The Effect of Welchol on Glucose Metabolism in Type 2 Diabetics

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Colesevelam
* Other: Placebo
* Behavioral: Diet
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colesevelam<br>Treatment with colesevelam hydrochloride in addition to Metformin and Diet | Drug: Colesevelam<br>* Colesevelam hydrochloride; three 625mg tablets taken orally twice per day before breakfast and before the evening meal over a 12-week treatment period.<br>* Other names: Welchol;Behavioral: Diet<br>* Subjects were instructed to follow a weight maintenance diet ( 55% carbohydrate, 30% fat and 15% protein) for the 12 week study period.<br>Drug: Metformin<br>* 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.<br>* Other names: Fortamet;|
| Placebo Comparator: Placebo<br>Treatment with placebo in addition to Metformin and Diet | Other: Placebo<br>* 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.<br>Behavioral: Diet<br>* Subjects were instructed to follow a weight maintenance diet ( 55% carbohydrate, 30% fat and 15% protein) for the 12 week study period.<br>Drug: Metformin<br>* 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.<br>* Other names: Fortamet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 12 weeks | 
| Plasma Glucose Concentration | Fasting glucose concentrations were measured at baseline and 2 hours post-meal using the glucose oxidase method. | Baseline, 12 Weeks | 
| 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. | Baseline, 12 weeks | 
| Insulin Concentration | Fasting insulin levels were measured in the plasma using a chemiluminescence assay and is reported in nanomoles over 6 hours. | Baseline, 12 Weeks | 
| 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. | Baseline, 12 Weeks | 
| 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. | Baseline, 12 Weeks | 
| 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). | Baseline, 12 Weeks | 
| Lipid Values | Lipids are fat-like substances in the blood. | Baseline, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Incretins, colesevelam, hepatobiliary circulation