Role of Pioglitazone and Berberine in Treatment of Non-Alcoholic Fatty Liver Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects and safety of pioglitazone and berberine on the basis of lifestyle intervention to non-alcoholic fatty liver disease patients with impaired glucose regulation or type 2 diabetes mellitus.

Detailed Description
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Sedentary lifestyle and poor dietary choices are leading to a weight gain epidemic and increasing the risk for developing nonalcoholic fatty liver disease (NAFLD). NAFLD is a group of diseases with too much fat in liver in the absence of excess alcohol consumption. NAFLD encompasses a histological spectrum ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. NAFLD is estimated to affect 25% of the worldwide population[1] and 15.35% of adults in shanghai urban area[2]. Epidemiological data showed that the fatty liver may predict, independent of other factors, the metabolic syndrome, type 2 diabetes, and cardiovascular disease. Therefore, we may prevent those diseases by treating NAFLD.Life style intervention including activity and reducing energy intake is recommended by health care providers for optimal health and is the most common prescribed therapy for individuals diagnosed with NAFLD. TZDs are oral glucose-lowering medications used to treat type 2 diabetes that enhance insulin sensitivity. The strong relationship between insulin resistance and NAFLD suggests that insulin sensitizing therapies such as TZDs might be beneficial in the prevention or improvement in NAFLD.TZDs bind to the peroxisome proliferator-activated receptors (PPARs), in part, by facilitating enhanced TG storage by adipocytes, suppressing the ectopic storage of lipids into liver and skeletal muscle. In addition, TZDs appear to have anti-inflammatory properties, inhibiting adipocyte gene expression and reducing circulating levels of TNFα[3] and resistin[4], and increasing adiponectin concentrations[5]. Some researches demonstrated that pioglitazone(a TZD) significantly reduced liver fat content of NAFLD, and ameliorated biological parameters and liver histology of NASH[6]. However, there have not been similar data of treating chinese NAFLD with pioglitazone. Berberine (BBR), a compound isolated from a Chinese herb was identified by Weijia [7] as a new cholesterol-lowering drug with a mechanism different from that of statin drugs. BBR elevates LDL receptor(LDLR) expression through a post-transcriptional mechanism that stabilizes the LDLR-mRNA. Considering the close relationship between NAFLD and lipid metabolism, we assume that BBR may be effective for NAFLD by improving lipid metabolism. In order to evaluate these hypotheses, we plan to treat a group of NAFLD patients with impaired glucose regulation (IGR) or T2DM with pioglitazone or BBR in a randomized, open, controlled trial for 16 weeks.

Official Title
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Role of Pioglitazone and Berberine in Treatment of Non-alcoholic Fatty Liver Disease(NAFLD) Patients With Impaired Glucose Regulation or Type 2 Diabetes Mellitus

Conditions
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Nonalcoholic Fatty Liver Disease

Intervention / Treatment
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* Behavioral: Life style intervention
* Drug: pioglitazone
* Drug: berberine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have an age range between 18 to 65 years (inclusive). Patients with fatty liver confirmed by ultrasound. Patients must meet the criteria for impaired glucose regulation or type 2 diabetes mellitus (FPG ≥ 5.6 mmol/L and/or a two hour glucose value ≥ 7.8 mmol/L). Course of diabetic mellitus no more than 1 years Diabetic patients have not received anti-diabetic drugs, including insulin, biguanides, sulfonylureas, thiazolidinediones, Alpha-glucosidase inhibitors, or glinides for 4 weeks before the time of enrollment Patients have not received lipid-regulating drugs (statins, fibrates)for 4 weeks before the time of enrollment Blood pressure < 160/100 mmHg,after receiving lifestyle therapy and effective anti-hypertensive drugs. Patients must stopped other drugs medications for four weeks prior to entering the treatment period, such as: silybin, ursodeoxycholic acid, Polyene Phosphatidylcholine, vitamin E, some herbs with effect of regulating lipid and protecting liver function, etc. Liver fat content(LFC) assessed by 1H MRS ≥ 13%(LFC was calculated by dividing the integral of the methylene groups in fatty acid chains of the hepatic triglycerides by the sum of methylene groups and water). Exclusion Criteria: Any causes of chronic liver disease other than NAFLD (such as - but not restricted to - alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, etc.); Patients with significantly impaired liver function: ALT or AST ≥ 2 times upper limit of normal; HBsAg (+) and/or HCV-Ab (+); Patients with type 1 diabetes mellitus or gestational diabetes or special type diabetes, and patients with BMI < 22 Kg/m2; Course of diabetes more than 1 years; Diabetics patients who have taken or are taking oral glucose-lowering drugs or insulin; Diabetics patients with a HbA1c > 7.5% on initial visit; Patients with severe diabetes complications (diabetes ketoacidosis, diabetes coma or with symptomatic of diabetes coma; dysfunction of nerve, retinopathy, dysfunction of kidney）; Patients with serum creatinine ≥ 1.5 mg/dL (133 umol/L); Patients with a history of clinically significant heart disease (myocardial infarct, heart failure, and or severe cardiac rhythm); Complicating severe infection, within 6 months after operation, severe trauma; Patients with excess alcohol consumption≥140g/week(male); ≥ 70g/week(female); Patients have participated other clinical trials within 24 weeks; Patients with a history of drug allergy to TZDs and berberine; Patients wth gestation or possible gestation or lactation, or males or females who expecting gestation during clinical trial; Mental diseases patients; Those who refuse to sign informed consent; Any other conditions, which, in the opinion of the investigators would impede competence or compliance or possibility of hindering completion of the study; Patients with serum triglyceride ≥ 5.0 mmol/L; Patients with thyroid disease, including hyperthyroidism or hypothyroidism.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Lifestyle intervention<br>Life style intervention including aerobic exercise and reducing energy intake(-500kcal) without drug | Behavioral: Life style intervention<br>* calorie limited diet: to subtract 500 kcal from daily mean calorie intake when entering the treatment activity: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate; or higher-intensity aerobic exercise for more than 90min per week with heart rate around 70% of the maximal heart rate<br>* Other names: aerobic exercise;|
| Experimental: Life style intervention, pioglitazone<br>Life style intervention with pioglitazone 15mg qd for 16 weeks | Behavioral: Life style intervention<br>* calorie limited diet: to subtract 500 kcal from daily mean calorie intake when entering the treatment activity: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate; or higher-intensity aerobic exercise for more than 90min per week with heart rate around 70% of the maximal heart rate<br>* Other names: aerobic exercise;Drug: pioglitazone<br>* pioglitazone tablet,15mg qd ,30 minutes before breakfast,for 16 weeks<br>* Other names: insulin sensitizer;|
| Experimental: Life style intervention, berberine<br>Life style intervention with berberine 0.5g tid for 16 weeks | Behavioral: Life style intervention<br>* calorie limited diet: to subtract 500 kcal from daily mean calorie intake when entering the treatment activity: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate; or higher-intensity aerobic exercise for more than 90min per week with heart rate around 70% of the maximal heart rate<br>* Other names: aerobic exercise;Drug: berberine<br>* berberine tablet 0.5g tid,30 minutes before each meal,for 16 weeks<br>* Other names: herb;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improved metabolic parameters(glucose, lipid, liver enzymes, etc.) | improvement of the metabolic parameters, including serum glucose of OGTT, fasting glucose,2 hour glucose,area under the glucose curve and HbA1c,lipid profile（TC、TG、HDL-c、LDL-c、ApoA、ApoB、ApoE and Lpa），liver enzymes（ALT,AST,ALP,γ-GT）. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| liver fat content | improvement of liver fat content by 1H NMR spectroscopy | 16 weeks | 
| serum insulin | improvement of serum insulin including fasting insulin,2 hour insulin and area under insulin curve. | 16 weeks | 
| the ratio of withdrawing because of inefficiency |  | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonalcoholic Fatty Liver Disease, Pioglitazone, Berberine, Impaired Glucose Metabolism