Diabetes Mellitus, Type 2, Endothelial Dysfunction
Conditions
Keywords
Sodium-Glucose Cotransporter-2 (SGLT2) inhibitor, Dapagliflozin, Endothelial cell (EC) Health, Vascular function, EC gene expression levels, Circulating miRNA, Biomarkers
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 Endothelial Cell (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. The study was terminated due to the inability to enroll the anticipated 50 participants to test the research hypotheses (only 3 participants were randomized in almost 3 years). There were too few samples to test for endothelial cell related outcomes, miRNA, and biomarkers.
Interventions
DRUGDapagliflozin
10 mg/day (in capsule form) of dapagliflozin for 6 weeks
OTHERPlacebo
Placebo capsule for 6 weeks
Sponsors
Boston University
American Heart Association
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Systolic Blood Pressure | 14 weeks | Supine blood pressures were measure in triplicate after 10 minute rest period using Omron blood pressure cuff |
| Mean Diastolic Blood Pressure | 14 weeks | Supine blood pressures were measure in triplicate after 10 minute rest period using Omron blood pressure cuff |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNaomi M Hamburg, MD
BU School of Medicine, Cardiovascular Medicine
Participant flow
Recruitment details
4 participants were enrolled but 1 was ineligible after screening so that 3 were randomized.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 |
| other Total, other adverse events | 0 / 1 | 0 / 2 |
| serious Total, serious adverse events | 0 / 1 | 0 / 2 |
Outcome results
None listed