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

NCT ID: NCT00633282

Last Updated: 2012-06-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 184 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-03-31
• Study Completion Date: 2011-08-31

Brief Summary

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

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.

Conditions

Nonalcoholic Fatty Liver Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lifestyle intervention

Life style intervention including aerobic exercise and reducing energy intake(-500kcal) without drug

Group Type: EXPERIMENTAL

Life style intervention

Intervention Type: BEHAVIORAL

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

Life style intervention, pioglitazone

Life style intervention with pioglitazone 15mg qd for 16 weeks

Group Type: EXPERIMENTAL

Life style intervention

Intervention Type: BEHAVIORAL

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

pioglitazone

Intervention Type: DRUG

pioglitazone tablet,15mg qd ,30 minutes before breakfast,for 16 weeks

Life style intervention, berberine

Life style intervention with berberine 0.5g tid for 16 weeks

Group Type: EXPERIMENTAL

Life style intervention

Intervention Type: BEHAVIORAL

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

berberine

Intervention Type: DRUG

berberine tablet 0.5g tid,30 minutes before each meal,for 16 weeks

Interventions

Life style intervention

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

Intervention Type: BEHAVIORAL

pioglitazone

pioglitazone tablet,15mg qd ,30 minutes before breakfast,for 16 weeks

Intervention Type: DRUG

berberine

berberine tablet 0.5g tid,30 minutes before each meal,for 16 weeks

Intervention Type: DRUG

Other Intervention Names

calorie limited diet; aerobic exercise; Actlns; PPAR agonist; Thiazolidinediones; insulin sensitizer; traditional Chinese medicine; herb

Eligibility Criteria

Inclusion Criteria

1. Patients must have an age range between 18 to 65 years (inclusive).

2. Patients with fatty liver confirmed by ultrasound.

3. 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).

4. Course of diabetic mellitus no more than 1 years

5. 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

6. Patients have not received lipid-regulating drugs (statins, fibrates)for 4 weeks before the time of enrollment

7. Blood pressure < 160/100 mmHg,after receiving lifestyle therapy and effective anti-hypertensive drugs.

8. 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.

9. 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

1. 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.);

2. Patients with significantly impaired liver function: ALT or AST ≥ 2 times upper limit of normal;

3. HBsAg (+) and/or HCV-Ab (+);

4. Patients with type 1 diabetes mellitus or gestational diabetes or special type diabetes, and patients with BMI < 22 Kg/m2;

5. Course of diabetes more than 1 years;

6. Diabetics patients who have taken or are taking oral glucose-lowering drugs or insulin;

7. Diabetics patients with a HbA1c > 7.5% on initial visit;

8. Patients with severe diabetes complications (diabetes ketoacidosis, diabetes coma or with symptomatic of diabetes coma; dysfunction of nerve, retinopathy, dysfunction of kidney）;

9. Patients with serum creatinine ≥ 1.5 mg/dL (133 umol/L);

10. Patients with a history of clinically significant heart disease (myocardial infarct, heart failure, and or severe cardiac rhythm);

11. Complicating severe infection, within 6 months after operation, severe trauma;

12. Patients with excess alcohol consumption≥140g/week(male); ≥ 70g/week(female);

13. Patients have participated other clinical trials within 24 weeks;

14. Patients with a history of drug allergy to TZDs and berberine;

15. Patients wth gestation or possible gestation or lactation, or males or females who expecting gestation during clinical trial;

16. Mental diseases patients;

17. Those who refuse to sign informed consent;

18. Any other conditions, which, in the opinion of the investigators would impede competence or compliance or possibility of hindering completion of the study;

19. Patients with serum triglyceride ≥ 5.0 mmol/L;

20. Patients with thyroid disease, including hyperthyroidism or hypothyroidism.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shanghai Jiao Tong University School of Medicine

OTHER

Sponsor Role: collaborator

Shanghai Municipal Science and Technology Commission

OTHER_GOV

Sponsor Role: collaborator

Xin Gao

OTHER

Sponsor Role: lead

Responsible Party

Xin Gao

MD. and Professor, Vice-President of Zhongshan Hospital, Director of Department of Endocrinology & Metabolism of Zhongshan Hospital Fudan University

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Xin GAO, MD

Role: PRINCIPAL_INVESTIGATOR

Fudan University

Locations

Endocrinology and Metabolism Department, Zhongshan Hospital, Fudan University,

Shanghai, Shanghai Municipality, China

Department of Endocrinology and Metabolism,Shanghai Clinical Center of Diabetes,Shanghai Institute of Diabetes,The sixth people's Hospital Affiliated to Shanghai Jiaotong University

Shanghai, Shanghai Municipality, China

Department of Endocrinology and Metabolism,The Fifth People's Hospital，Fudan University

Shanghai, Shanghai Municipality, China

Countries

China

References

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Reference Type: BACKGROUND

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Other Identifiers

07JC14011

Identifier Type: -

Identifier Source: org_study_id