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

Information source: Fudan University
Information obtained from ClinicalTrials.gov on November 03, 2008
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Nonalcoholic Fatty Liver Disease

Intervention: Life style intervention (Behavioral); pioglitazone (Drug); berberine (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Fudan University

Official(s) and/or principal investigator(s):
Xin GAO, master, Principal Investigator, Affiliation: unaffiliated

Overall contact:
Xin GAO, master, Phone: 86-021-64041990, Ext: 8021, Email: gao.xin@zs-hospital.sh.cn

Summary

The purpose of this study is to evaluate effect 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.

Clinical Details

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

Study design: Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study

Primary outcome: liver fat content by 1H NMR spectroscopy

Secondary outcome: OGTT(glucose, insulin, AUC of insulin);liver enzymes(ALT、AST、γ-GT、ALP);lipid profile(TC、TG、HDL-c、LDL-c、ApoA、ApoB、ApoE、Lpa);

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 LDLR expression through a post-transcriptional mechanism that stabilizes the 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 12 weeks.

Eligibility

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

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. 6mmol/L and/or a two hour glucose value≥7. 8mmol/L).Patients with a HbA1c>7. 5% will be excluded from the study.

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 <160/100mmHg,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.

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<22Kg/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. 5mg/dL(133umol/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.

Locations and Contacts

Xin GAO, master, Phone: 86-021-64041990, Ext: 8021, Email: gao.xin@zs-hospital.sh.cn

Endocrinology and Metabolism Department, Zhongshan Hospital, Fudan University,, Shanghai 200032, China; Recruiting
Xin GAO, master, Phone: 86-021-64041990, Ext: 8021, Email: gao.xin@zs-hospital.sh.cn
Hongmei YAN, master, Phone: 13761666976, Email: yan.hongmei@zs-hospital.sh.cn
Hongmei YAN, master, Sub-Investigator
Meng LIU, MD candidate, Sub-Investigator
Additional Information

Related publications:

Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005 Jul;42(1):44-52.

Fan JG, Zhu J, Li XJ, Chen L, Li L, Dai F, Li F, Chen SY. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol. 2005 Sep;43(3):508-14.

Miyazaki Y, Mahankali A, Wajcberg E, Bajaj M, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2004 Sep;89(9):4312-9.

Szapary PO, Bloedon LT, Samaha FF, Duffy D, Wolfe ML, Soffer D, Reilly MP, Chittams J, Rader DJ. Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome. Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):182-8. Epub 2005 Nov 10.

Shadid S, Stehouwer CD, Jensen MD. Diet/Exercise versus pioglitazone: effects of insulin sensitization with decreasing or increasing fat mass on adipokines and inflammatory markers. J Clin Endocrinol Metab. 2006 Sep;91(9):3418-25. Epub 2006 Jun 27.

Yoneda M, Endo H, Nozaki Y, Tomimoto A, Fujisawa T, Fujita K, Yoneda K, Takahashi H, Saito S, Iwasaki T, Yamamoto S, Tsutsumi S, Aburatani H, Wada K, Hotta K, Nakajima A. Life style-related diseases of the digestive system: gene expression in nonalcoholic steatohepatitis patients and treatment strategies. J Pharmacol Sci. 2007 Oct;105(2):151-6. Epub 2007 Oct 6. Review.

Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004 Dec;10(12):1344-51. Epub 2004 Nov 7.

Starting date: March 2008
Ending date: May 2009
Last updated: June 23, 2008

Page last updated: November 03, 2008

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