Clinical trial NCT05139914: Assessment of Dapagliflozin on Vascular Health in Patients With Type 2 Diabetes
Official title: Assessment of Dapagliflozin on Vascular Health in Patients With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Endothelial Dysfunction
Keywords: Sodium-Glucose Cotransporter-2 (SGLT2) inhibitor
Dapagliflozin
Endothelial cell (EC) Health
Vascular function
EC gene expression levels
Circulating miRNA
Biomarkers
Lead sponsor: Boston University
Sponsor class: OTHER
Collaborators: name: American Heart Association
First posted: 2021-12-01
Enrollment: 50
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Insulin-mediated endothelial nitric oxide synthase (eNOS) phosphorylation measured in endothelial cells (ECs) at 6 weeks
timeFrame: 6 weeks
measure: Insulin-mediated endothelial nitric oxide synthase (eNOS) phosphorylation measured in endothelial cells (ECs) at 14 weeks
timeFrame: 14 weeks
Secondary outcomes:
measure: Flow-mediated dilation of the brachial artery at 6 weeks
timeFrame: 6 weeks
measure: Flow-mediated dilation of the brachial artery at 14 weeks
timeFrame: 14 weeks
measure: Arterial stiffness at 6 weeks
timeFrame: 6 weeks
measure: Arterial stiffness at 14weeks
timeFrame: 14 weeks
measure: Microvascular dilator function by EndoPAT at 6 weeks
timeFrame: 6 weeks
measure: Microvascular dilator function by EndoPAT at 14 weeks
timeFrame: 14 weeks
measure: Plasma non-coding RNA (ncRNA) measurement at 6 weeks
timeFrame: 6 weeks
measure: Plasma non-coding RNA (ncRNA) measurement at 14 weeks
timeFrame: 14 weeks
measure: EC measures of noncoding RNA at 6 weeks
timeFrame: 6 weeks
measure: EC measures of noncoding RNA at 14 weeks
timeFrame: 14 weeks
measure: EC measures of coding RNA at 6 weeks
timeFrame: 6 weeks
measure: EC measures of coding RNA at 14 weeks
timeFrame: 14 weeks
measure: Circulating brain natriuretic peptide (BNP) biomarkers of vascular health at 6 weeks
timeFrame: 6 weeks
measure: Circulating brain natriuretic peptide (BNP) biomarkers of vascular health at 14 weeks
timeFrame: 14 weeks
measure: Circulating C-reactive protein (CRP) biomarkers of vascular health at 6 weeks
timeFrame: 6 weeks
measure: Circulating C-reactive protein (CRP) biomarkers of vascular health at 14 weeks
timeFrame: 14 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: BU School of Medicine Evans 748
state: Massachusetts
Study officials:
affiliation: BU School of Medicine, Cardiovascular Medicine
name: Naomi M Hamburg, MD
role: PRINCIPAL_INVESTIGATOR
References: