Assessment of Dapagliflozin on Vascular Health in Patients With Type 2 Diabetes (SFRNDM2)

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2; Endothelial Dysfunction
• Intervention / Treatment: Drug: Dapagliflozin; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Naomi Hamburg, MD; Phone Number: (617) 638-7260; Email: nhamburg@bu.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Recruiting
      • BU School of Medicine Evans 748
      • Contact: Leili Behrooz, MD; Phone Number: (617) 638-7260; Email: leili.behrooz@bmc.org
      • Contact: Naomi M Hamburg, MD; Phone Number: 617-638-7260; Email: naomi.hamburg@bmc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boston University
• Collaborators: American Heart Association
• Investigators: Principal Investigator: Naomi M Hamburg, MD, BU School of Medicine, Cardiovascular Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: November 19, 2021
• First Submitted That Met QC Criteria: November 19, 2021
• First Posted (Actual): December 1, 2021

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Dapagliflozin; Biomarkers; Vascular function; Circulating miRNA; Sodium-Glucose Cotransporter-2 (SGLT2) inhibitor; Endothelial cell (EC) Health; EC gene expression levels
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: H-41648; 20SFRN35120118 (Other Grant/Funding Number: American Heart Association)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes