Mechanisms of Glucose Lowering Effect of Colesevelam HCl

NCT00596427 | Completed Results

• 1 other identifier: KM-11A
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 3

Brief 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. 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.

Conditions

Diabetes

Keywords

type two diabetes; gluconeogenesis; glucose; lipid synthesis; hepatic insulin sensitivity; colesevelam HCl

Outcome Measures

Primary Outcomes (4)

• Fasting Endogenous Glucose Production (EGP)

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

  baseline and 12 weeks

• Fasting Gluconeogenesis

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

  baseline and 12 weeks

• Fasting Glycogenolysis

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

  baseline and 12 weeks

• 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.

  baseline and 12 weeks

Secondary Outcomes (6)

• Total Glucagon-like Peptide (GLP-1) Area Under the Curve (AUC)

  baseline and 12 weeks

• Total Glucose-dependent Insulinotropic Polypeptide (GIP) AUC

  baseline and 12 weeks

• Fasting Fractional De Novo Lipogenesis (DNL)

  baseline and 12 weeks

• Fasting Fractional Cholesterol Synthesis

  baseline and 12 weeks

• Postprandial Fractional Cholic Acid Synthesis

  baseline and 12 weeks

Other Outcomes (2)

• Glycosylated Hemoglobin (HbAlc)

  baseline and 12 weeks

• Glucose AUC

  baseline and 12 weeks

Study Arms (2)

Placebo tablet 3 tablets 2x/day

PLACEBO COMPARATOR

Type-2 diabetes mellitus patients

Drug: Placebo

Colesevelam HCL 625 mg: 3 tablets 2x/day

EXPERIMENTAL

Type-2 diabetes mellitus patients

Drug: Colesevelam HCL

Interventions

Colesevelam HCL DRUG

Colesevelam HCL 625 mg: 3 tablets twice per day

Also known as: WelChol

Colesevelam HCL 625 mg: 3 tablets 2x/day

Placebo DRUG

Placebo tablets: 3 tablets twice per day

Placebo tablet 3 tablets 2x/day

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Carine Beysen: lead

Study Sites (3)

Diablo Clinical Research, Inc

Walnut Creek, California, 94598, United States

Location

Clinical Pharmacology of Miami, Inc

Miami, Florida, 33014, United States

Location

Diabetes & Glandular Disease Research Associates

San Antonio, Texas, 78229, United States

Location

Related Publications (5)

• 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.

  PMID: 5569253 BACKGROUND

• 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.

  PMID: 7366673 BACKGROUND

• 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.

  PMID: 17379048 BACKGROUND

• 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.

  PMID: 647304 BACKGROUND

• 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.

  PMID: 22134839 DERIVED

Related Links

• KineMed, Inc.
• Diablo Clinical Research, Inc.
• WelChol

MeSH Terms

Conditions

Diabetes Mellitus

Interventions

Colesevelam Hydrochloride

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Allylamine; Amines; Organic Chemicals; Allyl Compounds; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons

Results Point of Contact

• Title: Carine Beysen, PhD
• Organization: Kinemed, Inc

cbeysen@kinemed.com

5106556525

Study Officials

• Carine Beysen, PhD

  KineMed

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director, Clinical Metabolic Research

Study Record Dates

• First Submitted: January 8, 2008
• First Posted: January 17, 2008
• Study Start: November 1, 2007
• Primary Completion: April 1, 2009
• Study Completion: April 1, 2009
• Last Updated: October 12, 2012
• Results First Posted: October 12, 2012

Record last verified: 2012-10

Locations

US (3)