Effect of Pioglitazone on Insulin Resistance, Atherosclerosis Progression and Clinical Course of Coronary Heart Disease
Condition: Adverse Effect; Atherosclerosis, Coronary; Insulin Resistance Syndrome
MeSH terms: Heart Diseases; Atherosclerosis; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Insulin Resistance; Metabolic Syndrome; Disease Progression
Study type: Interventional
Phase: Phase 4

Summary: 
      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: 
      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.
    

Intervention name(s): Pioglitazone 15 mg Tablet; Isosorbide Dinitrate 10Mg Tablet; Acetylsalicylic Acid 75Mg Tablet; Bisoprolol Fumarate 2.5 MG Oral Tablet; Rosuvastatin Calcium 20 MG Oral Tablet; Ramipril 5 MG
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Pioglar (Ranbaxy India):1 tablet per day in the morning for 6 months; 1-2 tablets 2 times a day; 1 tablet per a day; 1 tablet per a day; 1 tablet per a day; 1 tablet per a day
Other intervention name(s): Oral hypoglycemic agent; Antianginal, vasodilator agent; NSAID and antiplatelet agent; Lowering high blood pressure agent; Lipid- lowering agent; ACE inhibitor
Intervention MeSH terms: Aspirin; Pioglitazone; Hypoglycemic Agents; Ramipril; Bisoprolol; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate; Vasodilator Agents; Platelet Aggregation Inhibitors; Rosuvastatin Calcium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Pioglitazone, Insulin Resistance; Atherosclerosis, Coronary Heart Disease