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Sponsored by: |
KineMed |
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Information provided by: | KineMed |
ClinicalTrials.gov Identifier: | NCT00596427 |
The mechanism by which colesevelam HCl lowers glucose is not known. Knowledge of the potential mechanism of action is important for defining the role of the drug among oral antidiabetic agents available for use in subjects with diabetes. The objective of this study is to provide insight into the mechanisms of action of colesevelam HCl in T2DM. The mechanisms of interest include hepatic insulin sensitivity, rate of appearance of exogenous glucose and changes in incretin hormone concentrations.
Condition | Intervention |
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Diabetes |
Drug: Colesevelam HCL Drug: Placebo |
Study Type: | Interventional |
Study Design: | Basic Science, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Pharmacokinetics Study |
Official Title: | Effects of Colesevelam HCl on Hepatic Insulin Sensitivity, Gluconeogenesis, Glucose Absorption and Lipid Synthesis in Subjects With Type 2 Diabetes Mellitus |
Estimated Enrollment: | 60 |
Study Start Date: | November 2007 |
Estimated Study Completion Date: | November 2008 |
Estimated Primary Completion Date: | November 2008 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Placebo Comparator
Type-2 diabetes mellitus patients
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Drug: Placebo
Placebo tablets: 3 tablets twice per day
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2: Experimental
Type-2 diabetes mellitus patients
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Drug: Colesevelam HCL
Colesevelam HCL 625 mg: 3 tablets twice per day
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Colesevelam HCl (marketed in the U.S. as WelChol®) is a non-absorbed polymer that binds bile acids in the intestine, impeding their reabsorption, and is indicated to lower low-density lipoprotein cholesterol (LDL-C) in subjects with hypercholesterolemia. As the bile acid pool becomes depleted, the hepatic enzyme cholesterol 7-(alpha)-hydroxylase is upregulated, increasing the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase, and increasing the number of hepatic low-density lipoprotein (LDL) receptors. These compensatory effects increase the clearance of LDL-C from the blood, decreasing serum LDL C levels (1; 2).
Recently, it has been shown that colesevelam HCl also improves glycemic control in subjects with T2DM who are not controlled adequately on metformin, sulfonylurea or a combination of the two drugs (3). The mechanism of action for glucose lowering is not known. Improved glycemic control with colesevelam HCl treatment could be due to any of several mechanisms. Colesevelam HCl could reduce hepatic insulin resistance and lead to a decrease in hepatic glucose production (HGP). The observation by Schwartz et al (4) of significantly reduced fasting plasma glucose concentrations in colesevelam-treated T2DM patients suggests such a reduction in HGP, as fasting hyperglycemia is a direct function of HGP. Colesevelam HCl could also decrease post-prandial glucose absorption. Changes in glucose absorption with other bile acid sequestrants (BAS) (5) and bile acids (6) have been reported.
With regard to molecular mediators of the colesevelam effect on glucose metabolism, there is considerable evidence emerging about the role of bile acids and nuclear transcription factors, such as the farnesyl X receptor (FXR), in the regulation of glucose and lipid metabolism (7) (8) (9-15). Changes in cellular lipids or nuclear hormone receptors might directly alter HGP although mechanisms leading to changes in hepatic lipid and glucose metabolism by colesevelam HCl have not previously been investigated.
Significant changes in cholesterol and bile acid synthesis rates are expected with colesevelam treatment. BAS treatment can alter the transhepatic flux and compositional profile of the circulating bile acid pool (16), and thus its hydrophobicity, and this may effect the activation of nuclear receptors, including FXR (17; 18). Determination of the effect of colesevelam treatment on bile acid synthesis may provide evidence for its metabolic effects. The effects on hepatic fatty acid synthesis (de novo lipogenesis or DNL) have not been investigated and may provide further evidence for a metabolic effect of colesevelam.
Specific hypotheses about its mode of action will be tested, focusing on hepatic glucose metabolism and intestinal glucose absorption.
Ages Eligible for Study: | 30 Years to 70 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Subjects meeting the following criteria at the Screening Visit will be eligible to participate in the trial:
Male or Female
Females of childbearing potential who are on approved birth control method:
oral, injectable, or implantable hormonal contraceptives; intrauterine device; diaphragm plus spermicide or female condom plus spermicide
Exclusion Criteria:
Subjects are excluded from participation in the study if any of the following criteria apply:
United States, California | |
Diablo Clinical Research, Inc | |
Walnut Creek, California, United States, 94598 | |
United States, Florida | |
Clinical Pharmacology of Miami, Inc | |
Miami, Florida, United States, 33014 | |
United States, Texas | |
Diabetes & Glandular Disease Research Associates | |
San Antonio, Texas, United States, 78229 |
Principal Investigator: | Carine Beysen, PhD | KineMed |
Responsible Party: | KineMed, Inc. ( Anand Mehta/ Director of Translational Medicines ) |
Study ID Numbers: | KM-11A |
Study First Received: | January 8, 2008 |
Last Updated: | November 25, 2008 |
ClinicalTrials.gov Identifier: | NCT00596427 |
Health Authority: | United States: Institutional Review Board |
type two diabetes gluconeogenesis glucose |
lipid sysnthesis hepatic insulin sensitivity colesevelam HCl |
Colesevelam Metabolic Diseases Diabetes Mellitus, Type 2 Diabetes Mellitus Endocrine System Diseases |
Endocrinopathy Metabolic disorder Glucose Metabolism Disorders Insulin |
Antimetabolites Molecular Mechanisms of Pharmacological Action Therapeutic Uses |
Antilipemic Agents Anticholesteremic Agents Pharmacologic Actions |