The Effect of Colesevelam Hydrochloride (HCL) on Disposition Index and Incretin Concentrations in Subjects With Type 2 Diabetes
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Purpose
Welchol (colesevelam HCl), a bile acid sequestrant (BAS) was recently approved by the FDA for glucose lowering in patients with type 2 diabetes mellitus. Four randomized, controlled clinical studies in subjects with type 2 diabetes have demonstrated significant treatment difference in HbA1c (-0.5%). Study durations ranged from 12-26 weeks of therapy. In diabetes clinical studies, a therapeutic response to colesevelam HCl, as reflected by reduction in A1C was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment. Reductions in both fasting plasma glucose and postprandial concentrations have been demonstrated. Simple measures of insulin secretion and action have suggested that this is due to improved insulin action rather than improved insulin secretion. The mechanism by which bile acids interact with the key pathways regulating glucose concentrations is largely unknown. The investigators propose a randomized, double-blind, placebo controlled trial with a parallel-group design where subjects are randomized to receive colesevelam or matching placebo for a 12 week treatment period. A labeled mixed meal before and after treatment will be used to measure intestinal transit, postprandial and fasting glucose fluxes, insulin secretion and action as well as enteroendocrine secretion.
| Condition | Intervention | Phase |
|---|---|---|
|
Type 2 Diabetes |
Drug: Colesevelam Other: Placebo |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Basic Science |
| Official Title: | The Effect of Colesevelam HCL on Disposition Index and Incretin Concentrations in Subjects With Type 2 Diabetes Using a Double-blind, Placebo-controlled, Parallel-group Study Design |
- Bile acid sequestration lowers glucose concentrations by improving Disposition Index in humans with type 2 diabetes. [ Time Frame: One year ] [ Designated as safety issue: No ]
- Bile acid sequestration increases GLP-1 secretion. [ Time Frame: one year ] [ Designated as safety issue: No ]
| Enrollment: | 38 |
| Study Start Date: | August 2009 |
| Study Completion Date: | December 2012 |
| Primary Completion Date: | July 2012 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: colesevelam
Treatment with colesevelam in addition to metformin or diet
|
Drug: Colesevelam
Colesevelam hydrochloride 625mg tid
|
|
Placebo Comparator: Placebo
Placebo plus diet and metformin
|
Other: Placebo
Placebo tid
|
Eligibility| Ages Eligible for Study: | 35 Years to 70 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age 35-70 years old.
- BMI greater than 19kg/m2 or less than 40kg/m2 or a total weight less than 130kg.
- Negative pregnancy test for women of childbearing potential.
- Absence of gastrointestinal symptoms.
- Signed informed consent.
- Treatment with diet and or metformin. Subjects must be on stable therapeutic doses of metformin and or lipid-lowering agents for more than 3 months.
Exclusion Criteria:
- Structural or metabolic diseases/conditions that affect the gastrointestinal system, or functional gastrointestinal disorders. For screening the Bowel Disease Questionnaire will be used to exclude subjects with irritable bowel syndrome (17). Patients with a history of dysphagia or intestinal motility disorders will be excluded.
- Patients with a prior history of pancreatitis will be excluded.
- Patients with a prior history of hypertriglyceridemia will be excluded.
- Patients currently using a bile-acid binding resin such as colesevelam, colestipol, colestimide or cholestyramine will be excluded.
- To ensure homogeneity between treatment groups we will exclude subjects with insulin-treated type 2 diabetes mellitus, subjects who have received a DPP-4 inhibitor, Byetta or sulfonylurea agent in the past three months. Subjects with an HbA1c > 9.0% will be excluded. Subjects who have not been stable on all medications for a period exceeding 3 months will be excluded.
Use of drugs or agents within the past 2 weeks or planned use in the subsequent 4 weeks during the study period that:
- Alter GI transit including laxatives, magnesium or aluminum-containing antacids, prokinetics, erythromycin, narcotics, anticholinergics, tricyclic antidepressants, SSRI and newer antidepressants.
- Analgesic drugs including opiates, NSAID, COX 2 inhibitors
- Antihistamines
- Anticholinergic agents
- Female subjects who are pregnant or breast-feeding. Females must be either surgically sterilized, postmenopausal (>12 months since last menses), or, if of childbearing potential, using reliable methods of contraception as determined by the physician.
- Clinical evidence (including physical exam and ECG) of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric, or other disease that interfere with the objectives of the study. Any candidate participants with such disorders mentioned will be referred to their general physician.
Contacts and Locations More Information
No publications provided by Mayo Clinic
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Adrian Vella, Professor of Medicine, Mayo Clinic |
| ClinicalTrials.gov Identifier: | NCT00951899 History of Changes |
| Other Study ID Numbers: | 08-008284 |
| Study First Received: | July 31, 2009 |
| Last Updated: | January 18, 2013 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Mayo Clinic:
|
Incretins colesevelam hepatobiliary circulation |
Additional relevant MeSH terms:
|
Diabetes Mellitus Diabetes Mellitus, Type 2 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Colesevelam Incretins Anticholesteremic Agents Hypolipidemic Agents |
Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Lipid Regulating Agents Therapeutic Uses Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on June 13, 2013