Study to Evaluate the Effects of Colesevelam on Insulin Sensitivity and ß-Cell Function in Subjects With Impaired Fasting Glucose (Prediabetes)

A Single-Blind Study to Evaluate the Effects of Colesevelam on Insulin Sensitivity and ß-Cell Function in Subjects With Impaired Fasting Glucose (Prediabetes)

The objective of this study is to determine the effect of 8 weeks of treatment with colesevelam HCl 3.75 g once daily with the evening meal on ß-cell function by evaluating the acute insulin response (AIRg) to an intravenous glucose load in subjects with prediabetes (impaired fasting glucose).

Study Overview

• Status: Completed
• Conditions: Prediabetes; Impaired Fasting Glucose
• Intervention / Treatment: Drug: Colesevelam; Other: placebo

Detailed Description

Colesevelam is a bile acid sequestrant that was initially approved for treatment of patients with dyslipidemia. Subsequently it was observed that patients with type 2 diabetes receiving this medication had improved glucose control. However, the mechanism(s) by which it lowers glucose concentrations has not been determined.

Glucose metabolism is enhanced following oral nutrient ingestion by the action of the incretin hormones. The two major incretin hormones are the peptides glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are released from the intestinal tract wall in response to a meal. Of these two peptides, GLP-1 appears to be more important in regulating glucose metabolism. In the presence of elevated plasma glucose, GLP-1 promotes insulin release from the ß-cells of the pancreas. GLP-1 also suppresses glucagon release, and thereby inhibits hepatic glucose output. Administration of GLP-1 by infusion or by subcutaneous injection has been shown to improve glucose tolerance in type 2 diabetic patients.

The purpose of this study is therefore to determine in a cohort of individuals with prediabetes, who have an elevated fasting plasma glucose and are at increased risk of developing type 2 diabetes, whether the glucose lowering properties of colesevelam occur by it improving insulin sensitivity, islet ß-cell function or both. Further, by assessing the effect of colesevelam on incretin hormone release, it will be possible to determine whether any improvement in islet ß-cell function is due to enhanced incretin stimulation.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females (postmenopausal, surgically sterile or using double-barrier method of contraception), aged 18-75 years, FPG 100-115 mg/dl at screening (average of 2 measurements during screening; no individual measurement outside of the range 92-125 mg/dl)
• In good health as determined by past medical history, physical examination, electrocardiogram, laboratory tests and urinalysis
• HbA1c <6.5% at screening
• Body mass index (BMI) in the range of 22-40 kg/m2 inclusive and with a stable (+/-2.5 kg) weight for the last 6 months

• Subjects must be willing to:

  • Maintain prior exercise and dietary habits throughout the study
  • Comply with all study requirements
  • Provide written informed consent

Exclusion Criteria:

• Pregnant or lactating females
• Patients diagnosed with type 2 diabetes or that have taken glucose-lowering agents or insulin, except during pregnancy
• Chronic oral or parenteral corticosteroid treatment (>7 consecutive days of treatment) within 8 weeks prior to screening
• HIV protease inhibitors
• Warfarin or phenytoin use
• Triglycerides >500 mg/dl
• History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection
• History of dysphagia, swallowing disorders or intestinal motility disorder
• History of pancreatitis
• Uncontrolled hypothyroidism
• Individuals with clinical hepatic disease or liver function tests greater than ≥2 times upper limits of normal within 30 days preceding the first dose of study drug
• On a weight loss program with ongoing weight loss, or starting an intensive exercise program within 4 weeks of study initiation
• Current or prior (within the past 3 months) treatment with a bile acid sequestrant (colesevelam, colestipol, colestimide, or cholestyramine)
• Use of any investigational drug in the last 30 days
• Donation of one unit (500 ml) or more of blood, significant blood loss equaling at least one unit of blood within the past 2 weeks or a blood transfusion within 8 weeks prior to screening
• Employment by the research center

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Colesevelam Hydrochloride	Drug: Colesevelam; colesevelam HCl 3.75 g once daily orally with the evening meal; Other Names: colesevelam HCl; Other: placebo; tablet (s) orally given with evening meal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Insulin Response (AIRg) to Intravenous Glucose	Increase in insulin following glucose injection. AIRg is measured as the magnitude of the insulin response to an intravenous glucose injection calculated over the 10 minutes following glucose administration.	Baseline and 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Sensitivity	Tissue response to circulating insulin in the blood. Insulin sensitivity is measured using a mathematical model that quantifies the fractional rate of change in glucose concentrations per unit of insulin. Low values are insulin resistant and high values are insulin sensitive. *Please note: the "-1" in the Unit of Measure should be a superscripted value.	Baseline and 8 weeks
Glucose Disappearance Rate	Rate of fall of glucose in the blood	Baseline and 8 weeks

Collaborators and Investigators

• Sponsor: Seattle Institute for Biomedical and Clinical Research
• Collaborators: VA Puget Sound Health Care System
• Investigators: Principal Investigator: Steven E Kahn, MB CHB, VA Puget Sound Health Care System

Publications and helpful links

General Publications

• Marina AL, Utzschneider KM, Wright LA, Montgomery BK, Marcovina SM, Kahn SE. Colesevelam improves oral but not intravenous glucose tolerance by a mechanism independent of insulin sensitivity and beta-cell function. Diabetes Care. 2012 May;35(5):1119-25. doi: 10.2337/dc11-2050. Epub 2012 Mar 23.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: October 2, 2009
• First Submitted That Met QC Criteria: October 5, 2009
• First Posted (Estimate): October 6, 2009

Study Record Updates

• Last Update Posted (Estimate): November 21, 2012
• Last Update Submitted That Met QC Criteria: October 22, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: Impaired Fasting Glucose; PreDiabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperinsulinism; Hyperglycemia; Prediabetic State; Glucose Intolerance; Insulin Resistance; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Colesevelam Hydrochloride
• Other Study ID Numbers: 1.2