Clinical trial NCT02919345: Assessment of Dapagliflozin Effect on Diabetic Endothelial Dysfunction of Brachial Artery
Official title: Comparative Study of Dapagliflozin Versus Glibenclamide Effect on Endothelial Function of Coronary Artery Disease Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Coronary Artery Disease
Carotid Artery Diseases
Keywords: Dapagliflozin
Glibenclamide
Endothelial Function
Vascular Endothelial Cells
Flow Mediated Dilation
Lead sponsor: University of Campinas, Brazil
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2016-09-29
Enrollment: 98
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in flow mediated dilation (FMD) and its related endpoint (FMD post reperfusion lesion)
timeFrame: 12 weeks
Secondary outcomes:
measure: Change in plasma nitric oxide
timeFrame: 12 weeks
measure: Change in plasma isoprostane
timeFrame: 12 weeks
measure: Change in plasma nitric oxide after reperfusion injury.
timeFrame: 12 weeks
measure: Change in plasma isoprostane after reperfusion injury.
timeFrame: 12 weeks
measure: Change in plasma Intercellular Adhesion Molecule 1(ICAM-1)
timeFrame: 12 weeks
measure: Change in plasma Vascular Cell Adhesion Molecule 1 (VCAM-1)
timeFrame: 12 weeks
measure: Change in plasma Endothelin-1 (ET-1)
timeFrame: 12 weeks
measure: Change in plasma Leptin
timeFrame: 12 weeks
measure: Change in plasma Adiponectin
timeFrame: 12 weeks
measure: Change in plasma C-reactive protein (CRP)
timeFrame: 12 weeks
measure: Change in plasma Tumor Necrosis Factor alpha (TNF-α)
timeFrame: 12 weeks
measure: Change in plasma interleukin-6
timeFrame: 12 weeks
measure: Change in plasma interleukin-2
timeFrame: 12 weeks
measure: Change in weight
timeFrame: 12 weeks
measure: Change in body composition (% of fat mass and % free fat mass)
timeFrame: 12 weeks
Other outcomes:
measure: Change in Glycated Hemoglobin
timeFrame: 12 weeks
measure: Change in Systolic Blood Pressure
timeFrame: 12 weeks
measure: Change in Mean Arterial Blood Pressure
timeFrame: 12 weeks
measure: Change in Waist Circumference
timeFrame: 12 weeks
Locations:
city: Campinas
country: Brazil
facility: State University of Campinas
state: Sao Paulo
Study officials:
References:
citation: 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.