Assessment of Dapagliflozin Effect on Diabetic Endothelial Dysfunction of Brachial Artery (ADDENDA)

March 7, 2023 updated by: Andrei Carvalho Sposito, University of Campinas, Brazil

Comparative Study of Dapagliflozin Versus Glibenclamide Effect on Endothelial Function of Coronary Artery Disease Patients

Background Endothelial dysfunction is one of the early events in atherosclerotic plaque development. It is characterized by an increased ratio of substances with vasoconstrictive, pro-thrombotic, and proliferative properties over substances with vasolidatory, antithrombogenic and antimitogenic properties. Endothelial dysfunction is also associated with high-risk patients with coronary artery disease. Hyperglycemia, obesity, hypertension and fat mass also impair the endothelium by increasing the expression of cytokines, inflammatory markers and vascular markers.

Hypothesis Administration of dapagliflozin in addition to metformin background with clinical or subclinical cardiovascular atherosclerotic disease improves endothelial function when compared to those using glibenclamide in addition to metformin.

Objectives Evaluate the effect of dapagliflozin vs glibenclamide on a metformin background on endothelial function in patients with clinical or subclinical cardiovascular atherosclerotic disease and poorly controlled diabetes.

Enpoints Prymary Change in flow mediated dilation (FMD) and its related endpoint (FMD post reperfusion lesion) between the randomization visit and over 12 weeks of treatment.

Secondary Change in plasma nitric oxide, isoprostane, ICAM-1, VCAM-1, ET-1, leptin, adiponectin, C-reactive protein, TNF- α, interleukin-6, interleukin-2, weight and body composition (% of fat mass and % free fat mass) at the randomization visit and over 12 weeks of treatment.

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Design Randomized, parallel-group, comparative, prospective clinical study. The study is divided in two phases: Run-in and Randomization. In the former phase, which must have the maximum period of 16 weeks, patients will visit the outpatient to adjust metformin and blood pressure medications. After run-in phase, patients that fulfill inclusion criteria will perform an ambulatory blood pressure monitoring (ABPM) in order to asses BP; body composition will be assessed by dual x-ray absorptiometry (DXA); endothelial function as assessed by flow mediated dilation and vascular cytokines. Patients will by randomized to dapagliflozin or glibenclamide on a metformin background. After 12 weeks, the ABPM, DXA and endothelial function will be assessed.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

98

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Brazil
    • Sao Paulo
      • Campinas, Sao Paulo, Brazil, 13083-887
        • State University of Campinas

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

(i) chronic coronary artery disease as shown by angiogram or subclinical artery disease diagnosed by the presence of carotid atherosclerotic plaque or carotid Intima-Media Thickness (cIMT) ≥ 1mm;

(ii) T2DM using up to two oral hypoglycemic agents;

(iii) inadequate glycemic control (HbA1c ≥ 7%);

Exclusion Criteria:

(i) HbA1c > 9%;

(ii) contraindications to metformin use (Cr Clearance <60 ml/min, Cr> 1.5 mg/dL in men and> 1.4 mg/dl in women, liver failure - AST or ALT> 3x upper normal limit or other conditions that might increase the risk of lactic acidosis);

(vi) at the time of randomization, patient who is not on metformin XR 1500 mg/day monotherapy for at least 12 weeks;

(vii) patients who spend more than 16 weeks to adjust metformin before randomization;

(viii) BP ≥ 140 x 90 after 16 weeks of anti-hypertensive medication adjustment;

(iii) hospitalization for unstable angina or acute myocardial infarction within 2 months prior to enrolment;

(iv) acute stroke or transient ischemic attack (TIA) within two months prior to enrolment;

(v) less than two months post coronary artery revascularization;

(ix) patients with FMD <2% at the time of randomization;

(x) triglycerides > 500 mg/dL;

(xi) known allergy to any of the study drugs;

(xii) patients with severe coronary artery disease and heart failure;

(xiii) systemic vasculitis;

(xiv) conditions that lead to systemic inflammation;

(xv) patients using rosiglitazone;

(xvi) polyuria, polydipsia, weight loss, or others clinical signs of volume depletion;

(xvii) those who refuse to participate or sign the Statement of Informed Consent;

(xviii) pregnancy or women during reproductive age;

(xix) breastfeeding women;

(xx) history of gastrointestinal disorders that may interfere with the absorption of study medication;

(xxi) patients who are participating in other clinical studies or whose participation ended less than six months ago.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dapagliflozin
Dapagliflozin 10 mg in addition to Metformin 1500 mg
Drug: Dapagliflozin 10 mg
Dapagliflozin 10 mg in addition to Metformin 1500 mg/day
Other Names:
  • Farxiga
Active Comparator: Glibenclamide
Glibenclamide 5mg in addition to Metformin 1500 mg
Drug: Glibenclamide 5 mg
Glibenclamide 5 mg in addition to Metformin 1500 mg/day
Other Names:
  • Daonil, Glyburide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in flow mediated dilation (FMD) and its related endpoint (FMD post reperfusion lesion)
Time Frame: 12 weeks
12 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Change in plasma nitric oxide
Time Frame: 12 weeks
12 weeks
Change in plasma isoprostane
Time Frame: 12 weeks
12 weeks
Change in plasma nitric oxide after reperfusion injury.
Time Frame: 12 weeks
12 weeks
Change in plasma isoprostane after reperfusion injury.
Time Frame: 12 weeks
12 weeks
Change in plasma Intercellular Adhesion Molecule 1(ICAM-1)
Time Frame: 12 weeks
12 weeks
Change in plasma Vascular Cell Adhesion Molecule 1 (VCAM-1)
Time Frame: 12 weeks
12 weeks
Change in plasma Endothelin-1 (ET-1)
Time Frame: 12 weeks
12 weeks
Change in plasma Leptin
Time Frame: 12 weeks
12 weeks
Change in plasma Adiponectin
Time Frame: 12 weeks
12 weeks
Change in plasma C-reactive protein (CRP)
Time Frame: 12 weeks
12 weeks
Change in plasma Tumor Necrosis Factor alpha (TNF-α)
Time Frame: 12 weeks
12 weeks
Change in plasma interleukin-6
Time Frame: 12 weeks
12 weeks
Change in plasma interleukin-2
Time Frame: 12 weeks
12 weeks
Change in weight
Time Frame: 12 weeks
12 weeks
Change in body composition (% of fat mass and % free fat mass)
Time Frame: 12 weeks
12 weeks

Other Outcome Measures

Outcome Measure
Time Frame
Change in Glycated Hemoglobin
Time Frame: 12 weeks
12 weeks
Change in Systolic Blood Pressure
Time Frame: 12 weeks
12 weeks
Change in Mean Arterial Blood Pressure
Time Frame: 12 weeks
12 weeks
Change in Waist Circumference
Time Frame: 12 weeks
12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Campinas, Brazil

Collaborators

AstraZeneca

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2017

Primary Completion (Actual)

December 1, 2018

Study Completion (Actual)

March 1, 2019

Study Registration Dates

First Submitted

September 28, 2016

First Submitted That Met QC Criteria

September 28, 2016

First Posted (Estimate)

September 29, 2016

Study Record Updates

Last Update Posted (Estimate)

March 10, 2023

Last Update Submitted That Met QC Criteria

March 7, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 001 (NavyGHB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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