Effects on Re-endothelialisation With Bydureon Treatment in Type 2 Diabetes Subjects

Study Overview
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Brief Summary
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The aim of the study is to use Exenatide long-acting release (LAR) [Bydureon] to minimize vascular remodeling and neointima formation after Percutaneous Coronary Intervention (PCI) and to accelerate stent endothelialisation.

Detailed Description
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Exenatide LAR will be given as a once-weekly (s.c.) dose of Bydureon (2 mg) add on to Insulin in combination with Metformin. If patients are Insulin naïve (both groups) an initial dose of 10U (s.c.) at bedtime will be started, and further up-titrated to achieve a fP-glucose levels at 6 mmol/l. Standard care for post myocardial infarction will be given after PCI. Primary objectives: To test whether Bydureon, add on to Insulin Neutral Protamine Hagedorn (NPH) + Metformin, is superior vs. Insulin NPH + Metformin alone, in covered stent struts Secondary objectives: To test whether Bydureon, add on to Insulin NPH + Metformin, is superior vs. Insulin NPH + Metformin alone: in cardiac and endothelial functions

Official Title
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Effects on Re-endothelialisation With Bydureon Treatment Add on to Insulin Versus Insulin Alone, Both in Combination With Metformin in Type 2 Diabetic Subjects

Conditions
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Atherosclerosis, Diabetes, Restenosis

Intervention / Treatment
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* Drug: Bydureon
* Drug: Humulin kwickpen
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients eligible for PCI with application of DES, due to ACS. Patients with known or newly diagnosed T2D (type 2 diabetes is diagnosed according to current WHO criteria or by the use of anti-diabetic drugs) Male and female subjects 18-80 years. HbA1c (accordingly to IFCC) 47 mmol/mol - 110 mmol/mol. Signed informed consent form. Exclusion Criteria: Type 1 diabetes (autoantibody positive). Any history of receiving GLP-1 analogues or dipeptidyl peptidase inhibitors within 6 months Known severe heart failure, classified as NYHA 4. Active myocarditis; malfunctioning artificial heart valve. History of ventricular tachycardia within 3 months before study entry; second- or third-degree atrioventricular block. Supine systolic blood pressure <85 mm Hg or >200 mm Hg at screening. Primary renal impairment, creatinine clearance < 45 ml/min if treated with metformin. Uncorrected hypokalemia or hyperkalemia (potassium <3.5 mmol/l or >5.5 mmol/l). Significant anemia (Hb < 90 g/l) Severe gastrointestinal disease, including gastroparesis. As judged by the Investigator. Body mass index (BMI) > 45 kg/m2. Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Patients with intraepithelial squamous cell carcinoma of the skin treated with topical 5FU and subjects with basal cell skin cancer are allowed to enter the trial. Females of child bearing potential who are pregnant, breast-feeding or intend to become pregnant. Current drug and alcohol abuse. History of acute or chronic pancreatitis Subjects considered by the Investigator to be unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bydureon 2 mg Once Weekly<br>Patients randomised to Bydureon will be treated with Metformin 1g BID, and only receive 10U of Humulin kwickpen QD at bedtime, with no more up-titration of insulin during the study. | Drug: Bydureon<br>* 2 mg Once Weekly<br>* Other names: Exenatide;Drug: Humulin kwickpen<br>* Humulin kwickpen 10U QD at bedtime<br>* Other names: Insulin Aspart;Drug: Metformin<br>* Metformin 1g BID<br>* Other names: Biguanide;|
| Active Comparator: Humulin kwickpen<br>Patients randomised to the comparator group will be treated with Meformin 1g BID and Humulin kwickpen to reach a fP-glucose level of 6 mmol/l. For that reason patients will be instructed to increase the bedtime Insulin dose of 2-4U every third day until this goal is reached. | Drug: Humulin kwickpen<br>* Humulin kwickpen 10U QD at bedtime<br>* Other names: Insulin Aspart;Drug: Metformin<br>* Metformin 1g BID<br>* Other names: Biguanide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The degree of non-covered stent struts by Bydureon add on to Insulin over that of Insulin as analyzed by optical coherence tomography (OCT). |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fractional Flow Reserve (FFR) | FFR is a unitless index calculated as the ratio between distal coronary and aortic pressure during maximum hyperemia. | 12 weeks | 
| Coronary Flow velocity Reserve (CRF) | CFR is a unitless index calculated as the ratio between the the mean transit time recorded at maximum hyperemia and at baseline using the thermodilution. | 12 weeks | 
| Index of Microcirculatory Resistance (IMR) | IMR is a unitless index calculated by dividing the mean distal coronary pressure by the inverse of the mean transit time recorded using the thermodilution technique during maximum hyperemia | 12 weeks | 
| Fractional flow reserve positive re-stenosis |  | 12 weeks | 
| Target lesion failure | Need of unplanned PCI in the treated stenosis or significant re-stenosis in the follow-up | 12 weeks | 
| Acute coronary syndrome (ACS) and/or repeat revascularization |  | 12 weeks | 
| Late lumen loss/neointima thickness measured with OCT |  | 12 weeks | 
| Change in minimal lumen area by OCT |  | 12 weeks | 
| Left ventricular systolic and diastolic function assessed by echocardiography |  | 12 weeks | 
| Recovery from endothelial damage, measured by high resolution ultrasound, after PCI | Non-invasive ultrasound over the radialis artery after the PCI procedure using Standard 6-7F guiding catheters. | 12 weeks | 
| Plasma markers of endothelial activation i.e., E-Selectin, VCAM-1, ICAM-1, nitrotyrosine levels |  | 12 weeks | 
| Plasma markers of inflammation i.e., CRP, IL-1β, IL-6 and IL-8. |  | 12 weeks | 
| Plasma markers of matrix remodeling enzymes i.e., MMP-2 and MMP9 |  | 12 weeks | 
| Circulating endothelial progenitor cells |  | 12 weeks | 
| Gene expression (Affymetrix) e.g., transcription factors of sirtuins (SIRT) and nitric oxide synthase (NOS) |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucagon-like peptide-1, Endothelialization, Cardiac Function, Exenatide, Optical Coherence Tomography