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Completed

NCT Number: NCT02919345

Assessment of Dapagliflozin Effect on Diabetic Endothelial Dysfunction of Brachial Artery

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.

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Key information

Conditions

Diabetes Mellitus, Type 2 Arterial Occlusive Diseases Arteriosclerosis Brain Diseases Cardiovascular Diseases Carotid Artery Diseases Central Nervous System Diseases Cerebrovascular Disorders Coronary Artery Disease Coronary Disease Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Heart Diseases Metabolic Diseases Myocardial Ischemia Nervous System Diseases Nutritional and Metabolic Diseases Vascular Diseases

Age range

40 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

State University of Campinas

Campinas, São Paulo, 13083-887, Brazil

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Dapagliflozin 10 mg

Drug

Dapagliflozin 10 mg in addition to Metformin 1500 mg/day

Other names: Farxiga

Glibenclamide 5 mg

Drug

Glibenclamide 5 mg in addition to Metformin 1500 mg/day

Other names: Daonil, Glyburide

Primary outcomes

  1. Change in flow mediated dilation (FMD) and its related endpoint (FMD post reperfusion lesion)

    Time frame: 12 weeks

Secondary outcomes

  1. Change in plasma nitric oxide

    Time frame: 12 weeks

  2. Change in plasma isoprostane

    Time frame: 12 weeks

  3. Change in plasma nitric oxide after reperfusion injury.

    Time frame: 12 weeks

  4. Change in plasma isoprostane after reperfusion injury.

    Time frame: 12 weeks

  5. Change in plasma Intercellular Adhesion Molecule 1(ICAM-1)

    Time frame: 12 weeks

  6. Change in plasma Vascular Cell Adhesion Molecule 1 (VCAM-1)

    Time frame: 12 weeks

  7. Change in plasma Endothelin-1 (ET-1)

    Time frame: 12 weeks

  8. Change in plasma Leptin

    Time frame: 12 weeks

  9. Change in plasma Adiponectin

    Time frame: 12 weeks

  10. Change in plasma C-reactive protein (CRP)

    Time frame: 12 weeks

  11. Change in plasma Tumor Necrosis Factor alpha (TNF-α)

    Time frame: 12 weeks

  12. Change in plasma interleukin-6

    Time frame: 12 weeks

  13. Change in plasma interleukin-2

    Time frame: 12 weeks

  14. Change in weight

    Time frame: 12 weeks

  15. Change in body composition (% of fat mass and % free fat mass)

    Time frame: 12 weeks

Other outcomes

  1. Change in Glycated Hemoglobin

    Time frame: 12 weeks

  2. Change in Systolic Blood Pressure

    Time frame: 12 weeks

  3. Change in Mean Arterial Blood Pressure

    Time frame: 12 weeks

  4. Change in Waist Circumference

    Time frame: 12 weeks

Sponsors and collaborators

Lead sponsor

University of Campinas, Brazil

Other

Collaborators

  • AstraZeneca

Registry information

Official study title

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

Acronym: ADDENDA

Important dates

Study start
2017
Primary completion
2018
Study completion
2019
First posted
Sep 29, 2016
Registry last updated
Mar 10, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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