Mechanisms of Glucose Lowering Effect of Colesevelam HCl

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Carine Beysen, KineMed
ClinicalTrials.gov Identifier:
NCT00596427
First received: January 8, 2008
Last updated: October 10, 2012
Last verified: October 2012
  Purpose

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
Diabetes
Drug: Colesevelam HCL
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: Effects of Colesevelam HCl on Hepatic Insulin Sensitivity, Gluconeogenesis, Glucose Absorption and Lipid Synthesis in Subjects With Type 2 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by KineMed:

Primary Outcome Measures:
  • Fasting Endogenous Glucose Production (EGP) [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
    Changes from baseline of fasting EGP after 12 weeks of placebo or colesevelam treatment.

  • Fasting Gluconeogenesis [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
    Change from baseline of fasting gluconeogenesis after 12 weeks of placebo or colesevelam treatment.

  • Fasting Glycogenolysis [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
    Change from baseline of fasting glycogenolysis after 12 weeks of placebo or colesevelam treatment.

  • Rate of Appearance of Exogenous Glucose (Glucose Absorption) [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
    Change from baseline of the rate of appearance of oral glucose after 12 weeks of placebo or colesevelam treatment. Mean of values obtained between 0 and 300 min is reported.


Secondary Outcome Measures:
  • Total Glucagon-like Peptide (GLP-1) Area Under the Curve (AUC) [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]

    Changes from baseline of total GLP-1 AUC after 12 weeks of placebo or colesevelam treatment.

    AUC values were calculated by the trapezoid method using all results between 0 and 300 minutes


  • Total Glucose-dependent Insulinotropic Polypeptide (GIP) AUC [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]

    Changes from baseline of total GIP-1 AUC after 12 weeks of placebo or colesevelam treatment.

    AUC values were calculated by the trapezoid method using all results between 0 and 300 minutes


  • Fasting Fractional De Novo Lipogenesis (DNL) [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
    Changes from baseline in fasting fractional DNL after 12 weeks of colesevelam or placebo treatment were calculated. Fractional DNL represents the fraction of palmitate in very-low density lipoproteins-triglycerides (VLDL-TG) that was newly synthesized.

  • Fasting Fractional Cholesterol Synthesis [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
    Changes from baseline in fasting fractional cholesterol synthesis after 12 weeks of colesevelam or placebo treatment. Fractional Cholesterol synthesis represents the fraction of free cholesterol in plasma that was newly synthesised.

  • Postprandial Fractional Cholic Acid Synthesis [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
    Changes from baseline in fractional cholic acid synthesis after 12 weeks of colesevelam or placebo treatment were evaluated. Fractional cholic acid synthesis represents the relative amount of cholic acid that is made from newly synthesised cholesterol.

  • Glucagon AUC [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]

    Changes from baseline of glucagon AUC after 12 weeks of placebo or colesevelam treatment.

    AUC values were calculated by the trapezoid method using all results between 0 and 300 minutes



Other Outcome Measures:
  • Glycosylated Hemoglobin (HbAlc) [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
    Changes from baseline of HbA1c after 12 weeks of placebo or colesevelam treatment.

  • Glucose AUC [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]

    Changes from baseline of glucose AUC after 12 weeks of placebo or colesevelam treatment.

    AUC values were calculated by the trapezoid method using all results between 0 and 300 minutes



Enrollment: 60
Study Start Date: November 2007
Study Completion Date: April 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo tablet 3 tablets 2x/day
Type-2 diabetes mellitus patients
Drug: Placebo
Placebo tablets: 3 tablets twice per day
Experimental: Colesevelam HCL 625 mg: 3 tablets 2x/day
Type-2 diabetes mellitus patients
Drug: Colesevelam HCL
Colesevelam HCL 625 mg: 3 tablets twice per day
Other Name: WelChol

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   30 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects meeting the following criteria at the Screening Visit will be eligible to participate in the trial:

  • Have given written informed consent
  • Male or Female

    1. 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

    2. Females of non-childbearing potential: hysterectomy, tubal ligation 6 months prior screening or post-menopausal for at least 1 year
  • Previously diagnosed or newly diagnosed with T2DM
  • Age 30 to 70 years, inclusive
  • BMI ≥ 18.5 kg/m2 and ≤ 40 kg/m2
  • HbA1C 7-10%, inclusive (exceptions between 6.7-7% may be enrolled with prior approval of SPONSOR)
  • Fasting plasma glucose < 300 mg/dL
  • Diet controlled or on stable dose of a sulfonylurea and/or meglitinides and/or metformin for ≥ 90 days before screening
  • No history of liver, biliary or intestinal disease (AST/ALT < 2X upper limit of normal value)
  • Normal TSH
  • Agrees to maintain their regular diet and exercise routine
  • Agrees to refrain from consumption of alcohol 48 hours prior to start of infusions (week 0 and week 12)

Exclusion Criteria:

Subjects are excluded from participation in the study if any of the following criteria apply:

  • Type 1 diabetes mellitus or history of diabetic ketoacidosis
  • Treatment with lipid lowering medication other than statins
  • Treatment with statins that have not been stable for 3 months before screening
  • Treatment with colesevelam HCl, cholestyramine or colestipol for hyperlipidemia within the last 3 months of screening
  • Treatment with a thiazolidinedione (TZD) at any time
  • Treatment with acarbose at any time
  • Treatment with insulin in the past 6 months
  • Treatment with antibiotics within the last 3 months
  • Treatment with any medication affecting liver or intestinal function within the last 3 months
  • Pregnant
  • Breastfeeding
  • Has had unstable weight within the last 3 months of screening (± 5 kg)
  • History of an allergic or toxic reaction to colesevelam HCl
  • History of dysphagia, swallowing disorders, or intestinal motility disorder
  • Serum triglycerides ≥ 350 mg/dL at screening visit (exceptions up to 500 mg/dl may be enrolled with prior approval of SPONSOR)
  • Serum LDL-C <60 mg/dL at screening visit
  • Any condition or therapy which, in the opinion of the investigator, poses a risk to the subject or makes participation not in the subject's best interest
  • Use of any investigational drug within 3 months of screening
  • Chronic treatment with oral corticosteroids at any time or acute treatment within the last 3 months
  • History of drug or alcohol abuse, is currently a user (including "recreational use") of any illicit drugs, or has a positive urine drug screen at screening
  • Donated a unit of blood within 30 days before screening
  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: NCT00596427

Locations
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
Sponsors and Collaborators
Carine Beysen
Investigators
Principal Investigator: Carine Beysen, PhD KineMed
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Carine Beysen, Director, Clinical Metabolic Research, KineMed
ClinicalTrials.gov Identifier: NCT00596427     History of Changes
Other Study ID Numbers: KM-11A
Study First Received: January 8, 2008
Results First Received: April 19, 2012
Last Updated: October 10, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by KineMed:
type two diabetes
gluconeogenesis
glucose
lipid synthesis
hepatic insulin sensitivity
colesevelam HCl

Additional relevant MeSH terms:
Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Colesevelam
Anticholesteremic Agents
Antimetabolites
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014