the carotid, radial, and femoral arteries. | 14 weeks | 
| Microvascular dilator function by EndoPAT at 6 weeks | EndoPAT is a noninvasive test to measure the amount of blood flow through the arteries. It determines if the artery is healthy. | 6 weeks | 
| Microvascular dilator function by EndoPAT at 14 weeks | EndoPAT is a noninvasive test to measure the amount of blood flow through the arteries. It determines if the artery is healthy. | 14 weeks | 
| Plasma non-coding RNA (ncRNA) measurement at 6 weeks | Non-coding RNAs (ncRNAs) levels will be assessed using quantitative polymerase chain reaction (PCR) of RNA isolated from plasma. | 6 weeks | 
| Plasma non-coding RNA (ncRNA) measurement at 14 weeks | Non-coding RNAs (ncRNAs) levels will be assessed using quantitative PCR of RNA isolated from plasma. | 14 weeks | 
| EC measures of noncoding RNA at 6 weeks | Non-coding RNA levels will be assessed using quantitative PCR of RNA isolated from endothelial cells. | 6 weeks | 
| EC measures of noncoding RNA at 14 weeks | Non-coding RNA levels will be assessed using quantitative PCR of RNA isolated from endothelial cells. | 14 weeks | 
| EC measures of coding RNA at 6 weeks | RNA levels will be assessed using quantitative PCR of RNA isolated from endothelial cells. | 6 weeks | 
| EC measures of coding RNA at 14 weeks | RNA levels will be assessed using quantitative PCR of RNA isolated from endothelial cells. | 14 weeks | 
| Circulating brain natriuretic peptide (BNP) biomarkers of vascular health at 6 weeks | A BNP result greater than 100 pg/mL is abnormal. | 6 weeks | 
| Circulating brain natriuretic peptide (BNP) biomarkers of vascular health at 14 weeks | A BNP result greater than 100 pg/mL is abnormal. | 14 weeks | 
| Circulating C-reactive protein (CRP) biomarkers of vascular health at 6 weeks | Normal CRP is <10 mg/L. Results 10 or greater are considered abnormal. | 6 weeks | 
| Circulating C-reactive protein (CRP) biomarkers of vascular health at 14 weeks | Normal CRP is <10 mg/L. Results 10 or greater are considered abnormal. | 14 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sodium-Glucose Cotransporter-2 (SGLT2) inhibitor, Dapagliflozin, Endothelial cell (EC) Health, Vascular function, EC gene expression levels, Circulating miRNA, Biomarkers