The Effect of Liraglutide on the Treatment of Coronary Artery Disease and Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of combined glucagon-like-peptide-1 (GLP-1) analogue and metformin therapy on glucose metabolic and cardiovascular endpoints compared to metformin monotherapy in patients with coronary artery disease (CAD) and newly diagnosed type 2 diabetes (T2D). It is hypothesized that GLP-1 analogue added to backbone therapy of metformin in CAD patients with T2D will improve beta-cell function, left ventricular ejection fraction (LVEF), heart rate variability and lower 24h blood pressure among other selected endpoints. The present study on CAD patients with newly diagnosed T2D will address these selected endpoints during an investigator initiated, randomized, double blind, crossover, placebo-controlled 12 + 12 weeks intervention study with a 2 week wash-out period.

Detailed Description
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The total study period for each patient will be 26 weeks (12 plus 12 weeks of intervention with a 2 week wash-out period). The endpoints will be evaluated at baseline (week 0), at week 12, at week 14 (following 2 weeks of wash-out) and finally at week 26.

Official Title
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Adding Liraglutide to the Backbone Therapy of Biguanide in Patients With Coronary Artery Disease and Newly Diagnosed Type-2 Diabetes

Conditions
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Coronary Artery Disease, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stable CAD documented by one of the following: Previous MI (a minimum of 6 weeks after an acute MI) Previous coronary revascularization CAD confirmed by an abnormal coronary angiography (CAG) or CT-angiography showing stenosis > 50% of any major coronary arteries. Body mass index (BMI) >/= 25,0 kg/m2 Age >/= 18 years and </= 85 years Type 2 diabetes diagnosed by one of the following criteria: HbA1c >/= 6.5% HbA1c < 6.5 % and fasting plasma glucose >/= 7.0 mmol/l (confirmed) HbA1c < 6.5 % and a 2 h plasma glucose value during OGTT >/= 11.1 mmol/l The data for glucose metabolism are accepted provided that they have been obtained within 24 months prior to inclusion of the patient. The glucose metabolic categories are defined by ADA and WHO criteria. Exclusion Criteria: Type 1 diabetes mellitus defined as C-peptide < 450 pM Previously diagnosed diabetes mellitus for more than 24 months prior to the screening procedure for this trial, except from gestational diabetes Use of more than 2 types of oral antidiabetic medication and/or use of parenteral antidiabetic medication in the period of 3 months prior to the screening visit. It is accepted that the patient continues his usual antidiabetic medication after the screening visit but antidiabetic medication must be discontinued 2 weeks prior to the baseline visit. Significant heart disease (NYHA > 2; Ejection Fraction < 40% and unstable angina pectoris) and known severe valve disease Documented atrial fibrillation or atrial flutter within 6 weeks previous to the screening. Paroxysmal atrial fibrillation is accepted if sinus rhythm is achieved at the screening. Uncontrolled arterial hypertension (> 180/100 mmHg) at the time of screening Liver (transaminases greater than x 2 the upper normal level) or renal diseases (eGFR < 60 ml/min) Amylase greater than x 3 the upper reference value Any chronic medical condition to unduly increase risk for the potential enrollee as judged by study investigators Dysregulated myxedema or hyperthyroid condition defined by a value of TSH < 0,1 and > 10,0 milli U/L Anemia (< 85% of lower normal limit), leucopenia (< 85% of lower normal limit), or thrombocytopenia (< 85% of lower normal limit) Pregnancy or failure to comply with contraception planning within two years, or breastfeeding Abuse of alcohol or drugs, or any other co-existing condition that would make patients unsuitable to participate in the study, as judged by the investigators Use of immunosuppressive therapy in the preceding 12 months Chronic pancreatitis or previous acute pancreatitis Known or suspected hypersensitivity to trial product(s) or related products Treatment with oral glucocorticoids, calcineurin inhibitors, or dipeptidyl peptidase 4 (DPP4) inhibitors, or other GLP-1 mimetics (e.g. exenatide), which in the Investigator's opinion could interfere with glucose metabolism Cancer (except basal cell skin cancer or squamous cell skin cancer) or any other clinically significant disorder, which in the Investigator's opinion could interfere with the results of the trail Inflammatory bowel disease Previous bowel resection Clinical signs of diabetic gastroparesis Plasma calcium-ion >/= 1,45 mmol/L Plasma calcitonin >/= 50 ng/L Subjects with personal or family history of medullary thyroid carcinoma or a personal history of multiple endocrine neoplasia type 2 Refusal to sign informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo + metformin<br> | Drug: Placebo<br>* Volume-matched placebo injection pen is administered by the participant once daily by subcutaneous injection. It is given independent of meals. The starting dose is 0.6 mg volume-matched placebo. After 2 weeks the dose will be increased to 1.2 mg. The dose will be further increased after 4 weeks to 1.8 mg. After a total of 12 weeks of treatment, a wash-out period of 2 weeks follows. Subsequently, the participant will be crossed over to a second period of 12 weeks of treatment with liraglutide.<br>|
| Active Comparator: Liraglutide + metformin<br> | Drug: Liraglutide<br>* Liraglutide injection pen is administered by the participant once daily by subcutaneous injection. It is given independent of meals. The starting dose is 0.6 mg. After 2 weeks the dose will be increased to 1.2 mg. The dose will be further increased after 4 weeks to 1.8 mg. After a total of 12 weeks of treatment, a wash-out period of 2 weeks follows. Subsequently, the participant will be crossed over to a second period of 12 weeks of treatment with placebo.<br>* Other names: ATC Code: A10BX07;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beta-cell function | Beta-cell function (disposition index) as measured during an intravenous glucose tolerance test (By Bergman Minimal Model) | after 12 weeks of intervention | 
| LVEF | Changes in LVEF assessed by dobutamine stress echocardiography | after 12 weeks of intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucagon, incretin, glucose, NEFA, insulin and C-peptide response during meal test |  | Baseline (week 0), week 12, week 14, week 26 | 
| Insulin sensitivity (Si), acute insulin and C-peptide response to intravenous glucose (AIRg, ACRg), glucose clearance (Kg), glucose effectiveness (Sg) and hepatic extraction of insulin (HEXi) | Insulin sensitivity (Si), acute insulin and C-peptide response to intravenous glucose (AIRg, ACRg), glucose clearance (Kg), glucose effectiveness (Sg) and hepatic extraction of insulin (HEXi) derived from a standard frequent sampling intravenous glucose tolerance test (FSIGT, Minimal model) | Baseline (week 0), week 12, week 14, week 26 | 
| CRP, TNF-alfa and IL-6 in plasma and gene expression of IL6 and TNF-alfa in subcutaneous fat |  | Baseline (week 0), week 12, week 14, week 26 | 
| Non esterified fatty acids (NEFA) | NEFA during FSIGT by use of NEFA minimal model | Baseline (week 0), week 12, week 14, week 26 | 
| Heart rate variability (HRV) | HRV i.e. SDNN (standard deviation of all normal RR interval) assessed during HOLTER monitoring | Baseline (week 0), week 12, week 14, week 26 | 
| Maximal velocity of the myocardium in systole (s´) and in diastole (e´) | Maximal velocity of the myocardium in systole (s´) and in diastole (e´) during the dobutamine stress test | Baseline (week 0), week 12, week 14, week 26 | 
| Changes in exercise tolerance test variables: Total exercise duration (sec), time to limiting angina (sec) and time to 1 mm ST-segment depression (sec) | Changes in exercise tolerance test variables: Total exercise duration (sec), time to limiting angina (sec) and time to 1 mm ST-segment depression (sec) | Baseline (week 0), week 12, week 14, week 26 | 
| ST-depression and ectopic activity | ST-depression and ectopic activity assessed during 24h HOLTER monitoring | Baseline (week 0), week 12, week 14, week 26 | 
| Diurnal blood pressure |  | Baseline (week 0), week 12, week 14, week 26 | 
| Diastolic heart function (E/E*) | Diastolic heart function (E/E*) in rest and during stress | Baseline (week 0), week 12, week 14, week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Disease, Diabetes Mellitus, Left ventricular ejection fraction, Beta-cell function