The Effect of Welchol on Glucose Metabolism in Type 2 Diabetics

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Colesevelam; Behavioral: Diet; Drug: Metformin; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Daiichi Sankyo, Inc.; National Center for Research Resources (NCRR)

Publications and helpful links

General Publications

• 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.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: July 31, 2009
• First Submitted That Met QC Criteria: August 3, 2009
• First Posted (Estimate): August 4, 2009

Study Record Updates

• Last Update Posted (Estimate): November 11, 2013
• Last Update Submitted That Met QC Criteria: October 17, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: Incretins; colesevelam; hepatobiliary circulation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Metformin; Colesevelam Hydrochloride
• Other Study ID Numbers: 08-008284; UL1RR024150 (U.S. NIH Grant/Contract); R01DK078646 (U.S. NIH Grant/Contract); R01DK082396 (U.S. NIH Grant/Contract)