Effects of FXR Activation on Hepatic Lipid and Glucose Metabolism

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier:
NCT00465751
First received: April 24, 2007
Last updated: March 8, 2012
Last verified: March 2012
  Purpose

The purpose of this study is to determine whether chenodeoxycholic acid decreases de novo hepatic lipogenesis, hepatic fat content, hepatic triglyceride production and plasma triglyceride concentrations and improves hepatic glucose metabolism in patients with the metabolic syndrome, Familial Hypertriglyceridemia and Familial Combined Hyperlipidemia.


Condition Intervention Phase
Metabolic Syndrome
Familial Hypertriglyceridemia
Familial Combined Hyperlipidemia
Drug: chenodeoxycholic acid
Drug: placebo capsules
Phase 0

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Activation of the Farnesoid X Receptor (FXR) on Hepatic Lipid and Glucose Metabolism in Patients With the Metabolic Syndrome and Familial Forms of Hypertriglyceridemia

Resource links provided by NLM:


Further study details as provided by University Hospital, Basel, Switzerland:

Primary Outcome Measures:
  • plasma triglyceride concentrations [ Time Frame: 3 months ]

Secondary Outcome Measures:
  • hepatic insulin sensitivity [ Time Frame: 3 months ]
  • heptic triglyceride content [ Time Frame: 3 months ]

Enrollment: 30
Study Start Date: October 2004
Arms Assigned Interventions
Active Comparator: A
chenodeoxycholic acid treatment
Drug: chenodeoxycholic acid
chenodeoxycholic acid 500 mg capsules tid po
Placebo Comparator: B
placebo treatment
Drug: placebo capsules
placebo capsules containing mannitol tid po

Detailed Description:

Insulin resistance has been found to be the key pathophysiological factor of the metabolic syndrome and may precede the onset of impaired glucose tolerance, diabetes and dyslipidemia. Recently, nonalcoholic fatty liver disease (NAFLD), has been identified as another feature of this syndrome. Importantly, a close relation between liver fat content and hepatic insulin sensitivity has been described. We hypothesize that activation of FXR with chenodeoxycholic acid decreases hepatic de novo lipogenesis and subsequently hepatic fat content and triglyceride production. The decrease in liver fat content will be associated with improved hepatic insulin sensitivity and a decrease in hepatic glucose production.

Patients diagnosed with metabolic syndrome, familial hypertriglyceridemia or familial combined hyperlipidemia will be recruited from the the outpatients department of the Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Basel. Eligible patients will be admitted to the CRC for metabolic studies, including baseline blood samples for the measurement of hormones, cytokines and adipokines, euglycemic-hyperinsulinemic clamp studies for the assessment of glucose turnover and insulin sensitivity and in vivo NMR studies to determine intrahepatic and intramyocellular lipid content. Patients will alternatively receive chenodeoxycholic acid and placebo. The study population will be compared to a group of age, gender and weight matched normolipidemic controls.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Age between 18 and 65 years.
  2. Patients with a metabolic syndrome defined by the presence of >= 3 of the following criteria:

    • Abdominal obesity (waist circumference > 102 cm in men, > 88 cm in women)
    • Fasting plasma triglycerides > 1.7 mmol/l
    • HDL cholesterol < 1.0 mmol/l in men and < 1.3 mmol/l in women
    • Blood pressure > 130/85 mmHg or antihypertensive medication
    • Fasting plasma glucose > 6.1 mmol/l
  3. Patients with Familial Combined Hyperlipidemia characterized by the following criteria:

    • Fasting plasma triglycerides > 1.7 mmol/l
    • Fasting plasma apolipoprotein B concentrations > 1.2 g/l
    • Family history with hypertriglyceridemia and/or hypercholesterolemia present in at least 1 additional first degree family members
  4. Patients with Familial Hypertriglyceridemia characterized by the following criteria:

    • Fasting plasma triglycerides > 2.3 mmol/l
    • Family history of hypertriglyceridemia in at least 1 additional first degree family member
    • Absence of the metabolic syndrome as defined above
  5. Controls fulfilling the following criteria:

    • Non smoking.
    • No current or previous organ or systemic disease (including diabetes and lipid disorders).
    • Plasma triglycerides and cholesterol within the normal range (see exclusion criteria).
    • Plasma glucose concentrations <6.1 mmol/l Subjects meeting criterium 1 and any of the criteria 2. - 5. are eligible for the study.

Exclusion Criteria:

  1. Any significant hepatic, cardiac, pulmonary, renal, neurological, musculoskeletal, hematological or endocrine disease.
  2. Any form of primary or secondary hyperlipidemia other than the metabolic syndrome, FHTG or FCHL. [These may include: Familial hypercholesterolemia and Familial defective apolipoprotein B (to be assessed by family history and lipid profiles), and Familial Dysbetalipoproteinemia (to be assessed by apo E genotyping), hypothyroidism, nephrotic syndrome, diabetes mellitus, cholestatic liver disease, drug induced hyperlipidemia (thiazides > 25 mg/d, non cardioselective betablockers, isotretinoin, systemic glucocorticoids, cyclosporin A, tacrolimus, non nucleoside HIV protease inhibitors)].
  3. Plasma TG levels > 12 mmol/l in the past or at any time point during the study.
  4. History of acute pancreatitis
  5. History of cardiovascular disease, i.e. coronary artery disease, cerebrovascular disease, peripheral vascular disease, when assessed by medical history, physical exam. Additionally, a stress test will be performed in subjects with MS and FCHL at risk for CHD (see below).
  6. Pregnant or Breast Feeding women
  7. Woman of childbearing potential not using a reliable method of birth control such as oral contraceptives or IUD.
  8. Alcohol intake of greater than 1 drink daily.
  9. Cigarette smokers
  10. History of claustrophobia
  11. Ferromagnetic implants including pacemakers.
  12. Subjects refusing or unable to give written informed consent.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00465751

Locations
Switzerland
University Hospital Basel
Basel, Switzerland, 4031
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Investigators
Principal Investigator: Stefan Bilz, MD Cantonal Hospital of St. Gallen
  More Information

No publications provided

Responsible Party: University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT00465751     History of Changes
Other Study ID Numbers: EKBB 211/04 SB
Study First Received: April 24, 2007
Last Updated: March 8, 2012
Health Authority: Switzerland: Ethikkommission

Additional relevant MeSH terms:
Hyperlipidemias
Hyperlipidemia, Familial Combined
Hyperlipoproteinemia Type IV
Hypertriglyceridemia
Metabolic Syndrome X
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Chenodeoxycholic Acid
Cathartics
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 01, 2014