The Effect of Welchol on Glucose Metabolism in Type 2 Diabetics

Type 2 Diabetes Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00951899
• Other study ID #: 08-008284
• Secondary ID: R01DK078646R01DK
• Status: Completed
• Phase: Phase 4
• First received: July 31, 2009
• Last updated: October 17, 2013
• Start date: August 2009
• Est. completion date: December 2012

Study information

• Verified date: October 2013
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: December 2012
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 35 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

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:
• 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.

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.

Locations

Country	Name	City	State
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (4)

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

Country where clinical trial is conducted

United States, 

References & Publications (1)

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- — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	Plasma Glucose Concentration	Fasting glucose concentrations were measured at baseline and 2 hours post-meal using the glucose oxidase method.	Baseline, 12 Weeks	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Lipid Values	Lipids are fat-like substances in the blood.	Baseline, 12 weeks	No

External Links

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