Clinical trial NCT00476710: Effects of Colesevelam HCl On Bile Acid Kinetics
Official title: Effects of Colesevelam HCl On Bile Acid Pools And Kinetic Parameters in Normal Subjects, Subjects With Impaired Glucose Tolerance, And Subjects With Type 2 Diabetes Mellitus
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Type 2 Diabetes Mellitus
Impaired Glucose Tolerance
Keywords: Type 2 diabetes mellitus
Bile acid
Stable isotope
Colesevelam HCl
Impaired Glucose Tolerance
Lead sponsor: KineMed
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo
name: University Medical Center Groningen
name: Diabetes & Glandular Disease Research Associates
First posted: 2007-05-22
Enrollment: 36
Sex: ALL
Minimum age (years): 40
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: overweight and obese people with normal glucose metabolism, impaired glucose tolerance and frank type 2 diabetes

Brief summary: This project will compare the amount of bile acids and their kinetics in overweight and obese people with normal glucose metabolism, impaired glucose tolerance and frank type 2 diabetes. We hypothesize that bile acids will behave differently in these groups. We will also explore the effects of Colesevelam HCl, a medicine that lowers LDL cholesterol by binding bile acids, on bile acids in those groups. We hypothesize the drug may have different actions on bile acids in subjects with different degrees of abnormal glucose metabolism.

Detailed description: Bile acids, which are synthesized from cholesterol in the liver, play a key role in digestion as they solubilize dietary lipids and aid their absorption in the digestive tract. While for many years bile acids have been characterized by this digestive role, recent research indicates that bile acids play other important roles. Because bile acids have been shown to act in signaling pathways that affect metabolism, there has been renewed interest in investigations of their effects. This study explores potential differences in bile acid kinetics based on insulin resistance or type 2 diabetes at baseline.

Colesevelam HCl is a bile acid sequestrant, which in addition to its primary role in lowering serum LDL-C levels, has secondarily been implicated in lowering blood glucose levels. This study explores the relationship between insulin resistance and type 2 diabetes and changes in bile acid pool sizes and kinetics with colesevelam treatment. Isotopically labeled bile acids will be administered to subjects before and after treatment with colesevelam and comparisons will be made in bile acid pool size, fractional turnover rate, and synthesis rate in the three study groups.

Eligibility criteria: Inclusion Criteria:

* Have given written informed consent
* BMI 25-35 kg/m\^2, inclusive
* Normal liver and thyroid function
* No history of liver, biliary, or intestinal disease

Diabetic Subjects

* Diagnosed Type 2 Diabetes Mellitus
* HbA1C = 6.7-10%

Normal Subjects

* 2 hr OGTT glucose \< 140 mg/dL
* fasting glucose \< 100 mg/dL
* TG \< 150 mg/dL
* HDL cholesterol \>= 40 mg/dL

Impaired Glucose Tolerance Subjects

* 2 hr OGTT glucose \>= 140 and \< 200 mg/dL

Exclusion Criteria:

* T1DM or history of diabetic ketoacidosis
* treatment with blood pressure lowering therapy that has not been stable for three months before screening
* colesevelam HCl, cholestyramine, or colestipol treatment for hyperlipidemia within the last three months
* treatment with thiazolidinedione (TZD) at any time
* treatment with insulin within past 6 months
* treatment with antibiotics within last 3 months
* extreme sportsmen
* treatment with medication affecting liver or intestinal function within the last 3 months
* allergic or toxic rxn to colesevelam HCl
* history of dysphagia, swallowing disorders, or intestinal motility disorder
* Serum Triglycerides \> 500 mg/dL at visit 1
* Serum LDL-C \< 60 mg/dL at visit 1
* any condition or therapy investigator believes not in subjects best interest
* use of any investigational drug within 30 days before screening
* chronic treatment with oral corticosteroids at any time or acute treatment within last three months
* hyperthyroidism or treatment with thyroid hormone/levothyroxine

Primary outcomes:
measure: Bile Acid Pool Size and Kinetic Parameters
timeFrame: 60 days of treatment
Secondary outcomes:
measure: Resting Metabolic Rate
timeFrame: 60 days of treatment
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Diabetes & Glandular Disease Research Associates, Inc.
state: Texas
Study officials:
affiliation: KineMed, Inc.
name: Elizabeth J Murphy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Groningen
name: Folkert Kuipers, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Grundy SM, Ahrens EH Jr, Salen G. Interruption of the enterohepatic circulation of bile acids in man: comparative effects of cholestyramine and ileal exclusion on cholesterol metabolism. J Lab Clin Med. 1971 Jul;78(1):94-121. No abstract available.
citation: Shepherd J, Packard CJ, Bicker S, Lawrie TD, Morgan HG. Cholestyramine promotes receptor-mediated low-density-lipoprotein catabolism. N Engl J Med. 1980 May 29;302(22):1219-22. doi: 10.1056/NEJM198005293022202.
citation: Zieve FJ, Kalin MF, Schwartz SL, Jones MR, Bailey WL. Results of the glucose-lowering effect of WelChol study (GLOWS): a randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes. Clin Ther. 2007 Jan;29(1):74-83. doi: 10.1016/j.clinthera.2007.01.003.
citation: Abrams JJ, Ginsberg H, Grundy SM. Metabolism of cholesterol and plasma triglycerides in nonketotic diabetes mellitus. Diabetes. 1982 Oct;31(10):903-10. doi: 10.2337/diab.31.10.903.
citation: Andersen E, Karlaganis G, Sjovall J. Altered bile acid profiles in duodenal bile and urine in diabetic subjects. Eur J Clin Invest. 1988 Apr;18(2):166-72. doi: 10.1111/j.1365-2362.1988.tb02408.x.
citation: Bennion LJ, Grundy SM. Effects of diabetes mellitus on cholesterol metabolism in man. N Engl J Med. 1977 Jun 16;296(24):1365-71. doi: 10.1056/NEJM197706162962401.
citation: Hulzebos CV, Renfurm L, Bandsma RH, Verkade HJ, Boer T, Boverhof R, Tanaka H, Mierau I, Sauer PJ, Kuipers F, Stellaard F. Measurement of parameters of cholic acid kinetics in plasma using a microscale stable isotope dilution technique: application to rodents and humans. J Lipid Res. 2001 Nov;42(11):1923-9.
citation: Brufau G, Stellaard F, Prado K, Bloks VW, Jonkers E, Boverhof R, Kuipers F, Murphy EJ. Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatology. 2010 Oct;52(4):1455-64. doi: 10.1002/hep.23831.