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DiabetesNCT00596427

Mechanisms of Glucose Lowering Effect of Colesevelam HCl

A study testing Colesevelam HCL in people with Diabetes, run by Carine Beysen at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 30 to 70 years
Conditions the study is for
Diabetes
What is being tested?
Colesevelam HCL
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
60 participants
Where
3 sitesUnited States
Study dates
Nov 2007to Apr 2009
Phase
Interventional
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
  • 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
  • Females of non-childbearing potential: hysterectomy, tubal ligation 6 months prior screening or post-menopausal for at least 1 year
Show all 16Show fewer
  • 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)

Who cannot join

  • 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
Show all 22Show fewer
  • 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

Trial locations and contacts

3 sites in 1 country.

United States3 sites
  • Clinical Pharmacology of Miami, Inc

    Miami, Florida, 33014

  • Diabetes & Glandular Disease Research Associates

    San Antonio, Texas, 78229

  • Diablo Clinical Research, Inc

    Walnut Creek, California, 94598

Other trials in United States

About this study

Official title: Effects of Colesevelam HCl on Hepatic Insulin Sensitivity, Gluconeogenesis, Glucose Absorption and Lipid Synthesis in Subjects With Type 2 Diabetes Mellitus

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.

Read the 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.

Conditions
Diabetes
Being tested
Colesevelam HCL, Placebo
Keywords
type two diabetes, gluconeogenesis, glucose, lipid synthesis, hepatic insulin sensitivity, colesevelam HCl
Medical subject headings
Diabetes Mellitus

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Colesevelam HCLDrug

    Also called WelChol

    Colesevelam HCL 625 mg: 3 tablets twice per day

  • PlaceboDrug

    Placebo tablets: 3 tablets twice per day

Study groups in NCT00596427
Study groupRoleWhat they receive
Placebo tablet 3 tablets 2x/dayPlacebo comparatorType-2 diabetes mellitus patients
Receives: Drug: Placebo
Colesevelam HCL 625 mg: 3 tablets 2x/dayExperimentalType-2 diabetes mellitus patients
Receives: Drug: Colesevelam HCL

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Fasting Endogenous Glucose Production (EGP)

    Changes from baseline of fasting EGP after 12 weeks of placebo or colesevelam treatment.

    Measured: baseline and 12 weeks

  2. Fasting Gluconeogenesis

    Change from baseline of fasting gluconeogenesis after 12 weeks of placebo or colesevelam treatment.

    Measured: baseline and 12 weeks

  3. Fasting Glycogenolysis

    Change from baseline of fasting glycogenolysis after 12 weeks of placebo or colesevelam treatment.

    Measured: baseline and 12 weeks

  4. Rate of Appearance of Exogenous Glucose (Glucose Absorption)

    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.

    Measured: baseline and 12 weeks

Secondary outcomes (6)
  1. Total Glucagon-like Peptide (GLP-1) Area Under the Curve (AUC)

    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

    Measured: baseline and 12 weeks

  2. Total Glucose-dependent Insulinotropic Polypeptide (GIP) AUC

    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

    Measured: baseline and 12 weeks

  3. Fasting Fractional De Novo Lipogenesis (DNL)

    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.

    Measured: baseline and 12 weeks

  4. Fasting Fractional Cholesterol Synthesis

    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.

    Measured: baseline and 12 weeks

  5. Postprandial Fractional Cholic Acid Synthesis

    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.

    Measured: baseline and 12 weeks

  6. Glucagon AUC

    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

    Measured: baseline and 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Jan 2008 (estimated)
  2. Study startNov 2007
  3. Primary completionApr 2009
  4. Study completionApr 2009

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
60 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00596427
Sponsor's protocol ID
KM-11A
Status last verified
Oct 2012
First submitted
8 Jan 2008
Last updated
12 Oct 2012
Data monitoring committee
No

Publications

  • 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.

    PubMed 5569253
  • 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.

    PubMed 7366673
  • 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.

    PubMed 17379048
  • Jenkins DJ, Wolever TM, Leeds AR, Gassull MA, Haisman P, Dilawari J, Goff DV, Metz GL, Alberti KG. Dietary fibres, fibre analogues, and glucose tolerance: importance of viscosity. Br Med J. 1978 May 27;1(6124):1392-4. doi: 10.1136/bmj.1.6124.1392.

    PubMed 647304
  • Beysen C, Murphy EJ, Deines K, Chan M, Tsang E, Glass A, Turner SM, Protasio J, Riiff T, Hellerstein MK. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia. 2012 Feb;55(2):432-42. doi: 10.1007/s00125-011-2382-3. Epub 2011 Dec 2.

    PubMed 22134839

Questions about this trial

What is this clinical trial studying?

A study testing Colesevelam HCL in people with Diabetes, run by Carine Beysen at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Oct 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Oct 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Fasting Endogenous Glucose Production (EGP) (time frame: baseline and 12 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00596427, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Oct 2012.

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