Back to resultsThe Effect of Welchol on Glucose Metabolism in Type 2 Diabetics
Primary Purpose
Type 2 Diabetes
Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Colesevelam
Placebo
Diet
Metformin
Sponsored by
About this trial
This is an interventional basic science trial for Type 2 Diabetes focused on measuring Incretins, colesevelam, hepatobiliary circulation
Eligibility Criteria
Inclusion Criteria:
- Age 35-70 years old.
- Body Mass Index greater than 19kg/m^2 or less than 40kg/m^2 or a total weight less than 130 kilograms.
- 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. A screening Bowel Disease Questionnaire will be used to exclude subjects with irritable bowel syndrome. Patients with a history of dysphagia or intestinal motility disorders will be excluded.
- Prior history of pancreatitis.
- Prior history of hypertriglyceridemia (500mg/dL or greater).
- Currently using a bile-acid binding resin such as colesevelam, colestipol, colestimide or cholestyramine.
- To ensure homogeneity between treatment groups we will exclude subjects with insulin-treated type 2 diabetes mellitus, subjects who have received an inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors) or "gliptins" (a class of oral hypoglycemics), Byetta or sulfonylurea agent in the past three months.
- HbA1c greater than 9.0%.
- Patients who have not been stable on all medications for a period exceeding 3 months.
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, Selective Serotonin Reuptake Inhibitors (SSRIs) and newer antidepressants.
- Opiate-based analgesic drugs (Note: intermittent or chronic use of aspirin or non-steroidal anti-inflammatory drugs (NSAID) will be allowed).
- 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 Electrocardiogram) 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.
Sites / Locations
- Mayo Clinic
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Colesevelam
Placebo
Arm Description
Treatment with colesevelam hydrochloride in addition to Metformin and Diet
Treatment with placebo in addition to Metformin and Diet
Outcomes
Primary Outcome Measures
Total Disposition Index
Total Disposition Index (DI) is a calculated value which represents the ability of a person's pancreas to lower blood glucose. A higher number means the pancreas is better able to lower blood glucose and a lower number means the pancreas is less able to lower blood glucose.
Secondary Outcome Measures
Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration
GLP-1 is thought to increase insulin secretion and was measured in the blood and reported in picomoles per liter.
Plasma Glucose Concentration
Fasting glucose concentrations were measured at baseline and 2 hours post-meal using the glucose oxidase method.
Glycosylated Hemoglobin (HbA1c)
HbA1c is the percent of red blood cell hemoglobin with glucose attached to it and an indicator of average blood glucose over the previous two to three months.
Insulin Concentration
Fasting insulin levels were measured in the plasma using a chemiluminescence assay and is reported in nanomoles over 6 hours.
Fasting Endogenous Glucose Production (EGP)
EGP was measured using a triple-tracer mixed meal and calculated using the Steele's model, reported in micromoles per kilogram per minute.
Rate of Meal Glucose Appearance (Meal Ra)
Meal Ra was measured using a triple-tracer mixed meal and reported in micromols in 6 hours. Meal derived glucose is a function of both gastric emptying and splanchnic meal extraction. Meal Ra was calculated by multiplying rate of appearance of [1-^13C] glucose (obtained from the infusion rate of [6-^3H] glucose and the clamped plasma ratio of [6-^3H] glucose and [1-^13C] glucose) by the meal enrichment.
Rate of Meal Glucose Disappearance (Meal Rd)
Meal Rd is the rate at which glucose leaves the systemic circulation. It was measured using a triple-tracer mixed meal and reported in micromols over 6 hours. Meal Rd was calculated by subtracting the change in glucose mass from the overall rate of glucose appearance (i.e., meal Ra + EGP).
Lipid Values
Lipids are fat-like substances in the blood.
Full Information
NCT ID
NCT00951899
First Posted
July 31, 2009
Last Updated
October 17, 2013
Sponsor
Mayo Clinic
Collaborators
Daiichi Sankyo, Inc., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Center for Research Resources (NCRR)
1. Study Identification
Unique Protocol Identification Number
NCT00951899
Brief Title
The Effect of Welchol on Glucose Metabolism in Type 2 Diabetics
Official Title
The Effect of Colesevelam Hydrochloride on Disposition Index and Incretin Concentrations in Subjects With Type 2 Diabetes Using a Double-blind, Placebo-controlled, Parallel-group Study Design
Study Type
Interventional
2. Study Status
Record Verification Date
October 2013
Overall Recruitment Status
Completed
Study Start Date
August 2009 (undefined)
Primary Completion Date
July 2012 (Actual)
Study Completion Date
December 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Mayo Clinic
Collaborators
Daiichi Sankyo, Inc., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Center for Research Resources (NCRR)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The goal of this study was to determine the metabolic mechanism for a certain type medication's ability to lower blood sugar after a meal in Type 2 Diabetics, in order to develop a better understanding of it's potential role in the treatment of obesity.
Detailed Description
Welchol (colesevelam hydrochloride) is a bile acid sequestrant (BAS) 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 hydrochloride, 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes
Keywords
Incretins, colesevelam, hepatobiliary circulation
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
38 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Colesevelam
Arm Type
Experimental
Arm Description
Treatment with colesevelam hydrochloride in addition to Metformin and Diet
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Treatment with placebo in addition to Metformin and Diet
Intervention Type
Drug
Intervention Name(s)
Colesevelam
Other Intervention Name(s)
Welchol
Intervention Description
Colesevelam hydrochloride; three 625mg tablets taken orally twice per day before breakfast and before the evening meal over a 12-week treatment period.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Three placebo tablets matching the active drug colesevelam in appearance, taken orally twice per day before breakfast and before the evening meal over a 12-week treatment period.
Intervention Type
Behavioral
Intervention Name(s)
Diet
Intervention Description
Subjects were instructed to follow a weight maintenance diet (~55% carbohydrate, 30% fat and 15% protein) for the 12 week study period.
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage, Glucophage XR, Glumetza, Fortamet
Intervention Description
Subjects continued to take their pre-study therapeutic doses of metformin (Metformin 500mg tablets taken by mouth twice daily for a total daily dose of 1000 to 2000 mg) through the 12 week study period.
Primary Outcome Measure Information:
Title
Total Disposition Index
Description
Total Disposition Index (DI) is a calculated value which represents the ability of a person's pancreas to lower blood glucose. A higher number means the pancreas is better able to lower blood glucose and a lower number means the pancreas is less able to lower blood glucose.
Time Frame
Baseline, 12 weeks
Secondary Outcome Measure Information:
Title
Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration
Description
GLP-1 is thought to increase insulin secretion and was measured in the blood and reported in picomoles per liter.
Time Frame
Baseline, 12 weeks
Title
Plasma Glucose Concentration
Description
Fasting glucose concentrations were measured at baseline and 2 hours post-meal using the glucose oxidase method.
Time Frame
Baseline, 12 Weeks
Title
Glycosylated Hemoglobin (HbA1c)
Description
HbA1c is the percent of red blood cell hemoglobin with glucose attached to it and an indicator of average blood glucose over the previous two to three months.
Time Frame
Baseline, 12 weeks
Title
Insulin Concentration
Description
Fasting insulin levels were measured in the plasma using a chemiluminescence assay and is reported in nanomoles over 6 hours.
Time Frame
Baseline, 12 Weeks
Title
Fasting Endogenous Glucose Production (EGP)
Description
EGP was measured using a triple-tracer mixed meal and calculated using the Steele's model, reported in micromoles per kilogram per minute.
Time Frame
Baseline, 12 Weeks
Title
Rate of Meal Glucose Appearance (Meal Ra)
Description
Meal Ra was measured using a triple-tracer mixed meal and reported in micromols in 6 hours. Meal derived glucose is a function of both gastric emptying and splanchnic meal extraction. Meal Ra was calculated by multiplying rate of appearance of [1-^13C] glucose (obtained from the infusion rate of [6-^3H] glucose and the clamped plasma ratio of [6-^3H] glucose and [1-^13C] glucose) by the meal enrichment.
Time Frame
Baseline, 12 Weeks
Title
Rate of Meal Glucose Disappearance (Meal Rd)
Description
Meal Rd is the rate at which glucose leaves the systemic circulation. It was measured using a triple-tracer mixed meal and reported in micromols over 6 hours. Meal Rd was calculated by subtracting the change in glucose mass from the overall rate of glucose appearance (i.e., meal Ra + EGP).
Time Frame
Baseline, 12 Weeks
Title
Lipid Values
Description
Lipids are fat-like substances in the blood.
Time Frame
Baseline, 12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 35-70 years old.
Body Mass Index greater than 19kg/m^2 or less than 40kg/m^2 or a total weight less than 130 kilograms.
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. A screening Bowel Disease Questionnaire will be used to exclude subjects with irritable bowel syndrome. Patients with a history of dysphagia or intestinal motility disorders will be excluded.
Prior history of pancreatitis.
Prior history of hypertriglyceridemia (500mg/dL or greater).
Currently using a bile-acid binding resin such as colesevelam, colestipol, colestimide or cholestyramine.
To ensure homogeneity between treatment groups we will exclude subjects with insulin-treated type 2 diabetes mellitus, subjects who have received an inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors) or "gliptins" (a class of oral hypoglycemics), Byetta or sulfonylurea agent in the past three months.
HbA1c greater than 9.0%.
Patients who have not been stable on all medications for a period exceeding 3 months.
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, Selective Serotonin Reuptake Inhibitors (SSRIs) and newer antidepressants.
Opiate-based analgesic drugs (Note: intermittent or chronic use of aspirin or non-steroidal anti-inflammatory drugs (NSAID) will be allowed).
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 Electrocardiogram) 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adrian Vella, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
23250357
Citation
Smushkin G, Sathananthan M, Piccinini F, Dalla Man C, Law JH, Cobelli C, Zinsmeister AR, Rizza RA, Vella A. The effect of a bile acid sequestrant on glucose metabolism in subjects with type 2 diabetes. Diabetes. 2013 Apr;62(4):1094-101. doi: 10.2337/db12-0923. Epub 2012 Dec 18.
Results Reference
result
Links:
URL
http://clinicaltrials.mayo.edu
Description
Mayo Clinic Clinical Trials
Learn more about this trial
The Effect of Welchol on Glucose Metabolism in Type 2 Diabetics
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