Carotid Atherosclerosis: MEtformin for Insulin ResistAnce Study

Study Overview
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Brief Summary
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Hypothesis: Treatment with metformin in overweight non-diabetic individuals with coronary heart disease and on standard cardiovascular risk reducing agents including statins will have a beneficial impact on carotid artery atherosclerosis compared to placebo. Rationale: Once subjects have a heart attack, they remain at much higher than average risk of another heart attack and stroke, despite the best current therapies to lower their cholesterol and blood pressure and thin their blood. Many subjects with heart disease also have problems metabolising (i.e. processing) sugar even if they do not have diabetes. There is some evidence that metformin, a drug which improves sugar metabolism, decreases the risk of future heart attacks in diabetic patients. However, whether metformin further reduces the risk of heart disease beyond established treatments in people without diabetes is unknown. Method: The investigators will test the ability metformin, a drug with proven safety, to slow the progression of furring up (known as atherosclerosis) of blood vessels in non-diabetic subjects with heart disease. This will be achieved by treating 2 groups of subjects with metformin and placebo pills respectively. To measure atherosclerosis, the investigators will carry out ultrasound scans of the big blood vessels in the neck at the start of the study, after 1 year and after 1.5 years of therapy.The investigators will then be able to assess whether metformin has had a beneficial impact.

Official Title
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A Randomised Placebo-controlled Trial of Metformin on Progression of Carotid Atherosclerosis in Non-diabetic Patients With Cardiovascular Disease Treated With Conventional Risk Reducing Agents

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Proven coronary heart disease (prior acute coronary syndrome, prior CABG or angiographically proven CHD) Aged 35-75 years Elevated waist circumference as per the International Diabetes Foundation criteria (94 cm in men and 80 cm in women) All patients will be on statin Exclusion Criteria: Pregnancy and/or lactation at screening Premenopausal woman not on contraception Known or newly diagnosed diabetes mellitus on oral glucose tolerance testing (OGTT will be performed on subjects with HbA1C 6.0-6.9% and fasting plasma glucose [FPG] < 7.0 mmol/L at screening18) Screening results: HbA1C ≥ 7.0% and/or fasting plasma glucose ≥ 7.0 mmol/L Patients with Acute Coronary Syndrome within the last 3 months Clinically unstable heart failure Uncontrolled angina Contraindications to metformin

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br> | Drug: Metformin<br>* White film-coated tablets, 850mg tablet twice daily, 1.5 years duration<br>* Other names: Bolamyn SR;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* White coated tablet; one tablet twice daily; 1.5 years duration<br>* Other names: Dummy pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in progression of carotid intima-media thickness (measured in millimetres) between groups treated with metformin and placebo |  | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of HbA1C, t-PA, CRP, IL-6, HOMA-IR and ICAM-1 with change in carotid IMT in metformin- and placebo-treated groups will be evaluated. |  | 1.5 years | 
| Difference in progression of carotid total plaque area (measured in square millimetres) between groups treated with metformin and placebo |  | 1.5 years | 
| Difference in progression of carotid total plaque volume (measured in cubic millimetres) between groups treated with metformin and placebo |  | 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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No diabetes mellitus, Elevated waist circumference