Assessment of Dapagliflozin Effect on Diabetic Endothelial Dysfunction of Brachial Artery

NCT02919345 | Completed Phase 4

• 1 other identifier: 001
• Study Type: interventional
• Target: 98
• Locations: 1 country
• Sites: 1

Brief Summary

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. 3 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.

Conditions

Diabetes Mellitus, Type 2; Coronary Artery Disease; Carotid Artery Diseases

Keywords

Dapagliflozin; Glibenclamide; Endothelial Function; Vascular Endothelial Cells; Flow Mediated Dilation

Outcome Measures

Primary Outcomes (1)

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

  12 weeks

Secondary Outcomes (15)

• Change in plasma nitric oxide

  12 weeks

• Change in plasma isoprostane

  12 weeks

• Change in plasma nitric oxide after reperfusion injury.

  12 weeks

• Change in plasma isoprostane after reperfusion injury.

  12 weeks

• Change in plasma Intercellular Adhesion Molecule 1(ICAM-1)

  12 weeks

Other Outcomes (4)

• Change in Glycated Hemoglobin

  12 weeks

• Change in Systolic Blood Pressure

  12 weeks

• Change in Mean Arterial Blood Pressure

  12 weeks

Study Arms (2)

Dapagliflozin

EXPERIMENTAL

Dapagliflozin 10 mg in addition to Metformin 1500 mg

Drug: Dapagliflozin 10 mg

Glibenclamide

ACTIVE COMPARATOR

Glibenclamide 5mg in addition to Metformin 1500 mg

Drug: Glibenclamide 5 mg

Interventions

Dapagliflozin 10 mg DRUG

Dapagliflozin 10 mg in addition to Metformin 1500 mg/day

Also known as: Farxiga

Dapagliflozin

Glibenclamide 5 mg DRUG

Glibenclamide 5 mg in addition to Metformin 1500 mg/day

Also known as: Daonil, Glyburide

Glibenclamide

Eligibility Criteria

• Age: 40 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• (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%);

You may not qualify if:

• (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;

Sponsors & Collaborators

• University of Campinas, Brazil: lead
• AstraZeneca: collaborator

Study Sites (1)

State University of Campinas

Campinas, São Paulo, 13083-887, Brazil

Location

Related Publications (1)

• Cintra RMR, Soares AAS, Breder I, Munhoz DB, Barreto J, Kimura-Medorima ST, Cavalcante P, Zanchetta R, Breder JC, Moreira C, Virginio VW, Bonilha I, Lima-Junior JC, Coelho-Filho OR, Wolf VLW, Guerra-Junior G, Oliveira DC, Haeitmann R, Fernandes VHR, Nadruz W, Chaves FRP, Arieta CEL, Quinaglia T, Sposito AC; ADDENDA-BHS2 trial investigators. Assessment of dapagliflozin effect on diabetic endothelial dysfunction of brachial artery (ADDENDA-BHS2 trial): rationale, design, and baseline characteristics of a randomized controlled trial. Diabetol Metab Syndr. 2019 Jul 31;11:62. doi: 10.1186/s13098-019-0457-3. eCollection 2019.

  PMID: 31384310 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Coronary Artery Disease; Carotid Artery Diseases

Interventions

dapagliflozin; Glyburide

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Sulfonylurea Compounds; Urea; Amides; Organic Chemicals; Sulfones; Sulfur Compounds

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: September 28, 2016
• First Posted: September 29, 2016
• Study Start: January 1, 2017
• Primary Completion: December 1, 2018
• Study Completion: March 1, 2019
• Last Updated: March 10, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share

Locations

BR (1)