Effects of FXR Activation on Hepatic Lipid and Glucose Metabolism

Sponsor

University Hospital, Basel, Switzerland (Other)

Overall Status

Completed

CT.gov ID

NCT00465751

Collaborator

(none)

Enrollment

Location

Arms

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Metabolic Syndrome Familial Hypertriglyceridemia Familial Combined Hyperlipidemia	Drug: chenodeoxycholic acid Drug: placebo capsules	Early Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Non-Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, 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

Study Start Date :

Oct 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

plasma triglyceride concentrations [3 months]

Secondary Outcome Measures

hepatic insulin sensitivity [3 months]
heptic triglyceride content [3 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Age between 18 and 65 years.
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

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

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

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:

Any significant hepatic, cardiac, pulmonary, renal, neurological, musculoskeletal, hematological or endocrine disease.
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)].
Plasma TG levels > 12 mmol/l in the past or at any time point during the study.
History of acute pancreatitis
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).
Pregnant or Breast Feeding women
Woman of childbearing potential not using a reliable method of birth control such as oral contraceptives or IUD.
Alcohol intake of greater than 1 drink daily.
Cigarette smokers
History of claustrophobia
Ferromagnetic implants including pacemakers.
Subjects refusing or unable to give written informed consent.