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

Seattle Institute for Biomedical and Clinical Research

Status and phase

Completed

Phase 3

Conditions

Prediabetes

Impaired Fasting Glucose

Treatments

Other: placebo

Drug: Colesevelam

Study type

Interventional

Funder types

Other

Other U.S. Federal agency

Identifiers

NCT00990184

1.2

Details and patient eligibility

About

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).

Full 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.

Enrollment

21 patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

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