Effect of Pioglitazone on Insulin Resistance, Atherosclerosis Progression and Clinical Course of Coronary Heart Disease

Study Overview
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Brief Summary
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Pioglitazone, a medication of thiazolidinedione group, is capable of triggering the peroxisome proliferator-activated receptors (PPAR-γ). Activation of receptor PPAR-γ regulates carbohydrate and lipid metabolism, immune and inflammatory responses in heart tissues. Our aim will to study the effect of pioglitazone on insulin resistance, the clinical course of atherosclerosis and coronary heart disease (CHD). The study will include 43 patients with coronary artery disease. Patients will be divided into the study group - 20 patients, in whom pioglitazone will be included in the combined therapy at a dose of 15 mg 1 time per day in the morning, and the control group - 23 patients receiving standard complex drug therapy over 6 months. Patients will be underwent clinical examination, ultrasound of neck vessels, study of carbohydrate and lipid metabolism. The end primary points of the study will be the onset of death due to myocardial infarction, coronary revascularization procedures (coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI)), or hospitalization for acute coronary syndrome (ACS) or unstable angina (UA). Predefined secondary end points included carotic atherosclerotic leisure (carotic intima-media thickness, diameter of stenosis, presents of atherosclerotic plaque), systemic inflammation level (the level of C reactive protein), lipid metabolism (levels of serum total cholesterol, triglycerides, high and low density lipoproteins), level of insulin resistance ( oral glucose tolerance test, blood glucose).

Detailed Description
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The study will include 43 people aged between 45 and 68 who suffered from ischemic heart disease. Before starting the study, all participants will give written informed consent, will be obtained of the Commission on Bioethics at Ukrainian Medical Stomatological Academy. Inclusion criteria will be as follows: stable exertional angina, type 2 diabetes mellitus (DM) without receiving injectable antidiabetic drugs. Exclusion criteria will be: the presence of myocardial infarction history, intervention, malignant arterial hypertension (AH), chronic heart failure (HF) of III-IV functional class (FC), systemic connective tissue diseases, cancer and oncohematological diseases, severe infectious diseases, chronic inflammatory diseases, history of acute cerebrovascular accidents, disorders of cardiac rhythm by atrial fibrillation type. The end study will be the primary points: the onset of death due to myocardial infarction, coronary revascularization procedures (coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI)), or hospitalization for acute coronary syndrome (ACS) or unstable angina (UA). The diagnosis of CHD in patients will confirmed by the presence of FC I-III angina according to the classification of the Canadian Cardiovascular Society and the phenomena of circulatory insufficiency according to the classification of New York Heart Association (NYHA). Bicycle ergometry will perform on Veloergotest 05 (Ukraine) via step increasing loading capacity with a consequent increase under control of electrocardiogram (ECG) and BP. The force of step I will be 150 kgm / min (25 W); II - 300 kgm / min (50 W); III - 450 kgm / min (75 W); IV - 600 kgm / min (100 W); V - 750 kgm / min (125 W); VI - 900 kgm / min (150 W), the duration of each step was 3 minutes. Tolerance of CHD patients to exercise will calculate from the value of the threshold load capacity and volume of work performed. The threshold load capacity of 150 kgm / min (25 W) was considered very low and consistent with angina FC IV; 300 kgm / min (50 W) - low, FC III; 450-600 kgm / min (75-100 W) - average, FC II; 750 kgm / min (125 W) and above - high exercise capacity, FC I. The criteria will cease bicycle ergometry termination conventional clinical or ECG signs of myocardial ischemia. Prior to inclusion in the clinical trial, all patients will receive conventional treatment and will screening examination to verify the diagnosis of coronary heart disease and type 2 diabetes. After screening, we will selected 43 patients who received standard medical therapy complex: isosorbide dinitrate 10-20 mg 2 times a day, acetylsalicylic acid 75 mg 1 time a day, bisoprolol 2.5 mg 1 time a day, rosuvastatin 20 mg 1 time a day, ramipril 5 mg 1 time a day. Patients also will receive recommendations on diet and lifestyle changes. Patients will receive the conventional treatment for at least one month to achieve stable parameters. On the first day of the study, blood samples will take from all patients, clinical examination was conducted. After clinical and laboratory studies, patients will randomized by gender, age and severity of clinical manifestations of coronary heart disease. As a result of randomization, patients will divide into the study group (n = 20) and control group (n = 23). The complex therapy of the study group will include pioglitazone 15 mg 1 time per day in the morning (Pioglar, Ranbaxy, India) for 6 months. Patients of the control group will continue to receive only a standard set of drug therapy. Re-examination will carry out in 6 months. The examination will include the collection of medical history and objective data (gender, age, overweight and obesity, hypertension, type 2 diabetes). Patients will evaluate by anthropometric indicators (height, weight, body mass index (BMI)), blood pressure - systolic and diastolic (SBP and DBP), heart rate (HR) will measure, ECG will register. In order to determine the status of vascular bed, patients will underwent ultrasonography (US) of neck vessels on ULTIMA PA, sensor L5 - 12/40, in accordance with standard protocols in B-mode on the three levels of vascular bed and bilaterally at the end of diastole: in the proximal, medial and distal points at a distance of 1 cm from the bifurcation of the posterior wall of the right and left common carotid artery (RCCA and LCCA, respectively) as more distant from the transducer unit. Contour of the carotid arteries will register, their inner lumen, indicators for ASP presence (size, localization) will record, as well as IMT of the carotid arteries. IMT will measure as the distance between the first and the second echogenic lines of located site according to the procedure Pignoli P. et al. The diameter of RCCA, LCCA, and the internal carotid artery (ICA) will assess at the end of systole and diastole as the distance between the IMT. Normal IMT will consider less than 0.9 mm; CCA IMT > 1.4 mm was evaluated as ASP, and in the range of 1.0-1.3 mm as the thickening of IMT (ESH, ESC, 2007). The standard criteria for the diagnosis of hemodynamically significant stenosis are the narrowing of the arterial lumen by more than 50%. The volume of laboratory tests will includ general clinical and biochemical blood analysis. For the control of carbohydrate metabolism glycemic profiles will study determining fasting glucose and after 1 hour after taking 75 g of glucose (oral glucose tolerance test, OGTT) via glucose oxidase method; hyperglycemic factor will calculate. In all patients lipid profile will studied: total cholesterol (TC), triglycerides (TG) and cholesterol of high-density lipoproteins (HDL) (Diakon-DS, Russia), content of cholesterol in low-density lipoproteins (LDL) and very low density lipoproteins (VLDL) will calculate, as well as atherogenic factor (AF). Study of the inflammatory response will conduct by determining the concentration of basic biomarkers - high-sensitivity C-reactive protein (hs-CRP, DRG, USA), human tissue inhibitor of metalloproteinase-1 (TIMP-1, eBioscience, Austria) according to the manufacturer's protocols of test systems via immunoenzyme method. The presence of microalbuminuria will determine using test strips Mikroalbufan (Lachema, Czech Republic), the ratio albumin / creatinine in urine will calculated. Statistical processing will perform using software Statistica 6.0 (StatSoft, USA) with calculation of average (M) and standard error of the average (m). Methods of descriptive statistics will use, comparison of performance in groups will perform by parametric (Student's t-test) and non-parametric (Pearson χ2 test, Fisher's exact test, Mann-Whitney test) statistics. For all types of analysis the differences at p <0.05 will consider statistically significant.

Official Title
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Effect of Pioglitazone on Insulin Resistance, Progression of Atherosclerosis and Clinical Course of Coronary Heart Disease

Conditions
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Adverse Effect, Atherosclerosis, Coronary, Insulin Resistance Syndrome

Intervention / Treatment
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* Drug: Pioglitazone 15 mg Tablet
* Drug: Isosorbide Dinitrate 10Mg Tablet
* Drug: Acetylsalicylic Acid 75Mg Tablet
* Drug: Bisoprolol Fumarate 2.5 MG Oral Tablet
* Drug: Rosuvastatin Calcium 20 MG Oral Tablet
* Drug: Ramipril 5 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: stable exertional angina, type 2 diabetes mellitus (DM) without receiving injectable antidiabetic drugs Exclusion Criteria: the presence of myocardial infarction history, intervention; malignant arterial hypertension (AH); chronic heart failure (HF) of III-IV functional class (FC); systemic connective tissue diseases; cancer and oncohematological diseases, severe infectious diseases, chronic inflammatory diseases; history of acute cerebrovascular accidents; disorders of cardiac rhythm by atrial fibrillation type.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 68 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone + Standard Care<br>20 patients who received standard medical therapy complex: isosorbide dinitrate 10-20 mg 2 times a day, acetylsalicylic acid 75 mg 1 time a day, bisoprolol 2.5 mg 1 time a day, rosuvastatin 20 mg 1 time a day, ramipril 5 mg 1 time a day. Patients also received recommendations on diet and lifestyle changes. Included pioglitazone 15 mg 1 time per day in the morning for 6 months. | Drug: Pioglitazone 15 mg Tablet<br>* Pioglar (Ranbaxy India):1 tablet per day in the morning for 6 months<br>* Other names: Oral hypoglycemic agent;Drug: Isosorbide Dinitrate 10Mg Tablet<br>* 1-2 tablets 2 times a day<br>* Other names: Antianginal, vasodilator agent;Drug: Acetylsalicylic Acid 75Mg Tablet<br>* 1 tablet per a day<br>* Other names: NSAID and antiplatelet agent;Drug: Bisoprolol Fumarate 2.5 MG Oral Tablet<br>* 1 tablet per a day<br>* Other names: Lowering high blood pressure agent;Drug: Rosuvastatin Calcium 20 MG Oral Tablet<br>* 1 tablet per a day<br>* Other names: Lipid- lowering agent;Drug: Ramipril 5 MG<br>* 1 tablet per a day<br>* Other names: ACE inhibitor;|
| Other: Standard Care<br>23 patients who received standard medical therapy complex: isosorbide dinitrate 10-20 mg 2 times a day, acetylsalicylic acid 75 mg 1 time a day, bisoprolol 2.5 mg 1 time a day, rosuvastatin 20 mg 1 time a day, ramipril 5 mg 1 time a day. Patients also received recommendations on diet and lifestyle changes. | Drug: Isosorbide Dinitrate 10Mg Tablet<br>* 1-2 tablets 2 times a day<br>* Other names: Antianginal, vasodilator agent;Drug: Acetylsalicylic Acid 75Mg Tablet<br>* 1 tablet per a day<br>* Other names: NSAID and antiplatelet agent;Drug: Bisoprolol Fumarate 2.5 MG Oral Tablet<br>* 1 tablet per a day<br>* Other names: Lowering high blood pressure agent;Drug: Rosuvastatin Calcium 20 MG Oral Tablet<br>* 1 tablet per a day<br>* Other names: Lipid- lowering agent;Drug: Ramipril 5 MG<br>* 1 tablet per a day<br>* Other names: ACE inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Сardiovascular Death | Number of Participants with cardiovascular death | Baseline and 1 year | 
| Coronary Artery Bypass [Coronary Revascularization] | Number of Participants with revascularization coronary procedures (coronary artery bypass grafting) | Baseline and 1 year | 
| Cardiovascular Hospitalization | Number of Participants with acute coronary syndrome (ACS) or unstable angina (UA) | Baseline and 1 year | 
| Percutaneous Coronary Intervention [Coronary Revascularization] | Number of Participants with incidence of percutaneous coronary intervention. | Baseline and 1 year | 
| Safety and Tolerability 1 | Liver injury: mean values of ALT | Baseline, 6 month and 1 year | 
| Safety and Tolerability 2 | Liver injury: mean levels of total bilirubin | Baseline, 6 month and 1 year | 
| Safety and Tolerability 3 | Kidney injury: mean values of the microalbuminuria | Baseline and 1 year | 
| Safety and Tolerability 4 | Kidneys injury: mean values of creatinine | Baseline and 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thickness of the Intima-media Complex | Mean thickness of carotid intima-media complex | Baseline, 6 month and 1 year | 
| Diameter of Stenosis [Carotic Atherosclerotic Lesions] | Mean diameters of the stenosis of the right and left common carotid arteries | Baseline and 1 year | 
| Carotic Atherosclerotic Lesions | Number of Participants with presence of atherosclerotic plaque of the intima media of common carotid artery greater than 1.4 mm | Baseline and 1 year | 
| Systemic Inflammation Level | Number of Participants with C-reactive protein level above 3 mg/L | Baseline and 1 year | 
| Lipid Metabolism 1 | Mean levels of total serum cholesterol | Baseline, 6 month and 1 year | 
| Lipid Metabolism 2 | Mean values of the triglyceride levels | Baseline, 6 month and 1 year | 
| Lipid Metabolism 3 | Lipoproteine fractions:mean values of high-density lipoproteins and low density lipoproteins | Baseline and 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pioglitazone, Insulin Resistance, Atherosclerosis, Coronary Heart Disease