Clinical trial NCT00951899: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes
Keywords: Incretins
colesevelam
hepatobiliary circulation
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: Daiichi Sankyo
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: National Center for Research Resources (NCRR)
First posted: 2009-08-04
Enrollment: 38
Sex: ALL
Minimum age (years): 35
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: Total Disposition Index
timeFrame: Baseline, 12 weeks
Secondary outcomes:
measure: Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration
timeFrame: Baseline, 12 weeks
measure: Plasma Glucose Concentration
timeFrame: Baseline, 12 Weeks
measure: Glycosylated Hemoglobin (HbA1c)
timeFrame: Baseline, 12 weeks
measure: Insulin Concentration
timeFrame: Baseline, 12 Weeks
measure: Fasting Endogenous Glucose Production (EGP)
timeFrame: Baseline, 12 Weeks
measure: Rate of Meal Glucose Appearance (Meal Ra)
timeFrame: Baseline, 12 Weeks
measure: Rate of Meal Glucose Disappearance (Meal Rd)
timeFrame: Baseline, 12 Weeks
measure: Lipid Values
timeFrame: Baseline, 12 weeks
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Adrian Vella, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.